‘TUMORS OF THE SMALL AND LARGE INTESTINES, INCLUDING ANAL CANAL Jason L. Hornick CHAPTER OUTLINE SMALLINTESTINE 434 Epithelial Tumors 434 Neuroendocrine Tumors 435 Mesenchymal and Neuroectodermal Tumors 437 Tumors of Lymphoid Tissue 442 Secondary Tumors 447 Tumor-like Lesions 447 APPENDIX. 448 Epithelial Tumors 448 Neuroendocrine Tumors 450 Tumor-like Lesions 452 SMALL INTESTINE EPITHELIAL TUMORS Adenoma Clinical Features Adenomas of the small intestine are relatively uncor ‘mon, compared with adenomas of the large intestin Around 80% arise in the periampullary duodenum. Duo- dlenal adenomas occur over a wide age range (mean 60 years), with an equal sex distribution. Patients with fami ial adenomatous polyposis (FAP) have markedly increased incidence of duodenal and ampullary adenomas (nearly 100%), which are often detected by endoscopic screening after prophylactic colectomy.’ The mean age ‘of patients with FAP with such adenomas is two decades younger than that of patients with sporadic lesions. Small duodenal adenomas are asymptomatic, whereas large adenomas may present with occult gastrointestinal (GI) bleeding, or, rarely, obstruction, Ampullary ade- nomas may present with abdominal pain and biliary’ obstruction, ‘Macroscopic Appearances Duodenal adenomas are usually sessile polyps or plaque- like lesions, most less than Lem in size, Ampullary oy LARGE INTESTINE 452 Epithelial Tumors 452 Neuroendocrine Tumors 461 Mesenchymal and Neuroectodermal Tumors 462 ‘Tumors of Lymphoid Tissue 464 Secondary Tumors 465, ANAL CANAL 468 Epithelial Tumors 468 ANAL MARGIN. 469, Epidermal and Adnexal Neoplasms 469 adenomas often show a delicate, feathery appearance, correlating with villous architecture. Small. adenomas in patients with FAP may be subtle or endoscopically inapparen, Histologic Appearances Similar to adenomas of the large intestine, duodenal and ampullary adenomas may be classified as tubular, tubulo~ villous, or villous see later discussion on large intestine). Small duodenal adenomas are more often tubular, with hyperchromatic, elongated nuclei showing pseudostrasi- fication, extending to the mucosal surface (Fig. 9-1) Paneth cells are often prominent, which can be a helpful diagnostic clue, especially for the distinetion between adenoma and an inflammatory polyp (polypoid duodeni- tis). Villous adenomas predominate in the ampulla Adenocarcinoma Clinical Features Adenocarcinomas of the small intestine are rare. As with adenomas, the most common site is the periampullary duodenum; jejunal and ileal adenocarcinomas are par- ticularly rare.” slight male predominance is seen, and the peak incidence is in the seventh decade. Significant risk factors for adenocarcinoma of the small intestine include Crohn disease, celiae disease, Lynch syndrome,9 ‘Towors or THe SMALL aND Larcr Ivrestives, bvetupnve ANAL Casa 435; FIGURE 9.1 m Duodenal adenoms with low-grade dysplasis, Note the prominent Paneth cell differentiation. and FAP** Patients with Peutz-Jeghers syndrome, juve- Saar oe i emg eth geome as risk."* Adenocarcinomas rarely develop in ileostomies| and ileal pouches after colorectal surgery. Small intestine adenocarcinomas. are usually asymptomatic in early stages; most patients therefore present with advanced tumors when bowel obstruction occurs.’ The most ‘common symptoms include abclominal pain, weight loss, vomiting, and occtl GI bleeding, Duodens| adenocare- trons Tve a worse prin Urata sll intent tumors.” Macroscopic Appearances Duodenal adenocarcinomas are usually relatively circum- sesibed with @ polypoid appearance and eenial uleer~ ation, whereas jejunal and lel tumors most afen show circumferential involvement with extensive ulceration wl an annular appearance. Heal adenovarcinomas may mimic Crohn disease. Multifocalty and lack of a mucosal ‘component should raise the possibility of a metastasis. Histologic Appearances Adenocarcinomas of the small intestine resemble color- cectal adenocarcinomas and often contain a mucinous ‘component. Although they are more often poorly dif- ferentiated than their large intestinal counterparts, primary signet ring cell carcinomas of the small intestine are rare and should be distinguished from gastric metastasis, Immunohistochemistry In comparison with colorectal adenocarcinomas, adeno- carcinomas of the small intestine more often express cytokeratin 7 (CK7) 30%-50% of tumors) and less often, C20 (only around 60%).™"" CDX-2 is usually positive, but often with a more heterogeneous staining pattern, including areas with only weak staining of without demonstrable expression." TABLES-1 2010 World Health Organization Proliferation-Based Criteria for Grading of Neuroendocrine Tumors of the Gastrointestinal Tract ‘Mitotic Rete KiG? Grede Designation (ber 10 hpfl Index 4) ‘G1 (carcinoid) . 2 Neuroendocrine tumor 220 320 G2 3 Netroendoctine >20 220 ot, High-power fl. NEUROENDOCRINE TUMORS In the most recent (2010) World Health Organization (WHO) classification of tumors of the digestive system, a uniform nomenclature and grading system for (neuro) endocrine neoplasms of the GI tract and pancreas was introduced (Table 9-1). “Neuroendocrine tumors” (NETS) (formerly widely known as carcinotd tumors) are well-differentiated neoplasms composed of cells with fea- tures similar to those oftheir normal counterparts, usually including strong expression of chromogranin and synap- tophysin and various peptide hormones according to site, and generally only ai nuclear atypia. NE‘ ave sepa rated into two grades (G1 and G2), according to mitotic count and Ki67 proliferation index. This distinction has been shown 10 have prognostic significance for the stomach, duodenum, and pancreas but not yet for the jejunum, ileum, or large intestines. “Neuroendocrine eatcinoi” (NEC) is reserved for pootly differentiated (high grade) neuroendocrine neoplasms with marked nuclear atypia and a high mitotic rate (220 per 10 high- power Gekis [hpf]). This category includes small cell cinoma, large cell NEC, and poorly differentiated NEC (not otherwise specified). This classification should also beapplied to metastatic lesions, when possible (e.g, met- astatic NET should not be designated “carcinoma’—this should be reserved for high-urade, poorly differentiated neoplasms, and grading should be attempted ifthe biopsy specimen contains sufficient tissue). Clinical Features ‘The small intestine is the most common site for NETS within the GT tract, accounting for nearly 50% of all GI NETS.” Tleal primary tumors are much more frequent than jejunal or duodenal tumors. Small intestinal NETS occur over a wide age range with a peak incidence in the sixth decade. Patients. with jejunoileal serotonin- producing (enterochromaffin cell) NETS usually first present with vague abdominal complaines, which may progress to intestinal obstruction, A. small subset, of patients (5%-10%), predominantly those with distal ileal tumors associated with liver metastasis, manifest the “car- cinoid syndrome,” characterized by diarrhea, flushing,6 9 FIQURE $2 m Neuroendocrine tumor adjacent to the lleocecal valve. The tumors wall circumscribed with a yellow cut surfoce, and fibrosis of the endocardium and right-sided heare valves. Patients with duodenal NETS usually have no symptoms, although some present with obstruction or jaundice. Gastrin-producing duodenal NE Ts ("gastrino- mas"), which account for the majority of duodenal NETS, are associated with Zollinger-Ellison syndrome (severe peptic ulcer disease resulting from hypergastrinemia and uncontrolled secretion of gastric acid) in a large propor- tion uf eases." Gastrinuinas assuciavel sid sinultiple endocrine neoplasia type 1 (MEN-1) are nearly exclusive to the duodenum." Duodenal somatostatin-producing NETB are usually asymptomatic, unlike their pancreatic counterparts."* Patients with neurofibromatosis type 1 (NF) have a markedly increased risk of development of somalustatin-producing NETS of the duodenusn and periampullary region and may also have ganglioeytic paragangliomas (See Chapter 28).'* Macroscopic Appearances Jejunoileal NETS present as_mucosal_ or submucosal nodules with a yellow cut surface after formalin fixation Fig. 9-2). Most tumors are between 1 and 3 em. Around 30% of patients present with multiple primary tumors." Infiltration through the bowel wall into the mesentery, associated with a marked desmoplastic reaction with luminal narrowing and stricture formation, is common. Mesenteric and Iymph node metastases are often larger than the primary tumor. Duodenal NETS are usually less than. 2 cm, MEN-I-associated gastrinomas are_often ‘multiple and very small (<5 mm)and may be very difficult 10 identify grossly Histologic Appearances Jejunoileal serotonin-producing NET are composed of ‘uniform rounded cells arranged predominantly in nests, often with focal gland-like structures (Fig. 9-3). The tumor cells typically contain round nuclei with stippled chromatin, indistinet nucleoli, and small amounts of “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 23 mt Neuroendocrine tumor ofthe ileum composed of nests of uniform cells with granular chromatin, cytoplasm with indistinct cell borders. ‘The cytoplasm may be clear or contain brightly eosinophilic granules. Occasional cells may show marked pleomorphism, which 1s of no prognostic significance. Tumor cells miltrating through the muscularis propria are often arranged in delicate cords. Histologic features do not predict clinical behavior. Most tumors that invade beyond the submucosa are clinically malignant, although they typically pursue a telatively ilulent clinical eourse°! Gastrin-producing duodenal NET typically show a trabecular and cord-like architecture. Somatostatin-producing NETS show a pre~ dominantly. ghndular, ciibriform architecture, with uniform cells having small, hyperchromatic nuciei and palely eosinophilic cytoplasm." In around one third of such tuinors, psammiona bodies are observed within dhe glands (Fig. 9-4). Psammoma bodies are not specific for Somatostatin-producing NETs and may sometimes be FGURES4 m Somatostatin-producing neuroendocrine tumor of the duodenum showing glandular architecture and frequent eammoma bodies,9 ‘Toons of rie Swati aNp Laer brestives, bvctupnsc ANAL CANAL 437 Seta, Oy Gs ey FIGURE 8-5 m Gangliocytic paraganglioma. The tumor is com posed of spindled Schivann cells and epithelioid neuroendo: rimied with occasional ganglion cele seen in gastrinomas and other NETs. Ganghocytic para- gangliomas are composed of an admixture of spindle- shaped Schwann cells epithelioid neuroendocrine cells ‘with uniform round nucle: and amphophilic cytoplasm arranged in sheets and cords, and large ganglion cells with vesicular chromatin and cosinophilic cytoplasm Gig. 9-5)" Immunohistochemistry Small intestinal NETS chromogranin and synap NET show diffuse nuclear staining for CD. thyroid transcription factor I (TTF-1), PAX- are negative. "”* Duodenal NETS ate ofien posit both PAX-8 (polyclonal antibody) and CDX-2." gangliocytic paraganglioma, the spindle cells are strongly positive for 5-100 prowin, wheiexs the neuwendoctine cells express broad-spectrum keratins, chromogranin, and synapeophysin.™ re usually strongly positive for MESENCHYMAL AND NEUROECTODERMAL TUMORS Gastrointestinal Stromal Tumors Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasin of the small intestine Although originally classified as smooth muscle tumors, STs are now known to arse from interstitial cells of Cajal or precursors of such eells.""" The term gasrvin- testinal autonomic nerve timmor (GANT), which formerly applied to GISTs with particular ultrastructural features, isno longer used.” Around 30% of all GISTs arse in the jejunum and ileum, whereas 5% arise in the duodenum. Proper diagnosis i critical, bth for prognostication and for targeted therapy with tyrosine kinase inhibitors Neatly all small intestinal GISTs are positive for KIT «cin. Clinical Features Small intestinal GIST affect adults with a peak in the seventh decade and an equal sex distribution.” Most patients present with vague abdominal symptoms or pain, anemia, or GI bleeding: howel obstruction and rumor rupture may also occur. Small tumors may be discovered incidentally by radiology or at surgery. Minute incidental GISTs (microGIS 18” or GIST “tumorlets”) of the small intestine are much less common than those of the stomach.” Patients with NF have a high risk of develop- ment of multiple GISTs (usually clinically benign) at this site." Macroscopic Appearances Small intestinal GISTs range from small mural nodules to large exophytie, pedunculated masses (Pig. 9-6).” The average size is around 5 cm for duodenal tumors and 7 em for jejunal and ileal tumors." Large tumors may cause adhesions between multiple loops of bowel. They are generally well circumscribed with either a fibrous or soft and fleshy cut surface, Cystic degeneration and intra- tumoral hemorthage are common in large tumors. Histologic Appearances Small intestinal GISTs are nearly always composed of spindle cells, arranged in sheets, short fascicles, or a vaguely storiform architecture.”* The spindle cells contain tennarkably uniform, ovoid iw elongated nucle with fine chromatin, inconspicuous nucleoli, and fibrillary, palely eosinophilic or basophilic cytoplasm (Fig. 9-7, 4). Nuclear palisading may be observed. Pleomorphism is not a feature of small intestinal GISTs and should suggest an alternative diagnosis. The mitotic rate is usually low. Skeinoid fibers (extracellular globules of collagen) distinctive feature of GISTs at this anatomic site (sce F 9-7, B). Unlike GISTs of the stomach, epithelioid eyto- morphology in the simal intestine is usually associated with a high mitotic rate and malignant behavior.” FIGURE 96 m Gastrointestinal stromal tumor of the jejunum, The tumor extends from the serosa with 8 pedunculatedae 8 FIGURE 8-7 m Gastrointestinal stromal tumor, spindle cell type. A, The tumor consits of fascicles of bland spindle cells with ‘bundant fibrillary cytoplasm. B, Skeincid fibers are typical of Such tumors at this ate Immunohistochemistry Small intestinal GISTs are more consistently positive for KIT (round 98% of cases) than gastric GISTS, usually a strong and diffuse cytoplasmic staining pattern Gig, 9-8." DOGI Gnoctamin 1 [ANOI) shows similar sensitivity and specificity as KIT for small intestinal GIST.” KIT and DOGI are highly specific for GIST. among mesenchymal tumors of the GI tract. Around 50% of small intestinal GISTS are immunoreactive for CD34 or smooth muscle actin (SMA)." S-100 protein is positive in around 20% of duodenal GISTS but only 5% Of distal small intestinal GIST.” Desmin expression is rare in GISTS from these sites. Expression of succinate dehydrogenase subunit B (SDHB) is invariably retained in GISTs of the small intestine." ‘Molecular Pathology Nearly 90% of small intestinal GISTS harbor activating mutations in KIT, predominantly in. exon 11 (around 75%) o exon 9 (10%-15%); 1% of KIT mutations are “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 9-8 m Neary oll gastrointestinal stromal tumors of the ‘small intestine are strongly and diffusely postive for KIT. located in exons 13 or 17." In contrast to gastric GIST, PDGFRA mutations are rarely found in. small testinal GISTs, mostly m the duodenum,” GISTs that lack KIT and PDGFRA mutations are often referred to as, “wild-type” GISTS. NFl-associated GIST3 lack such mutations.” Recently a small subset of small intestinal GISTs with BRAF V6O0E. mutations has been identified (around 2% of GIS'TS at this “The sll myulewute tyrosine kinase inhibitor imatinib mesylate is first-line therapy for patients with metastatic or locally advanced GIST.” Patients with KIT exon 11-mutant GISTs show. the best response to imatinib." KIT exon 9-mutant tumors do not respond as well but may respond better to high-dose imatinib (800 ing as opposed w standard dose 400 mg)" Wild-type GISTs show limited responses." Imatinib is often also used as adjuvant therapy for patients| with lage primary cumors. Such an approach increases recurrence-free survival, but whether overall survival is improved remains unknown." Most treated patients ‘eventually develop resistance to imatinib, usually because (of the sclection of secondary mutations in the kinase domain of KIT: Many such patients benefit from treat- ‘ment with another tyrosine kinase inhibitor, such as suni- tinib malate." Prognostic Markers GISTR range from clinically indolent tumors to aggres- sive sarcomas, Around 40% of small intestinal GISTs are clinically malignant, much higher than the rate for gastrie GISTS." Typical sites of metastasis are the liver and peri- toneum, Even small tumors occasionally result in late metastases: the designation “benign” GIST should there- fore be avoided. Risk of aggressive behavior can be pre- dicted by a combination of anatomic sit, tumor size, and mitotic rate CFable 9-2). OF note, mitotic rate should be determined in 5mm‘, which corresponds to approxi- ‘mately 20 hpf in most modern microscopes. Small intes- tinal GIS TS have a higher risk of malignant behavior than9 ‘Tosors or THe SMALL AND Larcr Ivrestives, Dvetupnve ANAL Caxan 439 TABLE9-2 Criteria for Risk Stratification of Gastrointestinal Stromal Tumors for Progressive Disease (Metastasis or ‘Tumor-Related Death), Comparing Stomach and Small Intestine ‘Mitotie Rate Tumor (per 5mm‘) _ Size fem) s 2 >2and<$ Very low risk SBand<10 Low risk Moderate risk >10 Moderate risk High risk 6 2 No High risk S2and <8 Moderate risk High risk 2band.<10 Highick High risk >10 High risk High risk Modified from Mietinen M, Lasote J 2006 Gestrintestins stromal tumors: pathology and prognosis at efferent ses, Semin Diogn Patho! 23. 70:83, gastric GIST of similar size and mitotic rate. GISTS only rarely recur locally at anastomotic sites. Leiomyoma Leiomyomas of the small intestine are rare, nearly all of which arise in the muscularis propria, similar to those inv the esophagus and prosinral stomach.” ‘They ave benign and do not recur. Small polypoid leiomyomas of the muscularis mucosae (as seen in the colon and rectum) are extremely rare.” Mural leiomyomas are well- circumscribed tumors composed of fascicles of uniform. spindle cells with elongated, blunt-ended nuclei and abundant brightly eosinophilic eytoplasnn. Mitotic activ- ity is usually absent. Leiomyomas show strong, uniform expression of SMA, desmin, and caldesmon and are nega- tive for KIT and BOGI Leiomyosarcoma ‘Most small intestinal tumors formerly designated leio- myosarcomas are now known to represent GISTs. True GI primary leiomyosarcomas are exceedingly rare (around 1% of GI mesenchymal tumors) but are, most ‘often encountered in the small intestine and colon." The possibility of a metastasis (e.g, from the uterus or retro- peritoneum) should always be excluded. Leiomyosarco- mas re usually large tumors that involve the full thickness of the bowel wall and present with GT bleeding and obstruction, They are aggressive sarcomas that often metastasize to the peritoneum, liver, lungs, and bone, Histologie features are similar to those of leiomyosarco- mas at other sites (see Chapter 24). The degree of nuclear atypia, pleomorphism, and cytoplasmic eosinophilia serves to distinguish leiomyosarcoma from GIST. Leio- myosarcomas are often positive for SMA, desmin, and caldesmon to variable extents, but are negative for KIT and DOGI. Patchy expression of broad-spectrum kera- tins is common, Gastrointestinal Clear Cell Sarcoma-like Tumor Gl lear cell sarcoma-like tumor isa rare but increasingly recognized distinctive sarcoma type with a predilection for the small intestine (70% of cases)-"** Although cyto- genetic findings are similar, its histologic features, immu- nophenotype, and clinical behavior are distinet from those of conventional clear cell sarcoma of the distal extremities, arguing for classification in a separate diax- nostic category.” ‘The alternate designation “malignant gastrointestinal neuroectodermal tumor” (GNET) has recently been proposed.'