IRAP FOR SEPTEMBER, 2007



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ILLINOIS REGISTRY OF PATHOLOGY FOR 24 OCTOBER 2011

NORTHWESTERN MEMORIAL HOSPITAL

FEINBERG SCHOOL OF MEDICINE, NORTHWESTERN UNIVERSITY

CASE 1 (Dr. Brian McMillen, M.D.): Extrarenal Wilms Tumor with Diffuse Anaplasia.

Histology: Represenentative sections of tumor demonstrate a complex histologic pattern of primitive epithelial elements and stroma. Some areas show primitive glandular, tubular, and glomeruloid structures embedded within a densely cellular stroma. These stromal cells demonstrate a high degree of nuclear pleomorphism, with numerous atypical mitotic figures and large, hyperchromatic nuclei. Additional areas show small blue cells with high nuclear to cytoplasmic ratios and small, irregular glands within a desmoplastic stroma.

Special Studies:

WT1: Positive (nucleus)

CD56: Positive (cytoplasm)

MNF116: Positive in epithelial elements

P53: Rare nuclear positivity

ER: Negative

PR: Negative

AFP: Negative

Glypican: Negative

Inhibin: Negative

EMA: Negative

Differential Diagnosis:

• Carcinoma, including ovarian serous carcinoma and colon carcinoma: Do not have malignant stromal elements or glomeruloid and tubular structures, and usually arise in older-aged women

• Immature teratoma: Demonstrate multidirectional differentiation (ie, immature neuroectodermal elements). Tumor cells should not show diffuse expression of CD56 or WT-1.

• Yolk sac tumor: Commonly exhibits a reticular or microcystic architecture, presence of Schiller-Duval bodies, and neoplastic cells with hyaline globules. Tumor cells express AFP and demonstrate gains in chromosome 12p.

• Malignant mixed mullerian tumor (MMMT): Does not have glomeruloid and tubular differentiation, and epithelial component demonstrates distinct endometrioid, clear cell, or serous differentiation. Tumor presents in older-age women. Cells often express ER, PR and EMA.

Summary: Extrarenal Wilm’s Tumor is a rare triphasic neoplasm containing primitive blastomatous spindle or round cells and abortive primitive epithelial structures. By definition, no teratoma or renal neoplasm is identified. The tumor predilects to patients in the first decade of life, arising primarily in the retroperitoneum, uterus, and cervix, and has an association in a small number of cases with horseshoe kidney. The tumor has the same prognosis as its renal counterpart when matched for stage. Some studies indicate that cystic lesions have a better prognosis than solid variants.

References:

1) Current Therapy for Wilms’ Tumor. Metzger, M and Dome, J. The Oncologist November 2005: 10; 815-826.

2) Rosai and Ackerman’s Surgical Pathology, 9th edition, copyright 3004. Rosai, J. pp. 1240-1245

3) Sternberg's Diagnostic Surgical Pathology . Mills et al. Lippincott Williams & Wilkins; Fifth edition (August 2009).

4) Bonadio JF, Storer B, Norkool P, Farewell VT, Beckwich JB, D’Angio GJ. Anaplastic Wilms’ tumor. Clinical and pathologic studes. J Clin Oncol 1985:3;513-520.

5) Ratnam GV, Abu-Eshy S, Morad N, Almutawa AM. Adult extrarenal Wilms' tumour: A case report and review of literature. West Afr J Med. 2006:25;75-8.

6) Babaian RJ, Skinner DG, Waisman J. Wilms tumor in the adult patient: Diagnosis, management, and review of the world literature. C ancer 1980; 45:1713-1719.

7) Pure cystic nephroblastoma of the ovary with a reviewof extrarenal Wilms' tumors. Maria A. Isaac MD, Suseelan Vijayalakshmi MD, C hiramugathu S. Madhu MD, Luisanna Bosincu MD, Francisco F. Nogales MD. Human Pathology 2000:31, 761-764

8) Primary extrarenal Wilms' tumor in the inguinal canal: case report and review of the literature. Arkovitz MS, Ginsburg HB, Eidelman J, Greco MA, Rauson A. J Pediatr Surg. 1996:31;957-9.

