Illinois Registry of Anatomic Pathology

April 16, 2018

University of Wisconsin-Madison

CASE #1

Presenter: Michelle Stoffel, MD, PhD, PGY3

Attending: Christopher Flynn, MD, PhD

Clinical History: The patient is a 56-year-old woman with a history of multiple colonic polypsstatus post colectomy who presented with increasing abdominal pain. The clinical impression was of umbilical herniation associated with a prior procedure, and pelvicimaging was performed. Bilateral ovarian masses were found, and total abdominalhysterectomy with bilateral salpingo-oophorectomy was performed.

Final Diagnosis: Ovarian microcystic stromal tumor (MCST)

Differential Diagnosis

•Thecoma

•Granulosa cell tumor

•Steroid cell tumor

•Sertoli-Leydig tumor

•Microcystic stromal tumor

•Brenner tumor

•Carcinoma, primary or metastatic to ovary

Key Clinical, Morphologic and Immunohistochemical Features

•Clinical

•Presents in young to middle-aged women

•Usually unilateral

•Seldom associated with hormonal symptoms

•Benign course

•Morphologic

•Microcystic pattern and regions with lobulated cellular masses with intervening, sometimes hyalinized fibrous stroma

•Absence of morphologic features specific for any other entity in the sex cord-stromal category

•Absence of epithelial elements

•Absence of teratomatous or other germ cell elements

•Immunohistochemical

•Negative for keratins, calretinin, and inhibin

•Positive for CD10, beta-catenin (nuclear expression), and Cyclin D1

Discussion

•Ovarian microcystic stromal tumor is a rare ovarian tumor

•Usually presents as a unilateral adnexal mass in absence of hormonal features

•Most cases unassociated with other malignancy

•Benign course, surgery is curative

•Pathophysiology is driven by beta-catenin dysfunction

•Most cases harbor somatic CTNNB1 mutations

•Rarely has been associated with familial adenomatous polyposis (APC mutation)

•Should be in the differential when sex-cord stromal morphology with negative inhibin and calretinin immunoreactivity is encountered

References

  1. Irving JA, Young RH. Microcystic stromal tumor of the ovary: report of 16 cases of a hitherto uncharacterized distinctive ovarian neoplasm. Am. J. Surg. Pathol. 2009;33:367–375. doi:10.1097/PAS.0b013e31818479c3.
  2. Irving JA, Lee C-H, Yip S, et al. Microcystic Stromal Tumor: A Distinctive Ovarian Sex Cord-Stromal Neoplasm Characterized by FOXL2, SF-1, WT-1, Cyclin D1, and β-catenin Nuclear Expression and CTNNB1 Mutations. Am. J. Surg. Pathol. 2015;39:1420–1426. doi:10.1097/PAS.0000000000000482.
  3. Lee SH, Koh YW, Roh HJ, et al. Ovarian microcystic stromal tumor: A novel extracolonic tumor in familial adenomatous polyposis. Genes. Chromosomes Cancer 2015;54:353–360. doi:10.1002/gcc.22233.
  4. Liu C, Gallagher RL, Price GR, et al. Ovarian Microcystic Stromal Tumor: A Rare Clinical Manifestation of Familial Adenomatous Polyposis. Int. J. Gynecol. Pathol. Off. J. Int. Soc. Gynecol. Pathol. 2016. doi:10.1097/PGP.0000000000000289

CASE #2

Presenter: Alain Cagaanan, DO, PGY2

Attending: Rong Hu, MD, PhD

Clinical History: The patient is a 55-year-old woman with a history of multiple sclerosis who presented with left floor of the mouth (FOM) fullness that was observed by her dentist. Intraoral physical exam revealed healthy-appearing mucosa throughout and firmness upon palpation in the left FOM. A CT scan showed a vague soft tissue mass obliterating fat planes between the extrinsic tongue musculature. The patient underwent three incisional biopsies without definitive diagnosis despite extensive internal and external pathology consultation. The tumor resection was performed. A representative section of the resection specimen is provided for review.

