The University of Illinois Hospital & Health Sciences System Combined Residency

Program

Illinois Registry of Anatomic Pathology (IRAP)

Case Summaries

4/17/2017

Case 01: LipoblastomaPresenter: Christine J. Salibay, DO; Attending: Michael R. Pins, MD

Clinical History: The patient is a 15-month-old female with no significant past medical history who was noted by her mother to have a palpable, firm, and non-tender mass of the left buttock with enlargement over the course of 1 to 2 months. MRI of the pelvis revealed a heterogeneously enhancing lobulated mass measuring 8.3 x 4.1 x 3.7 cm in the left ischioanal and rectal fossa, displacing the anal canal and rectum to the right but without invasion (see figure). The mass also deviated the uterus and bladder anteriorly and superiorly. No attachment to pelvic structures were seen. The patient was referred for evaluation of possible malignancy and a biopsy was conducted.

Diagnosis: Lipoblastoma

Differential Diagnosis: Myxoid liposarcoma Primitive myxoid mesenchymal tumor of infancy (PMMTI) Lipofibromatosis Spindle cell lipoma Well-differentiated liposarcoma

Key Microscopic Features: Predominant myxoid stroma with indistinct fibrous septa admixed with mature adipose tissue Diffuse areas of a myxoid mesenchymal matrix with a delicate vascular network Stellate primitive mesenchymal cells admixed with cells morphologically suggestive of lipoblasts

and larger univacuolated mature adipocytes

Immunohistochemical stains: Positive: Desmin and Ki-67 (30%) Negative: S100 and myogenin

Karyotype: 46,XX,der(8)inv(8)(p?12q?12)add(8)(q22)[21] Derivative chromosome 8 with a complex rearrangement consisting of additional material of

unknown origin on the long arm and a pericentric inversiono Precise breakpoints may involve 8q12 bands

FISH break apart probe for PLAG1(8q12): Positive for rearrangement of the PLAG1 (8q12) locus

Discussion: Rare benign mesenchymal tumor of early childhood, accounting for less than 1% of all childhood

neoplasms Sites include trunk and extremities, but may rarely include retroperitoneum Composed of adipocytes, lipoblasts, and primitive mesenchymal cells within a myxoid stroma Associated with characteristic fusion genes involving chromosome 8 rearrangements resulting in

aberrant expression of PLAG1

Surgical resection is curative with low-rate of recurrence

References1. Alaggio R, Ningo V, Rosolen A, et al. Primitive myxoid mesenchymal tumor of infancy, a

clinicopathologic report of 6 cases. Am J Surg Pathol. 2006; 30: 388–394.2. Atlas of genetics and cytogenetics in oncology and haematology in 2013. Huret JL, Ahmad M,

Arsaban M, Bernheim A, Cigna J, Desangles F, Guignard JC, Jacquemot-Perbal MC, Labarussias M, Leberre V, Malo A, Morel-Pair C, Mossafa H, Potier JC, Texier G, Viguié F, Yau Chun Wan-Senon S, Zasadzinski A, Dessen P. Nucleic Acids Res. 2013 Jan; 41(Database issue): D920-4. PMID:23161685

3. Bartuma H, Domanski HA, Von Steyern FV, et al. Cytogenetic and molecular cytogenetic findings in lipoblastoma. Cancer Genet Cytogenet. 2008; 183: 60–63.

4. Chung EB, Enzinger FM. Benign lipoblastomatosis. An analysis of 35 cases. Cancer. 1973; 32: 482–492 .

5. Coffin CM, Lowichik A, Putnam A. Lipoblastoma: a clinicopathologic and immunohistochemical analysis of 59 cases. Am J Surg Pathol. 2009; 33: 1705–1712.

6. Coffin CM. Lipoblastoma: an embryonal tumor of soft tissue related to organogenesis. Semin Diagn Pathol. 1994; 11: 98–103.