CASE 2 (Dr Rajen Goyal, MD): Intraductal papillary mucinous neoplasm, oncocytic type (Intraductal oncocytic papillary neoplasm)

Histology: Representative sections show complex papillary growth pattern with papillae of variable width and thickness lined by single to multiple layers of cuboidal cells with oncocytic/densely granular eosinophilic cytoplasm. Other foci demonstrate a more solid growth pattern. The lining cells have round to slightly more oval nuclei and are uniform with minimal cytologic atypia and very low mitotic activity. Many cells showed eccentric nuclei with prominent nucleoli, but an even chromatin distribution. The cells also showed intraepithelial lumina containing mucin, thus imparting a cribriform architecture with round, “punched-out” spaces within epithelium. Also intermixed among the predominant oncocytic cell population are haphazardly distributed goblet cells. The lesion was confined to the duct wall and showed no invasion or infiltration into the duct wall.

Differential Diagnosis:

• Adenoma of bile duct-Polypoid, epithelial neoplasms composed of papillary, tubular or both kinds of structures, lined by dysplastic intestinal or biliary type epithelium.

• Biliary mucinous cystadenoma-Three layer structure – columnar epithelial lining, cellular ovarian-like stroma and hyalinized fibrous tissue layer similar to lesions in the pancreas.

• Biliary mucinous cystadenocarcinoma (papillary fronds projecting into cysts with columnar or cuboidal epithelial lining with stratification, marked cytologic atypia, and loss of polarity; tumors may have oncocytic features.

• Papilloma(tosis)- Usually multiple lesions as part of biliary papillomatosis; papillary proliferation with very delicate fibrovascular stalks lined by cuboidal-columnar epithelium; no oncocytic type cell lining.

Summary: Recent studies claim clinicopathological similarities between papillary lesions within the biliary duct system and the well-recognized and studied intraductal papillary mucinous neoplasms within the pancreas including differentiation of these lesions along intestinal (MUC2+), gastric (MUC5+), oncocytic (MUC1+/-;MUC5+), and pancreaticobiliary (MUC1+) lines with the latter showing a greater malignant tendency. Thusly, the current trend is to adopt a similar nomenclature for biliary tract lesions as used for papillary intraductal pancreatic tumors, and the appellation “intraductal papillary mucinous neoplasm of the bile duct” has replaced many of the alternate terms given to such lesions in the past.

References:

1) Adsay NV, Adair CF, Heffess CS, Klimstra DS. Intraductal oncocytic papillary neoplasms of the pancreas. Am J Surg Pathol 1996;20: 980-94

2) Choi SC, Lee JK, Jung JH et al. The clinicopathological features of biliary intraductal papillary neoplasms according to the location of tumors.. J Gastroenterol Hepatol 2010; 25(4):725-30

3) Grützmann R, Niedergethmann M, Pilarsky C, et al. Intraductal papillary mucinous tumors of the pancreas: biology, diagnosis, and treatment. Oncologist 2010; 15:1294.

CASE 3 (Dr. Mark C. Wang, M.D.): Pyloric gland adenoma of the gallbladder.

Histology: The polypoid lesion demonstrates a tubular to tubulopapillary growth pattern of cells that exhibit both pyloric and foveolar differentiation . The glands are uniform in size with occasional cysts identified. The epithelial lining ranges from simple cuboidal to simple columnar cells that possess eosinophilic cytoplasm and cytoplasmic mucin. Despite foci demonstrating architecturally complexity, the nuclei remain round to oval, basally oriented, and monomorphic without significant mitotic activity. Non-invasive extension of adenomatous epithelium into the Rokitansky-Aschoff sinuses is noted. The background gallbladder histology shows features of chronic cholecystitis.

Special Studies:

MUC6 (normally stains deeper pyloric glands of the stomach; consistently positive in pyloric gland adenomas)

MUC5AC (normally stains superficial foveolar epithelium of stomach; focally positive in significant minority [38%] of pyloric gland adenomas)

Differential Diagnosis:

• Gallbladder adenoma:

o Pyloric gland adenoma (adenoma lined by epithelium with gastric differentiation [pyloric gland or foveolar])

o Intestinal-type adenoma (adenoma lined by epithelium resembling that of a colonic tubular adenoma; keratin 20 and MUC-2)

o Biliary type adenoma (adenoma lined by epithelium resembling that of bile ducts or reactive gallbladder; MUC-1)

• Invasive carcinoma arising within an adenoma (haphazardly arranged, angulated, invasive nests of cytologically atypical cells with surrounding desmoplastic response)

o Papillary carcinoma (invasive or non-invasive papillae of tumor cells exhibiting marked cytologic atypia)

Summary: Although more commonly encountered in a stomach affected by autoimmune gastritis and intestinal metaplasia, histologically similar lesions occur in mucosae that demonstrate gastric or intestinal metaplasia such as the duodenum and, less often, pancreas, gastroesophageal junction and, as in this case, the gall bladder.