* Most tumors arise in young adults, who present with abdominal pain or bowe obstruction, Lymph node and liver, metastases are common. The average size is 5 cm. The tumors show infiltrative borders through the bowel wall and often ulcerate the mucosa and invade the mesentery. GI clear call sarcoma-Ike tumor 1s composed of uniform, pre- dominantly rounded to ovoid cells with indistinct or small nucleoli and palely eosinophilic to focally clear cytoplasm, In some areas, tumor cells may show a more epithelioid orspindle cell appearance. A sheet-like growth pattern usually predominates; a focally alveolar, pseudo- papillary, or nested architecture 1s commonly observed (Fig. 9-9). The uniform cytology and relatively low mitotic rate distinguish this tumor type from the much more common metastaticmelanoma. Scattered osteoclast- like giant cells are seen in around half of cases." Strong, Aliffase expression UF $-100 protein is typical (Pig. 9-10), whereas HMB-45, melan A, KIT, and DOGI are nega- tive. GI clear cell sarcomafike tumors usually have either the «(2,22Xq33,912) translocation resulting in EH'SRI— CREBI or t(12;22)(q13;ql2) involving ESRI and ATP1, with an approximately equal distribution." Fluores- cence in situ hybridization (FISH) for EIVSRT reatrange- ‘ment can therefore be used to confirm the diagnosis. Desmoid Fibromatosis ‘The mesentery of the small intestine is among the most common sites for intra-abdominal desmoid fibromatosis. Such tumors occur overa wide age range. Ifa mesenteric desmoid tumor is diagnosed ina child or young adul, of the Gardner variant of FAP should be 1° Most patients present with vague abdomi nal symptoms, As desmoid fibromatosis often inflerates deeply into the root of the mesentery, complete surgical excision is difficult, although the correlation between ‘margin status and local recurrence is inconsistent."! Mes- enteric desmoid fibromatosis is usually large and grossly relatively circumscribed with a fibrous cut surface (Fig. 9-11). The tumor is composed of long fascicles of spindle cells with ovoid or tapering nuclei, vesicular chromatin, small nucleoli, and indistinet cytoplasm, usually within a collagenous stroma (Fig. 9-12). Desmoid tumors at this site often resemble nodular fasciitis with focally prominent myxoid stroma (Fig. 9-13). Focal keloidal hyalinization is also common, Around 80% of desmoid fibromatosis cases show aberrant nuclear (and cytoplas- mie) staining for B-catenin (Fig. 9-14)," reflecting the‘Tomons oF re Sant aND Lance Iytrsrives, INcaupine Anat CANA FIGURES-9 m Cloar coll sarcoma-ike tumor ofthe smallintesting composed of sheets and vague nests of uniform rounded cells, ‘with small emounts of variably clear cytoplasm (A). A focally Siveolar growth pattern is commonly obearved (8). Note the indistinet nucleol and scant eytoplasm, FIGURE 8-10 m Strong immunoreactivity for $-100 protein is typical of gastrointestinal clear cell sarcoma-liko tumor. Mola noevtie markers are ususlly neaative (not shown) FIGURE 8:11 m Mesenteric desmaid fhromatasis. This taege tumor is grossly eireumseribed, (Courtesy Dr remy vss | presence of CTNNBI mutations (in sporadic tumors) or germline APC gene mutations (in patients with FAP). This finding is useful w confirm the diagnosis. Most tumors are positive for SMA, whereas KIT, DOGI, and caldesmon are negative.” Focal reactivity for desmin FGURES-12 m Desmoid fibromatasis composed of long fascicles of unitorm spindle cals9 ‘Lowors or THe SMALL aND Laer Ivresrives, bvetupnve ANAL Caxa, 441 IOURE 8-13 m Mesenteric desmoid fibromatosis often shows focally myxoid stroma. Note the plump, stollate nuclel with ‘small ncaa Inflammatory Fibroid Polyp Inflammatory fibroid polyp is a distinctive benign mes- ‘enchymal neoplasm with a predilection for the gastric antrum and ileum.” Patients. with small intestinal tumors may present with abdominal pain, GI bleeding, ‘or, more typically, intussusception (Fig. 9-13). Inflamma- tory fibroid polyps are usually mural masses centered in the submucosa, ufien betweets 3 and 6 om in size, with infiltrative borders into the mucosa and bowel wall. The tumors are composed of bland, stellate to short spindle cells arranged haphazarally in an edematous to mysoid stroma, with prominent inflammatory cells including conspicuous eosinophils (Fig. 9-16). Scattered small common (but not invariable) finding in desmoid fibromatosis. stromal blood vessels typically show perivascular fibrosis. ‘Most tumors are positive for CD34,” whereas KIT, DOGI, SMA, desmin, and S-100 protein are negate. ‘The majority of inflammatory fibroid polyps harbor acti- vating mutations in PDGFRA.**' Exon 12 mutations predominate in ileal tumors, in Contrast to exon 18 mmuta- tions in gastric tumors.” Hemangioma emangiomas of the small intestine are rare and infire- quently come to clinical attention, Larger hemangiomas and vascular malformations may present with GI tract FIGURE 15 m= Intussusception caused by an inflammatory fibroid polve, (Courtesy Or. Jeremy Jas.)aw 9 FIGURE 9-16 m Inflemmstory fibroid polyp of the ileum. The tumor is composed of spindled to stellate cells in an edematous stroma with seaiterad lymphocytes and eosinophil. bleeding. Most hemangiomas of the small intestine are of cavernous type and involve the submucosa.” Lymphan, Lymphangiomas of the GI tract are rare; the duodenum is the most common site, They are usually detected incidentally at endoscopy as a white spot or plaque. Lyinplsangionies ave cincunses ibe Tesins composed thin-walled dilated channels, often containing clear fluid, involving the mucosa and submucosa (Fig. 9-17). Such lesions should be distinguished from lymphangiectasia, which is generally diffuse. Angiosarcoma Primary angiosarcomas of the small intestine are very’ sare Some may avise in a prior radiation fied. Me- tastasis from more common sites (e.g. the scalp or face) FIGURES-17 = Lymphangioma of the duodenum, The lymphatic channels involve the mucosa and submucosa. “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL should always be excluded. Small intestinal angiosar- comas often present with GI tract bleeding and are nswally large mural masses with hemorrhage and ne- crosis. The tumors range from vasoformative lesions composed of irregular dissecting channels lined by Iypeeeansris ial le tthe anne taining spindled or epithelioid cells with amphophilic cytoplasm. ERG and CD31 are the most sensitive endo- thelial markers.” Keratin expression is often seen in angiosarcomas. Neurofibroma Neurofibromas of the small intestine are rare and are essentially diagnostic of NFI. Intra-abdominal neurofi- bbromas in NFT are often plexiform, may present with GI bleeding, and may extend through the muscularis propria into the mesentery. In the older literature, many NF -associated GI tumors thought to represent neuro- fibromas were likely wm fact GISTS, Ganglioneuromatosis, Diffuse ganglioneuromatosis is associated with NFI and ‘MEN-2B."" Patients may present with either constipa- tion or diarrhea. Ganghioneuromatosis is often a grossly ill-defined thickening of the bowel wall and may involve the small intestine, appendix, and colon.” MEN-2B- associated ganglioneuromatosis usually extends from the myenteric plexus, which is expanded in a band-like fashion, ints the muscukaiy propria, whereas NEI associated ganglioncuromatosis is more often centered in the submucosa. The lesion is composed ofa diffuse pro- liferation of 5-100 protein-positive Schwann cells, gan- lion cells, and their cellular processes. TUMORS OF LYMPHOID TISSUE Lymphoid Hyperplasia and Lymphoid Polyps Inestinal benign lymphoid polyps (representing reactive lymphoid follicular hyperplasia) are often encountered in children, especially in the duodenum. Diffuse nodular Iymphoid hyperplasia of the small intestine, which appears endoscopically as multiple mucosal polyps, is a rare finding in adults that is usually associated with a variety of immunodeficiency disorders.” Intestinal Lymphomas Although primary lymphomas of the small and large intestines are uncommon,” they represent a relatively high proportion of malignant neoplasms at these sites (nearly 50%), because eareinomas and mesenchymal neo~ plasms are also uncommon, Many systemic nodal Iym- phoma types may secondarily involve the intestines and other extranodal sites @ relatively limited group of lym phomas arises primarily in the intestines (Table 9-3). ‘Other than mantle cell lymphoma and Burkite lymphoma, which relatively commonly present in the colon, most of ‘these Iymphomtas are much more frequent in the small9 ‘Toons or THe SMALL AND Larcr Ivrestives, Ivetupnve ANAL Cana 443 TABLE 9-3 Most Common Primary Intestinal Lymphomas BrcellIymphomas Diffuse large B-cell Iymohome ‘Marginal zone lymphoma of mucose- Iymphoid tissue (MALT Immunoproliferstive small intestinal ‘ace Follicular lymphoma ‘Mantle cell Iymphoma Burkitt lymphoma Enteropathy-type T-cell lymphoma NEATL Mon T Teall lymphomas phic CDBE-positive intestinal iymphoma (“type 2 EATL") intestine” and will therefore be discussed in this section of the chapter. Diffuse Large B-Cell Lymphoma Diffuse large B-cell Iymphoma (DLBCL) is the most common lymphoma of the intestines, accounting for around 30% of all lymphomas.” DLBCL may present with abdominal pain, obstruction, a palpable mass, or perforation. A large polypoid mass or ulccrating circum- ferential lesion is typical (Fig. 9-18). The tumor is com= posed of sheets of large lymphoid cells (usually at least vee tines the size of nus al Iyrmpliocytes) with vesieu= lar chromatin, variably prominent nucleoli, irregular nuclear contours, and small amounts of cytoplasm (Fig, 9-19). Unlike in gastric DLBCL, a concomitant low- grade mucosa-associated lymphoid tissue (MALT) lym- phoma is uncommon.” The tumor cells almost invariably express the pan-B-cell matkers CD20, CD79, and PAXS. Either a germinal center phenotype (CD10 and BCL6) or an activated B-cell phenotype (MUMI) may be observed, aldhough dhe foriner is move conn FIOURE S-18 m Dittuse large B-cell lymphoma of the ileum. The large mass ulcerated the mucosa and shows e [Courtesy Br. Jeremy Js seatcneies FIGURE $419 m Diffuse lerge B-cell lymphoma [nfitrating the Similar to DLBCL of other sites, translocations involving BCL6 and the immunoglobulin heavy chain gene locus are relatively common” MYC rearrangements may also be detected in a small subset of cases.” Marginal Zone Lymphoma of Mucosa- Associated Lymphoid Tissue Aldiwugh uch less commun thar gasuie MATT tye phoma, MALT lymphoma is one of the most common primary intestinal lymphomas after DLBCL.*” Patients Usually” present with vague abdominal symptoms and weight loss, Some lesions are discovered incidentally. MALT Iymphoma may be seen as a polyp or mass. The Uistinetion fiom normal or hyperplastic MALT (e.g, Peyer patches) may sometimes be difficult, particularly in Similar to gastric MALT lymphoma, the juates around 1esidual lyniphoid follicles and is composed of uniform small lymphoid cells, with either rounded or irregular nucle, inconspicuous nucle- oli, and variable smounts of pale cytoplasm, sometimes with a “monocytoid” appearance (Fig. 9-20). Plasma cell differentiation may be seen. Unli MALT lymphomas, Iymphoepithelial lesions are usually not prominent. An infiltrative growth pattern (beyond the confines of the normal marginal zone) distinguishes MALT Iymphoma from reactive hyperplasia. The neo- plastic cells express pan-B-cell markers and are usually negative for CDS, C110, and CD23. Aberrant express of CD43 may be observed. Demonstration of immuno- globulin light chain restriction (hy immunohistochemis- tty) ot monoclonality may be required to confirm the diagnosis of lymphoma in histologically equivocal cases. ‘The 1(11:18)(q21:q21) translocation resulting in API2— -MALTI is detected in a subset of cases." Immunoproliferative Small Intestinal Disease Immunoproliferative stall intestinal disease (IPSID) {also known as alpha heavy chain disease) is a distinetivem9 lymphoma of the intestine. Note the Aymphoepitheal lesion). ration of the crypt variant of MALT lymphoma that is nearly exclusive to the Mediterranean region and the Middle East." Carmpy- lobacter runt infection ts strongly associated with IPSID and is believed to invoke a chronic antigenic stimulus for lymphoma development,” analogous to Helicobacter pylori in gastric MALT lymphoma.” Early lesions may be cured by antibiotic therapy. IPSID has a predilection for young aults and often presents with chronic diavihea and weight loss. A serum paraprotein (alpha heavy chain) is frequently detected.” The lymphoma shows similar cyto- logic features as other MALT lymphomas, with the exception that plasma cel differentiation is often exten- sive (Fig. 9-21). In early phases of disease, the small intestinal mucosa is grossly noxinal, and dhe inflate is confined to the mucosa. Later lesions show mucosal thickening and nodularity and histologic evidence of infiluative grows, Some cases progiess to DLBCL. The neoplastic cells show a similar immunophenotype as FIQURES21 m= Immunoproiferative smal intestinal disease. The lamina propria is expanded by an infiltrate of lymphoplasma- evi calls. (Courtesy Dr Jorenw Jase) “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 9.22 m Follicular Wymphoma of the duodenum. nodular lymphoid infitrte is composed of uniform amal other forms of MALT lymphoma, with the exception that immunoglobulin A heavy chain is consistently detected without light chains.” Follicular Lymphoma Primary small intestinal follicular lymphoma has a predi- fection for the duvxlenun’”" Te is usually diseoveredd incidentally as small polyps. Localized disease is clinically indolent and rarely spreads beyond the intestine, even without therapy.” The histologic features are similar to those of low-grade follicular lymphoma at other ites, characterized by a nodular infiltrate of small to inermediae-sized cells with inregular w folded nuclei and scant eytoplasta (Fg, 9-22) The neoplastic eels are positive for pan-B-cell markers, CD10, and BCL2 but ‘ave negative Tov CDS, cyclin Dl, and CD43.°" Coes pression of CD10 and BCL2 and a low Ki67 index dis- tinguish follicular lymphoma from reactive follicular hyperplasia. ‘The typical 1(14;18)(q343q21) translocation, with BCL2 rearrangement is usually found.” Mantle Cell Lymphoma “Manale eel! lymphoma may present primarily in the small intestine but is usually subsequently discovered systemi- cally in lymph nodes, spleen, and other sites. A classic presentation of mantle cell lymphoma is that of rmultiple Iymphomatous polyposis, wherein numerous polyps are dezeered throughout the GT tract by endoscopy. prefer- centally in the small intestine (Fig. 9-23)” A similar appearance may also be observed with follicular Iym- oma or MALT Iymphoma.”® Some cases present as a single polyp or mass. Mantle cell lymphoma isan aggres- sive disease with poor response to chemotherapy.” In most cases, a diffuse architecture is observed. The tumor is composed of uniform, small to intermediate-sized Iymphoid cells with slightly irregular nuclei, indistinct nucleoli, and seant cytoplasm (Fig. 9-24, A), Seattered9 ‘Toons or THe SMALL AND Lance Ivrestives, Ivetupnve ANAL Casa 445; meatal ye cd FIGURE 9.23 mA, Mantle cell lymphoma presenting as lympho- matous polyposis. B, The Iymphoid cells ere neatly entirely epithelioid histiocytes are a typical feature. In addition to pan-B-cell markers, CDS, eyelin D1 (see Fig. 9-24, B) and SOXII are positive, whereas CD10 is consistent!y negative." CDS expression is often weak. Nearly all ‘cases_harbor the t(11;14(q13q32) translocation with CCNDI (cyclin D1) rearrangement.” Burkitt Lymphoma Burkitt lymphoma, including endemic, sporadic, and human immunodeticieney virus (HIV)-associated forms, has a predilection for the small intestine, particularly the ileum, and often also involves the cecum and appendix Endemic Burkitt lymphoma is strongly associated with Epstein-Barr virus infection and usually affects chil- dren.” Burkitt lymphoma typically presents acutely ‘with obstruction or perforation but may also manifest a5 a large mass, Advanced stage is common at diagnosis, ‘Most patients ean be cured by high-dose combination chemotherapy. The tumor is composed of sheets of intermediate-sized cells with rounded nuclei, several dis- tinct nucleoli, and small amounts of basophilic eytoplasm, FIGURE $24 m Mantle cell lymphoma. A, The mucose is Ifl trated by uniform small cells with scant cytoplasm. B, Immun reactivity for eyclin D1 confirms the diagnosis. often with a high mitotic rate (Fig. 9-25). The classic “starry sky” appearance is due to numerous interspersed histiocytes phagocytizing nuclear debris. ‘The neoplastic cells are positive: for pan-B-cell markers and CD10 but are consistently negative for BCL2, CDS, and eyelin D1. The Ki67 index is nearly always greater than 95%. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) is positive in endemic cases but is rarely positive in sporadic Burkitt lymphoma. Nearly all cases harbor MYC gene rearrangements, most commonly with 68514)(q245932)""% FISH for MYC can therelore be used to confirm the diagnosis. Recent studies have sug- rested that immunohistochemistry for MYC. correlates translocation." Enteropathy-Associated T-Cell Lymphoma Enteropathy-associated T-cell lymphoma (EATL) is very ‘uncommon (although constituting nearly 90% of intes- tinal T-cell lymphomas), other than in populations with a high prevalence of celiac disease, which is a major risk factor." Most cases of EATL follow adult-onset celiae“5 9 FIGURES-25 m Burkit iymphome of the lleum. Note the frequent mitotic figures and apoptotic debris. Scattered tingible-body ‘macrophages impart the typical “stary eky" appearance disease (or are diagnosed concurrently), with a male predominance and a predilection for the jejunum and proximal ileum, Patients usually present emergently with, bowel perforation or obstruction. In.a small subsct of patients, overt Iymphoma develops after progression to, refractory celiac disease (“ulcerative jejunitis”)."”” Refrac- wry celiae disease may be chssified ay either type I in which intraepithelial lymphocytes have a normal (CD84) phenotype and are polyclonal, or type Tl, in_which intraepithelial Iymphocytes. lose expression of CD8 (which can be demonstrated by immunohistochemistry or flow })and show monoclonal T-cell receptor x "6 Type sefiactor disease has also been referred to as “ATL. in situ” and ‘traepithelial T-cell lymphoma.” ‘Type I refractory celiac disease unly rarely progeesses to ETL, EATL is an aggressive lymphoma; most patients succumb to the dlsease."™ “The tumor often appears as multiple ulcerative masses (ig. 9-26}, sometimes with perforation. ‘The tumor is composed of sheets of intermediate-sized to large k phoid cells with rounded nuclei, vesicular chromatin, prominent nucleoli, and moderate amounts of pale cyto~ plasm, often admixed with numerous inflammatory cell which may obscure the neoplastic nature of the infiltrate. ‘Some eases show marked pleomorphism (Fig. 9-27). The adjacent mucosa shows enteropathy, usually with villous Dlunting, an increased Iymphoplasmacytic infiltrate in the and often a striking intraepithelial Iym- phocytosis. The neoplastic cells are positive for CD3, CDF, and CD103 but are usually negative for CD4, CDS. CDS, and CD56." CD30 is variably positive. The intraepithelial lymphocytes in the adjacent mucosa show a similar aberrant phenotype (ie., CDS negative). Lack of CDS expression in intraepithelial T cells per se should not be overinterpreted as evidence of lymphoma, because normal cells in this compartment are often negative or weakly positive for CDS. Monoclonal ‘T-cell receptor gene rearrangement can be detected “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 926 m Enteropathy-associated T-cell lymphoma of the jejunum with multiple ulers, (Courtesy Or. Jeremy dass) ymphoid cals hucleoli, and sbundant eytoplasm. Monomorphic CD56-Positive Intestinal T-Cell Lymphoma ‘This rare type of intestinal ‘T-cell lymphoma, also referred to a3 “type II EATL,” is rarely associated with celine disease and shows distinct histologic and immuno- phenotypic features." The prognosis is, however, similarly poor, In contrast to classic BATT, the tumor cells are usually small, with hyperchromatie nuclei and seant cytoplasm, although the adjacent mucosa often shows enteropathy-like features, including a striking intraepithelial lymphocytosis (Fig. 9-28, 4).!"” The neo- plastic cells are positive for CD3, CD8 (see Fig. 9-28, B), and CDS6 (the latter «wo markers distinguishing this subtype from EATL).” EBER is negative (distin- {guishing this lymphoma from nasal-type NK/T-cell Iym- phoma, which may also occasionally present in the sinall intestine)9 ‘Towors or THe Swat aND Lance Ivrestivs, Ivetupnve ANAL Cana 447 FIGURE 9-28 m Striking {to monomorphic CD56-postive intestinal T- (CDB is positive (B), contrasting this lymphoma with conven: tional enteropatny-associated I-cell Iymphoms, SECONDARY TUMORS ‘The small intestine isthe site of predilection for metas- tases to the GI tract" Of note, secondary carcinomas are much more common than primary small intestinal ‘sdenocarcinomas, The most common tumor to metasta- size to the small intestine is melanoma (Fig. 9-29), fol- lowed by breast, lung, and ovarian carcinomas." Direct extension from the paneress, stomach, and colon is also relatively common. Colonization of the native sinall intestinal epithelium by metastatic adenocarcinoma may mimie a primary tumor. The possibilty of a metas- tasis from the colon should always be excluded when an intestinal-type adenocarcinoma is encountered. particu larly when the small intestinal mucosa is uninvolved and when a precursor lesion or significant risk factor is absent (eg, celiac disease or Crohn disease). TUMOR-LIKE LESIONS Brunner Gland Hyperplasia and Hamartoma Not uncommonly, Brunner glands may proliferate and extend into the lamina propria, often in the setting of FIGURE $30 Brunner gland hamartoma. Note the focal cystic dilation ofthe Brunner glands in this predominantly submuco- Sa leston. peptic duodenitis. This phenomenon usually: occurs in the duodenal bulb and manifests as a small polyp. Large Brunner gland lesions, particularly those containing: ggstically dilated glands and prominent stroma, have often been referred to as “Brunner gland hamartoma” Gig. 9-30), although the distinesion from hyperpla may be somewhat arbitrary.!" Such lesions may occa- sionally ulcerate and present with melena, anemia, or obstruction Gastric and Pancreatic Heterotopia Gastric heterotopia is a common incidental finding in the duodenal bulb: itis one of the most frequent duodenal polyps. It is composed of tightly apposed normal oxyntic glands (with parietal and chief cells); the overlying surface epithelium is often replaced by gastric foveolar mucous cells. Pancreatic heterotopia is uncommon and may be found throughout the GI tract, often in the duodenum. It may involve the mucosa and submucosa (in which ease it is seen as a small polyp) or muscularis propriauso (presenting as a mural mass, occasionally with stricture fEnmation or imussusception), Pancreatic heterotopia is usually composed of pancreatic acini and ducts. A small subset contains islets, and occasionally only pancreatic ducts are seen. In the latter situation, the possibility of a well-differentiared adenocarcinoma may he considered, especially atthe time of frozen section. Lobulated archi- tecture, well-formed ductal structures, and lack of atypia are reassuring features. Peutz-Jeghers Syndrome and Polyps Clinical Features Peutz-Jeghers syndrome is an autosomal dominant disorder caused by germline mutations in STKIT (LKB1).""