Pleomorphic carcinoma (PC) is a highly aggressive and rare form of cancer, representing a small fraction of all malignancies diagnosed annually. It is classified as a type of sarcomatoid carcinoma, meaning the tumor displays a mixture of two distinct cellular appearances. Its rarity and aggressive biological behavior contribute to challenges in diagnosis and therapeutic intervention. PC is characterized by a rapid growth rate and a high propensity for distant spread, often leading to a guarded outlook for patients.
The Unique Histological Features of Pleomorphic Carcinoma
The term “pleomorphic” translates to “many shapes,” describing the defining characteristic of this tumor under a microscope. Pleomorphic carcinoma is fundamentally a biphasic tumor, containing both malignant epithelial cells and a high-grade sarcomatoid component. This dual morphology differentiates PC from other cancers that typically exhibit only an epithelial or mesenchymal appearance.
The epithelial element is typically a poorly differentiated non-small cell carcinoma, such as adenocarcinoma or squamous cell carcinoma. The World Health Organization (WHO) classification requires the sarcomatoid component to constitute a minimum of 10% of the entire tumor mass for diagnosis. This sarcomatoid portion is composed of malignant spindle cells and/or bizarre, multinucleated giant cells.
Malignant spindle cells are elongated, tapered cells that resemble those found in a true sarcoma. The giant cells are particularly striking, featuring abnormally large and irregularly shaped nuclei with prominent nucleoli. These features reflect significant cellular disorganization, marked nuclear atypia, and a high mitotic rate, consistent with the tumor’s aggressive growth pattern.
The distinction between PC and a true sarcoma is confirmed through immunohistochemistry (IHC). PC cells, despite their spindle and giant cell morphology, maintain epithelial markers like cytokeratins, confirming their origin as a carcinoma. The sarcomatoid component often expresses mesenchymal markers, such as vimentin, illustrating the epithelial-to-mesenchymal transition (EMT) that creates the mixed appearance. This cellular plasticity contributes to the tumor’s resistance to standard treatments and capacity for invasion.
Diagnostic Procedures and Common Tumor Locations
The discovery of pleomorphic carcinoma is often initiated by non-specific symptoms that prompt imaging studies, such as computed tomography (CT) or positron emission tomography (PET) scans. Radiologically, these tumors often appear as large, solitary masses with ill-defined borders. They frequently show a rapid uptake of the radioactive tracer on a PET scan due to their aggressive metabolic activity. In the lung, the most common primary site, these tumors often present as peripheral masses involving the pleura or chest wall.
The most common primary location for PC is the lung, known as Pulmonary Pleomorphic Carcinoma (PPC). This malignancy also arises in other organs, including the pancreas, where it is referred to as pleomorphic giant cell tumor of the pancreas. A significant site is the salivary glands, where the tumor is often designated as carcinoma ex pleomorphic adenoma (CXPA), indicating malignant transformation within a previously benign tumor.
A definitive diagnosis requires a tissue biopsy, often obtained via a core needle biopsy guided by imaging. Due to the tumor’s heterogeneity, a small biopsy sample may miss the epithelial component, potentially leading to an initial misdiagnosis of a high-grade sarcoma. Pathologists must carefully examine the surgical specimen, if available, to ensure all tumor components are represented.
The diagnosis is ultimately confirmed by immunohistochemistry (IHC). The detection of both epithelial markers (like cytokeratin) and mesenchymal markers (like vimentin) within the tumor cells is a hallmark of pleomorphic carcinoma. This specific immunophenotype is necessary to differentiate PC from other spindle cell lesions that may mimic its appearance.
Treatment Modalities and Prognostic Factors
The management of pleomorphic carcinoma necessitates a multidisciplinary approach, often beginning with aggressive surgical resection when the tumor is localized. Complete surgical removal with negative margins (R0 resection) offers the best chance for long-term control, particularly for tumors in the lung. However, the tumor’s aggressive nature means that local recurrence and distant metastasis are frequent, even after successful surgery.
Systemic therapy, including chemotherapy, radiation, and targeted treatments, is often utilized in the adjuvant setting after surgery or as the primary treatment for advanced disease. Historically, PC has shown poor response rates to standard cytotoxic chemotherapy regimens, with efficacy reported as low as 0% to 17%. The mesenchymal-like component of the tumor is thought to contribute to this chemoresistance, making traditional non-small cell lung cancer protocols less effective.
Immunotherapy, specifically immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway, has introduced a promising treatment option. Pleomorphic carcinomas frequently exhibit high expression of the PD-L1 protein, which indicates a potential response to these agents. For patients with advanced disease, immunotherapy, alone or combined with chemotherapy, is increasingly considered a standard of care and has shown favorable outcomes.
The prognosis for patients diagnosed with pleomorphic carcinoma is less favorable than for those with conventional non-small cell carcinomas. Several factors influence the long-term outlook, including the primary location and the stage at diagnosis. Poor prognostic indicators include a large tumor size (greater than five centimeters) and the presence of lymph node or distant metastases. The extent of vascular invasion and a higher proportion of the sarcomatous component are also associated with a greater risk of early recurrence and shortened overall survival.