Final Diagnosis: Sclerosing Microcystic Adenocarcinoma of Mucosa

Differential Diagnosis

  • Squamous cell carcinoma
  • Salivary gland tumors (polymorphous low grade adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma)
  • Inflammatory etiologies, e.g. sclerosing chronic sialadenitis

Key Clinical, Morphologic and Immunohistochemical Features

  • Histology
  • Histologically resembles cutaneous microcystic adnexal carcinoma (MAC)
  • Relatively paucicellular with predominant stroma component ranging from densely collagenized stroma to basophilic desmoplasia
  • Widely infiltrative ducts and strands of cell nests with minimal cytological atypia
  • Microcystic spaces with eosinophilic secretions
  • Focal perineural invasion
  • Immunohistochemical Stains
  • Positive: myoepithelial markers (CK5/6, S100, p63, SMA), broad spectrum and high molecular weight cytokeratins
  • Negative: CD117 (c-KIT), which can be positive in the differential diagnostic consideration of adenoid cystic carcinoma
  • Reproducible genetic anomalies
  • Unknown, unlike some salivary gland tumors

Discussion

  • Sclerosing microcystic adenocarcinoma closely resembles MAC in skin morphologically, but occurs in the head and neck mucosa
  • A rare tumor, with few case reports and case series in the literature
  • Histologic diagnosis of this entity is difficult, especially in small incisional biopsies; margin assessment is challenging
  • Pathogenesis is not well understood, etiology unclear in the head and neck mucosa
  • Potential relationship to MAC of skin, but there are no adnexal structures in oral mucosa
  • Hypothesized to originate from a multipotent stem cell or von Ebner glands
  • Possible relationship to immunosuppression
  • Limited follow-up data to date, but appears to behave in an indolent fashion with good prognosis

References

  1. Goldstein DJ et al. Microcystic adnexal carcinoma: a distinct clinicopathologic entity. Cancer. 1982;50(3):566-72.
  2. Mills AM, et al. Sclerosing microcystic adenocarcinoma of the head and neck mucosa: a neoplasm closely resembling microcystic adnexal carcinoma. Head and Neck Pathol (2016) 10:501-508.
  3. Mino M, et al. Expression of KIT (CD117) in neoplasms of the head and neck: an ancillary marker for adenoid cystic carcinoma. Mod Pathol. 2003 Dec; 16(12):1224-31.
  4. Weinreb I. Translocation-associated salivary gland tumors: a review and update. AdvAnatPathol. 2013;20(6):367-77.

CASE #3

Presenter: Damodaran Narayanan, MBBS, PhD, PGY1

Attending: Ricardo Lloyd, MD, PhD

Clinical History: The patient is an 84-year-old woman who presented with four months of difficulty swallowing, reduced food intake and weight loss. CT scan of the neck revealed a heterogeneously enhancing 4.4 cm mass in the left thyroid lobe that was inseparable from the cervical esophagus. There were also prominent, centrally necrotic neck Iymph nodes. FNA of the left thyroid lobe demonstrated malignancy. A representative section of the subsequent thyroidectomy with laryngopharyngectomy and bilateral selective neck dissection is provided for review.

Final Diagnosis: Papillary thyroid carcinoma, hobnail variant

Differential Diagnosis

  • Tall cell variant of papillary thyroid carcinoma
  • Columnar cell variant of papillary thyroid carcinoma
  • Extension to the thyroid gland of squamous cell carcinoma of head and neck
  • Metastatic carcinoma to the thyroid gland

Key Microscopic Features

  • Papillary and micropapillary architecture
  • ≥30% of tumor cells exhibit hobnail features (apical placed nucleus with bulging of cells) with loss of polarity or cohesiveness
  • ≤10% of tumor cells are tall, columnar, or diffuse sclerosing
  • Eosinophilic, finely granular cytoplasm
  • Areas of dedifferentiation with squamoid and/or spindle cells can be seen
  • Necrotic foci, High mitotic rate
  • Lymphovascular invasion and extrathyroidal extension

Immunohistochemical Stains

  • Positive: TTF-1, Thyroglobulin, HBME-1, BRAF, p53, CK7, CK19, EMA, Cyclin D1
  • Negative: Anti-mitochondria

Molecular Mutations

  • BRAF V600E (most common)
  • TP53, TERT promoter, RET/PTC1 rearrangement

Discussion

  • Hobnail variant of papillary thyroid carcinoma is a rare, aggressive variant
  • ≥30% of tumor cells exhibit hobnail features (apical placed nucleus with bulging of cells) with loss of polarity or cohesiveness.
  • Can be associated with or show transformation to undifferentiated carcinoma
  • Associated with characteristic BRAF V600E and p53 mutations
  • Strongly associated with aggressive clinicopathologic features, radioactive iodine refractoriness, disease progression, and a higher mortality rate compared to classic PTC.