*"" Affected patients show characteristic muco- cutaneous pigmentation (particularly on the lips and peri- oral region), develop distinctive hamartomatous polyps, and have an increased nsk of carcinomas of the GI tract (stomach, small intestine, and colon), breast, and pan- creas." Other manifestations include adenoma malig- num of the uterine cervix, sex cord tumor with annular tubules of the ovary, and Sertoli cell tumor of the testis. In the absence of a family history or prominent mucocu- taneous pigmentation, it 1s recommended that three Peutz-Jeghers polyps be confirmed histologically before the diagnosis of the syndrome is made.''® Peute-Jeghers polyps occur throughout the Gi tract but are most common in the smal intestine. Most patients first have polyps in childhuwal ur adolescence. Patients may present with GI bleeding, abdominal pain, or intussusception. Polyps indistinguishable from Peutz-Jeghers polyps are very rarely detected sporadically.” Macroscopic Appearances Peutz-Jeghers polyps are usually pedunculated with a broad stalk, ranging in size from several millimeters to 5 em, The surface is lobulated and somewhat resembles an adenoma. Histologic Appearances Peute-Jeghers polyps typically contain arborizing bands of smooth muscle, extending from the stalk berween lobules of mucosa (Fig. 9-31), often with a villous appear- ance. The epithelium is uswally histologically unremsrl- able. The branching smooth muscle is best developed in large small intestinal polyps: gastric and colonic polyps ‘may contain little smooth muscle and therefore be diff- cult to recognize. In large pedunculated polyps, the ‘mucosa may prolapse into, the stalk or deeper into the dowel wall and mimic adenocarcinoma (pseudoinva- sion”). The absence of cytologic atypia and the pres- ence of mucin pools and hemosiderin deposition are helpful diagnostic features. Rarely, dysplasia may develop in Peutz-Jeghers polyps, Juvenile Polyposis and Polyps See section on large intestine. “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 9-31 m Peutz-Jeghers polyp ofthe smell intestine. Thick bands of smooth muscle emanate fram the polyp stalk Cowden Syndrome (PTEN Hamartoma Syndrome) and Associated Polyps See section on large intestine, Lipohyperplasia of the lleocecal Valve Variably termed lipomatous bypertropby, lypomatosis, and lipobyperplasia, an excess of submucosal adipose tissue ‘causing some degiee of pruwusion inte the Tune af che ‘cecum is a relatively common finding and may occasion- ally be prominent." As the endoscopic features are char- acteristic, biopsies of this lesion are rarely performed. APPENDIX EPITHELIAL TUMORS Adenomas and Serrated Polyps ‘The same spectrum of adenomasand serrated polyps well characterized in the colon may also occur in the appendi and are classified in a similar fashion (e., hyperpl polyp, sessile serrated polyp, and adenoma)!" with ‘one notable distinction: low-grade dysplastic mucin- secreting lesions of the appendix (often associaced with ‘ystic dilatation), when associated with rupture and extra- appendiceal mucin, are currently known as “low-grade appendiceal mucinous neoplasms” (LAMN)."" ‘Such lesions were formerly designated “mucinous cystadeno- mas.” When confined to the appendix, the latter nomenclature is reasonable (although many authors prefer simply “adenoma” because not all lesions are ‘ystic), but should be avoided when associated wich extra- appendiceal spread, because many such patients have pscudomyxoma peritonei and eventually succumb to disease (ve later discussion). The most common of these lesions in the appendix is the sessile serrated polyp,”* which was previously often referred to as diffuse hyper- plasia. Villous adenomas are more common than tubular9 ‘Towors or THe Swat aND Lance Ivrestivs, Ivetupnve ANAL Cana 449 adenomas. Serrated adenomas (often referred to as “tra ditional” serrated adenomas) are rare at this site. Clinical Features Most small adenomas and serrated polyps of the appenclix are discovered incidentally by the pathologist on exami- nation of an appendectomy specimen.'” However, ade- nomas that cover large areas of the mucosal surface associated with mucin secretion (mucinous cystadenoma; LAMN), often present as acute appendicitis. Macroscopic Appearances ‘The appendix is grossly normal in- many cases with adenomas and serrated polyps. Some cases with mucin secretion show sausage-like appendiccal dilatation, an appearance often described as a “mucocele.” However, iiucocele is not a specific diagnosis; such a gross finding may anise ether from a neoplastic process (which is more common) or after obstruction (retention cyst; see later discussion). Histologic Appearances ‘Adenomas and serrated polyps of the appendix are similar to their counterparts in the large intestine.” Sessile serrated polyps are distinguished from hyperplastic polyps by their large size, basal crypt dilatation and ser- ration, and distorted erypt architecture with anchor and L-shaped suuctures. Sessile serrated pulyps say show areas of progression to cytologic dysplasia, either conven~ tional dysplasia with hyperchromatic, elongated nuclei and slightly basophilic cytoplasm, or so-called serrated dysplasia with cosinophilic cytoplasm and more vesicular chromatin. Such polyps were formerly referred to as “wuixed polyps” (@g., mixed hyperplastic polyp-tubulae adenoma) hu are currently designated “stsie serrated Polyp with otclogie dysplasia” Conventional adenomas of the appends often have a villous architecture, but, in cases with a dilated Iumen and abundant intraluminal mucin, the adenoma may be entirely or nearly entirely flat. In the latter situation, the cystic appendix may be lined by a thin layer of low-grade dysplastic epithelium (which can be deceptively bland), oF entirely devoid of epithelium because of compression by mucin. If no lining found on initial sampling, more extensive sampling. is advisable to identify areas of residual adenoma. The ‘underlying submucosa often undergoes extensive fibrosis and may show dystrophic calcification. As mentioned above, even without overt evidence of invasion into the appendiceal wall, ithe appendix has ruptured with extra- appendiceal mucin on the peritoneal surface (with or without neoplastic epithelium), the term LAMN should be applied. Low-Grade Appendiceal Mucinous Neoplasm ‘Terminology applied to low-grade mucin-producing neo- plasms of the appendix associated with pseudomyxomta FIGURE 332 m Low-grade appendices! mucinous neoplasm. The epitholial lining of the appendix shows low-grade dysplasia, Nota the fibrosis ofthe underlying wal, peritonei has been varied and confusing." In recent years, the term LAMN has been gaining wide accep- tance.'*** However, some authors prefer to regard such lesions as low-grade mucinous adenocarcinomas, because many affected. patients eventually succumb to disease, resulting from uncontrolled intra-abdominal mucin accu mulation." Te is important to distinguish this disease enity from canventional (high-grade) mucinous acer carcinoma, as the clinical course and optimal treatment differ signficanely.”"™ Similar to mucin-producing ade- ‘nomas limited to the appendix, LAMN ofien presents as a sausage-like swelling, but the appendix may alterna- tively be completely obliterated by the neoplasm and Uifficule wo identify. The lining is similarly composed of low-grade dysplastic epithelium (Fig. 9-82), which is usually flat but may show areas of villous architecture. ‘The andletlying appendiceal wall is fibrotic and amy be extensively calcified. Pecuomysoma peritonei associated with LAMN usually spares the serosa of the intestines, instead involv- ing the omentum and pelvis. Patients often present with abilominal distention. Pseuddomyoma peritone! is over- whelmingly most often caused by an appendiceal neo- plasm," but may rarely result from tumors arising at other sites in the GI tract oF the urachus. OF note, although the ovary may be secondarily involved, it almost never the primary site."*"”” Histologically, pseu ddomyxoma peritonei may be classified as “lowe grade” . associated with LAMN), characterized by abundant ‘mucin and very limited strips of neoplastic epithelium with minimal to no nuclear atypia (Fig. 9-33), or “high grade” (associated with conventional mucinous adenocar- Ginoma). characterized by more abundant neoplastic epi- thelium showing at least focally marked atypia (sometimes with signet ring cell morphology), often with invasion of underlying tissue and a desmoplastic stromal response.” Low-grade pseudomyxoma peritonei_ was formerly referred to as “disseminated peritoneal adenomucino- sis,""" but this terminology is not favored.4509 “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 9-39 m Low-grade pseudomyxoms peritonel. Abundent ‘mucin is seen with only limited epithelium with mild atypia, “The natural history of low-grade pseudomyxoma peri- tonet is distincuve: the tumor is ustally confined to the abdominal cavity throughout the disease course, without ‘metastases to lymph nodes or liver or invasion of adjacent viscera, Radical cytoreductive surgery appears to improve survival”; heated intraperitoneal chemotherapy in this setting may be bencficial in sclected patients.” Many’ patients survive 5 to 0 years or longer after first presen= tation." Some patients have progression to. more invasive disease over time. OF note, patients wilt local ized periappendiceal disease at presentation appear to have a lower risk of development of pseudomyxoma peri- tonei, particularly when no epithelium is detected (ive when only acellular mucin is present). Adenocarcinoma Clinical Features Primary appendiceal adenocarcinomas of conventional ye are rare, with a peak incidence in the seventh decade anda slight male predominance.’ Patients often present with a clinical diagnosis of acute appendicitis.” Some patients present with an abdominal or pelvie mass, ox when associated with pseudomyxoma peritonei, abdomi- nal distention. Many patients present with ‘advanced disease, Metastases to the ovary are common at presenta~ tion and may easily be mistaken for an ovarian primary. “The prognosis is worse for nonmucinous adenocarcino- ‘mas and signet ring cell eareinomas. Macroscopic Appearances Appendiceal adenocarcinomas either form a mucocele (imilar to LAMN) or destroy the appendix, leaving a large, irregular mass in its place. Histologic Appearances Appendiceal adenocarcinomas resemble colorectal ade- nocarcinomas. Mucinous adenocarcinomas are more ‘an adenoma, The tumor is well ifferentiated with focal mucin production common than nonmucinous tumors (Fig. 9-34). An adjacent adenoma may sometimes be identified. Adeno- ‘earcinomas may also arise from goblet cell carcinoid ‘tumors (see later section on NETS).?” Immunohistochemistry and Molecular Pathology Adenocarcinomas of the appendix are usually diffusely positive for CK20 and CDX-2 (similar to colorectal tumurs) but more often express CK7 dan dhe later Immunoreactivity for MUC2 is also common." Appen- diceal adenocarcinomas often harbor KRAS mutations, but very rarely show microsatellite instability NEUROENDOCRINE TUMORS. NET are the most common neoplasms of the appendix, the vast majority of which are conventional grade 1 NET (widely known as carcinoid tumors). In contrast, goblet cell carcinoid rumors are uncommon." Overall, around 30% of NETS of the GI tract arise in the appendix. Carcinoid Tumor Clinical Features Appendiceal carcinoid rumors occur over awide age range, swith a peak in young adults and a female predominance. ‘They are nearly always asymptomatic, being found inci- dentally in appendectomy specimens. ‘The prognosis is generally excellent. Tumors less than 1 em have very low metastatic potential, those between I and ? em havea low risk, and tumors greater than 2 em (which account for at most 5% of appendiceal earcinoid tumors) have a signifi- ceant risk of lymph node metastases." Right hemicolee- tomy is therefore recommended for tumors greater than 2-em, Patients with appendiceal carcinoid tumors almost never develop carcinoid syndrome, which occurs in only’ a subset of those rare patients who have liver metastases.9 ‘Towors oF THe SMALL aND Lance Ivrestives, bectupeve ANAL Cana 451 FIGURE $35 m Csrcinold tumor of the sppendix composed of ‘small nests of uniform calls, Macroscopic Appearances Appendiceal carcinoid tumors are usually localized to the tip of the appendix. Most tumors are less than I em and grossly napparent. Larger tumors are often relatively well circumscribed and appear yellow after formalin fixation, Histologic Appearances ‘Most carcinoid tumors of the appendix resemble ileal (enterochromaffin cell) carcinoid tumors and are com posed of small nests of cells with round nuclei, granular ‘chromatin, inconspicuous nucleoli, and eosinophilic cyto- asm (Fig. 9-35), Fine cytoplasmic granules may be na subset of cells. A uabecular ur acinar areivecta also be seen. Rare tumors show clear cell morphology. Infiltration through the muscularis propria into subse- rosa, as well as Tymphatic and perineutal invasion, is ‘common but has no prognostic significance. Tubular ¢ar- cinoid tumors, composed of small tubules and trabecu- lae,'* may be mistaken for metastatic adenocarcinoma, Uniform cytomorphology with bland nuclei and expres- sion of chromogranin are helpful distinguishing features Immunohistochemistry Appendiceal carcinoid tumors are usually strongly and diffusely positive for broad-spectrum keratins, chromo- sranin (Fig. 9-36), and synaptophysin and consistently negative for CK7; a small subset expresses CK20."" $-100 prosein-positive sustentacular cells may he seen. CDX-2 is positive, whereas TTF-1, polyclonal PAXS, and ISL1 are usually negative." Goblet Cell Carcinoid Tumor Clinical Features Goblet cell carcinoid tumors (previously referred to as “adenocarcinoid” and “crypt cell carcinoma,” among: FIGURES.36 m Chromogranin is strongly positive in appendiceal carcinoid tumors. Nate the nested architecture, other terms) occur in middle-aged to older adults with an equal sex distribution."™"*"" Most patients present with acute appendicitis. Goblet cell carcinoid tumors are more aggressive than conventional carcinoid tumors of the appendix and may present with peritoneal dissemina- tion, with a predilection for the ovaries.'”""” Patients with localized discase at appendectomy rarely develop distant metastases. Patients with metastatic disease at presentation have a guarded prognosis, although their eal course may be relatively innlulent. Mixed aalewo- neuroendocrine carcinomas (adenocarcinomas arising in goblet cell carcinoid tumors; see histologic appearances) progress rapidly, an! affected patients usvally succumb to metastatic discase within § years." Macroscopic Appearances ‘The appendix may appear grossly unremarkable or show ‘mural thickening. Histologic Appearances Goblet cell carcinoid tumors typically infiltrate through the wall of the appendix in a concentric fashion. The tumor is composed of small nests of cells with abundant intracytoplasmic mucin and eccentric, compressed hyper- chromatic nuclei, resembling goblet cells or signet ring cells (Fig. 9-37). Occasional Paneth cells and neuroendo- crine cells are often (though not invariably) seen. Nuclear atypia is usually minimal, and mitotic activity is scarce. The entire appendix may be involved, although the mucosa is often relatively. spared. Small areas of the ‘tumor may contain extracellular mucin pools. Goblet cell carcinoid tumors may progress to con- ventional adenocarcinoma, in which case the term ‘mixed adenoneurvendocrine carcinoma (or adenocarcinoma ex-goblet cell carcinoid tumor) may be applied." Mixed carcinomas seem to be as common as “pure” goblet cell carcinoid tumors. In addition to areas with a Conventional (colorectal-like) adenocarcinoma compo- nent, any combination of the following features shouldFIGURES-37 m Goblet cell carcinoid ofthe appendix. Ocessional call contain eosinophilic cytoplasmic granules. lead to a diagnosis of mixed adenoneuroendocrine earei- noma: confluent growth (loss of nested architecture), extensive mucin pools containing single tumor cells oF cell clusters, infiltrative cords of cells (single-fle growth) or sheets of signet ring cells, and marked nuclear atypia, often accompanied by increased mitotic activity (Fig. '9-38)."" Such tumors have been subclassified into poorly differentiated adenocarcinoma and signet ring cell types; patients with dhe former category OF uinor have a worse prognosis.” ‘The absence of an in situ component (i. adenoma) favors a mixed adenoneuroendocrine carci noma over a conventional adenocarcinoma. ‘The signet ring cell carcinoma subtype may be mistaken for meta- i srcinoma; the pattern of growth FIGURE 8:38 mt Mixed adenonouroendocrine carcinoma of the ‘appendix (adenocarcinoma arsina in 8 aaolet cell carcinoid). 9 ‘Tumors of ne Swatt AND Lance bTESTINES, INCLUDING ANAL CANAL Immunohistochemistry TT lel eeepc eaten canteen antigen (CEA), CK20, CDX2, and MUC2 but is typi- cally negative for CK7 and MUCL."” Chromogranin zl epee iclain capaho ie one docrine component but are not required for the diagnosis. In mixed adenoneuroendocrine carcinomas, the poorly differentiated adenocarcinoma component ffien foses expression of MUC2 and is positive for MUCL and p33.'" TUMOR-LIKE LESIONS Simple Mucocele ‘The clinical term mucocele describes a sausage-like, dilated ross appearance of the aj lix, caused by the accumu- (oto seca he teen Auongi meet oc cased turn out to be mucin-producing adenomas, LAMN, ‘or mucinous adenocarcinomas, occasionally a “simple” Ce nine ing from obstruction of the appendiceal os. Nerve Sheath Proliferations Appendiceal “neuroma” (also known as_ncurogenic appendicopathy or neurogenous hyperplasia) sa common incidental histologic finding at the time of appendec- omy!" TCs mae evminon in uber patients, “The Tumen of the appendix is obliterated by a proliferation of $-100 protein-positive spindle cells with ovoid to taper- ing nuclei (Schwann cells, admixed with axons and smaller numbers of neuroendocrine cells, in a collage- nous stroma. This lesion is of no clinical significance. LARGE INTESTINE EPITHELIAL TUMORS Adenomas Clinical Features Adenomas are more common in countries with a high risk of colorectal adenocarcinoma (e.g, Europe and North America). Adenomas are more common in men, and the incidence increases with age, as does the number of adenomas." Outside of the setting of FAP and MUTYH-associated polyposis (MAP; see later discus- sion), adenomas are uncommon in patients under 40 years, Patients with Lynch syndrome have adenomas at a younger age, but they are usually few in. mumber.”" In ‘geographic areas with a high risk of colorectal cancer, the prevalence of adenomas is nearly 50% in patients over 50) years of age. Adenomas occur throughout the colon and rectum with a fairly even anatomic distribution, They are usually asymptomatic, eing detected at colonoscopic sereening for colorectal cancer. Large adenomas (parti- ccularly those >2 cm) may present with occult GI bleed- ing. anemia, or hematochezia, Not only is screening9 ‘Toons of Tne Swati aNp Laer boresTives, EvcLupnsc ANAL CANAL 453 colonoscopy helpful to detect occult colorectal cancer, but colonoscopic removal of adenomas also decrease mortality.