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Patient:

A 75-year-old man with a history of multiple skin lesions.

Initial referral:

The patient was referred to the Precision Care Initiative for advice on germline testing following a diagnosis of pleomorphic dermal sarcoma. The referring oncologist specifically asked about the need for BRIP1 and SDHC germline validation based on molecular profiling results.

Our approach:

Our multidisciplinary team conducted a comprehensive review of the patient's clinical history and molecular profiling results. We noticed several key factors that suggested a potential misclassification of the tumor:

1. High Tumor Mutational Burden (TMB) of 87 mutations/Mb
2. Predominance of C>T mutations, indicative of UV-induced DNA damage
3. Mutations in genes commonly associated with cutaneous squamous cell carcinoma (cSCC), including CDKN2A, TP53, and TERT

Value-added insights:

Based on our integrated analysis, we suggested that the tumour might actually be a poorly differentiated cutaneous squamous cell carcinoma (cSCC) rather than a pleomorphic dermal sarcoma. This reclassification had significant therapeutic implications:

1. Treatment options: Given the molecular profile strongly suggestive of cSCC, we advised considering immunotherapy options such as Cemiplimab, which is available through the PBS for metastatic cutaneous SCC in Australia.
2. Diagnostic perspective: We highlighted that poorly differentiated cSCC can mimic sarcoma histologically and may not show typical epithelial marker staining. The molecular features in this case strongly support a UV-induced skin cancer.
3. Germline assessment: We still advised germline assessment of BRIP1 and SDHC, addressing the referring oncologist's initial query, while noting that BRIP1 alterations could potentially arise from UV-induced genomic instability.

Outcome:

Our recommendations provided the referring oncologist with:

1. A new perspective on the tumor classification based on molecular features, potentially opening up additional treatment options
2. Guidance on interpreting the molecular data in the context of the patient's clinical history
3. Advice on relevant germline testing and its interpretation

This case demonstrates how the Precision Care Initiative's integrated approach to molecular and clinical data can lead to significant changes in diagnostic perspective and treatment strategies, even when traditional pathology methods may be inconclusive. Our insights can guide oncologists in making informed decisions about therapy options, potentially improving patient outcomes.