References

1.Amacher et al. Am J SurgPathol 2015; 39: 260–265

2.Ambrosi et al. EndocrPathol 2017; 28: 293–301

3.Asioli et al. Am J SurgPathol 2010; 34: 44–52

4.Asioli et al. DiagnCytopathol 2014; 42: 78–84

5.Baloch et al. Histopathology 2018; 72: 40–52

6.Hardin et al. Am J Pathol. 2014; 184(8): 2342–2354

7.Lee et al. Int J ClinExpPathol 2015; 8(7): 7988-7997

8.Lilo et al. Diagn Cytopathology. 2017; 45: 754–756

9.Montemayor-Garcia et al. Mod Pathol. 2014; 27(s2): A632.

10.Teng et al. Oncotarget. 2017; 8(13): 22023-22033

11.Watutantrige-Fernando et al. Thyroid. 2018

CASE #4

Presenter: Daniel Forsythe, DO, PGY1

Attending: Paul Weisman, MD

Clinical History: The patient is a 41-year-old female with extremely heavy vaginal bleeding who presented to the emergency department. Imaging showed a 7.6 cm mass with no evidence of lymphadenopathy. Biopsy of the mass showed superficial fragments of cervical mucosa with an atypical spindle cellproliferation. A representative section from the subsequent hysterectomy is provided for review.

Final Diagnosis: Mucosal spindle cell malignant melanoma

Differential Diagnosis

  • Mucosal spindle cell malignant melanoma
  • Malignant peripheral nerve sheath tumor (MPNST)
  • Embryonal/spindle rhabdomyosarcoma
  • Sarcomatoid carcinoma
  • Myxoid leiomyosarcoma
  • Myoepithelial carcinoma

Key Morphologic and Immunohistochemical Features

  • Malignant spindle cell proliferation with alternating hypercellular and hypocellular areas and numerous mitoses
  • Negative stains: Myogenin, desmin, AE1/AE3, smooth muscle actin, caldesmon, p63, GFAP
  • Positive stains: S100 and Sox10 (both with strong, diffuse expression), H3K27me3

Discussion

  • Malignant melanoma of the gynecological tract is a rare disease (2% of all melanomas)
  • The morphology of mucosal melanomas is unpredictable
  • Most pertinent to our case is its propensity to mimic malignant peripheral nerve sheath tumor (MPNST)
  • Malignant peripheral nerve sheath tumor (MPNST) is also rare (4% of all sarcomas); even more rare in the gynecologic tract
  • Approximately 50% of MPNSTs arise in patients with type 1 neurofibromatosis (NF1), 10% secondary to prior radiotherapy, and 40% are sporadic
  • Sporadic MPNSTs remain a diagnostic challenge due to the lack of specific IHC and molecular markers and their morphologic and immunophenotypic overlap with spindle cell melanomas
  • Commonality between MPNST and melanoma can be attributed to common neuroectodermal histogenesis
  • Both melanocytes and Schwann cells originate from the neural crest
  • Key IHC characteristics
  • Spindle cell melanoma: Strong diffuse S100 and Sox10 positivity
  • MPNST: Focal, weak S100 positivity and moderate to strong Sox10 positivity that usually is not diffuse
  • Over 90% of sporadic MPNSTs show loss of H3K27me3

References

1.Brown et al. Sarcomatoid carcinoma of the cervix. Gynecologic Oncology. 2003; 90(1): 23 – 28

2.Choi et al. Myoepithelial Carcinoma of Soft Tissue: A Case Report and Review of the Literature. Korean J Pathol. 2014 Dec; 48(6): 413-417.

3.Kaya et al. Myxoid leiomyosarcoma of the cervix: A case report.Journal of Obstetrics and Gynaecology,36:8,989-991

4.Kriseman et al. Rhabdomyosarcoma of the Cervix in Adult Women and Younger Patients.GynecolOncol. 2012 Sep; 126(3): 351-356.

5.Nitzan et al. Neural crest and Schwann cell progenitor-derived melanocytes are two spatially segregated populations similarly regulated by Foxd3. Proc Natl AcadSci USA. 2013 Jul 30; 110(31): 127709-12714

6.Prieto-Granada et al. Loss of H3K27me3 Expression Is a Highly Sensitive Marker for Sporadic and Radiation-induced MPNST.Am J SurgPathol. 2016 April; 40(4): 479-489.

7.Pusceddu et al. Primary Uterine CervixMelanoma Resembling Malignant peripheral Nerve Sheath Tumor: A Case Report.Int J GynecolPathol. 2008;27(4):596-600.