* The number and type of adenomas identified aids in stratifying patients for risk of subsequent cancer and therefore detetmsines surveillance interval. Speuifi- cally, any of the following features leads to heightened colonoscopic surveillance (typically a 3-year interval is Fecommenided, instead of the standard 10-year interval} three or more adenomas (of any type), an adenoma greater than I cm, an adenoma with a villous component (ubulovillous oF villous), vr an adenoma with high-grade dysplasia."® Large adenomas and adenomas with these histologic features are often referred to as “advanced” adenonas. Because both a villous womponent and! high- grade dysplasia are significantly associated with large size, itis difficult to determine whether such histologic fe tures have independent predictive value Macroscopic Appearances Adenomas are usually ess than I em and appear as sessile polyps. Small adenomas are grossly similar to hyperplas- tic polyps. Larger adenomas may be pedunculated and protrude into the lumen with a submucosal stalk (Fig, 9.39), Peduneulated adenomas are sometimes ulcerated Large sessile polyps may impart a carpet-like appearance to the colon (Fig. 9-40). A small subset of adenomas is flat or slightly depressed; such lesions are difficult to recognize endoscopically.” Histologic Appearances Adenomas are traditionally classified as tubular, tubulo~ villous, or villous, depending on the extent of villous architecture. The cutoffs for the latter two categories have been arbitrarily defined as 25% to 75% and more FIGURE S40 m Large sessile villous adenoma ofthe recturn. The tumor involves the entire circumference of the ractum, {Courtany Dr. sleremy Jossao “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE -41 m Adenomas of the colon showing tubular (A) and Villous (B) architecture. Both of these polyps have low-grade dysplasi. han 75% villous, Tubular adenomas contain tubular structures and have a relatively flat surface, whereas villous areas consist of finger-like projeetions containing small amounts of lamina propria (Fig. 9-41). “Tradi- tional” serrated adenomas are discussed in the section on serrated polyps. Most adenomas show low-grade (inild to moderate) dysplasia, with relatively uniform, elongated hyperchromatic nuclei showing pseudostrat” ‘fication but maintaining polarity with apical, often slightly basophilic cytoplasm, lining crypts or villi with, relatively even architectural distribution. Nucteoli are generally inconspicuous. Miotie activity is highly vari- able. Apoptotic nuclei are often seen in the basal aspects of adenomas. In high-grade (severe) dysplasia, nuclei show loss of polarity, often with a more rounded con- figuration, vesicular chromatin, prominent nucleoli, and variability, and architectaral complexity is seen, with erib- riforming’ and a back-to-back crypt configuration (Fig. 9-42), High-grade dysplasia encompasses lesions for- ‘erly designated “carcinoma in situ”; the latter term should not be used to avoid confusion. Intramucosal ad- enocarcinoma can be applied to lesions showing mark- edly complex architecture with severe nuclear atypia, FIGURES-42 m Adenoma of the colon with high-grade dysplasia ‘Tho adenoma shows architectural complexity, and the lesional calle contain rounded nucle! with vesicular chramstin single-cell infiltration of the lamina propria, or a des- ‘moplastic stromal response, although the latter finding is rare in the absence of submucosal invasion. Because ‘essentially no metastatic potential exists without sub- ‘mucosal invasion, some pathologists prefer not to use the designation intramucosal adenocarcinoma and in- stead retain the term high-grade dysplasia for all such lesions.'* Rare adenomas are associated with minute pro- Fiferations of well-lifferentiated neutoenndocrine cells adjacent to the dysplastic erypts (“composite adenoma- microcarcinoid”)™ Large pedunculated adenomas may sometimes. be associated with epithelial “displacement” (also. termed jon), is cases. dysplastic epithelium nied by kunina propria) hevncawes into Ik, likely as a result of torsion. In such tisk of overinterpreting the findings as nna, The presenee of lanina propia, hhemosiderin, rounded crypt contours, acellular mucin pools or pools of mucin partially surrounded by a strip ‘of dysplastic epithelium, and low-grade dysplasia favors a benign diagnosis, whereas a desmoplastic stromal response, irregularly infiltrative mucin pools, single neo- plastic cells floating within the mucin, and high-grade ‘dysplasia (particularly when the overlying adenoma shows low-grade dysplasia) argue for invasive adenocarcinoma, ‘The term malignant polyp has been used to refer to small polypoid adenocarcinomas (without an adenoma- ‘ous component) and adenomas that contain foci of ade- rnocarcinoma invading the submucosa. The former lesion, and sessile adenomas associated with adenocarcinoma invasive into the submucosa, should both be treated with segmental colectomy, when medically appropriate, owing to the significant risk of lymph node metastasis. In con= ‘rast, pedunculated polyps with invasive adenocarcinoma into the submucosa can be managed conservatively,” provided none of the following Cunfavorable”) features are identified: lmmphovascular invasion, poor differentia- tion, a positive submucosal margin, or tumor 1 to 2 mm_ from the margin." The presence of any of these features9 ‘Toons of Tne Swati aND Laer IuresTINes, ExcLUpIsG ANAL CANAL 455 is associated with a risk of residual adenocarcinoma or lymph node metastasis at surgery." Molecular Pathology Conventional adenomas are the precursors t0 the major= ity of colorectal adenocarcinomas. In the sporadic setting, such adenomas almost invariably harbor APC muta- tions," and a subset of adenomas (mostly tubulovillous and villous) also has KRAS mutations." A recent study has implicated GNAS in, the molecular pathogenesis villous adenomas as well." Other than a subset of adeno- mas in patients with Lynch syndrome, conventional ade~ nnomas are microsatellite stable." Familial Adenomatous Polyposis Clinical Features FAP is an autosomal dominant disorder caused by germ: line mutations in the adenomatous polyposis coli (APC) gene."* In around one third of patients, FAP is caused by a new germline mutation. Affected patients usually begin to have colorectal adenomas in the second decade, reaching hundreds or thousands by the fourth decade, typically more numerous distally. Without prophylact total proctocolectomy, nearly all patients will have colorectal adenocarcinoma by the age of 50 years, FAP-associated colorectal adenocarcinomas account for around 1% of cofon cancers overall. Other typical fea tures of PAP are multiple guste Fanuc glad polyp ancl periampullary duodenal adenomas. Upper endoscopic surveillance is important, as duodenal adenomas may also progress to cancer in affected patients, albeit usually later in life, Patients with the Gardner variant of FAP (widely referred to as Gardner syndrome) show extragastrointe inal manifestations, clinically dhe most important of which are desmoid tumors, but also epidermoid cysts dental abnormalities, and osteomas of the skull and jaw." Other associated lesions include congenital hyper wophy of the retinal pigment epithelium (CARPE), hepatoblas- toma, the eribriform-morular variant of thyroid carci~ noma, and medulloblastoma. The combination and medulloblastoma is often referred to as “Tarcot syndrome,” although this eponym has also been applied to patients with Lynch syndrome and astrocytoma or glioblastom: ‘Aetenvated PAD is « variant in which patients have fewer adenomas, usually between 30 and 100, which often spare the rectum." Such patients typically have colon cancer at an older age and much less often exhibit extragastrointestinal manifestations. Attenuated FAP is associated with mutations at the 5’ and 3” ends of the AP gene. Mutations in other particular regions of APC are associated with CHRPE, desmoid tumors, or an extre- mely high polyp burden Some patients in whom attenuated FAP is suspected are instead found to have germline mutations in the DNA base excision repair gene MUTYH.° MUTYH-associated polyposis is an autosomal recessive disorder. Affected patients have a similar polyp burden as in attenuated FAP {although some patients may have 10 or fewer adenomas), FIGURE 9.43 = Femilial adenomatous polyposis, The colonic ‘mucosa is covered by numerous small adenomas but they are more often found in the proximal colon. & subset of patients has gastric fundic gland. polyps and duodenal adenomas. Patients with this polyposis syn- drome typically have colon cancer at an older age than in conventional FAP. Macroscopic Appearances FAP-associated adenomas have a similar appearance to sporadic adenomas. Most polyps are small and sessile, although larger polyps may have a pecunculated appear™ ance. In patients with a severe phenotype, the entire wlurectal mucus nay be carpeted with dhuusanls of small polyps, as well as scattered large polyps (Fig. 9-43). Histologic Appearances ‘The majority of adenomas in patients with FAP are tubular Sections taken from grossly unremarkable mucosa often contain microscopic adenomas, which may consist of only a single dysplastic crypt, which has been seferred 1 as an “aberrant etypt fovus.” Carcinomas in FAP are indistinguishable from conventional sporadic colon cancers (see later discussion). Serrated Polyps Serrated polyps include hyperplastic polyps, sessile ser- rated polyps (SSP, also known as sessile serrated adeno- mas), and “traditional” serrated adenomas." The word traditional is applied to the latter lesion to avoid con- fusion with SSP. Significant changes have been made dover the past deeads in terms of both classification of these polyps, because of extensive research into their molecular genetics and possible association with earci- noma, as well as recommendations for surveillance." Ie is therefore increasingly important to classify st polyps properly ch Clinical Features Serrated polyps of all types are nearly always asymptom- atie, The most common serrated polyps (and the most commonly diagnosed polyps overall) are hyperplastic56 09 pps accounting for around 80% of such lesions lyperplastic polyps are diagnosed in patients over a wide a angea hears alert to teapneel oles and rectum. Reetosigmoid hyperplastic polyps are usually clinically insignificant with essentially no risk of malig- rant progression and require no change in colonoseopic surveillance. SSPs constitute nearly 20% of serrated polyps. These lesions are mostly found in the proximal colon and are somewhat more common in women. Although large follow-up studies are limited, on the basis| in part of the recognition that “interval” right-sided colon cancers arise between colonoscopic surveillance procedures, and the strong data implicating SSPs as the most common precursor for sporadic microsatellite tnstable colon cancer i widely belived that SSPS should be removed entirely, and lesions with superim- posed cytologic dysplasia (see later discussion) confer a significant risk of cancer (possibly higher than for patients with conventional “advanced” adenomas).'" Conse- quently, current recommendations for the latter lesions are similar to those for high-risk adenomas (i.e. a 3-year interval). Traditional serrated adenomas are rare, nearly exclusively arise m the sigmoid colon and rectum, and should be treated and followed in a similar fashion as conventional adenomas." ‘A recognition 1s emerging that some patients with multiple serrated polyps (and their first-degree relatives) have a significantly increased risk of development of colon cancer.""""* Diagnostic criteria for so-called ser- rated polyposis (formerly als referred to a hyperplastic polyposis) lave been propose in the must recent WHO chssification of tumors of the digestive system and include more than 20 serrated polyps throughout the colon, five or more serrated polyps proximal 10 the sigmoid colon with two or more more than 1 cm, or any’ number of serrated polyps proximal to the sigmoid colon ina patient with a fiastdegree velative with serrated pol- ysis (although serrated polyposis is rarely familial). ° Most patents have che diagnosis made frst in middle age 0 later in life, Tivo variants have been recognized, “type 1” characterized by multiple large predominantly proxi- mal SPs and “type 2” with numerous small hyperplastic polyps throughout the colon." The first variant is associ- ated with a substantial risk of colon cancer, whereas patients with the second variant have at most a small increase in risk!" So-called hereditary mixed polyposis syndrome is a rare, incompletely characterized autosomal dominant disorder in which serrated polyps develop, in addition to adenomas and polyps resembling juvenile polyps." Affected patients also have an increased risk of colorectal Macroscopic Appearances Hyperplastic polyps are small (usually <5 mm), barely’ raised lesions. SSPs are generally larger than hyperplastic polyps; around 20% are larger than I em. SSPs are sessile or flat with a similar color to that of the adjacent mucosa. ‘Traditional serrated adenomas have a more raised appear- ance than the other serrated polyps, similar to that of conventional adenomas. “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 9-44 mA, Hyperplastic polyp of the sigmoid colon. The ‘erration othe upper ery. ‘serrated polyp ‘of the cacum. The serration extende to the bases of the crypts, ‘whore thera is erypr llatation and branching, forming anchor” Tike structures. Histologic Appearances Hyperplastic polyps may be separated into two main types, but, because such classification is of limited clinical relevance, the unqualified term Ayporplastc polyp is sufli- cient for diagnostie purposes. The most common type is the “microvesicular” hyperplastic polyp, so named ‘because of the predominant population of columnar cells with abundant microvesicular mucin, usually interspersed with smaller numbers of goblet cells (Fig. 9-44, 4)..”” ‘The “goblet cell-rich” type is eomposed almost entirely ‘of goblet cells. Both types of polyp show crypt elongation, swith varying degrees of serration, imparting a sawtooth- like appearance. Serration is usualy limited to the upper aspect of the polyp; the erypt bases are narrow (see Fig, 9-44, 4), Serration in goblet cell-rich hyperplastic polyps ‘may be nearly inapparent. Hyperplastic polyps contain small, uniform, bland nuclei with no atypia. SSPs show morphologic overlap with microvesieular hyperplastic polyps but are distinguished by the presence ‘of architectural distortion, with basal erypt dilatation and branching, forming anchor-shaped and L-shaped erypts,9 ‘Toons oF THe Swat aND Lance Irestines, INctupine ANAL Caxat 487 ee, FIGURE 945 m Sessile serrated polyp of the transverse colon with superimposed cytologic dysplasia (ight sc) swell a serration extending to the lower portion of the crypts (see Fig. 9-44, B)." In some cases, the distinction between hyperplastic polyp and SSP is difficult; some investigators have suggested that mmunohistochemical expression of the gastric pyloric-type mucin MUCS can. help in this differential diagnosis."""! As a practical guideline, rectosigmoid polyps with microvesicular mucin are nearly all hyperplastic polyps, whereas such polyps in. the proximal colon (yar ticukitly’ those 3 nnn gt larger) are predominantly SSPs, Usual SSPs lack cytologic fea- tures of dysplasia but may contain occasional cells with vesicular nuclei and prominent mucleoli. However, SPS ‘may contain discrete areas indistinguishable from a tubular adenoma (sometimes with high-grade dyspla- 9 Such lesions were formerly ufven referred was “mixed $SP/tubular adenoma,” but “SSP with (superim- posed) cytologic dysplasia” is preferred, because this rep- fesents a form of progression toward adenocarcinoma” Other SSPs contain foci of “serrated” dysplasia with ‘eosinophilic eytoplasm and nuclear atypia (Pig. 9-45). Some serrated polyps in patients with hereditary mixed polyposis syndrome resemble SSPs but also contain ccl- lular, inflamed lamina propria, mimicking the stroma of a juvenile polyp.” ‘Traditional serrated adenomas show a complex, vili- form architecture with prominent serration and are com- posed of tall columnar cells with elongated muclei and densely eosinophilic eytoplasm (Fig. 9-46). Another char- acteristic feature is the presence of “ectopic erypts” budding from the villous structures. Traditional serrated adenomas sometimes contain areas of conventional (or higher-grade serrated) dysplasia. Molecular Pathology ‘The majority of both microvesicular hyperplastic polyps and SSPS harbor BRAF mutations, whereas many goblet cell-rich hyperplastic polyps and’ some traditional ser- rated adenomas have KRAS mutations."°" SSPs with cytologic dysplasia often show methylation of the MLHI FIGURE £45 m Traditional serrated adenoma of the sigmoid colon. Note the tall columnar celle with densely eosinophilic tytopiasm, promoter (accompanied by loss of the ML protein by immunohistochemistry), resulting in high-level micro- satelite instability (MSL-H.'" Such lesions are believed to be the precursors of most sporadic microsatellite unstable colon cancers. ‘The molecular gonctic basis for most patients with serrated polyposis is unknown, although a subset of patients (.e., those in whom multiple adenomas also Uevelup) is found instead us have MUTYT-assox ated polyposis." Several genetic defects have been implicated in hereditary mixed polyposis syndrome, including muta- tions in CRACT anda duplication spanning the SCGS gene, the latter resulting in increased expression of the GREMI protein and likely decreased signaling through the bone morphogenetic protein (BMP) palway similar functional consequence as in juvenile polyposis syndrome)."