7. Ende L, Upton J, Richkind KE, et al. Lipoblastoma: appreciation of an expanded spectrum of disease through cytogenetic analysis. Arch Pathol Lab Med. 2008; 132: 1442–1444.

8. Fallon SC, Brandt ML, Rodriguez JR, et al. Cytogenetic analysis in the diagnosis and management of lipoblastomas: results from a single institution. Journal of Surgical Research. 2013; 184: 341-346.

9. Fetsch JF, Miettinen M, Laskin WB, et al. A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis. Am J Surg Pathol. 2000; 24: 1491–1500.

10. Fletcher JA, Kozakewich HP, Schoenberg ML, et al. Cytogenetic findings in pediatric adipose tumors: consistent rearrangement of chromosome 8 in lipoblastoma. Genes Chromosomes Cancer. 1993; 6:24–29.

11. Gisselsson D, Hibbard MK, Dal Cin P, et al. PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms. Am J Pathol. 2001; 159: 955–962.

12. Hibbard MK, Kozakewich HP, Dal Cin P, et al. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res. 2000; 60: 4869–4872.

13. Kubota F, Matsuyama A, Shibuya R, Nakamoto M, and Hisaoka M. Desmin-positivity in spindle cells: Under-recognized immunophenotype of lipoblastoma. Pathology International. 2013; 63: 353–357.

14. Liu Q, Xu Z, Mao S, Zeng R, Chen W, et al. Perineal lipoblastoma: a case report and review of literature. Int J Clin Exp Pathol .2014; 7(6): 3370-3374.

15. Morerio C, Nozza P, Tassano E, et al. Differential diagnosis of lipoma-like lipoblastoma. Pediatric Blood Cancer. 2009; 1: 132–134.

16. O’Donnell KA, Caty MG, Allen JE, et al. Lipoblastoma: better termed infantile lipoma? Pediatr Surg Int. 2000; 16: 458–461.

17. Pedeutour F, Deville A, Steyaert H, et al. Rearrangement of HMGA2 in a case of infantile lipoblastoma without PLAG1 alteration. Pediatr Blood Cancer. 2012; 58: 798.

18. Van Meurs DP. The transformation of an embryonic lipoma to a common lipoma. Br J Surg. 1947; 34: 282–284.

19. Voz, M. L., Agten, N. S., Van de Ven, W. J., and Kas, K. PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res. 2000; 60: 106–113.

20. Vellios F, Baez J, Shumacker HB. LPBtosis: a tumor of fetal fat different from hibernoma; report of a case, with observations on the embryogenesis of human adipose tissue. Am J Pathol. 1958; 34: 1149–1159.

21. Warren M, Turpin BK, Mark M, Smolarek T, and Li X. Undifferentiated myxoid lipoblastoma with PLAG1–HAS2 fusion in an infant; morphologically mimicking primitive myxoid mesenchymal tumor of infancy (PMMTI)—diagnostic importance of cytogenetic and molecular testing and literature review. Cancer Genetics. 2016; 209: 21–29.

Case 02: Endocrine mucin producing sweat gland carcinoma with invasive mucinous carcinomaPresenter: Diana Oramas, MD; Attendings: Amy Lin, MD; John V. Groth, MD

Clinical HistoryA 77-year-old female presented with right madarosis and a right upper eyelid lesion for at least 8 months with rapid growth over the last 2 months. Physical examination showed an 8 x 8 mm lesion, well demarcated with telangectatic vessels. Past medical history is not contributory. Gross examination showed firm tan skin, with a tan homogeneous cut surface. Excisional biopsy was performed.

