This presentation by Jared Gardner covers several complex and often confusing cases in soft tissue and dermatopathology, focusing on rare tumors and the diagnostic pitfalls associated with them. The session reviews five distinct cases, emphasizing the critical role of morphology, clinical context, and targeted immunohistochemistry/molecular testing in arriving at the correct diagnosis. Key entities discussed include a rare $PDGFD$-rearranged Dermatofibrosarcoma Protuberans ($DFSP$), an unusual ALK-positive Cutaneous Epithelioid Myoepithelioma, a classic Angiomatoid Fibrous Histiocytoma ($AFH$), a case of Primary Cutaneous Alveolar Rhabdomyosarcoma (RMS), and an Epithelioid Malignant Peripheral Nerve Sheath Tumor ($MPNST$) mimicking melanoma. The presenter stresses the importance of not jumping to conclusions based solely on initial findings, referencing historical diagnostic confusion and the utility of specific markers (like $ALK$, $EWSR1$, $Desmond$, $S100$, $SOX10$, $INI1$) to differentiate overlapping morphologies.
Diagnostic Pearls from CPC Session One (Soft Tissue Pathology Cases)
0:00 Case 1: Pigmented DFSP Variant (Foot Nodule):
Morphology: Highly cellular lesion with spindle cells in fascicles exhibiting the "ramen noodle sign" (wavy collagen) and areas showing a "herringbone pattern."
Key Takeaway: Despite classic fibrosarcomatous morphology and being located on the foot (unusual site), the case was negative for standard $COL1A1/PDGFB$ fusion but positive for the rare $PDGFD$ rearrangement, confirming a fibrosarcomatous DFSP variant. Highlights the need for molecular testing when morphology is challenging.
0:09 Case 2: Epithelioid Fibrohistiocytoma ($EFH$):
Morphology: Dome-shaped papule filling the superficial dermis with a prominent epithelial collarette (often derived from adnexal structures) and sometimes showing signet-ring cell change or foamy cytoplasm.
IHC: Positive for $ALK1$ (often weak/focal).
Key Takeaway: $EFH$ is a benign entity. The speaker recommends the $ALK1$ D5F3 clone for stronger, more robust staining compared to other clones. Rule out melanocytic processes ($S100$ negative) and xanthomas.
0:17 Case 3: Cutaneous Epithelioid Myoepithelioma (Sheet-like Proliferation):
Morphology: Superficial, sheet-like proliferation of bland cells with associated nexal/eccrine duct collarettes.
IHC: Co-expression of $EMA$ and $S100$, but negative for $SOX10$ and pan-keratin. Also positive for $ALK1$ protein.
Molecular: Rearrangement for $EWSR1-PBX3$ fusion confirmed.
Key Takeaway: This case exhibited an immunophenotypic overlap with $EFH$ ($ALK1$ positive). FISH confirmation of $EWSR1$ rearrangement (negative for $ALK$ fusion) established the diagnosis as Cutaneous Epithelioid Myoepithelioma, an $EWSR1$-rearranged, benign entity.
0:26 Case 4: Cellular Neurothekeoma (Deep Thigh Nodule in Young Adult):
Morphology: Biphasic lesion with a highly cellular/pleomorphic component (large nuclei, atypia, atypical mitoses) next to a hypocellular, myxoid component with spindle cells in chains/swirls (resembling Nerve Sheath Myxoma). Tumor giant cells are common.
IHC: Negative for neural markers ($S100$, $SOX10$).
Key Takeaway: Cellular Neurothekeoma is not a true nerve sheath tumor. The presence of the myxoid component is a strong clue. Despite malignant-appearing cytology (atypia/mitoses), this tumor has a good prognosis and is benign.
0:42 Case 5: Primary Cutaneous Alveolar Rhabdomyosarcoma (Atypical Biphasic Tumor):
Clinical Context: 80-year-old female, painful erythematous nodule (mimicking Merkel Cell Carcinoma based on initial IHC).
Morphology: Sheets of round blue cells with pale, vesicular chromatin, and areas showing fascicular/herringbone patterns. Scattered neutrophils were a helpful clue in the spindle areas.
