Abstract:

This presentation, "CPC Session One," by Jared Gardner, covers the differential diagnosis and pathology of several challenging soft tissue tumors, emphasizing the importance of clinicopathologic correlation and appropriate ancillary testing.

The session details four primary cases:

1. Case 1: Fibrosarcomatous Dermatofibrosarcoma Protuberans (DFSP): A well-circumscribed nodule mimicking fibrosarcoma due to its cellular, herringbone pattern, but distinguished by its strong CD34 positivity and a rare $PDGFD$ gene rearrangement in the absence of the typical $COL1A1-PDGFB$ fusion.
2. Case 2: Epithelioid Fibrous Histiocytoma (EFH): A superficial, dome-shaped papule with a collarette, characterized by epithelioid cells, often exhibiting signet-ring change, and confirmed by $ALK1$ gene fusion/expression. A tip on using the D5F3 $ALK1$ clone for better staining is provided.
3. Case 3: Cutaneous Sheet-like Myoepithelioma: A lesion that showed an overlap in markers ($EMA+$ and $S100+$) but was definitively diagnosed as a cutaneous sheet-like myoepithelioma (a variant of myoepithelioma) based on the presence of an $EWSR1-PBX3$ fusion and negativity for the $ALK1$ gene rearrangement by FISH.
4. Case 4: Alveolar Rhabdomyosarcoma (RMS): A highly worrisome, cellular, round blue cell tumor in a young patient that was nearly misdiagnosed as Merkel cell carcinoma due to focal keratin and neuroendocrine staining. The diagnosis was secured by positive desmin and strong myogenin expression, confirming it as an aggressive RMS (specifically alveolar subtype), despite its rare presentation in the skin of an older adult.

The session concludes with further cases in CPC Session Two, highlighting the diagnostic pitfalls and key molecular markers necessary for accurate classification of complex spindle cell and round blue cell tumors.

Key Takeaways from CPC Session One (Cases 1-4):

• 0:00 Case 1: Fibrosarcomatous DFSP:

  • Key Morphology: Circumscribed nodule with pink, collagenized zones showing bland spindle cells in elongated, parallel fascicles—the "ramen noodle sign" (wavy collagen fibers). Other areas show cellular, blue zones with fascicles intersecting at sharp angles ("herringbone pattern," formerly associated with fibrosarcoma).
  • Immunohistochemistry (IHC): Strongly and diffusely positive for CD34; negative for S100 and keratin.
  • Molecular Finding: Rearrangement of the $PDGFD$ gene, noted as a rare fusion variant in DFSP that lacks the traditional $COL1A1-PDGFB$ fusion.
  • Clinical Note: Unusual location (dorsal foot) and older patient age (68).

• 0:09:02 Case 2: Epithelioid Fibrous Histiocytoma (EFH):

  • Key Morphology: Dome-shaped papule in superficial dermis with an epithelial collarette (often involving overlying adnexal structures, not just epidermis). Cells show cytoplasmic clear vacuolation ("signet ring appearance") or foamy cytoplasm. Dilated, staghorn vessels may be present.
  • IHC/Molecular: Positive for $ALK1$. The speaker recommends the $ALK1$ D5F3 clone for stronger staining than standard clones.
  • Differential Diagnosis: Xanthoma, Juvenile Xanthogranuloma, Melanocytic process.
  • Key Takeaway: EFH is considered benign and is characterized by $ALK$ gene fusion.

• 0:17:03 Case 3: Cutaneous Sheet-like Myoepithelioma:

  • Key Morphology: Superficial dermal sheet-like proliferation of bland, histiocytoid cells with clear/foamy cytoplasm, sometimes mimicking xanthoma or EFH. Pushed against the epidermis (or eccrine duct).
  • IHC Overlap: Co-expression of EMA and S100, but negative for Sox10 and Keratin (unlike typical myoepitheliomas).
  • Molecular Confirmation: FISH confirmed $EWSR1$ rearrangement, specifically with the $PBX3$ fusion partner.
  • Distinguishing Feature: Negative for $ALK1$ fusion, differentiating it from EFH.