Diagnosis: Endocrine mucin producing sweat gland carcinoma (EMPSGC) with invasive mucinous carcinoma

Differential Diagnosis based on morphology and location: • Dermal duct tumor• Hidradenoma/carcinoma• Basal cell carcinoma• Sebaceous carcinoma• Cutaneous metastasis of solid papillary breast carcinoma

Key Microscopic Features: Multinodular lesion with a solid and cystic component Pseudorosettes, papillary structures, and hyalinized fibrovascular cores Tumor cells are medium sized, usually round to oval, with moderate eosinophilic cytoplasm, salt and

pepper chromatin, and inconspicuous nucleoli Rare intracytoplasmic vacuoles Extracellular pools of mucin

Immunohistochemical stains: Focally positive: Synaptophysin and chromogranin Diffusely positive: ER, PR, CEA, CK7, EMA

Special stain: Mucicarmine positive

Discussion: Rare low grade eccrine tumor with many of the histological and immunohistochemical features seen

in solid papillary carcinoma of the breast Predilection of the lower eyelids of elderly women Multiple solid and cystic nodules of varying sizes formed by a proliferation of medium sized

epithelial cells with neuroendocrine differentiation Pools of extracellular mucin are often present WT1 overexpression plays a role in tumor cell proliferation and progression

References:

1. Zembowicz A, Garcia CF, Tannous ZS, Mihm MC, Koerner F, Pilch BZ. Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas. Am J Surg Pathol. 2005; 29(10): 1330-1339.

2. Dhaliwal CA, Torgersen A, Ross JJ, Ironside JW, Biswas A. Endocrine mucin-producing sweat gland carcinoma: report of two cases of an under-recognized malignant neoplasm and review of the literature. Am J Dermatopathology. 2013; 35(1): 117-124.

3. Shon W, Salomão DR. WT1 expression in endocrine mucin producing sweat gland carcinoma: a‐ study of 13 cases. International journal of dermatology. 2014; 53(10): 1228-1234.

4. Brett MA, Salama S, Gohla G, Alowami S. Endocrine Mucin-Producing Sweat Gland Carcinoma, a Histological Challenge. Case Reports in Pathology. vol. 2017, Article ID 6343709, 4 pages, 2017.

Case 03: Hereditary Leiomyomatosis-Like Renal Cell Carcinoma (HLRCC)Presenter: Oluwatobi T. Adelaja MD; Attending: John V. Groth MD

Clinical History:A 66-year-old female with a history of hysterectomy for fibroids and breast cancer treated with resection and chemotherapy 23 years prior presents for evaluation for a right retroperitoneal mass. She reports weight loss, shortness of breath, rapidly enlarging abdominal girth, and leg edema. Imaging studies were significant for a right retroperitoneal mass with cystic and solid components, innumerable enhancing hepatic lesions, multiple pulmonary nodules, and a single 6 mm brain lesion, likely a metastasis, in the right frontal lobe. Palliative resection, including radical nephrectomy, was performed.

Diagnosis:Hereditary Leiomyomatosis-like Renal Cell Carcinoma (HLRCC)

Differential Diagnosis: Metastatic Breast Cancer Succinate Dehydrogenase Deficient Renal Cell Carcinoma Type II Papillary Renal Cell Carcinoma Xp11 Associated Renal Cell Carcinoma

Key Microscopic Features: The presence of large nuclei with very prominent orangeophilic or eosinophilic nucleoli, surrounded

by a clear halo in a renal neoplasm coupled with or without clinical history of leiomyoma should warrant suspicion

A mixture of architectural patterns including solid, papillary, tubular, and sarcomatoid

Immunohistochemical Stains: Positive: PAX-8, AE1/3, Melan-A, Cam5.2, CD10, CK5/6, Vimentin, CA-IX, P504S, SDHB, FH, 2-SC Negative: Myogenin, Desmin, CK20, MITF, S100, EMA, p63, CDX2, CD34, CK7, TTF1, CD45

Discussion: Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) described in patients with a

history of skin and/or uterine leiomyomata and renal cell carcinoma Syndrome is due to mutations in the fumarate hydratase gene, leading to an accumulation of

fumarate Renal cell carcinomas in these patients can have a variety of architectural patterns A distinguishing feature is the prominent eosinophilic nucleolar inclusion with a surrounding

perinucleolar halo Negative fumarate hydratase staining and diffuse nuclear and cytoplasmic positive staining for S-(2-

succino)-cysteine is a useful ancillary test Definitive diagnosis is made with genetic testing for loss of heterozygosity of the fumarate hydratase

gene on 1q42.3-q43

References:

1. Merino MJ, Torres-Cabala C, et al. The morphologic spectrum of kidney tumor in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007; 31: 1578-1585.