*"7 Clinical Features countries and are responsible for a significant proportion of cancer-related deaths, whereas the incidence is much lower in most of Asia and Africa. For example, colorectal cancer is cur- rently the third most common cancer in both men and women in the United States and also ranks thied in mor- tality among cancers.'” The striking geographic differ- ences in incidence are believed in large part to be related to diet; one notable example is the high consumption of meats ((.., animal fat) in industrialized countries, which has been strongly linked to colorectal cancer. The peak incidence isin the seventh decade, and a male predomi- nance is seen. The sigmoid colon and rectum are the ‘most commonly affected sites. ‘Most patients under 40 years in whom colorectal cancer develops have an inherited predisposition, the most common of which is Lynch syndrome (formerly458 9 known as hereditary nonpolyposis colorectal cancer), an autosomal dominant disorder caused by deleterious germline mutation ina DNA mismatch repair gene, most Often MLHI or MSH2, but sometimes PMS2 or MSH6, leading to deficient mismatch repair. Approximately 15% oF sporadic enlorectal adenocarcinomas also dem onstrate mismatch repair deficieney (predominantly proximal colonic tumors with a female predominance), because of methylation of the MLHT_ promoter." Colorectal adenocarcinomas with mismatch repair defi- ciency manifest MSI-H. Tmmunohistochemistry can be used to screen for loss of mismatch repair proteins (see section on immunohistochemistry), whereas polymerase chain reaction-based methods can evaluate for MSI. Patients with Lynch syndrome have colon cancers at an average age of about 50 years, and these show a predilec- tion for the cccum, ascending colon, and transverse colon, Multiple primary tumors are relatively common. Patients with Lynch syndrome are also at significantly increased nsk of development of cancer at other visceral sites, the most common of which are the endometrium, ureter and renal pelvis, small intestine, and ovaries." ‘The Munr-Torre syndrome refers to patients with Lynch syndrome who have sebaceous tumors." As mentioned in the section on FAP, ‘Turcot syndrome refers to the combmation of colon cancer and a brain tumor; patients with Lynch syndrome may have astrocytoma or glioblas- toma, Clinical guidelines have been established to attempt to identify patients with Lynch syndrome; the Revised Bethesda Guidelines have been widely used and include uth clinical and histologic parameters. More recently, several algorithms have been developed to predict the likelihood of MSI-H ina given tumor (assigning different scores to various clinical and histologic parameters), although institutional practices vary widely, ranging from specific age cutofis to universal MSI and/or mismatch repait protein esting. Other inherited” syndromes associated with an increased risk of colorectal cancer inchude FAP, MUTYH- associated polyposis, serrated polyposis, hereditary nixed polyposis syndrome, Peutz-Jeghers syndrome, juvenile polyposis, and PTEN hamartoma syndrome (Cowden syndrome). The latter two disorders are discussed in sec- tions later in this chapter. Chronic inflammatory bowel diseases (ulcerative colitis and Crohn disease) are also, associated with an increased risk for colon cancer (begi ning after 8-10 years of disease), especially in patients pancolits. Patients with colorectal cancer have varied clinical presentations, in part depending on primary site. Anemia and weight loss are common to cancers throughout the colon, whereas hematochezia and constipation are most typical for rectosigmoid cancers. Some patients present with obstruction or perforation. Macroscopic Appearances Colorectal carcinomas show a range of gross appear- ances, including fungating, intraluminal masses: ulcerat- ing tumors with heaped-up edges (Fig. 9-47); and circumferential, stricturing tumors (Fig. 9-48). They are usually firm, with a uniform, white cut surface. Around “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE 8.47 m Uleerating adenocarcinoma of the rectum with ralsed edges. (Courtesy Dr. Jeremy Joss) 10% of colorectal cancers (mucinous adenocarcinomas) have a soft, mucoid cut surface. Foci of visceral peritoneal invasion may appear as serosal puckering; such areas shoul be samples dhotoughly for accurate staging. Histologic Appearances Adenocarcinomas account for more than 90% of calore tal carcinomas. Glandular differentiation is usually easily appreciated. As mentioned in the section on adenomas, colorectal adenocarcinomas acquire metastatic potential ‘when the submucosa is infiltrated. The elassie colorectal adenocarcinoma is composed of irregularly distributed tubular structures in a desmoplastic stroma, with areas of ‘complex, cribriform architecture and intraluminal “dirty” necrosis (Fig. 9-49). Mucinous adenocarcinoma is char- acterized by abundant extracellolar macin pools (by defi- nition, >50% of the tumor area) Fig. 9-50); around 10% of colon cancers are mucinous. Signet ring cell carcino- mas, which are rare in the colon, are composed of diffuse, infiltrative cords, nests, and sheets of cells with abundant intracytoplasmic mucin forming large vacuoles, often ‘compressing the nuclei to the periphery (Fig. 9-51) Tn some signet ring cell carcinomas, the neoplastic cells float ‘within mucin pools. Again, more than 50% of the adeno- carcinoma must show a signet ring cell appearance to be9 ‘Toons oF THe Swat aND Lance Intestines, INctupine ANAL Caxat 459 FIGURE 9-48 & Stricturing adenocarcinoma of the colon arising in patient with long-standing ulcerative cats. The proximal and latel mucose fs atrophic, [Courtesy Dr. Jeremy sss) classified as such, The mucinous or signet ring cell com- ponent should be reported even when an adenocarci- oma does not fulfill the 50% criterion, both. for prognostic purposes and as predictive markers of MST (Gee iter discussion). Medullary carina is another rare type of adenocarcinoma consisting of sheets of large epithelioid cells with vesicular nuclei, prominent nucleoli, and eosinophilic or amphophilic cytoplasm (Fig. 9-52), sometimes admixed with numerous tumor- infiltrating’ lymphocytes." Other rare variants include “serraved” adenocarcinoma" Gin which dhe component resembles serrated dysplasia with tooth architecture, microvesicular or eosinophil plasm and generally uaform nuclear wah 7 FIGURE 8-49 m Low-grade adenocarcinoma of the colon with intraluminal “dire” necrosis adenosquamous carcinoma (small foci of squamous differentiation are not uncommon in otherwise typical colorectal adenocarcinomas; this category 1s reserved for tumors with a large squamous component). Small cell Ccucinas ata large cell NECs very rately ave front colorectal adenoma or in association with a conventional non NETS)."5"” to young age at diagnosis and_ proximal location, particular histologic features are associated with MSI-H. Some of these include mucinous, signet ring cell, infiltrating Iymiph cytes (Fig. 9-53) or a Crohn-like reaction (Fig. 9-54); an expansile border; poor differentiation; and marked intra- ‘cumoral heterogeneity." ‘tumor ealls are floatina in abundant extracellular musi.4609 By convention, the grading system for colorectal ade~ nocarcinomas is. based Ga the extent of well-formed and, ether well iferentiated (295%), moderarely di Ferentiated (50%-95%), or poorly differentiated (€50%). However, in practice, most pathologists will usea “gestalt” agree grag colori eatencinay ha vay of cases (around two thirds) will be graded as moderately differentiated. Well-differentiated adenocarcinomas may closely resemble tubular adenomas; such morphology is overrepresented in ulcerative elt-asocaed careno- mas.” In addition to large areas of solid growth and infiltrative ‘nests and single cells, poorly differentiated adenocarcinomas often show more striking nuclear het- frogeneity. Carcinomas ‘without glandular (or other forms of) dilferentiation are classified as undifferentiated carcinomas. To reduce interobserver variability in grading, many groups are advocating a two-tiered grading System: low grade (incorporating well and moderately are compressed toward intracytoplasmic mucin FIGURE 8-52 m Medullary carcinoma of the colon composed of shoots of large undifferentiated colls with vesicular chromatin ‘nd prominent nual “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL differentiated) and high grade (poorly differentiated).” However, this grading system is of prognostic value ‘lyfe micrastllie-sa aemocarcinnmaylshongh signet ring cell carcinomas and medullary carcinomas (as trell as some mucinous adenocarcinomas) are histlogi- cally “high grade,” those with MSI-H (either sporadic oF inthe setting of Lynch syndrome) have a relatively favor- able promos and should therefore be considered low grade.” Prognostic Markers The most important prognostic factor for colorectal adenocarcinoma is tumor stage. In particular, determin- ing whether visceral peritoneal invasion and lymph node metastases are present is critical for the surgical patholo gist. As such, careful sampling of any areas of grossly abnormal serosa is indicated, When tumor cells reach the Prominent tumor-infitrating lymphocytes are Instability. FHOURE 9-54 Adenocarcinoma of the colon associated with a CCrohmike inflammatory reaction, Note the Iymphoid agare- ‘aates bevond the muscularis arooria,9 ‘Lowors or rie SMALL aND Larcr Ivresrives, bvetupnve ANAL Caxa 461 peritoneal surface, associated with an inflammatory reac- tion and mesothelial hyperplasia, the tumor should be classified asa. Numerons studies demonstrate that lowe numbers of evaluated Innph nodes (presumably over looking lymph node metastases and therefore understa ing) are associated with a worse prognosis. Iris generally recommended that at least 12 lymph nodes should be obtained from all segmental colonic resection. speci- mens.”” Icis difficult to identify numerous lymph nodes from rectal resection specimens after neoadjuvant therapy; in some cases, extensive sampling ofthe perirec- tal adipose tissue is required. Other histologic predictors of poor outcome include ‘extramural venous invasion, Iymphovascular invasion, an infiltrative (as opposed 10 expansile or circumscribed) tumor border, tumor budding at the in front (characterized by loss of cellular cohesion with single cells or small clusters of cells, often showing marked nuclear atypia), and perineural invasion.” Histologic ee a at tumor-infiltrating lymphocytes, a peritumoral lymphoid response, and a Crohn-like ‘reaction (with discrete lymphoid aggregates beyond the mfiltating edge of the tumor in the muscularis propria or subserosa). As ‘mentioned, these latter features are highly associated with MSL-H, which 1s a strong favorable prognostic indicator." Immunohistochemistry and Molecular Pathology Conventional (microsatellite stable) colorectal aeenucar~ cinomas express CEA and are usually strongly positive for CK20 and the transcription factors CDX-2 and SAT2,"" whereas TTF-1, PAX8, and WTI are neg- ative, CK7 is focally positive in a small subset (5%-10%) of tumors. Strong immunoreactivity for p53 is observed nust cases, as is nuc of SMAD4 (DPC4) protein expression is identified in around 20% of tumors, more often with advanced stage. Colorectal carcinomas with MSILL often show less extensive CK20 expression, and around 20% are entirely negative for this marker." Reduced expression of CDX-2 isalso seen in some MSI-H tumors.** Of note, medullary carcinomas often show very limited CK20 and CDX-2 “expression or can sometimes be entirely negative; sereen= ing for mismatch repair deficiency can help confirm the diagnosis in such cases. ‘When immunohistochemistry for MLII, MSH2, PMS2, and MSH6 is performed as a screening test for Lynch syndrome and sporadic MSI-H colorectal carci- rnomas, it should be remembered that MLH and PMS2 are heterodimers, as are MSFI2 and MSH6.™ As such, sporadie MSI-H cancers (with MLHT promoter methyla- tion) show loss of expression of both MLH1 and PMS2 (Fig. 9-85), Lynch syndrome-associated carcinomas from, patients with a germline mutation in either MLHT or PMS? also usually (though not invariably) show loss of both proteins, whereas tumors from patients with an MSH? or MSH6 mutation usually show loss ofthis latter set of proteins. After neoadjuvant therapy for rectal adenocarcinoma, expression of MSH may be weak or negative, which is a potential diagnostic pitfall." FIGURE 955 m Adenocarcinoma of the ascending colon from 2 patient with Lynch syndrome. Loss of expression of MLHT ie teen. Note the nix ing in endothelial calls and fibro: Blasts, which serve as an internal control Occasional tumors will show loss ofa single protein; this is almost always diagnostic of Lynch syndrome and can direct germline sequencing. ‘Most patients whose tumors show loss of MLIII/ PMS? have sporadic MSI-H carcinomas; because the majority of such tumors arise from a BRAF-mutant SSP, identification of a BRAF V600E mutation can be helpful tw canfirin the sporadic nature of dhe wannor.” I BRAP is wild-type, testing for MH promoter methylation can distinguish sporadic MSI-H tumors from Lynch syn- drome, although this assay is not widely available. Oth- cnwise, germline testing is required, Identification of the specific mutation isalso helpful to screen family members, ‘which hs a significant impact on surveillance for Lyneh syndrome-associated. tumors in mutation carriers. As previously mentioned, MSI-H carcinomas have a more Tavorable prognosis than microsatellite stable cancers MSI status may also determine further therapy. for patients with stage III rumors or distant metastases, as MSFH cancers show 2 poor response to conventional 5-fluorouracil-based chemotherapy.” KRAS mutations are present in, 40% 0 50% of colorectal carcinomas, and another 5% to 10% harbor BRAF mutations; these proteins are downstream of the epidermal growth factor receptor (EGFR) signaling pathway." KRAS genotyping is routinely performed before initiation of chemotherapy that includes EGFR- targeted agents (e.g, the monoclonal antibody cetux- mab), because KRAS-mutant tumors are resistant to such treatment." At some centers, BRAF testing is per- formed in KRAS wild-type tumors, because BRAF-mutant tumors are also poorly responsive to cetuximab. NEUROENDOCRINE TUMORS NEB of the proximal colon are uncommon and are clini- cally and histologically similar to (enterochromaffin cell) NE of the jejunum and ileum (midgut), These tumorsa2 9 Bp Mili eT BRS ae SSP eS operons ically show an insular and solid growth pattern and ive high nsk of mph node and liver meastases In contrast, rectal (hindguty L-cell) NETS are relatively common, accounting for 25% to 30% of all GINET." ‘Most rectal NETIs are less than 1 cm; small tumors only rarely metastasize and can be managed conservatively by endoscopic resection.""?! Management for rectal NET between I and 2 cm is variable and somewhat controver- sial. The small subset of rectal NETS that are more than 2 uw often sow a higher mitutie rate (WHO grade 2), ‘more often exhibit malignant behavior, and are typically ‘managed by surgical resection, These tumors may be discovered incidentally at_ screening colonoscopy. or present with bleeding. Rectal NETs show a characteristic irabecular architecture and are composed of uniforn cells with rounded nuclei, granular ehiomatia, and eosin ophilic eytoplasm (Fig. 9-56). The mitotic rate is usually low. Rectal NETsare positive for general neuroendocrine markers but ate negative for CDX-2 (unlike midgut NET).” Polyclonal PAXS is usually positive.” A recog- nized diagnostic pitfall is the common diffuse expression of prostatic acid phosphatase." High-grade NECs of the colon and rectum are rare aggressive neoplasins that usually present with metastatic disease and are associated with short survival?” They have a predilection for the proximal colon and are endo- scopically and grossly similar to conventional adenocar- cinomas. Colonic NECs are often associated with an adenoma and sometimes an adenocarcinoma.” They ‘may be of either small cell ( 9-58), or mixed type.”” Tan in si ponent is absent, they are very difficult (if nat impossible) to distinguish from metastases from the lung. Similar to pulmonary primary tumors, small cell NEC of the colon is positive for broad-spectrum keratins (ofien with a dot- like pattern), chromogranin, and synaptophysin, although expression of neuroendocrine markers is often heteroge- neous. Both TTF-1 and CDX-2 may be positive; these markers cannot be used to determine primary site for stnall cell NEC Large cell NECs more often contain an adenocarcinoma component: when more than 30% of “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL IGURESS7 m Smal cell carcinome ofthe ascending colon. This tumor arose from a villous adenoma, Repae AIGURES-58 m Large cell neuroendocrine carcinoma of the colon ‘showing a trabecular architecture. the tumor is glandular, the designation “mixed adenoneu- roendocrine carcinoma” (MANEC) may be applied.!” Because variable synaprophysin expression is relatively common in conventional colorectal adenocarcinomas, this marker alone (unless strong and diffuse) should not hho overinterpreted as evidence of neuroendocrine dif- ferentiation. Chromogranin is more reliable in this contest, but scattered single positive cells may also be ‘observed in typical adenocarcinomas. MESENCHYMAL AND NEUROECTODERMAL TUMORS. Gastrointestinal Stromal Tumor GIST of the colon are very rare (1%), whereas rectal primaries account for around 5% of all GIST" GISTS of both sites are nearly all of spindle cell type and, characteristic of GISTS, show typically uniform9 ‘Toons or THe SMALL AND Lance Ivrestives, Dvetupnve ANAL CaxaL 463 cytomorphology. Nuclear palisading may be prominent. Recal CASTS are typically immunoreactive for KIT DOG, and CD34, whereas SMA and desmin are nega- tive.™"* Most tumors at this site harbor KIT exon 11 mutations. Because of their rarity, criteria for risk strati- fication for colonic GISTs have nat heen established Rectal GIS13 are stratified for risk of aggressive behavior by using size and mitotic rate, similar to small intestinal GISTs Gee Table 9-2)." Loiomyoma of the Muscularis Mucosa Leiomyomas are among the most common mesenchymal tumors of the large intestine. They have a predilection for the sigmoid colon and rectum, are typically discov- «ered incidentally at screening colonoscopy, and appear as| small polyps (usually <1 em).** In contrast, mural Ieio~ myomas of the rectum are very rare.”” Colorectal polyp- id leiomyomas are sharply circumscribed, contiguous with the muscularis mucosae, and composed of fascicles of well-differentiated smooth muscle cells with tapering ‘or blunt-ended nuclei and abundant brightly eosinophilic cytoplasm (Fig. 9-59). The tumor cells are strongly and diffusely positive for SMA, desmin, and caldesmon; KIT. and DOGI are negative.” Leiomyosarcoma Leiomyosarcomas of the large intestine are rare (sce small intestine seetion).* Lipoma Lipomas ofthe colon are a common incidental finding at sereening colonoscopy. They involve the submucosa, are well circumscribed, and often protrude into the lumen. Lipomas ate soft on with an endoscope, suliciendly characteristic dat «biopsy is usually not per formed. Submucosal lipomas are not infrequently identi- fied in colon resections for other teasons. FIGURE 8-59 m Polypoid leiomyoma of the sigmoid colon. This tumor type arises from the muscularis mucosae, Note the abun- dant briahtv eosinophilic evoolasm. Vascular Tumors See section ain small intestine. Neurofibromas See section on small intestine, Schwannoma Colorectal schwannomas are much less common than their counterparts in the stomach and usually: affect middle-aged to elderly adults.” They may present with hematochezia or obstruction. Colorectal schwannomas typically arise in the submucosa and are often grossly pol- ypoid lesions that ulcerate the mucosa, Similar to gastric schwannomas, they characteristically have a peripheral lymphoid cuff and lack the zonation and Verocay bodies of conventional schwannomas.”” ‘These schwannomas are usually composed of spindle cells with tapering nuclet showing some nuclear ara, in vaiably prominent collagenous stroma. A subset has epithelioid morphology (see also Chapter 2/). 5-100 protein is srongiy positive, whereas KIT, DOGI, and desmin are negative. Mucosal Perineurioma ‘Mucosal perincurioma is a relatively common benign lesion that is found incidentally on screening colonoscopy, most often in the rectosigmoid area.” Most are less than 5 mum. Aroutnl 70% of mucus periveurinnay ae assvi- ated with a serrated polyp (Fig. 9-60, 4), usually hyper- plastic, but sometimes an SSP2""2"" They involve the propria and are composed of uniform spindle cells, with ovoid to clongated nuclei and indistinct eosinophilic lagenous stroma (sce Fig. 9-60, B), sipping ig around colonic eiypts. “The tumor cells are positive for epithelial membrane antigen (EMA) Glthough expression soften weal) and often for Ulaudin-L, wheteas $-100 protein is negative." The ser- rated epithelial component usually contains a BRAP mutation.” The lesion previously reported as “fibroblas- tic polyp” likely represents mucosal perineurioma. Mucosal Schwann Cell Hamartoma This is a recently described lesion detected as a small sessile polyp at colonoscopy.”” They are typically less than 5mm. Mucosal Schwann cell hamartoma is com- posed ofa diffuse proliferation of uniform, bland spindle cells with tapering nuclei and dense, eosinopl plasm with limited stroma (Fig. 9-61, 4). The cells entrap but minimally distore and do not whorl around) erypss. The lesional cells ae strongly positive for $-100 protein (Gee Fig. 9-61, B) but are negative for EMA, CD34, SMA, and KIT. These polyps are of no clinical signifieance and are not associated with NF1."" Granular Cell Tumor Granular cell tumors of the colon are much less common than those in the esophagus." ‘Chey are foundao ‘embedded in fine collagenous stroma, incidentally as small polyps (usually <1 em), with a pre- dilevtion for the prosinial colon, Muluiple lesions may occasionally be identified, Colonic granular cell tumors involve the submucosa with somewhat irregular margins and are composed of sheets of large polygonal to spindled cells with small hyperchromatic nuclei and abundant granular eosinophilic cytoplasm. The overlying mucosa may show regenerative changes. The lesional cells are diffusely positive for $-100 protein, Ganglioneuroma Most colonic ganglioneuromas are polypoid lesions found incidentally, often between 1 and 2 em in size.” ‘They are more frequent in the distal colon and rectum. Polypoid ganglioneuromas are composed of an admixture of spindled Schwann cells (which usually predominate) and ganglion cells, entrapping colonic erypts (Fig. 9-62). ‘The Schwann cells ean be highlighted with S-100 protein, whereas the ganglion cells are positive for synaptophysin, neuron-specific enolase, and neurofilament protein. However, immunohistochemistry is rarely needed, as the histologic features are distinctive. Solitary polypoid gan- slioneuromas are usually sporadic." Multiple polypoid “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL . ee A one \ FIGURE 9.61 mA, Mucosal Schwann cell hamartoma composed 1d spindle cells with eosinophilic cytoplasm filing the ropria. B, 5-100 protein is strongly postive. inglioneuromas (ganglioneuromatosis polyposis) may: Feel wath STEN tematic omen syndrome; see later section).""