What Is Pleomorphic Carcinoma: A Look At This Rare Cancer

Pleomorphic carcinoma is a rare, aggressive form of cancer most often found in the lung, where it accounts for roughly 0.1 to 0.4 percent of all lung malignancies.¹ It belongs to a family of tumors called sarcomatoid carcinomas, which means that under a microscope the cancer cells look partly like a typical carcinoma and partly like a sarcoma, a cancer of connective tissue. That dual personality makes it harder to diagnose, harder to treat with standard chemotherapy, and generally more aggressive than common forms of non-small cell lung cancer. Because it is so uncommon, much of what doctors know about it comes from case reports and small studies rather than large randomized trials, and the picture is still evolving.

What Makes Pleomorphic Carcinoma Different Under the Microscope

The defining feature of pleomorphic carcinoma is its mixed appearance. The World Health Organization classifies it as one of five subtypes of sarcomatoid lung carcinoma. To earn the label, a tumor must contain a recognizable conventional carcinoma component, usually adenocarcinoma, squamous cell carcinoma, or large cell carcinoma, combined with spindle-shaped or giant cells making up at least 10 percent of the tumor.² Alternatively, the tumor can be made up entirely of giant and spindle cells without any conventional carcinoma component at all. In practice, pathologists often see a patchwork: one reported case, for instance, was roughly half spindle cells, 30 percent giant cells, and 20 percent adenocarcinoma cells.²

This mixture matters for diagnosis because a small biopsy might sample only one part of the tumor. If the needle hits the adenocarcinoma portion, a pathologist could easily call it ordinary lung adenocarcinoma. If it hits the spindle-cell portion, the tumor could be mistaken for a sarcoma or another rare lung cancer. Getting enough tissue, often through surgery rather than a needle biopsy, is important for an accurate diagnosis.

Who Gets It

Pleomorphic carcinoma of the lung overwhelmingly affects older men with a history of smoking. Population-level data from the United States show a mean age at diagnosis of about 66 years, with roughly 58 percent of patients being male and 80 percent being white.¹ Surgical case series tend to skew even more male; one study of 45 consecutive patients who had surgery for pulmonary pleomorphic carcinoma found 41 men and just 4 women.³ Smoking is the dominant risk factor, though asbestos exposure has also been implicated and the two appear to act together synergistically.⁴ Rare cases in lifelong non-smokers with occupational asbestos exposure have been documented, but the overwhelming majority of patients have a significant smoking history.

Most tumors show up in the upper lobes of the lung, with about 56 percent found there, and a slight preference for the right lung over the left.¹ These tumors also tend to sit toward the outer edges of the lung rather than centrally near the major airways.

Symptoms and How It Shows Up on Imaging

The symptoms of pleomorphic carcinoma are frustratingly generic. Patients commonly report a persistent cough, coughing up blood, chest pain, shortness of breath, and fever.⁵ Some patients have no symptoms at all and discover the tumor incidentally on a chest scan done for another reason. Nothing about the symptom profile points specifically toward pleomorphic carcinoma rather than any other lung cancer, which is one reason it so often comes as a surprise at the pathology stage.

On CT scans, the tumors tend to be peripheral masses, sitting at the lung’s outer edge rather than blocking a central airway. Larger tumors, those over five centimeters, typically show a ring of enhancement around a dark center when contrast dye is used. That central low-density area usually corresponds to dead tissue, hemorrhage, or a jelly-like degeneration called myxoid change.⁶ Smaller tumors tend to light up more evenly. Radiologists have also noted that some of these tumors grow remarkably fast; in one study, two large tumors visibly increased in size in under three weeks of follow-up.⁶ Invasion of the chest wall or the lining of the lung is not unusual, which can sometimes be the first clue that this is not a run-of-the-mill lung cancer.

Nailing Down the Diagnosis

Because the tumor’s mixed composition can fool a small biopsy, pathologists rely on a combination of tissue appearance and specialized staining. Pleomorphic carcinomas typically light up for cytokeratin markers like AE1/AE3 and CAM5.2, which confirm an epithelial (carcinoma) origin, along with vimentin, which tags the sarcoma-like component. Lung-specific markers such as TTF-1 and Napsin-A are often positive in the carcinoma portion, helping confirm the tumor started in the lung rather than spreading there from somewhere else.⁷

One study of 75 sarcomatoid lung carcinomas concluded that cytokeratin 7 and TTF-1 are the most useful stains for telling these tumors apart from true sarcomas, and that the evidence supports the idea that the sarcomatoid cells arise from ordinary carcinoma cells that have transformed, rather than being a separate cancer growing alongside them.⁸ The practical takeaway for patients is that if an initial biopsy calls the tumor a sarcoma but it is in the lung, pathologists should consider pleomorphic carcinoma and run additional stains.

