Illinois Registry of Anatomic Pathology (IRAP)

Illinois Registry of Anatomic Pathology (IRAP)

Case Summaries

March 31, 2014

Case 1: Dedifferentiated Gastrointestinal Stromal Tumor

Presenter: Jacqueline Choi MD

Attending: Elliot Weisenberg MD

Clinical History: A 52-year-old obese female presented with worsening fevers, abdominal pain, non-bloody diarrhea and malaise. Physical exam found a large palpable mass in the center of her abdomen, CT scan revealed a 17 cm heterogenous, cystic mass in the mesentery that was densely adherent to surrounding structures. The specimen was resected en-bloc including the mass, multiple loops of small bowel, mesentery, and rectosigmoid colon.

Diagnosis: Dedifferentiated Gastrointestinal Stromal Tumor

Differential Diagnosis:

• Leiomyoma/leiomyosarcoma

• Undifferentiated Sarcoma

• Dedifferentiated liposarcoma

• Solitary fibrous tumor

• Melanoma

• Poorly differentiated carcinoma

• GIST

Key Microscopic Features:

· Majority of the specimen was necrotic

· Approximately 98% of viable mass was solid sheets of pleomorphic epithelioid cells with prominent nucleoli and numerous mitotic figures

· Approximately 2% of the mass demonstrated bland spindle cell morphology, was arranged in a fascicular pattern with oval nuclei, blunt ends, clumpy chromatin and abundant eosinophilic, vacuolated cytoplasm with nondistinct membranes.

Immunohistochemical stains:

• Positive: CD117 (spindle cell only), DOG1 (spindle cell only), CD34 (spindle cell only)

• Negative: S100, AE1/AE3, HMB45, CD31, Smooth muscle actin, Smooth muscle myosin, Myogenin, LCA

Ancillary Study:

• No chromosomal mutations on PCR

Discussion:

· Dedifferentiated GISTs can arise from a conventional GIST without history of tyrosine kinase inhibitor treatment

· Dedifferentiated GISTs lose the immunohistochemical staining properties of conventional GIST and are CD117, DOG1 and CD34 negative.

· Sufficient tissue sampling is crucial in identifying the area of conventional GIST to establish diagnosis

References:

1. Antonescu CR. The GIST paradigm: lessons for other kinase-driven cancers. J Pathol. 2011;223:251-261.

2. Antonescu CR: Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas. Mod Pathol . 2008 May;21 Suppl 2:S31-6.

3. Antonescu CR, Besmer P, Cuo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutations. Clin Cancer Res. 2005;11:4182-4190.

4. Antonescu CR, Romeo S, Zhang L, et al. Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: A diagnostic pitfall. Am J Surg Pathol. 2013 Mar;37(3):385-392.

5. Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): natural history, adrenocortical component, and possible familial occurrence Mayo Clin Proc. 74 (6): 543-52, 1999.

6. Choi JJ, Sinada-Bottros L, Maker AV, Weisenberg E. Dedifferentiated gastrointestinal stromal tumor arising de novo from the small intestine. Pathol Res Pract. 2014 Apr;210(4):264-6.

7. Corless CL, Heinrich MC: Molecular pathobiology of gastrointestinal stromal sarcomas. Annu Rev Pathol. 2008;3:557-86.

8. Debiec-Rychter M, Cools J, Dumez H, et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inibitor against imatinib-resistant mutatnts. Gastroenterology. 2005;128:270-279.

9. Diaz DM, Hernandez AA, Pereira GS, et al. Gastrointestinal stromal tumors: morphological, immunohistochemical and molecular changes associated with kinase inhibitor therapy. Pathol Oncol Res. 2011;17:455-61.

10. Miettinen M, Lasota J: Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med. 130 (10): 1466-78, 2006.

11. Pauwels P, Debiec-Rychter M, Stul M, et al. Changing phenotype of gastrointestinal stromal tumours under imatinib mesylate treatment: a potential diagnostic pitfall. Histopathology. 2005;47:41-47.

Case 2: Prostate Stromal Tumor of Uncertain Malignant Potential (PSTUMP)

Presenter: Oliver Graf MD

Attending: Elizabeth Wiley MD

Clinical History: A 52-year-old male presented to clinic with nocturia and occasional hesitancy. Abnormal rectal exam: R prostate lobe firm, estimated size 40, PSA = 0.99 ng/mL

MRI: R prostate lobe suspicious for cancer. A core needle biopsy was performed, followed by a robot-assisted laparoscopic nerve sparing prostatectomy.