=" Diffuse ganglioneuro- matosis is discussed in the small intestine section. TUMORS OF LYMPHOID TISSUE Benign Lymphoid Polyps Prominent mucosal lymphoid tissue with reactive hyper- plasia is often seen as a small polyp, typically. several rillimeters in size, which may be mistaken for adenomas and therefore have a biopsy performed. Such benign lym- phoid polyps are most common in children. Larger ‘examples in the rectum (0.5-1 em) have been referred to, as the “rectal tonsil” Gn analogy to a normal finding in rodents), which may be found at colonoscopy or present with bleeding.’ The lymphoid proliferation may extend into the superficial submucosa and usually contains lym- phoid follicles, sometimes with germinal centers (Fig, 19-63). The relative circumscription and the presence of follicles help distinguish normal mucosal Iymphoid tissue with reactive hyperplasia from Iymphoma. Deeper levels9 “Toons oF THe Swat 4ND Lace IvrestiNes, INctupine ANAL Cann 465 FIGURE 5-82 m Polypoid ganglioneuroms composed of spindled ‘Schwann cells and scattered ganglion cells. FIGURE 8-69 m Benion Iymphoid polyp of the rectum, Note the ‘germinal centers. ‘orimmunohistochemical staining for CD21 or other fol- licalar dendritic cell markers may help to identify follicles ‘when they are inapparent histologically." CD10 is posi- tive, but BCL-2 is negative in the reactive follicles, in contrast to follicular lymphoma, Lymphomas Primary lymphomas of the colon and rectum are rare, much less common than. in the small intestine.” The most frequent primary Iymphoma at this site is diffuse large B-cell lymphoma, although a similar spectrum of low-grade B-cell lymphomas that arise in the small intes- tine may also present in the colon, Similar to elsewhere in the GI tract, mantle cell lymphoma may present as, lymphomatous polyposis (see Fig. 9-23) but is usually a systemic disease when detected at colonoscopy. Primary ‘T-cell lymphomas of the large intestine are exceptionally rare, Primary intestinal lymphomas are discussed in the small intestine seetion, tse (Sonat Pia FIGURE 9.64 m Systemic mastocytosis involving the colon. The ‘mucoss contsins inconspicuous mononuclear cells with sbun- dant pale cytoplasm. Note the occasional eosinophils. Mast tells may be easily Overlooked as histiocytes SECONDARY TUMORS “Metastases to the colon are uncommon, Miillerian serous carcinoma may extend into the large intestine from the serosa and present with hematochezia, Prostatic adeno- carcinoma may invade directly into the rectum, Systemic mastocytosis may occasionally involve the mucosa of the colon and present with diarrhea or malab- surption aldiough sinilar GE wae sysnptonns i order may be related to mast cell mediators released into the circulation.” Systemic mastocytosis at thissite ranges from small clusters to confluent sheets of mononuclear cells with abundant pale eytoplasm (Fig. 9-64), admixed with variable numbers of eosinophils. Unlike the charac- ‘eristie spindled morphology in the bone marrow, when neoplastic mast cells infiltrate the GI mucosa, they are more often rounded or ovoid, Involvement may be focal and subule, being easily dismissed as normal histiocytes ‘The prominent cosinophils (which sometimes obscure the mast cells) may lead to misdiagnosis as eosinophilic (entero)colitis. Neoplastic mast cells are strongly positive for KIT and tryptase and show aberrant membranous staining for CD25, whereas CD25 is negative in normal mucosal mast cell in inflammatory conditions:""A KIT stain easily highlights the abnormal distribution of mast cells and is most useful for diagnosis, TUMOR-LIKE LESIONS: Peutz-Jeghers Polyps and Polyposis Peutz-Jeghers polyps are discussed in detail in the small intestine section, Small Peutz-Jeghers polyps in the colon may contain litte arborizing smooth muscle and there- fore be difficult to diagnose. A likely inflammatory (pos- sibly prolapse-related). polyp designated “inflammatory myoglandular polyp” shows a histologic resemblance to Peutz-Jeghers polyps but contains less organized, branch- ing smooth muscle.”466 9 ‘Towons oF vn Swat an Lance bvresrives, Ive Juvenile Polyps and Polyposis Juvenile polyposis is an antasomal dominant disorder ‘sometimes caused by deleterious germline mutations in SMAD4 or BMPRIA (in around half of patients)."*""" ENG mutations have heen reported in small numbers af affected patients’; the genetic cause of juvenile polypo- sis in other families is unknown. Around half of patients have no family history and presumably harbor a new mutation. Juvenile polyps often arise throughout the GI tract in affected patients. Because one to several colonic juvenile polyps are commonly found in children, the diagnosis requires either three to five or more colorectal juvenile polyps, jvenile polyps throughout the GI tract, for any juvenile polyps with a family history.” Most patients present in childhood and young adulthood with hematochezia, anemia, or abdominal pain. particularly severe variant presents in infancy with diarrhea and mal absorption and is rapidly form of juvenile polyposis chromosome 10q involv al; some patients with this ave a germline deletion on both BMIPRIA and PTEN."* Patients with juvenile polyposis have a significant lifetime nisk of colorectal carcinoma (30%-30%),"" as well as a smaller risk of carcinomas of the upper GI tract and pancreas. Penetrance is highly variable among families, mn terms of both polyp numbers (Fy cd the risk of carcinomas. Juvenile polyps are typically pedunculated lesions (Fi 9-60), which may be Up to several centimeters in st FIGURE 9.65 Jeremy Jess, Juvenile polyposis of the colon, pine Awa Casa FAGURE #6 a Juvenile polyp trom @ patient with juvanto pat- Yyposis syndrome. Note the multlobulated appearance and the Tong polyp stalk. (Courtesy Dr leremy Jase) with smooth, rounded surfaces, and are characterized histologically’ by inregular and visiably eysticaly dilated crypts, surrounded by edematous, cellular stroma con- taining inflammatory cells and fibroblasts, often with surface erosion (Fig, 9-67). Smaller juvenile polyps im juvenile polyposis syndrome are indistinguishable from FIGURE 357 m Juvonile polyp with cystcaly dilated erypts and cellule, inflamed lamina prooria,9 ‘Towors or THe Swat AND Lace Ivrestives, Ivetupnve ANAL Cana 487 sporadic polyps, but larger, multilobulated or villiform Citypieal) jwenile polyps often with more abundant and eample epithelinm, are distinctive ta this disorder Dysplasia (and adenocarcinoma) may arise in the epithe- lial component of syndromic juvenile polyps" but may he dificult to distingnish from reactive changes cansed by inflammation and erosion. Juvenile polyposis of infancy is distinguished by diffusely abnormal mucosa, ‘even between polypoid lesions. Cowden Syndrome (PTEN Hamartoma Syndrome) and Associated Polyps Cowclen syndrome is an autosomal dominant disorder caused by deleterious germline mutations in PTEN, asso~ ciated with an. inereased risk of breast, thyroid, and colorectal carcinomas, wel a fibrocystic disease Of the breast, multiple adenomatous nodules and follicular ade- ‘nomas of the thyroxd, cutaneous trichilemmomss, dys- plastic gangliocytoma of the cerebellum (Lhermitte- Duclos disease), and highly variable hamartomatous polyps throughout the GI tract, most often identified in the large intestine.” Recent studies have indicated that the risk of colorectal carcinoma in patients with Cowden, syndrome with PIEN mutations 1s 10% 1 15% ‘Cowden syndrome-associated polyps are usually small {<1 em)and histologically range from hyperplastic polyps to lesions indistinguishable from smal juvenile or inflam- auury polyps, wo those widh either filnublastic, alipo- ‘yt, or ganglioneuromatous proliferations in the lamina propria.”"°*” Ganglioneuromatous polyposis is uncom mon but seems t be relatively: distinetive wo Cowden syndrome. Patients also often have glycogenie acanthosis ‘ papillomatosis of the esophagus. Cronkhite-Canada Syndrome Unlike the guher hamartomatous polyposis syndtome, Gronkhite-Canada is nonhereditary and usually appears in older adults. Patients present with diarrhea, protein- losing enteropathy, and weight loss, as well as alopecia, nail dystrophy, and skin hyperpigmentation.”* Hamarto- matous polyps occur throughout the GI tract and are somewhat similar to juvenile polyps, but more often sessile, with elongated, dilated crypts or glands and ‘edematous lamina propria lar lamina propri changes are observed in nonpolypoid mucosa. Inflammatory Polyps Inflammatory polyps of the Tange intestine are a typical feature of inflammatory bowel diseases but are also com- monly detected incidentally in patients without those disorders and are of no elinical consequence. ‘They may. resemble juvenile polyps with focally eystie erypts and inflamed lamina propria, but typically with less cellular stroma, and they often show erosion and contain pro~ ‘minent granulation tissue, sometimes being composed nearly entirely of granulation tissue without residual epithelium, FIGURE 9.68 m Inflammatory closvogenic polyp (mucosal pro- lapse polyp) ofthe anorectal junction. Note the elongated crypts with regeneration and superficial granulation teste Mucosal Prolapse Polyps Somewhat distinctive inflammatory polyps arise as a con- sequence of mucosal prolapse, both in specific clinical contexts or not uncommonly m isolation (found at screening colonoscopy), and they are believed to result from peristalsis-associated mucosal injury. Associations include solitary rectal ulcer syndrome and diverticular disease, Various terms have been used for mucosal pro- lapse polyps inflarnmasory aaogenic polyp veers w dure arising at the anorectal junction.’ Histologic features include elongated crypts with regenerative epithelium, strands of smooth muscle between the crypts oriented perpendicular to the mucosal surface, mucosal erosion, variably prominent granulation tissue, and lamina propria inflamination, Inflammatory clowcogenie polyps olen show avilliform architecture Fig. 9-68) and may some- times be mistaken for adenomas, nammatory myogtane ular polyps, which may be mistaken for Peute-Jeghers polyps (ee section on Peutz-Jeghers polyps), belong to this group of lesions." Endometriosis Endometriosis involving the large intestine may present with abdominal pain, obstruction, or a mass but is some- times asymptomatic. The distal colon is most often in- volved. Endometriosis may present either asa mural mass (linically mimicking carcinoma or diverticulitis) or as @ ‘mucosal polyp." Involvementof the mucosa and subrmu- cosa is common, Mural disease is often associated with fibrosis, inflammation, and smooth muscle hypertrophy. PAXS can be used to identify the epithelium, whereas CD10 .can highlight the endometrial stroma in cases where itis scant, Rarely, GI endometriosis is complicated by malignancy, most often endometrioid adenocarcinoma. Malakoplakia Afier the urinary bladder, the distal large intestine is the ‘most common site for malakoplakia.”” The lesion may4B 9 histiocytes with sss inophilie cytoplasm. (Courtesy Dr. Jererny appear as polyps or ill-defined mucosal thickening. Mala- plata characterized by a dffse infiltrate of lange, distinctive eosinophilic histiocytes (Fig. 9-69) with occa~ sional Michaelis-Gutmann bodies, which can be high- lighted by stains for calewum (von Kossa) and iron, Rarely malakoplakia is found adjacent to colorectal adenocarei- nomas, especially rectal tumors. ANAL CANAL EPITHELIAL TUMORS Anal Squamous Intraepithelial Neoplasia Anal squamous intraepithelial neoplasia (ASIN), which is| strongly associated with human papillomavirus (HPV) infection, has traditionally been graded by using a three- tiered system, but move secently a gvo-tiered systenn has been advocated by the WHO and other groups." ASIN typically shows acanthosis, along with varying degrees of Squamous dysplasia, characterized by nuclear hyperchro- masia and enlargement, pleomorphism, and_ mitotic activity, along with loss of normal maturation. In low- grade ASIN (ASIN-L), the nuclear changes are limited to the lower half of the epithelium, whereas high-grade ASIN (ASIN-LI) also shows nuclear abnormalities in the upper half of the epithelium, often full thickness (Fig. 9-70), ASIN-HT usually harbors high-risk HPV types." Stains for Ki67 and p16 (CDKN2A) may be helpful to, confirm the diagnosis of ASTN-H.”"" Squamous Cell Carcinoma Clinical Features ‘Squamous cell carcinoma (SCO) of the anal canal is most common in middle-aged to elderly adults, with a slight female predominance, and is highly associated with chronic infection by high-risk HPV types (especially HPV=16 and HPV-18)."" Other risk factors include HIV. “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE#-70 m High-grade squamous intraepithelial neoplasia of the anus, Note the loss of normal maturation with fll thickness nuclear atypia, infection, receptive anal intercourse, and immunosup- pression." The anal transition zone and lower rectum, are most often involved. Macroscopic Appearances Anal canal SCC rarely forms a discrete mass, instead ‘often showing indistinct thickening or ulceration. Histologic Appearances Anal canal SCC was formerly subclassified into large cell keratinizing, large cell nonkeratinizing, and basaloid (cloacogenic) types; however, as most tumors show mixed histologic patterns, and they have no clear prognostic significance, subelasification has recently fallen out of favor.” Foci of ASIN-H are often seen adjacent to the invasive component. Over half of anal canal SCCs are basaloid, composed of nests and sheets of small vells with hyperchromatic nuclei, seant cytoplasm, and peripheral nuclear palisading (Fig. 9-71), often with central FIGURE 971 m Squamous coll carcinoma of the anal canal of basaloid type. Peripheral nuclear palisading and focal keratini= zation are present,9 ‘Towors or THe Swat aND Lance Ivrestivs, Ivetupnve ANAL Cana 469) necrosis." Foci of keratinization are common in SCC ‘with and without basaloid morphology. Grading of SCC. ar this site is not clearly associated with prognosis, although by convention basaloid tumors, those with marked pleomorphism, and tumors showing inflation as single cells and small clusters are considered high grade, Small cell (neuroendocrine) carcinoma rarely aus in the anal canal, sometimes asocged with an SCC component, and has a poor prognosis.” Staging of anal canal SCC fs based on tumor sie and lymph node status; inguinal Iymph nodes are the typical pattern of spread. Radiation and chemotherapy are standard treat- ment; surgical resection is rarely performed, Verrucous Carcinoma Verrucous carcinoma (formerly also known as_giant condyloma) rarely arises in the anal canal. Such tumors are typically large at presentation, sometimes 10 em or tore. Verrucous carcinoma i characterized by marked (verruciform) acanthosis usually with minimal nuclear atypia, limited to the basal epithelium, and blunt-type myasion (Fig. 9-/2). On small biopstes, the tumor may ‘easily be mistaken for a benign process. Verrucous carci- noma shows locally destructive growth but does not metastasize.” Adenocarcinoma Anal canal adenocarcinomas usually arise from the distal rectal clumiar epitheliunr adjacent wy dhe uransition zone and are otherwise indistinguishable from rectal adenocarcinomas, Adenocarcinomas at this site rarely arise in the sewing of chronic fistulae; such tumors are ‘usually mucinous." Adenocarcinomas very rarely arise from anal glands.* Anal gland adenocarcinomas present as mural camors chat usually spare the mucosa and are therefore difficult to diagnose until locally advanced, Such tumors typically show relatively uniform, tubular achitecuute, [n-contsast w rectal adenocarcinonnas, anal FIGURES-72 = Verrucous carcinoma showing marked acanthosis ‘and blunttvoe invasion. land adenocarcinomas are positive for CK7 but negative CRI and CD22" = ‘Melanomas of the anal canal are rare tumors that usually present as large, exophytic masses, sometimes extending Into the rectum, often with overlying ulceration. ‘Th pursue an aggressive clinical course with both Iymp! trode and distant metastases, especially wy dhe liver. Anal melanomas often lack melanin pigment. Although epithelioid morphology is typical, some tumors are com posed of small cells with scant cytoplasm, Identifying a junctional component or pagetoid spread in the adjacent squamous epithelium is helpful to suggest the diagn (Fig. 9-73). In addition w $-100 protein, HMB-45, MART-1, anal melanomas may be positive for KIT, a potential diagnostic pitfall. Anal melanomas (similar'to ‘nucusal mekinomas at other sites) nay harbor activating KIT motations and may respond to therapy with tyrosine Kinase inhibitors. Cystic Hamartoma Retrorectal cystic hamartoma (also known as sailgue cyst) isa rare lesion that presents as an anal canal mass with bleeding or pain. It consists of multiple eysts lined by squamous, columnar, or transitional epithelium (Fig. 9°74)."" These lesions may become infected. Very rare cases with malignant transformation have’ been reported ANAL MARGIN EPIDERMAL AND ADNEXAL NEOPLASMS Fibrocpithelial polyps are commonly removed from the anal margin and distal anal canal, Condyloma acumina- tum may arise in the perianal region and more rarely in the anal canal. Identical to genital warts, condylomataam 9 FIGURE 9-74 m Rotrorectal cystic hamartoma {tallgut eyst). The cysts are lined by wansitional epithelium. (Courtesy Dr Jeremy sass show a papillary appearance with acanthotie epithelium with parakeratosis, scattered cells with hyperchromatie nuclei and perinuclear vacuolation (koilocytes), and dys- eratotic cells. The degree of nuclear atypia and loss of stratification 1s highly variable; some authors report the sade of superimposed squamous intraepithelial neopla- sia, but this is inconsistent. Condylomas are usually negative for pl6."”="" Perianal squamous intraepithelial neoplasia (also known as Bowen disease, but unrelated to Bowen disease uf sun-esposedl shin) is histologically ils tical to, and often occurs concurrently with, ASIN, Papil- lary hidradenoma (hidradenoma_papilliferum) rarely arises in the perianal skin (Fig. 9-75), although itis the ‘most common cutaneous adnexal tumor at this site. Extramammary Paget disease may arise in the perianal shin and presents asx scaly plague. Ics characterized by nests and single Inge ephteliod cell with sbundank eosinophilic or clear cytoplasm infiltrating the squamous epithelium (Fig, 9-76). Some cells may show a signet ring appearance. The tumor cells in primary Paget disease are FIGURE 9.75 m Papillary hidradenoma of the anal margin, The slandular structures consist of two cell avers. “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL FIGURE-76 m Perianal Paget disease. Large cells with abundant ‘eosinophilic eytoplasm infitate the squamous o sitive for CK7, gross eystic disease fluid protein-15 (GCDFP- 15), CEA, and EMA and contain intracytoplas- ‘mie mucin that can be highlighted by a muciearmine oF periodic acid-Schiffstain.”” Extramammary Paget disease should be distinguished from secondary involvement by rectal adenocarcinoma, which should be positive for ‘CK20 and CDX-2 and negative for GCDPP-15, and from malignant melanoma. REFERENCES 1. Schowenfeld D, Becbe-Dimmer J L, Vigneau F D 2009 The ‘epidemiology and pathogenesis of neoplasia in the small intestine ‘San Epidemiol 19 58:69 2, Lepiswo A, Kivluou 'T, Haltrunen Jet al. 2009 Surveillance and -omatois in familial adenomatous pol 14509 ‘Menck Her al, 1999 The American ‘Cancer Soces-Adenocareinoma of the small bowel: review ofthe National Cancer DataBase, 1988-1995. Cancer 86: 2698-2708, 4. Lin ICM, Sushil incidence of eolorcetal and excrcolonie cancers in MIL and MSH? mutation exrier of hereditary nonpolyposs colorectal cancer Gastrointest Surg 2: 67-71 5. Pan $Y, Monson T2011 Epidemiology of cancer ofthe stall intestine. Word J Gastroinestinal Oncol 3: 3842 6, Shaulat A. Vieng D Howard D etal. 2011 Grob disease and spall bowel adenocarcinoma: population-based case-control pidemiol Biomark Prevent 20: 1120-1123, 'B 2002 Celiac disesne and other precursors to 8, Goodenberger M Lindor N/M 2011 Lynch yndome and MYH- ‘sociated poposis review and esting strategy} Clin Gaston terol 1: 8300 9. Chang HK, Yu, Ki etal 2010 Adenocareinoma ofthe sal ingesting: 4 mulsnsdetional sly of 197 surgi resected ses Tum Pathol 41 1087-1096 = 10, Osernan M | Poradaes J, Kopet etal. 2010 Insnuopheno: ‘ype and molecular characterisation of adenocarcinoma of Be Bra ncestine Br} Cancer 102,114 150 11, Chen 2 Ml Wang HTL 2008 Skeration of cytokeratin 7 and cnenin 20 etesin pro nk odd wh tumorigenesis of primary adenocarcinoma ofthe sal intestne, Ian) Song Pathol 26159291599 12, Bouman FT, Carneiro F, Fron R Het al, 2010 WHO lasitiation of rumours of the digestive sytem, TARG Pres, yon, France4 as », 0. 