CASE #5

Presenter: Byron Barksdale, MD, PGY1

Attending: Rao Watson, MD

Clinical History: The patient is a 66-year-old man with hypertension and aortic stenosis who underwent ultrasound screening for an abdominal aortic aneurysm, in which a 3.9 cm irregular hypoechoic mass was incidentally discovered in the liver. A followup MRI scan revealed a 4 cm indeterminate lesion within the left lobe of the liver without overt signs of cirrhosis. A left hepatectomy was performed and gross examination revealed a firm white-tan mass that appeared to abut the capsule and grossly involved the vasculature. A representative section is provided for review.

Final Diagnosis: Lymphoepithelioma-like variant of cholangiocarcinoma (LEC-ICC)

Differential Diagnosis

  • Cholangiocarcinoma, including: lymphoepithelioma-like variant (LEC), poorly differentiated, and sarcomatoid
  • Hepatocellular carcinoma, including: LEC variant, poorly differentiated, and undifferentiated
  • Two discrete primary carcinomas
  • Metastatic carcinoma

Key Morphologic and Immunohistochemical Features

•Two distinct morphologic patterns with a gland-forming adenocarcinoma and a poorly differentiated component characterized by small nests and single tumor cells within a co-existing dense background of benign lymphocytes and plasma cells

•Tumor cells within the poorly differentiated areas have vesicular chromatin, prominent nucleoli and syncytial cytoplasm.

•Both components are CK7 and CK19 positive and negative for hepatocellular markers.

•EBV is implicated in the majority of cases and most are positive for EBER.

Discussion

  • Though cases of LEC-ICC are rare, they represent a distinct group of tumors that carry an excellent prognosis compared to conventional cholangiocarcinoma.
  • They generally arise in patients with chronic hepatitis, are more common in women and are frequently associated with EBV.
  • Multiple features can be helpful to identify and diagnose LEC-ICC:
  • Abundant tumor infiltrating lymphocytes present within the background of a poorly differentiated tumor.
  • Morphologic evidence of gland formation in combination with CK7 and CK19 positivity supports biliary origin.
  • EBER can be helpful if positive, but is seen in approximately 75% of cases.
  • The molecular characteristics of EBV driven carcinomas have yet to be elucidated fully, but it appears that latent membrane protein-1 (LMP1) alters expression of DNA-methyl transferase 1 (DNMT1) through the JNK-pathway resulting in hypermethylation of CpG islands.
  • Conventional cholangiocarcinomas also demonstrates hypermethylation of CpG islands but in LEC-ICC the level of hypermethylation more closely resembles that of nasopharyngeal carcinoma than conventional cholangiocarcinoma.

References

  1. Labgaa et al. Lymphoepithelioma-Like Carcinoma in Liver. American Journal of Pathology. Vol 187, No 7, July 2017.
  2. Solinas et al. Lessons from rare tumors: Hepatic lymphoepithelioma-like carcinomas. World Journal of Gastroenterology. Vol 21, No 12, March 28, 2015.
  3. Chan et al. Epstein Barr virus-associated lymphoepithelioma-like cholangiocarcinoma: a rare varient of intrahepatic cholangiocarcinoma with favorable outcome. Histopathology. Vol 65, No 5, May 7, 2014
  4. Tsai et al. Activation of DNA Methyltransferase 1 by EBV LMP1 involves c-Jun NH2-terminal kinase signaling. Cancer Research. Vol 66, No 24, December 15, 2006
  5. Kwong et al. Epigenetic Silencing of Cellular Retinol-Binding Proteins in Nasopharyngeal Carcinoma. Neoplasia. Vol 7, No 1, January 2005.
  6. Sun et al. Long-term outcomes of intensity-modulated radiotherapy for 868 patients with nasopharyngeal carcinoma: an analysis of survival and treatment toxicities. Radiotherapy and oncology. Vol 110. No 3. 2014

CASE #6

Presenter: S. Krisztian Kovacs, MD, PGY2

Attending: Darya Buehler, MD

Clinical History: The patient is a 31-year-old man who presented with left knee pain and difficulty walking and weight-bearing for approximately 6 month, without an inciting incident. Imaging studies showed a permeative mass in the distal femoral diaphysis with erosion of the posterior cortex and extension into the soft tissue, and a separate soft tissue nodule. Internal densities suggestive of osteoid matrix were present. A core needle biopsy of the femoral mass revealed a cellular, bone-forming epithelioid neoplasm interpreted as conventional high-grade osteosarcoma. After completion of neoadjuvant chemotherapy, a radical resection of the left distal femur was performed. A representative section of the lesion is provided for review.