• 0:26:08 Case 4: Alveolar Rhabdomyosarcoma (RMS):

  • Key Morphology (Cellular Areas): High cellularity, large nuclei, vesicular/pale chromatin, increased mitotic activity, and atypical mitoses; tumor giant cells are common. Resembles epithelioid fibrocystic cytoma cytologically.
  • Key Morphology (Mixoid Areas): Thin, spindly cells in elongated, swirling, chain-like structures within a loose myxoid background (resembling nerve sheath myxoma/conventional neurothekeoma).
  • Diagnostic Pitfall Avoided: Initially misread due to skipping the desmin/myogenin workup while focused on Merkel cell carcinoma (due to focal keratin/neuroendocrine markers).
  • IHC/Molecular: Positive for Desmin and strongly positive for Myogenin (Myf4); negative for S100/Sox10. Confirmed by $PAX3/PAX7-FOXO1$ fusion (though $EWSR1$ was rearranged).
  • Prognosis: Despite looking malignant, the literature suggests a good outcome for cutaneous RMS, though this case was highly aggressive, resulting in death.

• 0:42:29 Case 5 (Mentioned): An 80-year-old with a painful nodule initially suspected as Merkel cell carcinoma (positive for focal CK20, Chromogranin, CD56) but ultimately diagnosed as CK20-negative Merkel Cell Carcinoma (a known rare variant).

• 0:53:09 Case 6 (Mentioned): Discussed Cellular Neurothekeoma (CT), emphasizing it is not a nerve sheath tumor (negative for S100/Sox10) and often has abundant myxoid change and characteristic pale, washed-out nuclear chromatin. Atypical features do not predict malignancy.

• 1:05:26 Case 7: Angiolymphoid Hyperplasia with Eosinophilia (ALHE) / Epithelioid Hemangioma:

  • Key Features: Nodule with sheets of histiocytoid cells, central cystic space (blood/serum), and a peripheral fibrous pseudocapsule with a dense lymphoplasmacytic/eosinophilic infiltrate.
  • Distinction: Crucial to differentiate from Epithelioid Hemangioendothelioma (EHE) and Aneurysmal Dermatofibroma.
  • Molecular/IHC: Often positive for $FOS$ or $FOSB$ fusions; patchy Desmond/EMA; often positive for $ALK1$ IHC, but $ALK$ fusion is typically absent.

• 1:39:03 Case 9: Epithelioid Hemangioendothelioma (EHE):

  • Key Presentation: Tumor arising within the Lumen of a vein, expanding and invading adjacent soft tissue.
  • Key Morphology: Epithelioid cells forming cords, chains, and nests, often containing intracytoplasmic vacuoles (blister cells) with red cell fragments. Keratin positive; strong ERG positive.
  • Molecular Hallmark: $WWTR1-CAMTA1$ fusion is most common.
  • Behavior: Intermediate malignant potential; can metastasize, often to the lungs.

• 1:53:09 Case 11: Epithelioid Angiosarcoma:

  • Key Morphology: Ugly epithelioid cells forming solid sheets, nests (due to filled lumens), cords, and chains, with marked atypia. Look for vascular channels (though sometimes focal or absent in biopsies).
  • IHC: Diffusely positive for ERG and CD31, but often negative for CD34 (a critical pitfall).
  • Clinical Lesson: The "blue-gray/slate blue" cytoplasm color is a useful clue. Must include vascular markers when sarcomas or ugly epithelial tumors are considered.

• 1:59:02 Case 12: Epithelioid Malignant Peripheral Nerve Sheath Tumor (MPNST):

  • Key Location: Deep intramuscular nodule centered around or tracking a large nerve bundle (perineural invasion is common).
  • Mimics: Looks cytologically like metastatic melanoma or epithelial angiosarcoma due to ugly epithelioid cells, sheets, and nests.
  • IHC Differentiation: Strongly and diffusely positive for S100 and Sox10 (unlike conventional spindle MPNST, which is often negative). Crucially, it shows loss of INI1/SMARCB1 expression, distinguishing it from melanoma.