Pleomorphic Dermal Sarcoma: Tissue and Treatment Insights

Pleomorphic dermal sarcoma (PDS) is a rare, aggressive skin cancer primarily affecting older adults with extensive sun exposure. It shares similarities with atypical fibroxanthoma but has deeper tissue invasion and a higher risk of recurrence or metastasis. Early detection and proper classification are crucial for guiding treatment decisions.

Advancements in histopathology, immunohistochemistry, and genetic profiling have improved the understanding of PDS, leading to more targeted therapeutic approaches.

Clinical Presentation

PDS typically appears as a rapidly growing, ulcerated nodule on sun-exposed areas, most commonly the scalp, face, and neck of elderly individuals. The lesions are often erythematous or flesh-colored with irregular borders, and their aggressive nature can cause significant local tissue destruction. Unlike atypical fibroxanthoma, which remains confined to the superficial dermis, PDS frequently infiltrates deeper structures, including subcutaneous fat and sometimes musculature.

Patients often report a previously stable lesion that has recently changed in size, texture, or ulceration. The tumor’s rapid evolution, sometimes within weeks to months, raises clinical suspicion, especially in individuals with extensive actinic damage. While not always painful, some lesions become tender or bleed when traumatized. Given its association with sun-damaged skin, PDS often arises in individuals with a history of other cutaneous malignancies, such as squamous or basal cell carcinoma, complicating differential diagnosis.

On dermatologic examination, PDS presents as a firm, exophytic mass with a necrotic or hemorrhagic surface, often misdiagnosed as a non-melanoma skin cancer. The tumor lacks a well-defined capsule, contributing to its locally aggressive behavior. Dermoscopy may reveal polymorphic vascular patterns and white structureless areas, reflecting the tumor’s disorganized architecture. Due to its clinical overlap with other high-grade sarcomas and poorly differentiated carcinomas, biopsy and histopathological evaluation are necessary for accurate diagnosis.

Histopathological Features

The microscopic characteristics of PDS provide essential diagnostic criteria that differentiate it from other cutaneous malignancies. Histopathology reveals a highly cellular tumor with significant pleomorphism, atypical mitotic figures, and infiltrative growth beyond the superficial dermis. Unlike atypical fibroxanthoma, PDS demonstrates deeper tissue invasion, perineural involvement, and, in some cases, lymphovascular infiltration, contributing to its more aggressive clinical course.

Tissue Organization

PDS exhibits a disorganized architectural pattern with sheets and fascicles of pleomorphic spindle and epithelioid cells within a fibrotic or myxoid stroma. The tumor lacks a well-defined capsule, allowing irregular infiltration into the surrounding dermis and subcutaneous fat. In some cases, the neoplasm extends into skeletal muscle. Necrotic foci are frequently observed in larger tumors, reflecting high proliferative activity and inadequate vascular supply. The stromal composition varies, with some tumors displaying dense collagen deposition, while others have a more myxoid or edematous background. This heterogeneity necessitates thorough sampling to capture the full spectrum of morphological features.

Tumor Cell Diversity

PDS is composed of spindle, epithelioid, and multinucleated giant cells. Spindle cells have elongated, hyperchromatic nuclei with irregular contours, while epithelioid cells show abundant eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli. Multinucleated tumor giant cells, resembling those seen in undifferentiated pleomorphic sarcoma, are common. Atypical mitotic figures, including tripolar and quadripolar mitoses, underscore the tumor’s aggressive proliferative capacity. Some cases exhibit rhabdoid differentiation, characterized by cells with eccentric nuclei and eosinophilic cytoplasmic inclusions. This cellular diversity can complicate diagnosis, particularly in distinguishing PDS from other high-grade sarcomas or poorly differentiated carcinomas.

Morphological Identifiers

Several histological hallmarks aid in PDS identification. Marked nuclear pleomorphism, with bizarre, hyperchromatic nuclei, is a defining characteristic. Tumor necrosis, often with a geographic pattern, is another distinguishing feature, particularly in larger lesions. PDS frequently extends beyond the dermis into subcutaneous fat and deeper structures such as fascia or muscle. Unlike atypical fibroxanthoma, PDS often exhibits perineural invasion, which increases the risk of local recurrence. Additionally, the absence of a well-formed capsule and irregular tumor margins further support its aggressive nature. These features, combined with clinical and immunohistochemical findings, are essential for accurate diagnosis and treatment planning.