Diagnosis: PSTUMP

Differential Diagnosis:

• Leiomyosarcoma

• Stromal hyperplasia with atypia

• Prostate stromal sarcoma (PSS)

• Prostate stromal tumor of uncertain malignant potential (STUMP)

Key Microscopic Features:

· Low power: stromal overgrowth, compresses but does not invade the capsule and absent necrosis.

· High power: spindle cells in a fascicular pattern

· Oval nuclei with inconspicuous nucleoli are admixed with scattered atypical cells some of which have multinucleated forms and others which exhibit enlarged hyperchromatic irregular nuclei

Immunohistochemical and special stains:

• Positive: PR, Desmin (strong), SMA, ER, Ki-67 (10%)

• Negative: CD34, CD117, ALK-1

Discussion:

• STUMPs are neoplastic lesions

• Strong Desmin positivity does not rule out STUMP

• 4 histological subtypes of STUMP

• Resection recommended

References:

1. Gaudin PB, Rosai J, Epstein JI, Sarcomas and related proliferative lesions of specialized prostatic stroma: a clinicopathologic study of 22 cases. Am J Surg Pathol 1998 Feb;22(2):148-62.

2. Herawi M, Epstein J., Specialized stromal tumors of the prostate: a clinicopathologic study of 50 cases. Am J Surg Pathol 2006 Jun;30(6):694-704.

3. Bostwick D, Hossain D, Qian J, et al., Phyllodes tumor of the prostate: long-term followup study of 23 cases. J Urol. 2004 Sep;172(3):894-9.

Case 3: Stage IV Non-Gastric Extra-Nodal Marginal Zone Lymphoma

of the MALT Type with Gamma Heavy Chain Disease

Presenter: Betty Chung, DO, MPH, MA

Attendings: Sujata Gaitonde, MD, Fred Behm, MD

Fellow: Bing Zhu, MD

Clinical History: The patient is a 15-year-old African American male who presented with a 3 month history of non-tender infra-mandibular neck swelling and 20 lb weight loss. Lymphadenopathy was unresponsive to three different courses of antibiotics. Mass enlargement in the palatal region required tonsillectomy, adenoidectomy, and uvulectomy.

Diagnosis: Stage IV non-gastric extra-nodal marginal zone lymphoma of the MALT type with gamma heavy chain disease

Differential Diagnosis:

• Florid reactive hyperplasia

• Follicular lymphoma

• Small lymphocytic lymphoma

• Mantle cell lymphoma

• Extra-nodal marginal zone lymphoma

Key Microscopic Features:

· Salivary gland and tonsil; bone marrow was uninvolved

· Extensive lymphoid infiltrate focally effacing normal salivary gland architecture

· Numerous monocytoid cells with admixed larger lymphoid cells

· Scattered plasmacytoid cells at periphery of lymphoid infiltrate

· Lymphoepithelial lesions

· Scattered mitotic figures

· No well-formed follicles

Immunohistochemical and Special Stains:

· Positive: CD20, CD79a, CD21, CD43, CD138, MUM1, scattered IgA/IgM and kappa/lambda, IgG but lacking kappa/lambda,

· Additional positive: few EBER+ (<5% of lesional cells); CD3, CD4, and CD8 highlighting background T-cells with normal CD4:CD8 ratio (4:1)

· Negative: CD5, CD10

· Equivocal: Bcl-2

Flow Cytometric Findings:

· 3 subsets of B-cells that do no express CD5, CD10, CD23, CD103, or CD25

o 13% expressing surface lambda light chain expression

o 19% expressing surface kappa light chain

o 8% without surface light chain expression

· T-cells expressing pan-T cell markers with CD4:CD8 in normal ratio (4:1)

Cytogenetic and Molecular Findings:

· Normal male karyotype with negative FISH for MYC

· No clonality detected for IgH, kappa, TCR gene rearrangements

Ancillary Studies:

· Normal serum protein electrophoresis

· Immunofixation detected an abnormal IgG band

Discussion:

· One should consider heavy chain disease in lymphomas lacking both kappa and lambda chains

· PCR may show lack of gene rearrangements for heavy, kappa, and lambda chains

· SPEP may be normal (17%) and may need IFE to detect the specific abnormal heavy chain

· No current consensus on whether gamma heavy chain disease is a variant of MZL or LPL or is a unique lymphoproliferative disorder

References:

1. Bieliauskas S, Tubbs CM, Bacon, et al. Gamma heavy-chain disease: defining the spectrum of associated lymphoproliferative disorders through analysis of 13 cases. Am J Surg Pathol. 2012 Apr; 36(4): 534-43.