References:

1) Albores-Saavedra, J., D. E. Henson, and L. H. Sobin. World Health Organiziation Histological Typing of Tumors of the Gallbladder and Extrahepatic Bile Ducts. Berlin...[etc.: Berlin, 1991. Print.

2) Chang HJ, Jee CD, Kim WH: Mutation and altered expression of beta-catenin during gallbladder carcinogenesis. Am J Surg Pathol 2002; 26:758-766.

3) Chen ZM, et. al. Pyloric gland adenoma: an entity distinct from gastric foveolar type adenoma. Am J Surg Pathol. 2009 Feb;33(2):186-93.

4) Iacobuzio-Donahue, Christine A., and Elizabeth Montgomery. Pathology of the Gallbladder and Extrahepatic Bile Ducts. Gastrointestinal and Liver Pathology. Philadelphia: Elsevier/Saunders, 2012. Print.

5) Lee SH, et. al. Histopathologic analysis of adenoma and adenoma-related lesions of the gallbladder. Korean J Gastroenterol. 2010 Feb; 55(2):119-26.

6) Nagata S, Ajioka Y, Nishikura K, et al: Co-expression of gastric and biliary phenotype in pyloric-gland type adenoma of the gallbladder: Immunohistochemical analysis of mucin profile and cd10. Oncol Rep 2007; 17:721-729.

7) Odze, Robert D., and John R. Goldblum. Benign and Malignant Tumors of the Gallbladder and Extrahepatic Biliary Tract. Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas. 2nd ed. Philadelphia, PA: Saunders/Elsevier, 2009. 845-75. Print.

8) Vieth M, et. al. Immunohistochemical analysis of pyloric gland adenomas using a series of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67, and p53. Virchows Arch. 2010. 457: 529-536.

9) Vieth M, et. al. Pyloric gland adenoma - how to diagnose? Institute of Pathology, Klinikum Bayreuth, Germany. Cesk Patol. 2006 Jan;42(1):4-7.

10) Wistuba II, et. al. Gallbladder adenomas have molecular abnormalities different from those present in gallbladder carcinomas. Hum Pathol 1999; 30:21-25.

CASE 4 (Dr. Amy Lo, M.D.): High-grade sinonasal adenocarcinoma, nonintestinal type

Histological and Immunohistochemical Results: Representative sections taken of the lesion reveal large expansile nests of small, round, back-to-back glands separated by little to no intervening stroma. A higher power evaluation reveals glands lined by non-ciliated cuboidal to columnar cells that possess round nuclei exhibiting moderate nuclear pleomorphism and demonstrate high mitotic activity with presence of atypical forms. Immunohistochemically, the cells exhibited strong and diffuse expression of CK7, but no expression of CK20, CDX-2, p16 and p53.

Differential Diagnosis:

• Low-grade sinonasal adenocarcinoma, non-intestinal type- usually tubular or papillary architecture; low-grade nuclei with low mitotic activity and no necrosis.

• Nasopharyngeal adenocarcinoma- predominantly papillary architecture with low-grade cytological features including optically clear nuclei and psammoma bodies; positive for epithelial mucin and TTF-1.

• Sinonasal adenocarcinoma, salivary gland type- any salivary gland carcinoma can occur at this site, but most common variant is adenoid cystic carcinoma with cribriform, tubular or solid architecture; cells express CK7, c-Kit, CD43 and p63.

• Sinonasal adenocarcinoma, intestinal type –occupational exposure such as wood working; histologic features of intestinal differentiation present; cells express keratin 20, CDX-2 and MUC2.