Immunohistochemical Profiles

The immunohistochemical (IHC) profile of PDS helps distinguish it from histologic mimics, including atypical fibroxanthoma, undifferentiated pleomorphic sarcoma, and poorly differentiated carcinomas. While PDS lacks a distinct molecular signature, its immunophenotypic characteristics provide valuable diagnostic markers. The tumor typically expresses vimentin, a mesenchymal marker, but is negative for cytokeratins, differentiating it from spindle cell squamous cell carcinoma and other epithelial malignancies.

PDS often stains positive for CD10, a marker that overlaps with atypical fibroxanthoma, and CD68, a histiocytic marker, though neither is exclusive. More diagnostically relevant is the absence of S100, SOX10, and Melan-A, which helps exclude melanoma. Similarly, the lack of nuclear STAT6 expression rules out solitary fibrous tumor, while desmin negativity differentiates it from myogenic sarcomas. These negative markers are as important as positive ones in narrowing the diagnosis, particularly in cases with ambiguous morphology.

The MIB-1 (Ki-67) proliferation index provides insight into tumor behavior. PDS generally exhibits a high Ki-67 index, often exceeding 20%, indicative of its aggressive growth. Some cases also show p53 overexpression, suggesting a potential role for TP53 mutations in tumor pathogenesis. While not a definitive diagnostic marker, p53 immunoreactivity may correlate with more aggressive disease features.

Genetic Characteristics

Genetic analyses of PDS reveal a landscape of molecular alterations that align with its aggressive nature. Unlike well-characterized sarcomas with distinct driver mutations, PDS exhibits a heterogeneous genetic profile with frequent somatic mutations affecting tumor suppressor pathways. TP53 mutations are among the most common, contributing to unchecked cell cycle progression and genomic instability.

Beyond TP53, whole-exome sequencing has identified recurrent mutations in CDKN2A, a gene encoding the tumor suppressors p16 and p14^ARF. Loss-of-function alterations in this locus disrupt cell cycle regulation, further promoting uncontrolled tumor growth. Additionally, copy number variations, particularly deletions in chromosome 9p21, reinforce the role of CDKN2A loss in disease progression.

Treatment Modalities

Managing PDS requires a multimodal approach due to its aggressive behavior and potential for recurrence. Surgical excision remains the primary treatment, with a focus on achieving histologically clear margins. Mohs micrographic surgery (MMS) is often favored for tumors on cosmetically sensitive areas like the face or scalp, as it allows precise removal while sparing healthy tissue. Wide local excision (WLE) with at least a 1 cm margin is another standard approach, though larger margins may be necessary for deeply invasive lesions. Margin status is a critical determinant of recurrence, with positive or close margins significantly increasing regrowth risk. In cases with perineural invasion, extended resection may be warranted.

For high-risk patients—such as those with deep invasion or perineural spread—adjuvant radiation therapy may help reduce recurrence risk, particularly when achieving negative margins is challenging. Systemic therapy is generally reserved for metastatic disease, though data on chemotherapy or targeted agents in PDS remains limited. Some oncologists have explored anthracycline-based regimens, but responses vary. Immunotherapy, particularly checkpoint inhibitors targeting PD-1 or CTLA-4, is an emerging area of interest, though further research is needed. Multidisciplinary management involving dermatologists, surgical oncologists, and radiation specialists is essential for tailoring treatment based on individual tumor characteristics.

Prognosis

PDS outcomes depend on factors such as tumor depth, perineural invasion, and surgical margin adequacy. While the overall prognosis is more favorable than that of other high-grade sarcomas, recurrence rates range from 10% to 30%, particularly in cases with incomplete excision. Metastasis, though less common, occurs in up to 20% of cases, primarily affecting the lungs and regional lymph nodes.

Long-term follow-up protocols include routine dermatologic examinations and imaging studies for high-risk patients. Some clinicians advocate for ultrasound surveillance of surgical sites, particularly in anatomically complex regions. While the five-year survival rate for localized PDS is high, distant metastases significantly worsen outcomes. Identifying high-risk patients allows for more intensive follow-up strategies aimed at early detection of recurrence or metastatic spread.