2. Faguet GB. Gamma Heavy Chain Disease. Editor: Besa EC. Medscape, last updated Jan 10, 2012. Accessed on 3/24/14 at http://emedicine.medscape.com/article/200675-overview

3. Rajkumar SV. The heavy chain diseases. Editors: Kyle RA, Connor BF. UpToDate, Inc., last updated Sept 25, 2013. Accessed on 3/24/14 at http://www.uptodate.com/contents/the-heavy-chain-diseases

4. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition: Gamma Heavy Chain Disease. World Health Organization,2008; 196-197.

5. Wahner-Roedler DL, Witzig TE, Loehrer LL, and Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore). 2003 Jul; 82(4): 236-50.

6. Wahnder-Roedler DL and Kyle RA. Heavy chain diseases. Best Prac Res Clin Hematol. 2005 Dec; 18(4): 729-746.Chennuri, Rohini

1. Hi John, Is this the standard format for the Reference citation: Ainsworth SM, Nagy SB, Morgan LA, et al. Interpretation of gram-stained sputa containing Moraxella catarrhalis. J Clin Microbiol.1990;28(3):2559-2560 And I understand you said we can list 6 authorsTue 1:34 PM

Case 4: Absence of Interstitial Cells of Cajal

Presenter: Aaron Halfpenny, DO

Attending: Michael Pins, MD

Clinical History: The patient is a 15-year-old female with PMH of chronic constipation of at least 8 years, asthma, and depression. She presented multiple times over several years with nausea, vomiting, anorexia, and abdominal pain that required hospitalization for administration of osmotic laxative via NG tube and manual disimpaction. She received social work and nutrition consults on many occasions, was sent home on laxatives multiple times without relief. GI studies including transit time and manometry did not further characterize a source.

Diagnosis: Chronic intestinal pseudo-obstruction with absence of interstitial cells of Cajal

Differential Diagnosis:

· Myopathic CIPO: Type III sporadic visceral myopathy and Non familial South African leiomyopathy

· Neuropathic CIPO: Autosomal recessive neuropathic CIPO, sporadic degenerative inflammatory neuropathy, non inflammatory neuropathy, or focal Hirschprungs or variant

· Mesenchymal CIPO: Disorders of interstitial cells of Cajal

Immunohistochemical and special stains:

· CD117: did not identify interstitial cells of Cajal.

· Actin/Desmin: demonstrates thickened muscle layers without fibrosis

· S100: demonstrates normal distribution of neural networks

· Trichrome: demonstrates lack of fibrosis amongst thickened muscle

Discussion and Summary:

• CIPO is a rare disorder of mechanical obstruction in the absence of an anatomic lesion

• Thinking of CIPO as intestinal failure emphasizes the severity of the condition

• Clinicopathologic differential is broad and correlation exceedingly important

• Lack or maldistribution of ICC are a potential cause of CIPO and CD 117 is highly recommended

• No definitive criteria to establish lack of ICC

References:

1. Amiot A, Cazals-Hatem D, Joly F, et al. The role of Immunohistochemistry in Idiopathic Chronic Intestinal Pseudoobstruction (CIPO). Am J Surg Pathol. 2009 May;33(5):749-58.

2. Garrity M, Gibons S, Smyrk T, et al. Diagnostic challenges of motility disorders : Optimal detection of CD 117 positive interstitial cells of Cajal. Histopathology. 2009 February; 54 (3): 286-294.

3. Hagger R, Gharaie S, Finlayson C, Kumar D. Regional and transmural density of interstitial cells of Cajal in human colon and rectum. Am J Physiol.1998 Dec;275(6 Pt 1): (Gastrointest. Liver Physiol.38) G1309-G1316.

4. Maeda H, Yamagata A. Nishikawa S. et al. Requirement of c-kit for development of intestinal pacemaker system. Development. 1992; 116: 369-75.

5. Moore SW, Schneider JW, Kaschula RDC. Non-familial visceral myopathy: clinical and pathologic features of degenerative leiomyopathy. Pediatric Surgery International 2002; 18: 6-12

6. Odze R, Goldblum J, et al. Surgical Pathology of the Gastrointestinal tract, Liver, Biliary Tract and Pancreas. 2nd edition. 2009. Saunders Elsevier.