2. Delahunt B and Srigley JR. The evolving classification of renal cell neoplasia. Semin Diagn Pathol .2015; 32: 90-102.

3. Kiuru M, Launonen V, et al. Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J Pathol. 2001; 159: 825-829.

4. Chen YB, Brannon AR, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associate renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Pathol .2014; 38: 627-637.

5. Linehan WM, Ricketts CJ. The metabolic basis of kidney cancer. Semin Cancer Biol. 2013; 23: 46-55.

6. Takahashi M, Kahnoski R, et al. Familial adult renal neoplasia. J Med Genet. 2002; 39: 1-57. Linehan WM, Srinivasan R, et al. The genetic basis of kidney cancer: a metabolic disease. Nat Rev

Urol .2010; 7: 277-2858. Bodmer D, van der Hurk W, et al. Understanding familial and non-familial renal cell cancer. Hum

Mol Genet. 2002; 11: 2489-2498.9. Launonen V, Vierimaa O, et al. Inherited susceptibility to uterine leiomyomas and renal cell

cancer. Proc Natl Acad Sci. 2001; 98: 3387-3392.10. Tomlinson IP, Alam NA, et al. Germline mutation in FH predispose to dominantly inherited

uterine fibroids, skin leiomyomatosis and papillary renal cell cancer. Nat Genet. 2002; 30: 406-410.

11. Linehan WM, Rouaualt TA. Molecular Pathways: fumarate hydratase-deficient kidney cancer—targeting the Warburg effect in cancer. Clin Can Res. 2013; 19: 3345-3352.

12. San-Ortega J, Vocke C, et al. Morphologic and molecular characteristics of uterine leiomyoma in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2013; 37: 74-80.

13. Van Heiden MG, Cantley LC, et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324: 1029-1033.

14. Xia Q, Wang XT, Zhan XM, et al. Xp11 Translocation Renal Cell Carcinomas (RCCs) With RBM10-TFE3 Gene Fusion Demonstrating Melanotic Features and Overlapping Morphology With t(6;11) RCC: Interest and Diagnostic Pitfall in Detecting a Paracentric Inversion of TFE3. Am J Surg Pathol. 2017;41:663–676.

15. Williamson SR, Eble JN, Amin MB, et al. Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma. Modern Pathology. 2015;28, 80–94.

16. Reed WB, Walker R, Horowitz R. Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973; 53: 409–416.

17. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–410.

18. Trpkov K, Hes O, Agaimy A, et al. Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome. Am J Surg Pathol. 2016;40:865–875.

Case 04: Low-grade endometrial carcinoma (microglandular hyperplasia-like type)Presenter: Osama Elfituri, MD; Attendings: Amy Lin, MD and John V. Groth, MD

Clinical HistoryA 37-year-old woman with an obstetric history of six pregnancies, including five miscarriages and one living delivery, presented with abdominal pain and vaginal bleeding. She was currently pregnant (estimated to be at six weeks gestational age), preceded by ovarian induction therapy with clomiphene citrate. Complete abortion was diagnosed and dilatation and curettage was performed.

Diagnosis:Low grade endometrial carcinoma, microglandular hyperplasia-like type

Differential diagnosis: Exogenous hormonal effect eg. Clomiphene citrate Pregnancy related changes eg. Arias Stella reaction Microglandular hyperplasia of cervix Complex atypical endometrial hyperplasia

Key Microscopic Features: Complex architecture with secondary branching > 3 mm in greatest dimension Marked well-developed cribriforming Cytologic atypia Exophytic micropapillae

Immunohistochemical stains: Ki-67 labeling index of 40-50%

Discussion: Rare type of endometrial adenocarcinoma that presents in a plaque-like proliferation More mature and less aggressive than conventional endometrial adenocarcinoma Cancers associated with pregnancy are typically limited to a small focus and are well-differentiated Increased progesterone in pregnancy induces changes on the endometrium and endometrial

adenocarcinomas in pregnancy can exhibit a variety of unusual alterations

References:

1. Karateke A, Haliloglu B, Atay V, Gurbuz A, Kir G. A case of microglandular adenocarcinoma of the endometrium. Gynecol Oncol. 2005;99(3):778-81.