Genetic Landscape and Why It Matters for Treatment

Pleomorphic carcinoma does not share the same mutation profile as ordinary lung adenocarcinoma, and that has real consequences for treatment. In one study using next-generation DNA sequencing on nine patients, TP53 mutations were the most common, found in five patients. MET alterations showed up in two patients, and single cases carried mutations in ALK, ERBB2, PIK3CA, APC, NF1, and CDKN2A. No EGFR mutations were detected at all.⁹ EGFR mutations drive a large share of lung adenocarcinomas and are the target of several highly effective drugs, so their absence in pleomorphic carcinoma rules out one of the most successful treatment pathways in lung cancer.

MET exon 14 skipping mutations, however, appear to be more common in pleomorphic carcinoma than in typical lung cancers.¹⁰ That is clinically relevant because targeted drugs against MET already exist and are approved for other lung cancers. For the minority of pleomorphic carcinoma patients who do carry a targetable mutation, molecular testing can open a door that standard chemotherapy cannot. One case report described a patient whose tumor carried uncommon complex EGFR mutations and responded to osimertinib, an oral targeted therapy, with shrinkage of both the lung tumor and brain metastases.¹¹ These are exceptions rather than the norm, but they illustrate why comprehensive genomic profiling matters even in a cancer this rare.

Surgery, Chemotherapy, and a Difficult Prognosis

For tumors caught early enough, surgery is the main treatment, and it offers the best shot at long-term survival. Even so, the numbers are sobering. In a surgical series of 45 patients, five-year overall survival was about 39 percent and disease-free survival was about 47 percent.¹² Two features stood out in that study. First, vascular invasion was remarkably common even in patients whose lymph nodes tested negative, occurring in over half of such cases. Second, when the cancer recurred, it usually showed up at distant sites rather than locally, and half of all recurrences happened within just six months of surgery.¹² That rapid pattern of distant spread is what makes this cancer so dangerous and what separates it from more common lung cancers at the same stage.

Chemotherapy has historically been a weak tool against pleomorphic carcinoma. The response rate to regimens that work reasonably well for standard non-small cell lung cancer has been reported at only 0 to 17 percent in pleomorphic carcinoma.¹³ That said, some patients do respond. A report of two patients treated with carboplatin plus paclitaxel showed marked tumor shrinkage and long-term survival without progression, suggesting that platinum-based doublet chemotherapy can sometimes work even against a cancer known for chemoresistance.¹³ The difficulty is predicting in advance which patients will benefit and which will not.

The same study that confirmed this cancer has a worse prognosis than conventional non-small cell lung cancer also found that disease stage at diagnosis remained the strongest predictor of outcome, just as it is for more common lung cancers. The difference is that at the same early stage, pleomorphic carcinoma patients fared worse than those with conventional tumors.⁸

The Promise of Immunotherapy

The most encouraging development in recent years has been the potential role of immunotherapy, specifically checkpoint inhibitors that target PD-1 or its partner PD-L1. Pleomorphic carcinomas appear to express PD-L1 at unusually high rates. In one study, 60 percent of patients had PD-L1 expression at 50 percent or above, a level that generally predicts a better response to checkpoint inhibitors in lung cancer.¹⁴ A separate study found that about 75 percent of sarcomatoid lung carcinomas, the broader family that includes pleomorphic carcinoma, were PD-L1 positive.¹⁵

The relationship between PD-L1 expression and prognosis in this cancer is not straightforward, though. High PD-L1 in the sarcomatoid portion of the tumor was linked to shorter relapse-free survival in one analysis, while high PD-L1 in the conventional carcinoma portion was actually an independent favorable factor for overall survival in another.¹⁶ What this means in practice is that PD-L1 status in pleomorphic carcinoma should be interpreted carefully, and the specific component of the tumor being tested may matter more than in a typical lung cancer biopsy.

Still, case reports show genuinely dramatic responses. One 73-year-old man with pulmonary pleomorphic carcinoma received a single dose of pembrolizumab, a PD-1 inhibitor, before treatment had to be stopped due to drug-related pneumonitis. Despite never receiving a second dose, his tumor continued shrinking and the response lasted more than 17 months.¹⁷ Another report described two patients who responded to a combination of a PD-1 inhibitor and anlotinib, a multi-target drug that blocks new blood vessel growth in tumors.¹⁰ These are individual cases, not trial data, but for a cancer that resists conventional chemotherapy, they represent a meaningful shift in how oncologists think about treatment options.

Unusual Metastatic Behavior

Pleomorphic carcinoma does not always follow the metastatic playbook of ordinary lung cancer. While the brain, bones, and liver are common destinations for most lung cancers, pleomorphic carcinoma has a tendency to spread to the gastrointestinal tract, a site that other lung cancers rarely target. Bowel metastases can cause bleeding, bowel obstruction, perforation, and in rare cases intussusception, where one section of the intestine telescopes into another.¹⁸ Small bowel metastasis has also been reported after curative surgery for the primary lung tumor.¹⁹

This matters clinically because abdominal symptoms in a patient with a history of pleomorphic carcinoma should not be dismissed as unrelated. A sudden onset of abdominal pain, bleeding, or signs of obstruction could represent metastatic disease that needs prompt attention, even years after the original lung tumor was removed.