Key Takeaway: This was a triple rarity: RMS in the skin, alveolar subtype, and in an elderly patient. The speaker stressed the lesson learned: skipping the standard soft tissue panel (specifically $Desmond$) led to a near-miss diagnosis, as the initial workup focused on Merkel cell carcinoma due to dot-like keratin and neuroendocrine markers.
Clinical Context: 17-year-old female, slow-growing nodule (4 years duration), clinically thought to be a vascular malformation.
Morphology: Uniform, monotonous sheets of round blue cells with some necrosis and dyscohesion (pseudovascular spaces).
IHC/Molecular: Strongly positive $CD99$ (Level 11). Negative for $EMA$. Molecular confirmation of $EWSR1-FLI1$.
Key Takeaway: Primary cutaneous Ewing Sarcoma is rare but possible in children/young adults. Uniformity suggests a gene fusion tumor. While $EWSR1$ is common in $AFH$, the morphology and strong $CD99$ favored Ewing Sarcoma. This case had a good outcome after treatment.
1:05 Case 7: Angiomatoid Fibrous Histiocytoma ($AFH$):
Morphology: Highly heterogeneous, fragmented lesion showing cellular areas (herringbone/spindle cells), myxoid change, hemorrhage, and an outer lymphoplasmacytic infiltrate with fibrosis.
IHC: Patchy $EMA$/$Desmond$ and $ALK1$ expression (molecularly negative for $ALK$ fusion).
Key Takeaway: $AFH$ is an intermediate malignant tumor unrelated to Dermatofibroma. The classic triad (sheets of cells, central cystic space/blood, peripheral lymphoid cuff) may be obscured by procedural artifact (fragmentation). $ALK1$ IHC positivity is a helpful marker, despite the absence of the gene fusion.
1:39 Case 9: Epithelioid Perivascular Tumor (Intravascular Presentation):
Morphology: Epithelioid cells arranged in cords, chains, and nests within the lumen of a vein, invading outward. Background showed chondromyxoid/sclerotic stroma. Classic feature: Blister cells (vacuoles containing RBC fragments) in tumor cells.
IHC: Positive for endothelial markers ($ERG$) and Keratin.
Molecular: $WWTR1-CAMTA1$ fusion confirmed.
Key Takeaway: Diagnosis is Epithelioid Hemangioendothelioma ($EHE$). Crucially, it can present in soft tissue/veins and be strongly keratin positive, mimicking carcinoma. Needs follow-up due to potential for late metastasis.
1:53 Case 10: Pseudomyogenic Hemangioendothelioma ($PMH$):
Morphology: Ugly epithelioid cells forming nests/sheets, resembling Epithelioid Sarcoma. Key finding: scattered neutrophils in the background.
IHC: Strong Keratin, positive $ERG$ and $CD31$, but retained nuclear $INI1$ (unlike Epithelioid Sarcoma, which typically loses $INI1$).
Key Takeaway: This tumor looks like Epithelioid Sarcoma or Angiosarcoma. The key differentiating factor against Epithelioid Sarcoma is retained $INI1$. Its classification as a vascular tumor is based on IHC/molecular findings ($PHOXB$ fusions), despite lacking classic vascular channels.
2:59 Case 12: Epithelioid Malignant Peripheral Nerve Sheath Tumor ($MPNST$):
Morphology: Deep intramuscular nodule centered around a large nerve bundle, showing perineural invasion. Ugly epithelioid cells in nests/sheets, resembling metastatic melanoma or Epithelioid Angiosarcoma.
IHC:Strong, diffuse $S100$ and $SOX10$ positive (like melanoma), but loss of nuclear $INI1$.
Key Takeaway: Epithelioid $MPNST$ is a distinct entity from conventional spindle $MPNST$. Its strong $S100/SOX10$ positivity in a young patient with a deep nerve nodule, coupled with $INI1$ loss, distinguishes it from melanoma (which usually doesn't show $INI1$ loss) and conventional $MPNST$ (which is usually $S100$-negative).