1M, 9 ‘Towors or THe SMALL AND Lance Ivrestives, bsetupeve ANAL Caxa, 471 Yio ©, Hassan M, Phan A etal. 2008 One hundred yeas afer “exci epidemiology of and prognostic ators for nen ocrin eamoren 35828 eassin the United Sets} Clin Oneal Jensen RT, NiedeseB, Miz Feral 2006 Gastrinoma aodenal and panereuio), Neuroendocrinol 8 173-182 Garbrecht N, Anlauf M, Schmit A et sl 2008 Somatostatin producing neuroendocrine tumors of the ducenun and pancten Incidence, types, biologiea lekavion, sociation with inherited ‘mlm snd fevers airy Eviesine Boar Caneor 241 Ralls D, Back J, Witiewicz A et al. 2010 Periampullary and dduodena neoplssms in neurofibromatasseype Tz evo cases and an updued ZO-year review of the lnratae piling 76 cates Jlaerintest Sarg 14 1052-1061 Nant R K, Odze RD, Faraye F A tab 2003 Solitary versus tnulple carinoid eamors of te leam: «clinical and prholage Feview of 6 cases An) Surg Pathol 27 SLL-ST? Anlaué M, Enosawa Ty Henopp Teta. 2008 Primary lymph nee gactinoma or occ duodenal microgatinom wich Hmph tinder: in a MENI patra the nod fre 2 seman search for the primary tunic Aon J Surg Pathol Sor 110 110s Darke A 1 Thomas RM, Played A M et a, 1997 Carcinoid of the jejunum and eum an inmunohistochemieal and linia pathologie tay of 167 cases. Cancer 7 1086-1093 Perrone, Sibley R K, Rosi J 1985 Duodenal ganglioevte para {fingloma, An fnimunohispehemical and utesuctra Sy Andet hypothesis concerning its origin. Am J Surg Patol 9 sieat Schmitt AM Rinker FE Anlauf Meta. 2008 Isl 1 (lD expres sion sa rebble marker for pancreti endocrine tors ad their metastases. Am J Surg Pathol 32: 420-25 Tong KB, Srivastava A, Hirch MUS ct 2010 PAX expression lavwalbditcrensated pancreatic endocrine tumors: cofclaion ‘with elncopathologicfenures and comparison with yatrointes- tinal and pulmonary carcinoid tumors, Am J Surg Pathol 34 Snvastaa A, Homick J L 2009 Immunohistocherial stain for CDX-2, PDX, NESP-55, and TTF-L can help ding {gtroinestina! carcinoid tumors from pancreatic endocrine 4nd pulmonary carcinoid rumors. Am | Surg Pathol 33: 626- 6 Burke A 8 Helwig ¥ 11989 Gangliocyic paraganglioma, Am J (Gh Pathol 92.1 Tigl-Avavanger B, Pletcher A Fletcher CD 2010 Gastroimes- tial stromal tumors. Virchows Arch 456: 111-127 Rubin BP, Heinrich MC, Corlss C L 2007 Gaszoinestna Stromal tumour, Lanece 69 1/3121 /41 Lee] R Jen V; Gin JW Jeet 2001 Gastoinexinal auto nome nerve tumor imnolistochenicl and molecu deity ‘wih gastoinestnal stromal tamor. Am T Surg” Pathol 25 Sr.08F Mictnen M, Malkloaf H,Sobin LH etal. 2006 Gastrointestinal ZAvomal tumors of the jejunum and Alums a elnicopathlogt, immunohicochemial, and moleclar genetic study of 906 cases tefore imatinib with long-term follow-up. Am} Sarg Pathol 30 477-489 Agumy A, Wunsch PIL, Dirnhofer $ et al. 2008 Microscopic _gstroinestinal stromal narors in esophageal ad inesinalsrgi- ‘al resection spccimens 9 clinicopathologc, immanohiscochem= fal and molerular study of 19 lesions. Atm T'Surg Pathol 32 6.993 Andersson J, Sito H, Meis-Kindblom J Met al. 2005. NF1- erciated gstroincrtinal roma tumors have unique clini [Dhenowypi, and genotypic characteristics Am } Sung Pathol 29: Troe, ‘Miettinen M, Fetch JF, Sobin LH et al, 2006 Gastrointestinal seroma tumors in patients with nevrosbeomatoss 1: 4 lnieo- puthologie snd molecular genetic sm of 45 cases. Am J Soe Pathol $0: 90-96 Mietines M, Kopezmshi J, Makhlouf H R etl. 2003 Gastroin- testinal stromal eumors nsamural Iomyomas, an leiomyosar= «comasinehe dusenuracliicupathologcimmunohistoherica spdolclan gene dy of 167 cnc. An} Sry Pahl 33, Mietinen M, Wang ZF, Leta | 2017 DOG andy in the irene digas of gastintstinl stromal tui sy Sf 1840 cases Am} Sar Patol 33: 1401-1408 34, Misti i Wg 2 Sao Rilals M2011 Sexe deiyrogensse detent GISTs + clicopstholog, immanchis- ‘ochemish and molecular genetic study of 66 gate GISTs wich econ to young age Am] Sty Patha 9517121721 3s, Pal Cones Cis nat A Cera 2008 Clnteptinogie profile of garni ermal tumors (GISTS) with priary EVI Sson‘Ta ar muon 17 mina 1 mbicmon ony an 8 costs Mod Pathol 21: 476-384 46, Gores CL, Seroeder A, Grit D etal. 2005 PDGERA mas Sons in gutointestinal stromal senor frequency spectrum snd in iuo sony to ana J Cl Oncol 335557364 37, Agia NR Wang GC. Clu eta 2008 Novel VSD BRAB ‘utavons in Snaunibaive and tnaniberesitant gases Sal stromal tumors Genes Chromownes Cancer 472 853. 339 38, Hostein I Fur N, Pritois © oa 2010 BRAF mri status in gastrointestinal somal tamore. Am J Clin Pathol 133 tase 38, Antone © R 2011 The GIST paradiga: lesions for other Einssedrven cancers. J Pathol 22%281-261 40, Ilcnsch MG, Corks C by Demewi GD ef al. 2003 Kinase ‘taons sd mati response inpatient ath meta se ‘tintin toma ashe) Clin Oncol 1. 4342-4349 441 Maran, Wagner J, Hock JL 2012 Precio of response Targeted tempi for grteincestnal stoma rumors Arch Pata Lab Med 136: 485-89 42, DebiceRychter M, Scot R, Le Cesne A eal. 2006 KIT mts Sioned done selection foe iat ingens with advanced fvocincestnl somal ramon Ear} Caner 8210931108 43, Wang D, Zhang , Banke © D et al, 2012 Phase Tl wal of nccjvanadnva iain ext for aan primary and Sctuesccfeenreat opershkgetromernind mrtbel ors longer follow-up result of Radon ‘Therapy Oncology Group 0132. Ann Strg Oncol 19: 1074-1080, 44, Ligght, Repter I Le € etal 2008 Heterogeeryof kinase fun tor resistance mechani sn GIST. J Pathol 216: 644 48, Mietinen M, Tavots 1 2006, Gastvintenal seroma tumors: ppthology an prognosis st diferent sites. Semin Diagn Pathol Brod 46, Mictinen M, Sobin LH, Lasoe J 2009 Tiue smooth muscle ‘tumors of che small intestine a clintopathologi,immunohsto Semis, snd makeuar genetic sy of 2S ence Awe) Sy Pathol 3 ostse ° * 47, Antonescu C Ry Nafi K, Segal N'H ot 2006 EWS CREB: + recurrent varia fison in ler call sarcoms—esoeiton with fPorramesoal loeazon and sisene of melanacyec tere fon, Clin Canoe Res 1: 5856-5362 48 Stoman D Ie Mietinen Ml Sestr Soa. 2012 Nahi ‘Scmnahistocheical, usta, and molecule anal {icases with capris of clear cel somali tumors ofthe stone! tut An) Sarg thal 3857 868 49, Kosemetmemgla K, Foipe AL 2010 Clea ell sarcoma of tendons and sponetous, and tocar ch amour ofthe ‘rintsinal tae with fentres resembling clear ell sarcoma of Soft parte aren and update J Chin Patol 03: 510-403 50, Gert AK; Gidea F M, Petersen G M etal 1994 Desmoid ukcomatus polyps. Gat 35 377-381 51, Mel, Zager 8, Sondak VK 2008 Muon managetcar tdci amos how spartan a negate sry arg! arg Once 98 54-602 52, Corb} Wi, Fleisher D 2007 lmmunoinochemiey fr bea {Sten i the dierent diagnose of pnd coil ison anal Sofa series and review ofthe erature: Histopathal 51 502.514 53, Montgomery E, Foie A 1 2008 The dagnomic valve of ba {ates inlunohschemary, ad Ast Patol 13. 50856 54, TeparS, Noe, 4 C ea 1999 Predominance of et-stein mutations and bet-eatenin dysregulation in sporadic aggresive romans (no tor): Oncogene 18: 4515-6520 58, Nienweahois Mth Lefevre J H, Bulow $ etal. 2011 Family Iistrysrger, and ADC maton ae rink factors for devon tumor nfl adenomas polyposis an internation ahr Sty Di Clon Rec 8 120-1238moo 56, Hlomice JL, Fletcher © D 2002 Immanohitachemial saining for KIT (CDI?) in sof cise scons very ited in ist Inson. Ara J Clin Pach 117. 188-193 57, Jolacne} By Miso BG 1978 Lanny Kono polyp the gestrontesinal eat. Histopathology 2: 49-361 st, Onolsk} Ay Saxomi E Sealy Be 2008 latamatny fibroid polyps ofthe gastoinestina ac: cine, pathologic rear arate Ap Hmunolistchs ol Nforgha 2, 59-65 40. Hs joo Ving B Kegnes No a. 1997 CDM espersion hy inlanmatory fibroid paps of the stomach, Mod Pathol 10: Sie 0, Schldhos HU, CavlarT, Biot Eo a. 2008 Inlmat cod pops hartour tuts ia the psie-deved growth {seer seep ha (PDGHA gene) Patol 216176182 4 Lao , Wang 2 & Sabin L Het a. 2009 Gain-offation BDGERA mansions, ever reporced i gates oral furmors, are common in stall snestnal inflammatory bond polip A stdy of 0 ces. Mod Path 22: 108-1056 «a, Phage, Wardelmann Gar D eta. 2012 Acting PDGERA ‘muaions ninfemmony Si pele ae im ene 1, 1 Sed 18 and te axocted wih rns lnaeason, Tssopaol at s.68 65, Tishman 53, Dacrows 11 Leiner & Metal: 1998 Gas tcriml maiferadons of cular anomalies in chlo ved clgir require mpl herpetic madabes.) Pediat Sing Si tleiti6 6, yl iy ak 1995 Solitary cavernous hemangioms of sal ines. Cae report and erature review. Arch Pathol Lab Med ian 65, Trade T 2012 Patloge observations of the dodenam in 615 consecutive doen specimens Bang lesions Ie} Clin Exp Patol 546-51 (6, Alinon KH, Yoder BJ, Bronner MP ct sl 20 Angiosarcoma ertrng ch prone wat arn f pina ode Senccnea An Sarg Pathol 28: 298-07 67, Mistnen M, Wang ZF, Pac etal. 2011 ERG tanseipion facsor esos tuna atonal arb fo asulr endo tumors and prestaic earinons. Am) Sing Pathol 3432-441 68, Park) 2007 Messmer ples newrofrarain an U-yearold boy wth von Recklinghassen diss. 1 Peat Song S2E15~ 8 (8, Carvey} A, Go VL, Sizemore G W etal 1976 Aimentary-tract fangoneuromatoss. A major compooent of the syndrome of ‘lupe cndoctine neoplasia, spe 2b. N’ Engl J Med 298 Tarde 70, dinre ES, Manel JC Pei G 199 Ines ngloncoromstons ixonal and transmral ype. Alinco Fostoge and semonohuocheruel seudy of cas at Dich 2: 276-286 71 le Willan 19 Gaines mnieatins Sopatheogy 19.11 Koda A, Aghsmobammad A, Pranch N et a. 2007 Gas- fceieeetl melon im plinth common weracla Snomalefcony Dig Din Se $2: 2977-2083 213, Nalumars 8, Mstsmtto lla Atal 2008 Primary gastos texnal ymphoma in Jags eliniopatologic analy of 458 vents with spa felernce tow ame tends, Cancer 9 240-2473 74, Koch Fl Valle F Beniel W Fal. 2001 Primary gstintes ‘ial non-Hogkisymphoma: [Anite an hsologi dase thon cline eure sd sural data 371 patent regen inthe German Multicenter Study GIT NHL 1/02) Cli Oncol ou deei- 3 78, Connor) Ashton-Key M2007 Gastric nd intestinal dif large Bel Irnphomasarécinkaly and immunophenorypiclly die fecent, An smmolinochemical an elise. Histopathol 16, Schl KA, Pin WG, Owens SR 208 Difrences in geri tal conte and non-gersng cent phenorpe nse and esi ifselrge Boel Imphoxta. Lek Lymphoma 4 ines 277, Chang 88, Ye H, Yang Feta. 208 Perforation predicts promos in pens wath primary scsi dite large Heel Rraphoms 1ropntology 83+ 432-430 “Tuwons oF tHe Sant ap Lance byresmives, INenupine Anat CANAL 78, Akasaka Akasaka H, Ueda C al. 2000 Moleclr an ina features of non-Burkie tose larg-eelImphoma of Bell ra secede eA Cnmanogltainhey-cnn ‘Wy Mun YC eal 2011 Malicenter respec: ve anal $8 patent wat peimary intestinal non odin Tempo fom the Consort for Imprenng Suri of Lym piss (CISL) BNIC Cancer 1 321 10, Remain ED, Dogan A, Eines RR eal. 2006 The incidence sed cnotere sin ethyl chrereenral mares primary extranodal gina sone Bell yma of mucose ‘Ssocited Imphosl tase (MALT Ipnphoma)in North Amen fm Sung Pathol 80: 1546-1583 1, DuM G2007 MALT Impl: ccene advances in scsi tnd mlkcalsr genetics Clin Esp Hemampatha 4 2 42, Fine K D, Stone M J 1999 Alphaheny chain dss, Mader tansan hmphoms, “a snmmunopedtenive sal" intestinal Aisensearevew of clinicopathologeal femur pathogenesis ad ‘ern diagnos. nj Castrol 9. 1139-1152 43, Tern A, Aburhin fi, Morn or 3018 Temperate seal inate diene ascited wih Conpybtarer s N Engl J Med 350-259-248 ‘4 Sumer I Lertolary O, Hermine © al, 2006 Infection tssocated lymphomas derived fom marginal zone B cells 4 trodel af antigen sven Iymiphoprleration. ‘Blood 107 Sos 30H4 45, Salem PA, Kaephan F 2005 tmuunoproitrsve smal ites tna disease: erent concepts. Cancer] e374 382 186, Isc PG, Dogan &, Pace SK etal. 1989 lnmunopekiacve sealers) dues, An iervunohisochenical tad Am J Sor Patol Ii: 10 87, Mista Haris NT, Mason RP eal 2011 Primary ollie inelympboma of the gasrtetnal tice: Am J Sarg Pathol 35 488, SchmasA, Stcabel B, Kretchmer-Choer Eta 2011 Primary fio: poms of he demas» Stine mal! sulanucceal veant of fille phos a setrepeste dy {6 eves] Chin Oncol 29: 15-1851 9, Shia} TeryscFeibtsn j, Pai D et al, 2002 Primary foliar Inpho ih geste ac ie and patie Jot Xe caves um) Surg Patol 36: 216-224 90, Takata K, Okada Hy, Ohya N et a. 2011 Pray grins sal folicalar phoma involving the duodenal second portion s 2 ebninct ening mubiecnser, sesompective aly open ince Se a2 gs sh mie 91, Moynihan M], Bas ATA, Chan WC era. 1996 Lymphomatous polos A neoplasm of eter folic mane or germinal Eente cell nant Amy Sung Patol 20: 442430 92, Kodama T, Ohshina K, Nomura K ct al. 2005 Lyexphomatous Dobos of the gstoinetnl tice ielng mance call my thoma, focal’ hmphoma and macoscanoctted.pmphold fEsue inphoma, Histopathology 47: 467-478 98, Bere-islan 8 Drying M, Weesner 2011 Mant elt hon Domo: logy, progsaes auth molar sso scr tren inthe genom er lon 117: 26:38 94, E'S, Dict M,Jerkeman NI et al, 2008 Nuclear expression of the non Bel ineage Sow easeripion ftor denies mantle {ell fymphoma Bd 111: 8-05 98, Chen YH, Gao], Fan Geta 2010 Nectar expression of sox is highly associ with man sl rmphoma es independens ‘of (11 14Xq13932) in noneance ell Deel noplasat. Mad Path 230 05-112 96, Sarer 2011 Mantle cl pom scene insights nt pho: Genet cle abo and mew digesters Bea Binge Pathol 28°24 497, Molyneus EM, Rochord Grif Bet 2012 Burke ye toma. Lanoee 379 1235-1241 ox, Noung LS, Ricinson AB 2004 Epscin-Batr vin 40 yeas on, Nat Rey Caneer 787-768 99, Heche} Ly Aster) € 2000 Molecular biology of Barkin phon J Chin Oncol 13707-4721 ton, Sack GW, Gaseryne RD 2011 MYC and aggresive Bell ipmphoras’Ady-Anat Pathol 18, 219.228 101, Risinoea MB, Caran I, Roig 8 J 2010 Altered suber locaton of lye prominent appronive Bell10. 106, soe, uo, 12s, 6 9 ‘Lowors or vie SMALL aN Larer Ivrestives, IvetuDivG ANAL CANAL Ipmphomas harboring 2 e MYC translocation. Am J Surg Pathol Be BR2-89L Green T M, Nieken O, de Seicker K et al. 2012 High levels of hnuclear MYC prose prey dhe presence of NVC veanange: ment in difise large Brcell ymphoma. Am J Surg Pathol 36 612-619 Corrao G, Corazra G R, Bagman V et al. 2001 Moray in patents with ence daeise tad ther ratves a cobore study Lancet 358: 356-361 Sienisli MK. ennard& 1.2011 Bnterapasy-assoiae Toll Fhmphoma: epdemioiogy, clinical features, and curren ereatment strategies. Curr Hematol Magn Repons 6: 231-240, Callie C, Delabesse FE, Helmer Cet al 2000 Refraceory sprue, colic disene, and enteropathy-asacinved Teall Kye ‘Dhoma. French Coeliac Disease Sty Croup. Lancet 386: 203- das de Mascarel A, Bellesnee G, Stans S ee al. 2008 Mucos inerapithelial"-lymphocyes in rectory celiac disease: a neo poste popltion with «variable CDS phenotype. Am J Song Pathol 32: 744-751 Malarnat @, Ahain P.Verkarr V eta 2000 Presentation and long-term follow-up of refractory case disease: comparioa of type Lith type I Gastroenterol 136: 81-90 Zea ay de.ceuw Ry ITaralabievs I etal. 2007 Enteropathy-ype ‘Teall ymphoma, Am J Clin Pathol 127: 701-706 (Chan JK, Cha A C, Cheuk W et al. 2011 Type Il enteropathy: associated T-cell ymphoma: distinct aggressive Iraphoma with frequent gammadele T-cell receptor expression, At) Sung Pathol 35° 1557-1509 (Chott A, Haedicke W, Mosberger I etal, 1998 Most CD56 intestinal lymphomas are CD8«CDS- T-cell imphomas af mono ‘morphic smal to sme size histology. Am} Pathol 133 183-1490, Disibio G, French SW 2008 Mersstatc patterns of cancer resale from a large auropay study. Arch Pachol Labs Med 132 Sa189 2. Flayed A M, Albahra M, Nzcako UG et al. 1996 Matignane ‘nelaonnes eh sll neste: toy of 1US patents mJ {Gastroenterol 91: 1001-1006 Washington K, MeDonagh 1995 Secondary tumors of the _astointestinal tract sora pathologie findings ancl comparison ‘vith autopsy survey. Md Pathol 8487-385, Kim K, Jing 8], Song Jet. 2012 Clnicopathologiccharae- terses and mucin expression in Brunner gland proliferating Keions, Dig Dis Si Peliahed line ol 27 TELE, Tompkins 8 K 1986 Heteroropic pancreas, Review of a 2 year experience Am Surg 151: 697-700, Begs A.D, Latchiord A R, Vasen HF etal. 2010 PeutJeghers syndrome systemane fev and recommendations or anage ment. Cue 59 975986 hk KM, Eng C 2007 Hamartomatous polyposis syromes KatClin Pract Gasuoemerol Hepatol 492-902 Heare N, Sehuiacher V Mesko ¥ Het a. 2006 Frequency and spectrum of cancer in the Peu-Jeghers syndrome. Clin Cancer ‘Mehenn TI, Resta N, Pasky G etal, 2006 Cancer rks in LKBL germline mation catirs Gut $3: 984-090 |. Burkart AL, Sheridan T, Lewin Metal 2007 Do sporadic Pew Jeghers polyps exist? Experience ofa large teaching hospital. An J Sarg Pathol 31: 1209-1214 |. Shepherd N A, Bussey HJ Joss) R 1987 Epithelial misplacemene in PeutzTeghers polyps.‘ diagnostic pil, Am T Surg Pathol Th 3-199 “Taw O W, MeGregor D H1 1992 Lipahyperplasia of the ieoce- sgalvalew, An J Gasroonterl 8s 8287 Yanuss 8 K, Banceykawsks A, Mind J eta. 2007 A comprehen ‘ve study of nonysplstic and dysplastic seated polyps of the ‘vermaforma appendix. Am J Surg Batol 31: 1742-1783 Bellz A‘, Rock J, Matsh W L eta. 2010 Serrated lesions of ‘the append a morphologic nd immoanohisrachemial appr ‘Am J Clin Pathol 153: 625-632 Misc J, Yantiss RK, Graeme-Cook F Met al 2003 Appendli- ‘eat melnous neoplans. A clinicopathologic analysis of 107 ceases Am Surg Patel 2: 1089-1103 isd) 2010 Appendiceal rmcinous neoplasms: controversial ions ich Pathol aly Med 1s, 864-870; 1B 127, Renshaw A A, Kish R, Gould E W 2006 Sesile serrated adenoma Js associated with acute appendicitis inpatient 30 years or older. Aum] Clin Pathol 126 875-877 PARK, Lomgace TA 2005 Appelical suainous suum and pseudomyxoma peritne: histologic features, diagnostic problems, and proposed classification. Adv Ana Pathol 13: 291- Si y Care NJ, Finch Jeske EC eral. 2012 Pathology and progoess in peuomysoins pete revew of 274 cen Clin Pathol aloo Ronnett 8M, Yan H, Kurman RJ et 2001 Paes wh pseu- domyscina pesto! atuacated wih disaminatedpertonal denomocinosis have 4 sicandly more favorable proses Oks 151, Ronse BM, Zahn C M, Kura R Je. 1995 Disseminated eviewelsdenemacinosand perionsal ricinousexenorat ESIA"Ginicopahlogie anasto 109 canes with emphais tinsngnishing pathologic fetaes, site of ain, prognosis snd ‘clconcipto peu pesitones” An |Sarg Pathol 19. ont 152, Chun TC, Moran B J Suarbaker PH et al 2012 Ray and Tonge outcome dt of pen with seidomysoma peitones fom appends origin texted by 4 sratey of eroredctive surgery sod hyperthermic intrapertonel hemodherapy | Clin Oncol si 24383356 13, Vans RK, Shia J, Klinstra D 8 cl 2009 Prono sig Cance nf localized Gxs-appendcel mucin deposition i 29pm cel mucinous neoplasm A} Surg Pathol 3248-255 MeCusher ME, Cove TR Clegg LN etal 2002 Primary malg- tant songs ofthe apgenti spolason-baed sty fue ‘he Siren: Epidemiology and End-Resls progam, 1973. 1998, Caner 94 3307-33 135, Benedv Reimer A, Gastnger Teta 2010 Primary appendices! Carcnoma—cpldcniclogy, surgery sod sonia ertae of + (German soltcnter tly. Eat J Sung Oncol 36 765-771 MeGiory ML, Maggard MCA, Kang Fe 2005 Malignancies ofthe append beyoa cave senes reports. Ds Uolon Mectn Ss: 226b07T1 157, Tang LH, Sha, Sostow RA eta 2008 Puhologe easifcaion and clini kebisior of the Specirum of goblet cell carcinoid tumor ofthe spend Am J Sarg Patol $2, 1429-1443 Tce J Lee H'S, Km W Het 2003 Expression of mucins and okra in primary eareinomas of the digestive ser Mod Pathol 16. 1030010, Kabban W, Houlthan P S, Lathra Re a. 2002 Macinous and onmucinods sppenicel adenoesnomas s0 260, 261 Arch Pathol 202. 26. 264, ine Abel ALE, Chiu ', sll T Rt a, 1995 Adenocarinom of the anal glands. Resse of & suney. Dis Colon Rectum 36 oa Loveky M, Patel K, Cymes K et sl, 2007 immanophenoypic