Final Diagnosis: Primary sclerosing epithelioid fibrosarcoma of the bone

Differential Diagnosis

  • Osteosarcoma of bone

Key Morphologic and Immunohistochemical Features

  • Small, mildly atypical epithelioid cells growing in cords, nests and sheets in a dense collagenous matrix
  • Short, cytologically spindle cellsin a vaguely fascicular or storiform pattern in a fibromyxoid stroma, reminiscent of low grade fibromyxoid sarcoma (LGFMS)
  • MUC4 diffusely positive in both components
  • Dystrophic calcifications and metaplastic ossification can occur
  • However, this case showed true lace-like osteoid matrix suggestive of true osteoblastic differentiation, which resembled osteosarcoma to a tee
  • Genetic testing for EWSR1 and FUS gene rearrangements:the tumor cells were positive for EWSR1gene rearrangement
  • Minimal response to chemotherapy

Discussion

  • Sclerosing epithelioid fibrosarcoma (SEF) is a rare aggressive sarcoma
  • It usually presents as a deep soft tissue mass involving or the torso but it may occur in subcutis or in unusual locations like head and neck
  • SEF arising in bone is very rare, with only a handful of case reports and a series of 8 cases in the literature
  • A few series have demonstrated that LGFMS and SEF are related entities and the histologic evidence for this relationship comes from the identification of hybrid LGFMS-SEF tumors
  • LGFMS-like areas are a helpful feature to recognize SEF
  • SEFis characterized by recurrent translocations t(7;16) FUS-CREB3L2, t(11;16) FUS-CREB3L1

andt(11;22) EWSR1-CREB3L1; the latter occurs commonly in “pure” SEFs, while the first two are seen in tumors features hybrid features of SEF and LGFMS

  • With regard to intraosseous SEF, dense collagenous matrix, dystrophic calcifications or metaplastic bone associated with the lesion can be misinterpreted as osteoid, leading to misdiagnosis as osteosarcoma
  • Additional features can help to determine if a lesion is primary SEF of bone or osteosarcoma
  • The combination of MUC4 positivity and SATB2 negativity by immunohistochemistry can help support the diagnosis of SEF
  • These results are opposite in osteosarcoma, which tends to be MUC4 negative and SATB2 positive
  • Demonstration of FUS or EWSR1 gene rearrangements can also help to diagnose SEF
  • This case is unusual as it showed bona fidelace-like osteoid matrix suggestive of true osteoblastic differentiation; such cases require further study and might need to be identified prospectively since SEF of bone tends to respond poorly to neoadjuvant chemotherapy

References

  1. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fibrosarcoma. A variant of fibrosarcoma simulating carcinoma. Am J SurgPathol. 1995;19:979–993.
  2. Wojcik JB et al. Primary sclerosing epithelioid fibrosarcoma of bone: analysis of a series. Am J SurgPathol. 2014 Nov;38(11):1538-44. doi: 10.1097/PAS.0000000000000265.
  3. Grunewald TG, von Luettichau I, Weirich G, et al. Sclerosing epithelioid fibrosarcoma of the bone: a case report of high resistance to chemotherapy and a survey of the literature. Sarcoma. 2010;2010: 431627.
  4. Wang G, Eyden B. A primary sclerosing epithelioid fibrosarcoma of the pubic bone, with evidence of divergent epithelial differentiation. UltrastructPathol. 2010;34:99–104.
  5. Chow LT, Lui YH, Kumta SM, et al. Primary sclerosing epithelioid fibrosarcoma of the sacrum: a case report and review of the literature. J ClinPathol. 2004;57:90–94.
  6. Abdulkader I, Cameselle-Teijeiro J, Fraga M, et al. Sclerosing epithelioid fibrosarcoma primary of the bone. Int J SurgPathol. 2002;10:227–230.
  7. Doyle LA, Moller E, Dal Cin P, et al. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J SurgPathol. 2011;35:733–741.
  8. Doyle LA, Wang WL, Dal Cin P, Lopez-Terrada D, Mertens F, Lazar AJ, Fletcher CD,HornickJL. MUC4 is a sensitive and extremely useful marker forsclerosingepithelioidfibrosarcoma: association with FUS gene rearrangement. Am J SurgPathol. 2012 Oct;36(10):1444-51.
  9. Arbajian E, Puls F, Magnusson L, Thway K, Fisher C, Sumathi VP, Tayebwa J, Nord KH, Kindblom LG, Mertens F. Recurrent EWSR1-CREB3L1 gene fusions insclerosingepithelioidfibrosarcoma. Am J SurgPathol. 2014 Jun;38(6):801-8.