Diagnosing the primary cutaneous SMARCA4-deficient cutaneous tumor: You don’t know what you got ‘til it’s gone

By Warren R. Heymann, MD, FAAD
Nov. 5, 2025
Vol. 7, No. 44

Understandably, dermatologists are often surprised to receive a histopathologic diagnosis of Merkel cell carcinoma, given the relatively nondescript clinical features that suggest a basal cell carcinoma or inflamed cyst. The purpose of this commentary is to introduce dermatologists to another tumor that will likely not be diagnosed clinically — the primary cutaneous SMARCA4-deficient cutaneous tumor (PCSDCT) that is in the family of SMARCA4-deficient undifferentiated malignant neoplasms (SD-UMN), which are highly aggressive cancers.

According to Ye et al., “The SWI/SNF (switch/sucrose non-fermentable) related BAF (BRG1/BRM-related factor) chromatin remodeling complex subunit ATPase 4 (SMARCA4) is a gene [on chromosome 19p] with a high mutation frequency in the SWI/SNF complex. It plays a role as an ATP-dependent catalytic subunit, participates in remodeling chromatin structure and regulation of gene expression, and is closely related to the poor prognosis of malignant tumors… SMARCA4 loss of function (mutations, episodic silencing, or lack of protein expression) occurs in malignant tumors, including non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic ductal adenocarcinoma, and lymphoma. Conversely, overexpression of SMARCA4 has been observed in advanced gastric cancer, prostate cancer, melanoma, colorectal cancer (CRC), and neuroblastoma.” (1,2)

The defining feature of SD-UMNs is the presence of inactivating SMARCA4 mutations, resulting in the loss of protein expression, which is detectable by immunohistochemistry. Common histopathologic features include an undifferentiated epithelioid large cell or rhabdoid cytomorphology. Atypical mitoses, apoptotic debris, and tumor necrosis are also common findings. The undifferentiated appearance yields a broad histologic differential diagnosis, including a poorly differentiated squamous cell carcinoma, melanoma, Merkel cell carcinoma, and others, thereby requiring a large panel of immunohistochemical stains.

SD-UMN may metastasize to the skin. The first report of a cutaneous metastasis was in a 63-year-old man with a SMARCA4-deficient thoracic sarcoma. (2) By definition, primary cutaneous SMARCA4-deficient cutaneous tumors (PCSDCT) arise in the skin. To date, four cases of PCSDCT have been reported — all in older men. The diagnosis of a PCSDCT can only be secured after a thorough assessment (i.e., imaging such as a PET scan), ruling out a visceral primary tumor.

Russell-Goldman et al. reported two cases of PCSDCT in 84- and 70-year-old men, respectively. The first patient died 18 months following the histologic diagnosis (clinically appearing as a papule on the neck, thought to be a basal cell carcinoma). His cancer was unresponsive to surgical excision or radiation therapy. The second patient presented with a rapidly growing keratotic papule of the right cheek that was successfully treated with excisional surgery. “The cutaneous cases showed strikingly similar morphologic, immunohistochemical, and molecular features to the visceral cases, strongly suggesting that they belong to this family of tumors. In addition to biallelic inactivation of SMARCA4, both cutaneous tumors also showed biallelic inactivation of TP53 and CDKN2A, findings which also appear common in visceral cases.” (3)

Gumusgoz et al. reported the case of a 67-year-old man who presented with a rapidly growing, ulcerated, and bleeding nodule on his right cheek. Histopathology demonstrated a highly cellular dermal tumor consisting of pleomorphic epithelioid cells with prominent mitotic figures and necrosis, lacking any morphological evidence of differentiation. Immunohistochemical analysis showed a complete loss of SMARCA4 and SMARCA2 expression. Ten months after a surgical excision and negative sentinel node biopsy, the patient was tumor-free. (4)

Pradhan et al. detailed the case of a PCSDCT in a 72-year-old man. The primary lesion was a raised skin lesion that metastasized to the left axilla. He also had squamous cell carcinomas of the head that metastasized to the neck. He died 11 months later, unresponsive to palliative radiotherapy. (5)