También podría gustarte

• Manual para Premiembros

  

  Documento127 páginas

  Manual para Premiembros

  javalive4

  Aún no hay calificaciones
• Deteccion Anticuerpos Irreg

  

  Documento18 páginas

  Deteccion Anticuerpos Irreg

  82lau

  Aún no hay calificaciones
• Marcadores de Activación Alternativa de Macrófagos DC-SIGN y FRβ

  

  Documento146 páginas

  Marcadores de Activación Alternativa de Macrófagos DC-SIGN y FRβ

  Cristian Gutiérrez Vera

  Aún no hay calificaciones
• • Revistas
  • Podcasts
  • Partituras
• Técnicas de Ahorro de Sangre

  

  Documento5 páginas

  Técnicas de Ahorro de Sangre

  Cristian Gutiérrez Vera

  Aún no hay calificaciones
• Hemostasia y Activación Plaquetaria

  

  Documento38 páginas

  Hemostasia y Activación Plaquetaria

  Jesús Mendoza

  Aún no hay calificaciones
• Manual de Inmunohematología y Medicina Transfusional

  

  Documento145 páginas

  Manual de Inmunohematología y Medicina Transfusional

  Cristian Gutiérrez Vera

  100% (21)
• 03b. Macrofagos PDF

  

  Documento14 páginas

  03b. Macrofagos PDF

  Katherine Zapata Rios

  Aún no hay calificaciones
• Activacion de La Coagulacion

  

  Documento8 páginas

  Activacion de La Coagulacion

  Karito Castro

  Aún no hay calificaciones
• Fisiopatologia Hemostasia

  

  Documento15 páginas

  Fisiopatologia Hemostasia

  El Estudio

  Aún no hay calificaciones
• Hemostasia PDF

  

  Documento5 páginas

  Hemostasia PDF

  Fernanda Granillo

  Aún no hay calificaciones
• Fisiología de La Hemostasia

  

  Documento17 páginas

  Fisiología de La Hemostasia

  Irene Cristina

  100% (7)
• Coagulacion 2009 Una Vision Moderna de La Hemostasia

  

  Documento5 páginas

  Coagulacion 2009 Una Vision Moderna de La Hemostasia

  Arturo Canseco Lopez

  Aún no hay calificaciones
• Fenotipos de R en Gram POsitivos PDF

  

  Documento8 páginas

  Fenotipos de R en Gram POsitivos PDF

  Cristian Gutiérrez Vera

  Aún no hay calificaciones
• Pregrado de Hematologia

  

  Documento706 páginas

  Pregrado de Hematologia

  Hola Soy Bramby

  Aún no hay calificaciones
• Depresion Minsal

  

  Documento144 páginas

  Depresion Minsal

  Estefania Moscoso Cárdenas

  100% (1)
• Fenotipos de R en Gram Negativos PDF

  

  Documento11 páginas

  Fenotipos de R en Gram Negativos PDF

  Cristian Gutiérrez Vera

  Aún no hay calificaciones
• Fenotipos de R en Gram Negativos PDF

  

  Documento11 páginas

  Fenotipos de R en Gram Negativos PDF

  Cristian Gutiérrez Vera

  Aún no hay calificaciones
• Anti Nuclear Es

  

  Documento7 páginas

  Anti Nuclear Es

  Srta_Peonza

  Aún no hay calificaciones
• Manual Bioseguridad ISPCH

  

  Documento46 páginas

  Manual Bioseguridad ISPCH

  João José Damian Salazar

  100% (1)
• Revision Dra Toche

  

  Documento7 páginas

  Revision Dra Toche

  Cristian Gutiérrez Vera

  Aún no hay calificaciones
• Errores Relacionados Con El Laboratorio Cli 769 Nico

  

  Documento6 páginas

  Errores Relacionados Con El Laboratorio Cli 769 Nico

  Cristian Gutiérrez Vera

  Aún no hay calificaciones