Soft tissue

• Ossifying fibromyxoid tumor (OFMT) is a distinctive mesenchymal neoplasm of uncertain differentiation, with cords, nests, clusters and sheets of uniform ovoid cells embedded in a variable myxoid, fibromyxoid or hyalinized stroma, often with an incomplete peripheral shell of bone (Am J Surg Pathol 1989;13:817)
• Has potential for local recurrence and metastasis (especially when showing malignant features) (Am J Surg Pathol 2003;27:421)

• Slow growing, painless mass (Am J Surg Pathol 2008;32:996)
• Longstanding clinical course, ranging from 1 to 20 years or even of longer duration (median, 4 years) (Arch Pathol Lab Med 2016;140:371)

• Tissue sampling is the gold standard for a definitive diagnosis
• At least 85% harbor PHF1 gene rearrangement (Genes Chromosomes Cancer 2010;49:1114, Head Neck Pathol 2015;9:32)

Contributed by Borislav A. Alexiev, M.D.

• 26 year old man with painless mass in the tongue (Head Face Med 2013;9:16)
• 36 year old man with left thigh mass (Oncol Lett 2013;5:1301)
• 43 year old woman with mediastinal mass (Int J Clin Exp Pathol 2015;8:2139)
• 46 year old man with intracranial mass (Cureus 2020;12:e10662)
• 52 year old man with subcutaneous, supraclavicular mass (J Cutan Pathol 2006;33:749)

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• Circumscribed nodular or multinodular mass (Am J Surg Pathol 2008;32:996)
• Fibrous capsule with or without a shell of bone (Am J Surg Pathol 1989;13:817)
• Cut surface is glistening and varies from white to pink-tan in color (Am J Surg Pathol 2008;32:996)
• Consistency is rubbery to firm (Am J Surg Pathol 2008;32:996)

Contributed by Borislav A. Alexiev, M.D.

• Well circumscribed with a fibrous capsule / pseudocapsule and fibrous septa producing a lobular appearance (Am J Surg Pathol 2003;27:421)
• Complete or incomplete peripheral shell of woven or lamellar bone is present in many cases (Am J Surg Pathol 1989;13:817, Am J Surg Pathol 2008;32:996)
• Tumor may invade through the capsule and form satellite nodules in adjacent tissues (Am J Surg Pathol 2008;32:996)
• Uniform round, ovoid or spindle shaped cells with bland round to oval nuclei, inconspicuous nucleoli and scant eosinophilic cytoplasm (Am J Surg Pathol 2003;27:421, Am J Surg Pathol 2008;32:996)
• Tumor cells are arranged in cords, nests and sheets (Am J Surg Pathol 1989;13:817, Am J Surg Pathol 2003;27:421)
• Cellularity varies from low to moderate to high
• Variably fibrous or myxoid stroma (Am J Surg Pathol 1989;13:817, Am J Surg Pathol 2003;27:421)
• The following morphologic subtypes have been proposed (Am J Surg Pathol 2003;27:421):
  • Typical:
    • Low cellularity, low nuclear grade and mitotic activity of < 2 mitoses/50 high power fields
  • Atypical:
    • Deviating from typical OFMT but falling short of proposed criteria for malignant OFMT
  • Malignant:
    • High nuclear grade or high cellularity and > 2 mitoses/50 high power fields
• Cellularity:
  • Low cellularity: abundant fibromyxoid matrix between and around individual tumor cell and nests (Am J Surg Pathol 2003;27:421)
  • Moderate and high cellularity: progressively less intercellular matrix and in cases with high cellularity, frequent nuclear overlapping (Am J Surg Pathol 2003;27:421)
• Nuclear grade
  • Low: small round nuclei with fine chromatin and indistinct nucleoli (Am J Surg Pathol 2003;27:421)
  • Moderate: significant nuclear enlargement and occasional small nucleoli but lack the irregular nuclear contours, coarse chromatin and macronucleoli that characterize cells with high nuclear grade (Am J Surg Pathol 2003;27:421)
  • High: significant nuclear enlargement, irregular nuclear contours, coarse chromatin and macronucleoli (Am J Surg Pathol 2003;27:421)

Contributed by Borislav A. Alexiev, M.D.

Contributed by Borislav A. Alexiev, M.D.