2. Zamecnik M, Skalova A, Opatrny V. Microglandular adenocarcinoma of the uterus mimicking microglandular cervical hyperplasia. Annals of Diagnostic Pathology. 2003;7(3):180-186

3. Ayhan A, Gunlap S, Karaer C, Gokoz A, Oz U. Endometrial Adenocarcinoma in Pregnancy. Gynecol Oncol. 1999;75(2):298-9.

4. Vaccarello L, Apte SM, Copeland LJ, Boutselis JG, Rubin SC. . Endometrial Carcinoma Associated with Pregnancy: A Report Of Three Cases and Review of the Literature. Gynecol Oncol. 1999;74(1):118-22.

5. Wheeler DT, Bristow RE, Kurman RJ. Histologic Alterations in Endometrial Hyperplasia and Well-differentiated Carcinoma Treated With Progestin. Am J Surg Pathol. 2007;31(7):988-98.

6. McKenney JK, Longacre TA. Low-grade Endometrial Adenocarcinoma. A Diagnostic Algorithm for Distinguishing Atypical Endometrial Hyperplasia and Other Benign (and Malignant) Mimics, Adv Anat Pathol. 2009;16(1):1-22.

7. Mittal K, Salem A, Lo A. Diagnostic criteria for distinguishing endometrial adenocarcinoma from complex atypical endometrial hyperplasia. Hum Pathol. 2013;45(1):98-103.

8. Kurman RJ, Norris HJ. Evaluation of criteria for distinguishing atypical endometrial hyperplasia from well-differentiated carcinoma. Cancer. 1982;49(12):2547-59.

9. Medeiros F, Bell DA. Pseudoneoplastic lesions of the female genital tract. Arch Pathol Lab Med. 2010;134(3):393-403.

10. Thatcher SS, Donachie KM, Glasier A, Hillier SG, Baird DT. The effects of clomiphene citrate on the histology of human endometrium in regularly cycling women undergoing in vitro fertilization. Fertil Steril. 1988;49:296–301 .

Case 05: Adenomatous Hyperplastic Nephrogenic RestPresenter: Julia Rewerska, MD; Attending: Michael Pins, MD

Clinical History: A 4-year-old boy presents with an incidental finding of a right renal mass on imaging for evaluation of tuberous sclerosis, diagnosed two years prior. As the patient matured, the accuracy of the diagnosis was questioned and further evaluations were performed; including an MRI of the abdomen revealing a round, well-localized, heterogeneous mass that appeared inseparable from the surrounding renal parenchyma at the inferior pole. The patient underwent a partial nephrectomy that was submitted for histopathologic evaluation. Serial sectioning revealed a 2 cm, encapsulated yellow-white-gray, slightly nodular, solid lesion.

Final Diagnosis: Adenomatous Hyperplastic Nephrogenic Rest

Differential Diagnosis: Papillary Renal Cell Carcinoma Metanephric adenoma Nephroblastoma (Wilms’ tumor)

Key Microscopic Features: Well circumscribed mass with irregular nests surrounded by a pseudocapsule Tubules and lobules with a papillary appearance Cells with pale eosinophilic cytoplasm, bland nuclei, and small nucleoli