• Rosette-forming neuroectodermal tumors – Olfactory neuroblastoma (ONB): Wide age range, but mostly adults; upper nasal cavity (cribriform plate); rosettes and abundant fibrillary matrix; S-100 marks peripheral sustentacular cells, variable expression of neuroendocrine markers. Primitive neuroectodermal tumor of the Ewing type (PNET): Children and young adults; extremely rare in non-osseous areas of sinonasal tract (less common than ONB); composed of primitive glycogenated cells with/without rosette formation and little or no fibrillary matrix; t(11;22) and t(21;22) in most cases; cells demonstrate strong and diffuse membranous CD99 expression and Fli-1 expression (in t(11;22) tumors).

• Teratocarcinosarcoma(TCS)-mixture of benign and malignant glandular elements, clear cell squamous nests (75% of cases) and sarcomatous components. Neuroectodermal rosettes and glandular elements of TCS may mimic high-grade sinonasal adenocarcinoma on limited biopsies, but adequate sampling will disclose the multidirectional differentiation that typifies the former lesion.

Summary: Three variants of sinonasal adenocarcinoma are recognized: 1.) intestinal, 2.) salivary-gland type, and 3.) non-intestinal type. The non-intestinal type is further divided into cytomorphologically low- and high-grade subtypes. The composition of the high-grade variant includes primitive blastomatous glands and rosettes (like our case), tumors with apocrine or mixed oncocytic/mucinous features (latter associated with oncocytic Schneiderian papillomas), and poorly differentiated or undifferentiated carcinomas. Prognosis of sinonasal adenocarcinoma depends in part on histologic grade.

References:

1) Heffner et al. Teratocarcinosarcoma (Malignant Teratoma?) of the nasal cavity and paranasal sinuses. Cancer 1984; May 53(10):2139-54.

2) Moran CA et al. Primary adenocarcinoma of the nasal cavity and paranasal sinuses. Ear Nose Throat J. Dec 1991;70(12):821-8.

3) Stelow et al. A histologic and immunohistochemical study discribing the diversity of tumors classified as high-grade sinonasal adenocarcinomas. Am J Surg Pathol 2011; Jul 35(7):971-80.

4) Stelow et al. Adenocarcinoma of the upper aerodigestive tract. Adv Anat Pathol 2010; Jul 17(4):262-9.

CASE 5 (Dr Paul Weisman, MD): Telangiectatic variant of hepatic adenoma

Histology: Representative sections show a cellular hepatocellular lesion with loss of the normal portal-central architecture, areas of sinusoidal dilatation alternating with foci exhibiting normal sinusoidal caliber, aberrant naked vessels, and abortive portal tracts (consisting only of arteries with no bile ducts or portal vein branches). Some portal areas exhibit inflammation and a ductular reaction (highlighted by CK7 immunostaining).

Differential Diagnosis:

• Telangiectatic variant of hepatic adenoma (HA):

o The above-described features are classic for this lesion; in addition, fibrous bands and nodular pattern of classic focal nodular hyperplasia (FNH) should be absent; immunostains for C-reactive protein and serum amyloid A may be helpful in differentiating this lesion from classic FNH in difficult cases.

• Classic focal nodular hyperplasia:

o A central scar, fibrous septa, and a nodular architecture can help to differentiate classic FNH from the telangiectatic HA, as classic FNH also exhibits portal tract-like structures and a ductular reaction, with normal hepatic plate thickness, causing diagnostic confustion in many cases. This case did not have a central scar, fibrous septa, or a nodular architecture.

• Hepatocellular adenoma:

o The loss of normal liver architecture with preservation of normal hepatic plate thickness and the presence of aberrant naked vessels characterizes conventional hepatocellular adenoma. However, the presence of portal tract-like structures and a ductular reaction rule out conventional HA in the present case.

• Well-differentiated hepatocellular carcinoma (HCC):

o The loss of normal liver architecture may make one think of well-differentiated HCC; however, normal hepatic plate thickness, normal nuclear density and hepatocytes with normal nucleocytoplasmic ratio mitigate strongly against well-differentiated HCC in the present case.