It is challenging to draw definitive conclusions based on only four reported cases of PCSDCT; however, the following considerations are reasonable. 1) PDSDCT appears in older men; 2) The tumor may be aggressive; 3) Excisional surgery with sentinel node biopsy is warranted; 4) Future studies are required to determine the efficacy of radiation, chemotherapy, immunotherapy, and targeted oncotherapy. Ye et al. state that current investigative strategies encompass two principal approaches: 1) indirect modulation of SMARCA4-associated pathways; and 2) exploitation of synthetic lethal interactions. (1)

As a dermatologist/dermatopathologist, it is fascinating that diagnoses may be rendered by what is not seen. Think of the BAP1-tumor predisposition syndrome (BAP1-TPDS), where the diagnosis is confirmed histologically by the loss of the tumor suppressor BAP1. (6) PDSDCT is analogous to the deficiency of the tumor suppressor SMARCA4. To quote Joni Mitchell from Big Yellow Taxi:

Don’t it always seem to go
That you don’t know what you got ‘til it’s gone?

Point to Remember: Dermatologists may rarely encounter SMARCA4-deficient undifferentiated malignant neoplasms, either as primary cutaneous tumors or as metastatic lesions.

Our expert’s viewpoint

Dr. Renukadas P. Sakalkale, FRCPA
Staff Specialist Pathologist, NSWHP
Coffs Harbour, NSW, Australia

Mutations at stem cell level are arguably the holy grail of undifferentiated high-grade tumors of various sites, and cutaneous tumors are no exceptions. SMARCA4 is one such primitive protein complex involved in complex embryonic regulated development and is a tumor suppressor. Deficient SMARCA4 expression is diagnostic histologically in very rare but fatal tumors, with the cutaneous origin being only rarely seen, recently described and should not be overlooked. The clinical pointers are unusual rapid growth, primary histology report showing undifferentiated or poorly differentiated neoplasm negative for almost all usual diagnostic markers available in smaller laboratories. In such cases, SMARCA4 deficiency must be excluded, and if found, an aggressive and thorough clinical workup is necessary. Wide local excision and oncologic involvement are a must.

Be SMART about SMARCA4!

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References

1. Ye W, An D, Ou WB. SMARCA4: Promises and challenges in the treatment of cancers. Cancer Lett. 2025 Aug 10;625:217811. doi: 10.1016/j.canlet.2025.217811. Epub 2025 May 19. PMID: 40398707.

2. Leckey BD Jr, Selim MA, Al-Rohil RN. Cutaneous metastasis of SMARCA4-deficient thoracic sarcoma: A diagnostic dilemma with therapeutic implications. J Cutan Pathol. 2020 Jun;47(6):561-565. doi: 10.1111/cup.13652. Epub 2020 Feb 13. PMID: 31995235.

3. Russell-Goldman E, MacConaill L, Hanna J. Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm: first two cases with clinicopathologic and molecular comparison to eight visceral counterparts. Mod Pathol. 2022 Dec;35(12):1821-1828. doi: 10.1038/s41379-022-01152-1. Epub 2022 Sep 9. PMID: 36085356.

4. Gumusgoz E, Graham BS, Hosler GA. Primary cutaneous SMARCA4-deficient undifferentiated malignant neoplasm: A rare case report and literature review. J Cutan Pathol. 2024 Apr;51(4):262-266. doi: 10.1111/cup.14576. Epub 2023 Dec 20. PMID: 38124373.

5. Pradhan S, Lehman M, Tahir AM, Su M, Kossard S, Sakalkale R. Primary Cutaneous SMARCA4-Deficient Tumor With Metastases. J Cutan Pathol. 2025 Aug;52(8):533-538. doi: 10.1111/cup.14828. Epub 2025 Jun 4. PMID: 40464459.

6. Heymann WR. Nailing the diagnosis of the BAP1 tumor predisposition syndrome. Dermatology World Insights and Inquiries. June 5, 2024, vol 6, no. 23. https://staging.aad.org/dw/dw-insights-and-inquiries/archive/2024/bap1-tumor-predisposition-syndrome

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