Immunohistochemical Stains: Positive: WT1, CD57 (patchy) Negative: AMACAR, CD7

Molecular Studies: Negative for BRAF V600E mutation

Discussion: Differentiating between an atypical nephrogenic rest and nephroblastoma can pose a diagnostic

challenge The maturation of nephrogenic rests is a waxing and waning process which increases the

likelihood of further mutations in susceptible cells Nephroblastoma is a neoplastic process originating from a single rest cell producing a spherical

expanding nodule within the originating rest Whereas pure hyperplastic rests are composed of embryonal cells with high mitotic activity

indistinguishable from nephroblastoma, adenomatous hyperplastic rests have more mature cells with eosinophillic cytoplasm, and less mitotically active appearance

References:1. Udager AM, Pan J, Magers MJ, et al. Molecular and immunohistochemical characterization

reveals novel BRAF mutations in metanephric adenoma. Am J Surg Pathol. 2015; 39(4): 549-57

2. Cardoso LC, DeSouza KR, Reis AH, et al. WT1, WTX and CTNNB1 mutation analysis in 43 patients with sporadic Wilms' tumor. Oncology Reports. 2013; 29: 315-320

3. Murphy WM, Beckwith JB, Farrow GM. Tumors of the Kidney, Bladder, and Related Urinary Structures. Armed Forces Institute of Pathology. Washington D.C; 2001 Pages 1-52.

4. Chang, A. Wilms Tumor vs. Nephrogenic Rests. BasicMedicalKey.com website. http://basicmedicalkey.com/kidney-3/. Accessed March 2, 2017.

5. Holcomb G, Murphy J, Ostlie D, et al. Renal Tumors. In: Ehrlich PF, Shamberger RC. Ashcraft's pediatric surgery. 6th ed. London: Saunders Elsevier; 2014 pages 859-882.

6. Beckwith BJ. Precursor Lesions of Wilms Tumor: Clinical and Biological Implications. Medical and Pediatric Oncology. 1993; 21: 158-168

7. Mills S, Sternberg S. Renal Neoplasms in Childhood. In: Pedram A, Beckwith BJ. Sternberg's diagnostic surgical pathology. 6th ed. Philadelphia, PA: Lippincott Williams et Wilkins; 2015; Pages 2018-2048

8. Al-Hussein T, Ali A, Akhtar M. Wilms Tumor: An Update. Advances in anatomic pathology 21(3): 166-73 · May 2014. Web. March 4, 2017.

9. Charles AK, Brown KW, Berry J. Microdissecting the Genetic Events in Nephrogenic Rests and Wilms’ tumor Development. American Journal of Pathology. 1998;153(3): 991-1000.

10. Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder, and Related Urinary Structures. Armed Forces Institute of Pathology. Washington D.C; 2004 Pages 1-46.

11. Papillary type, renal cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneytumormalignantrccpap.html. Accessed March 6th, 2017.

12. Papillary type, renal cell carcinoma. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneytumormalignantrccpap.html. Accessed March 6th, 2017.

Case 06: Angiofibroma of soft tissuePresenter: Haoliang Xu, MD; Attendings: Steven A Garzon MD and John Groth, MD

Clinical History: A 67-year-old woman was referred to our institution for consultation due to a mass on the right thigh for approximately 4 years. MRI scan performed at outside hospital showed a 5.4 cm, multiseptated soft tissue mass involving the right sartorius muscle. She denied recent change in size of the lesion and any associated pain. Physical examination showed a 5 cm to 6 cm mass within the sartorius muscle on the anterior medial aspect of the right thigh. No cervical, axillary, or inguinal adenopathy was identified. Core needle biopsy of the mass revealed a spindle cell lipomatous lesion concerning for possible sarcoma. A radical mass excision was performed, and the surgical specimen was submitted for histopathological evaluation. Serial sections of the lesion revealed a 7.9 x 4.1 x 3.5 cm, well-demarcated, yellow-tan to red-brown heterogeneous intramuscular mass.