• PHF1 gene rearrangement has been observed in 80%, including benign, atypical and malignant subtypes with fusion to EP400 in 44% of cases (Arch Pathol Lab Med 2016;140:371, Hum Pathol 2013;44:2603)
• ZC3H7B-BCOR and MEAF6-PHF1 fusions occur predominantly in S100 negative and malignant OFMT (Genes Chromosomes Cancer 2014;53:183)
• Recurrent PHF1-TFE3 fusions in a subset of OFMTs with aggressive clinical behavior (Genes Chromosomes Cancer 2019;58:643)

• Extraskeletal myxoid chondrosarcoma:
  • Desmin negative
  • Characteristic translocations, typically t(9;22(q22;q12.2), fusing EWSR1 to NR4A3 genes (Cancer 2008;113:3364)
• Soft tissue myoepithelioma:
  • Consistently expresses keratins and GFAP positivity is relatively common (Am J Surg Pathol 2008;32:996)
  • SOX10 positive in most myoepitheliomas (about 80%) and a subset of myoepithelial carcinomas (30%) (Arch Pathol Lab Med 2019;143:1504)
  • Desmin usually negative
  • No PHF1 gene rearrangements
• Low grade fibromyxoid sarcoma:
  • Alternating fibrous and myxoid areas (Ann Diagn Pathol 2017;28:60)
  • Bland spindle cells in a whorled or fascicular growth pattern (Head Neck Pathol 2016;10:161)
  • MUC4 positive, diffuse and strong (Ann Diagn Pathol 2017;28:60, Head Neck Pathol 2016;10:161)
  • Desmin negative
  • Recurrent (7;16)(q34;p11) translocation resulting in the FUS-CREB3L2 fusion gene, with less common fusion events including FUS-CREB3L1 or EWSR1-CREB3L1 (Ann Diagn Pathol 2017;28:60, Lab Invest 2005;85:408, Am J Surg Pathol 2006;30:1077)
• Sclerosing epithelioid fibrosarcoma:
  • MUC4 positive, diffuse and strong (Genes Chromosomes Cancer 2017;56:695)
  • Desmin negative (Arch Pathol Lab Med 2019;143:1504)
  • Most harbor a recurrent EWSR1-CREB3L1 fusion, with less common fusion events including EWSR1-CREB3L2 and FUS-CREB3L2 (Genes Chromosomes Cancer 2017;56:695, Arch Pathol Lab Med 2019;143:1504)
• Myxofibrosarcoma, epithelioid variant:
  • c-MET overexpression (Diagn Pathol 2018;13:56)
  • S100 negative (Am J Surg Pathol 2007;31:99, World J Surg Oncol 2012;10:245)
  • Desmin negative
  • No PHF1 rearrangement
• Myxoid leiomyosarcoma:
  • HMGA2, h-caldesmon and desmin positive (Hum Pathol 2017;59:139, Hum Pathol 1999;30:392, Am J Surg Pathol 2000;24:927)
  • S100 negative (Hum Pathol 1991;22:569)
  • No PHF1 rearrangement
• Epithelioid schwannoma:
  • SOX10 positive (differentiates epithelioid nerve sheath tumors from OFMT) (Arch Pathol Lab Med 2019;143:1504)
  • Desmin negative
  • No PHF1 rearrangement
• Epithelioid malignant peripheral nerve sheath tumor (MPNST):
  • SOX10 positive (differentiates epithelioid nerve sheath tumors from OFMT) (Arch Pathol Lab Med 2019;143:1504)
  • Desmin negative
  • Loss of H3K27me3 expression has good sensitivity and robust specificity for the diagnosis of MPNST; however, H3K27me3 expression is retained in epithelioid MPNST (Am J Surg Pathol 2016;40:479, Histopathology 2017;70:385)
  • No PHF1 rearrangement

The most common gene rearranged in ossifying fibromyxoid tumor is

1. EWSR1
2. FUS
3. PHF1
4. ZNF444
5. FOS

C. PHF1

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Reference: Ossifying fibromyxoid tumor

A 53 year old man presented with a right foot mass. Hematoxylin eosin stains demonstrate a well circumscribed tumor with thick fibrous capsule and incomplete peripheral shell of metaplastic bone. Invasion through the capsule and extracapsular nodules in the surrounding fat are noted. The tumor is composed of lobules of uniform, round to spindle shaped cells with bland round to oval nuclei with inconspicuous nucleoli and eosinophilic or pale cytoplasm in abundant fibromyxoid background. Occasional mitotic figures are identified (2 mitoses/10 high power fields). Immunohistochemical stains for S100, CD10, desmin and keratin AE1 / AE3 (focal) are positive in tumor cells while all of the following are negative: CD34, SOX10, ERG, GFAP, h-caldesmon and MUC4.

Which of the following is most likely the correct diagnosis?

1. Extraskeletal myxoid chondrosarcoma
2. Ossifying fibromyxoid tumor
3. Epithelioid schwannoma
4. Low grade fibromyxoid sarcoma
5. Myoepithelioma

B. Ossifying fibromyxoid tumor

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Reference: Ossifying fibromyxoid tumor