7. Struis MC, Diamond IR, Pencharz PB, et al. Absence if the interstitial cells of Cajal in a child with chronic pseudoobstruction. Journal of Pediatric Surgery. 2008 Dec; 43(12):e25-9.

8. Sung-Hye P, Hyesook M, Je G. Chi. Immunohistochemical Studies of Pediatric Intestinal Pseudo-Obstruction. Am J Surg Pathol 2005 August;29(8): 1017-1024.

Case 5: Endometrioid adenocarcinoma, dedifferentiated type and a bladder adenocarcinoma in the setting of Lynch syndrome

Presenter: Ramayee Periakaruppan MD

Attendings: John Groth MD; Rajyasree Emmadi MD

Clinical History: The patient is a 47-year-old female who presented with menorrhagia.

An endometrial biopsy prompted a further workup including PET and CT scans, which showed a uterine body mass and a 3 cm bladder anterior dome mass with no additional extrauterine disease. Colonoscopy and endoscopy were unremarkable.

Diagnosis Uterus: Endometrioid adenocarcinoma, dedifferentiated type in the setting of Lynch syndrome

Differential Diagnosis:

· Endometrioid Adenocarcinoma, Grade 3

· Dedifferentiated Endometrioid adenocarcinoma

· Carcinosarcoma

Diagnosis Bladder: Bladder adenocarcinoma (urachal type is favored)

Differential Diagnosis:

· Metastasis from the uterus

· Bladder Adenocarcinoma

· Metastasis from the gastrointestinal tract

Key Microscopic Features:

· Endometrioid adenocarcinoma, dedifferentiated type:

o Full thickness invasion of two juxtaposed, but not intermingled patterns

o One component has well formed cribriform glands with columnar cells and oval, pseudostratified nuclei, with inconspicuous to small nucleoli arranged perpendicular to the base

o Other component is composed of sheets of cells without nesting, trabecular or glandular formation, with a relatively monomorphic population of polygonal cells with moderate amphophilic cytoplasm and round to irregular vesicular nuclei with prominent nucleoli that is distinct from the glandular component.

o There is no spindle cell component.

· Bladder adenocarcinoma:

o Glands composed of columnar cells with oval, pseudostratified, hyperchromatic nuclei with inconspicuous nucleoli and scattered goblet cells in a desmoplastic stroma.

Immunohistochemical and special stains:

· Endometrioid adenocarcinoma, dedifferentiated type:

o Positive: Vimentin, ER, CK7, p53 (focal)

o Negative: CEA, CK20, CDX2, B-catenin (nuclear)

· Bladder adenocarcinoma:

o Positive: CEA, CK20, CDX2, p53

o Negative: Vimentin, ER, CK7, B-catenin (nuclear)

Discussion:

· When tumor heterogeneity is found, one must consider dedifferentiated endometrioid adenocarcinoma and test for microsatellite instability

· MSH2 is the most commonly involved molecular abnormality in Lynch syndrome associated endometrial carcinoma.

· Screening for mismatch repair is advised in all endometrial carcinoma patients.

· Bladder adenocarcinoma is now associated with Lynch syndrome with MSH2.

References:

1. An HJ, Kim KI, Kim JY et al. Microsatellite Instability in Endometrioid Type Endometrial Adenocarcinoma is Associated With Poor Prognostic Indicators. Am J Surg Pathol. 2007;31:846–853.

2. Barrow PJ, Ingham S, O’Hara C et al, The spectrum of urologic malignancy in Lynch syndrome. Familial Cancer. 2013;12:57-63.

3. Bonadona V , Bonaiti B, Olschwang S et al. Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome. JAMA. 2011; 305(22):2304-2310.

4. Crum CP, Nucci MR, Lee KR. Diagnostic Gynecologic and Obstetric Pathology. 2nd Ed. Philadelphia, PA: Elsevier Saunders. 2011. Print.

5. Folkins A, Longacre, T, Hereditary gynecological malignancies: advances in screening and treatment. Histopathology. 2013; 62:2-13.

6. Geiersbach K, Wade S. Microsatellite Instability and Colorectal Cancer. Archives of Pathology and Laboratory Medicine. 2011;135:1269–1277.

7. Grady W, Carethers JM. Genomic and Epigenetic Instability in Colorectal Cancer Pathogenesis. Gastroenterology. 2008;135:1079-1099.