Diagnosis: Angiofibroma of soft tissue

Differential diagnosis: Low-Grade Fibromyxoid Sarcoma Myxoid Liposarcoma Low Grade Myxofibrosarcoma Solitary Fibrous Tumor

Key Microscopic Features: Well circumscribed lesion encapsulated by fibrous tissue Bland uniform spindled cells in myxoid and collagenous stroma with rare mitoses Very prominent thin-walled vessels in stroma Variable perivascular hyalinization or fibrosis Focal stromal chronic inflammatory infiltrate presents

Immunohistochemical stains: Positive: p16, Ki67 (focal), Desmin (focal) Negative: SMA, CAM 5.2, CD34, and S100

Cytogenetic studies: Positive: rearrangement of the NOCA2 (8q13.3) gene locus Negative: rearrangement of the USP6 (17q13) gene locus

Discussion:• Fibrovascular soft tissue tumor that pursues a benign clinical course, with rare local recurrences

and no evident metastatic potential• Most cases have a balanced translocation of t(5;8)(p15.1;q13) with AHHR-NCOA2 fusion • Awareness of the unique histopathologic and genetic features of angiofibroma of soft tissue is

especially important to avoid misdiagnosing it as a more aggressive malignant tumor

References:1. Rizzo M A, Lauer SR, Bridge JA, Rizzo M. Soft Tissue angiofibroma: report of 2 cases of a recently

described tumor. Human Pathology. 2013;44:438-441.2. Marino-Enriquez A, Fltecher CD. Angiofibroma of soft tissue: clinicopathologic characterization

of a distinctive benign fibrovascular neoplasm in a series of 37 cases. Am J Surg Pathol. 2012; 36(4):500-8.

3. Yamada Y, Yamamoto H, Kohashi K, et al. Histological spectrum of angiofibroma of soft tissue:histological and genetic analysis of 13 cases. Histopathology. 2016;69(3):459-69.

4. Schoolmeester JK, Sukov WR, Aubry MC, Folpe AL: Angiofibroma of Soft Tissue: Core Needle Biopsy Diagnosis, With Cytogenetic Confirmation. Am J Surg Pathol. 2012;36(9):1421-3.

5. Zhao M, Sun K, Li C, Zheng J, Yu J, Jin J, et al. Angiofibroma of soft tissue: clinicopathologic study of 2 cases of a recently characterized benign soft tissue tumor. Int J Clin Exp Pathol. 2013;6(10): 2208-2215.

Case 07: PAX-8 Positive Pediatric Malignant Mesothelioma Presenter: David Loeffler, DO; Attending: John Groth, MD

Clinical HistoryA 16-year-old female presented to an outside hospital Emergency Room with severe left lower quadrant pain. A CT scan was performed and demonstrated a 17 cm adnexal mass. Exploratory laparotomy was performed showing diffuse intraperitoneal disease. A biopsy was performed, our institution was consulted, and subsequent resection was performed.

Diagnosis: Pediatric Malignant Mesothelioma

Differential Diagnosis: • Serous Carcinoma• Well-differentiated papillary mesothelioma

Key Microscopic Features: Papillary or tubular pattern Single layer of mesothelial cells Fibrovascular cores with hyalinized stroma Mild to variable nuclear atypia Conspicuous eosinophilic cytoplasm

Immunohistochemical stains: Positive: Calretinin, PAX-8, WT-1, D2-40, CA125, CK7, CAM5.2, p16, p53, CK5/6 (focal), EMA (focal) Negative: CD15, MOC31, Monoclonal CEA, CK20, Inhibin, PR, ER, BerEP4

Electron Microscopy: Wavy apical villi ten times longer than they are wide Intracytoplasmic vacuoles with villi Microvilli within cellular tight junctions

Molecular Studies: TMP1-ALK fusion

Discussion: Calretinin and PAX-8 do not reliably differentiate between serous carcinoma and peritoneal

malignant mesothelioma in pediatric patients Electron microscopy may be needed to definitively differentiate between serous carcinoma and

peritoneal malignant mesothelioma Pediatric peritoneal malignant mesotheliomas may harbor an ALK translocation that could be used

for targeted therapy

References:

1. Bollinger, DJ; Wick, MR; Dehner, LP; Mills, SE; Swanson, PE; Clarke RE. Peritoneal malignant mesothelioma versus serous papillary adenocarcinoma. A histochemical and immunohistochemical comparison. Am J Surg Pathol. 1989;13(8): 659-70.