Pleomorphic Carcinoma Outside the Lung

Although the lung is the most studied and discussed site, the term “pleomorphic carcinoma” is not exclusive to it. Pleomorphic carcinomas of the pancreas, for example, have been described as a distinct pathological entity. These pancreatic tumors share the same bizarre giant cells and sarcoma-like growth pattern seen in the lung version, and they tend to arise in the body or tail of the pancreas rather than the head. Compared with ordinary pancreatic adenocarcinoma, pleomorphic carcinoma of the pancreas spreads more often through the bloodstream, nearly always metastasizes, and carries an even shorter median survival.²⁰ Pleomorphic carcinomas have also been documented in other organs, including the thyroid, salivary glands, and skin. These are all exceedingly rare and share the common thread of aggressive behavior, mixed cell populations, and generally poor response to standard treatments for cancers at those sites.

Living With the Diagnosis

Because pleomorphic carcinoma is so rare, newly diagnosed patients often find little information and few fellow patients to talk to. The psychological burden of a rare cancer diagnosis can be acute: you are dealing with all the distress of a cancer diagnosis plus the isolation of having something almost no one has heard of, including some doctors. Advanced lung cancer patients in general report high levels of pain, fatigue, shortness of breath, cough, depression, and anxiety, and surveys consistently show that more than half continue to suffer from many of these symptoms even a year after diagnosis.²¹ Patients with lung cancer also tend to experience higher levels of psychological distress than those with many other cancer types.²¹

Early integration of palliative care, which focuses on symptom management and quality of life rather than cure, has shown benefits in advanced lung cancer broadly and is especially relevant for a subtype where aggressive treatment options are limited. Palliative care does not mean giving up on treatment; it means adding a layer of support focused on comfort, communication, and helping patients make informed decisions about what matters most to them.

Emerging Tools for Monitoring

One of the newer areas of research involves liquid biopsy, the analysis of blood samples for circulating tumor cells, tumor DNA fragments, or tiny cell-derived particles called extracellular vesicles. For a cancer that is hard to biopsy repeatedly and prone to early distant spread, a blood test that could track disease activity would be a significant step forward. Early work suggests that liquid biopsy could help characterize the aggressiveness of pleomorphic carcinoma and track its relationship to recurrence and death, although the research remains at the case-report stage.²² The concept is especially appealing because tumor tissue from surgical resections may not reflect the mutation profile of a recurrent or metastatic tumor months later, and a blood draw is far less invasive than a repeat biopsy of the lung or a distant metastatic site.

For now, liquid biopsy for pleomorphic carcinoma is a research tool rather than a clinical standard. But given the rapid pace of liquid biopsy development across oncology more broadly, it is an area worth watching, particularly for patients who are already undergoing molecular profiling and immunotherapy and whose treatment could be adapted in real time based on what their blood reveals.

1
PubMed Central. Clinicopathological characteristics, survival outcomes and prognostic factors in pleomorphic carcinoma: a SEER population-based study
2
PubMed Central. Pulmonary pleomorphic carcinoma: A case report and review of the literature
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PubMed. Pleomorphic carcinoma of the lung: a surgical outcome
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PubMed. Pleomorphic carcinoma of lung: comparison of CT features and pathologic findings
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PubMed Central. Pulmonary Pleomorphic Carcinoma Mimicking Primary Sarcoma of the Neck: A Case Report and Literature Review
8
PubMed. Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: a clinicopathologic and immunohistochemical study of 75 cases
9
PubMed Central. Analysis of targeted somatic mutations in pleomorphic carcinoma of the lung using next-generation sequencing technique
10
PubMed. Two different patients with pulmonary pleomorphic carcinoma response to PD-1 inhibitor plus anlotinib
11
PubMed Central. A rare case of double primary lung adenocarcinomas with uncommon complex EGFR G719X and S768I mutations and pleomorphic carcinoma
12
Journal of Thoracic & Cardiovascular Surgery. Pleomorphic carcinoma of the lung: A surgical outcome
13
PubMed Central. Successful treatment of two consecutive cases of pulmonary pleomorphic carcinoma with platinum chemotherapy
14
PubMed Central. A High PD-L1 Expression in Pulmonary Pleomorphic Carcinoma Correlates with Parietal-pleural Invasion and Might Predict a Poor Prognosis
15
PLOS ONE. PD-L1 expression in pleomorphic, spindle cell and giant cell carcinoma of the lung is related to TTF-1, p40 expression and might indicate a worse prognosis
16
PubMed. Prognostic impact of the tumor immune microenvironment in pulmonary pleomorphic carcinoma
17
Respiratory Medicine Case Reports. Single pembrolizumab treatment causing profound durable response in a patient with pulmonary pleomorphic carcinoma
18
PubMed Central. Colonic metastases from pleomorphic carcinoma of the lung presenting as an ileocecal intussusception
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Tuberculosis and Respiratory Diseases. Single Small Bowel Metastasis after Curative Operation in a Pleomorphic Lung Carcinoma
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PubMed. Pleomorphic carcinoma of the pancreas: an analysis of 15 cases
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PubMed Central. The role of palliative care in the management of patients with lung cancer
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PubMed Central. Liquid biopsy perspectives in pleomorphic carcinoma of the lung: case report