Summary: The inclusion of the “telangiectatic focal nodular hyperplasia” into an HA category is in part due to advances in the molecular classification of HAs. From a molecular perspective, HAs can be assigned to one of four categories: Somatic mutation in hepatic nuclear factor-1 (HNF-1) accounts for nearly 40% of HAs. These tumors histologically resemble convention HA with most exhibiting significant steatosis. Approximately 10% of HA harbor beta-catenin mutations (and show beta-catenin nuclear expression). Histologically, over one-half of these lesions exhibit cytological atypia and/or pseudogland formation and this subtype is associated with malignant transformation. Inflammatory HA (50% of HAs) are so named because of their inflammatory infiltrates and overexpression of acute-phase reactants (ie., C-reactive protein and serum amyloid A) by lesional hepatocytes. Approximately 60% of cases exhibit mutations in a key component of the IL-6 receptor. These tumors also microscopically demonstrate presence of dystrophic arterioles, sinusoidal dilatation, and ductular reaction; all features identified in the telangiectatic HA which, in most cases, are now included in the “inflammatory HA” molecular category.

References:

1) Mounajjed T, Wu TT. Telangiectatic variant of hepatic adenoma: Clinicopathologic features and correlation between liver needle biopsy and resection. American Journal of Surgical Pathology. 2011;35(9):1356-1363.

2) Bioulac-Sage P, Rebouissou S, Sa Cunha A, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology. 2005;128(5):1211-1218. . Accessed 10/2011.

3) Bioulac-Sage P, Balabaud C, Zucman-Rossi J. Subtype classification of hepatocellular adenoma. Digestive Surgery. 2010;27:39-45.

4) Rosai J. Liver. In: Houston M, Scott J, eds. Rosai and Ackerman’s Surgical Pathology. Philadelphia, PA: Elsevier; 2011:857-980

5) Walther Z, Jain D. Molecular pathology of hepatic neoplasms: classification and clinical significance. Pathol Res Int. Apr 7;2011:403929.

CASE 6 (Dr. Celina Villa, MD): Sarcomatoid carcinoma of the pancreas

Histology: Representative sections reveal a tumor with central necrosis and a rim of viable tissue. The lesion contains two components including an epithelioid component and spindle shaped cells in a background of abundant myxoid material. The lesion is mostly comprised of spindle-shaped cells with slight pleomorphism, with foci displaying cells with a primitive appearance. The nuclei are round to oval with a vesicular chromatin pattern and scant slightly eosinophilic cytoplasm. Frequent mitoses are present. The epithelioid component ranges in morphology from a glandular elements to a poorly differentiated epithelioid component. The glands are lined with pleomorphic cells with a high nuclear to cytoplasmic ratio and prominent nucleoli.

Special Studies:

Cytokeratins immunostain both the epithelioid and sarcomatous component. Ki-67 shows a high proliferative index and p53 immunostain demonstrates nuclear upregulation.

Differential Diagnosis:

• Carcinosarcoma- no differentiated sarcomatous component identified.

• Primary sarcoma of the pancreas or metastatic sarcoma/direct extension of peritoneal sarcoma

• Mucinous cystic neoplasm with sarcomatous nodule- no cystic mucinous tumor found in the pancreas.

Summary: Pleomorphic carcinomas of the pancreas are rare and include giant cell carcinoma, pleomorphic large cell carcinoma, and sarcomatoid carcinoma. The latter represents 5% to 7% of non-endocrine carcinomas encountered in the pancreas.

References:

1) Higashi M, Takao S and Sato E. Sarcomatoid carcinoma of the pancreas: a case report with immunohistochemistry study. Path Int, 1999. 49:453-456

2) Rosai and Ackerman’s Surgical Pathology, Ninth Edition. Volume 2. p1074-1075.

3) Yonemasu H, Takashima M, Nishiyama KI et al. Phenotypical characteristics of undifferentiated carcinoma of the pancreas: A comparison with pancreatic ductal adenocarcinoma and relevance of E-cadherin, α catenin and β catenin expression. Oncology reports, 2001. 8(4).

4) WHO Classification of tumors of the digestive system, by The International Agency for Research on Cancer, F.T. Bosman, F. Carneiro and R.H. Hruban, Oct 2010.

5) Paal E, Thompson LDR, Frommelt A et al. A Clinicopathologic and Immunohistochemical Study of 35 Anaplastic Carcinomas of the Pancreas with a Review of the Literature. Ann Diag Path, 2001. 5(3)129-40.

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