2. Vang, R; Shih, L; Kurman, RJ. OVARIAN LOW-GRADE AND HIGH-GRADE SEROUS CARCINOMA: Pathogenesis, Clinicopathologic and Molecular Biologic Features, and Diagnostic Problems. Adv Anat Pathol. 2009; 16(5): 267–282.

3. Movahedi-Lankarani, S; Kurman, RJ. Calretinin, a more sensitive but less specific marker than alpha-inhibin for ovarian sex cord-stromal neoplasms: an immunohistochemical study of 215 cases. Am J Surg Pathol. 2002;26(11): 1477-83.

4. Comin, CE; Saieva, C; Messerini, L. h-caldesmon, calretinin, estrogen receptor, and Ber-EP4: a useful combination of immunohistochemical markers for differentiating epithelioid peritoneal mesothelioma from serous papillary carcinoma of the ovary. Am J Surg Pathol. 2007;31(8): 1139-48.

5. Ordonez, NG. The diagnostic utility of immunohistochemistry and electron microscopy in distinguishing between peritoneal mesotheliomas and serous carcinomas: a comparative study. Mod Pathol. 2006;19(1): 34-48.

6. Laury, AR; Hornick, JL; Perets, R; Krane, JF; Corson, J; Drapkin, R; Hirsch, MS. PAX8 reliably distinguishes ovarian serous tumors from malignant mesothelioma. Am J Surg Pathol. 2010; 34(5): 627-35.

7. Ordonex, NG. Value of PAX8, PAX2, claudin-4, and h-caldesmon immunostaining in distinguishing peritoneal epithelioid mesotheliomas from serous carcinomas. Mod Pathol. 2013; 26(4): 553-62.

8. Wang, Y; Wang, Y; Li, J; Yuan, Z; Yuan, B; Zhang, T; Cragun, JM; Kong, B; Zheng, W. PAX8: a sensitive and specific marker to identify cancer cells of ovarian origin for patients prior to neoadjuvant chemotherapy. J Hematol Oncol. 2013;19(6):

9. Baker, PM; Clement, PB; Young, RH. Malignant peritoneal mesothelioma in women: a study of 75 cases with emphasis on their morphologic spectrum and differential diagnosis. Am J Clin Pathol. 2005;123(5):724-37.

10. Moran, CA; Albores-Saavedra, J; Suster, S. Primary peritoneal mesotheliomas in children: a clinicopathological and immunohistochemical study of eight cases. Histopathology. 2008; 52(7): 824-30.

11. Bowen, NJ; Logani, S; Dickerson, EB; Kapa, LB; Akhtar, M; Benigno, BB; McDonald; JF. Emerging roles for PAX8 in ovarian cancer and endosalpingeal development. Gynecol Oncol. 2007; 104(2): 331-7.

12. Banet, N; Kurman, RJ; Two types of ovarian cortical inclusion cysts: proposed origin and possible role in ovarian serous carcinogenesis. Int J Gynecol Pathol 2015;34(1): 3-8.

13. Varesano, S; Leo, C; Boccardo, S; Salvi, S; Truini, M; Ferro, P; Fedeli, F; Canessa, PA; Dessanti, P; Pistillo, MP; Roncella, S. Status of Anaplastic Lymphoma Kinase (ALK) in malignant mesothelioma. Anticancer Res.2014;34(5): 2589-92.

14. Loharamtaweethong, K; Puripat, N; Aoonjai, N; Sutepavarnon, A; Bandidwattanawong, C. Anaplastic lymphoma kinase (ALK) translocation in paediatric malignant peritoneal mesothelioma: a case report of novel ALK-related tumour spectrum. Histopathology. 2016;68(4):603-7.

15. Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28:496–504 .