Sarcomatoid Transformation in Carcinomas: Is Precision Medicine the Answer?

Sarcomatoid transformation in a carcinoma is a rare event but frequently associated with advanced disease stage, aggressive clinical behavior and dismal prognosis. It’s likely a result of stepwise gene mutations in pluripotent stem cell and involves the epithelial to mesenchymal transition (EMT). In this review, we discuss the sarcomatoid transformation in various types of cancers. Sarcomatoid transformation in a carcinoma should always be in the differential when there is a sudden increase in size of the tumor during neoadjuvant therapy. Use of agents that interfere with the tyrosine kinase pathway might be the new potential addition to the chemotherapy regimen in these cases. Precision medicine, a rapidly emerging field, seems to be promising in the management of these cancers.


Introduction
Occurrence of biphasic tumors has been known since 1940s. However, it is being increasingly recognized that this is mainly due to the sarcomatoid transformation in cancer which involves a decrease in epithelial component and increase in mesenchymal component. This morphology is associated with distant metastases, resistance to conventional neoadjuvant therapy and dismal prognosis. Several hypotheses have been postulated to explain its biological process. However, there is increasing evidence supporting the origin of these tumors from a single pluripotent stem cell. Multiple stepwise mutations in these cells leads to sarcomatoid transformation 1 . Increased proliferation of mesenchymal component or increased epithelial-to-mesenchymal transition (EMT), is likely responsible for this process 2 .

Epithelial to mesenchymal transition
One important feature is that after the transformation, a portion of the tumor become spindle in shape and shows immunoreactivity to mesenchymal markers such as vimentin, fibronectin, and smooth muscle actin, with a decreased expression of originally epithelial cytokeratin markers 3 . The underlying molecular mechanisms is not entirely clear at this moment. Tumor growth factor-β (TGF-β), epithelial growth factor (EGF) and insulin like growth factor (IGF) have been implicated in the sarcomatoid transformation 4 . The tumors upon treatment (radiotherapy and/or chemotherapy) may also acquire resistance through mutations and leads to biphasic appearance.
The sarcomatoid transformation frequently occurs when the tumor cells undergo EMT to manifest aggressive behavior and invasion [5][6] . EMT enables the carcinoma cells to overcome physical barrier imposed by intercellular junctions 7 . It's also associated with an alteration in the tumor microenvironment 5 . The EMT can be induced in vitro by interfering with the tyrosine kinase signaling pathway and oncogene expression. The transformed mesenchymal cells show decreased expression of beta-catenin, E-cadherin and Alpha catenin 5,7 . Meanwhile the upregulation of cytoskeletal proteins confers motility and pseudopod formation and hence increased invasiveness of these cells 7 .

Molecular alterations involved in Epithelial Mesenchymal transition
TGF-β is an important regulator of tumor progression. It acts as a tumor suppressor through activation of Smad mediated signaling pathway (Smad 2, Smad 3 and Smad 4). However, it could also contribute to tumorigenesis and in particular promote EMT through the mitogen-activated protein kinase (MAPK) Pathway 8 . Upregulation of Hic-5, a focal adhesion protein in epithelial cancer cells, is seen due to TGF-β stimulation 9 . Hic-5 is responsible for maintaining the mesenchymal phenotype with continued activation of RhoA 9 .
Ras, Src, Phosphatidylinositol-3 kinase (PI3K), RhoC, Rac1 and MAPK are considered as the downstream kinases implicated in the EMT 7,10 . These genes in turn regulate the expression of cadherin proteins. EMT is mainly driven by Ras/MAPK pathway 10 . Increased expression of Src was found in a study on cancer cell lines with sarcomatoid transformation 11 . These changes lead to mesenchymal morphology, with increased motility and invasiveness of the tumor cells (Figure1). NF-κB is also implicated in the EMT pathway, though its role is poorly understood 7,10 . EGFR T790M mutation and MET amplification have also been implicated in the sarcomatoid transformation of lung cancer 12 .

Sarcomatoid transformation in Head and neck cancers
For head and neck cancers, the sarcomatoid transformation most commonly occurs in larynx 13-14 but could also be found in tongue 15 , gingiva 16 , hypopharynx, oral cavity, oropharynx 17 and nasopharynx. 18 Ionizing radiation therapy is implicated as one of the etiologic agents 14 . Co-expression of keratin and intermediate filaments was identified in these tumors 19 . The loss of heterozygosity in chromosome 17p was the most remarkable finding in sarcomatoid component while both epithelial and sarcomatoid components shared other mutations. These findings support a single epithelial origin of these tumors and molecular progression responsible for this transformation 13,20 .

Sarcomatoid transformation in Lung cancer
Lung cancer is the leading cause of cancer related deaths worldwide. In lung cancers with typical gene mutations (EGFR and ROS1) and morphology of adenocarcinoma, sarcomatoid transformation was observed after treatment with tyrosine kinase inhibitor after a mean interval of 31.5 months. Transformation to sarcomatoid type is present along with giant cell changes, discohesive cells, strong vimentin expression, loss of E-cadherin expression and high PDL-1 expression 21 . c-MET gene overexpression was also observed in 5 out of the 6 cases in this study 21 . This transformation might represent a resistance mechanism upon neoadjuvant therapy 21,22 .
There is a recent case report on a patient with an initial diagnosis of pulmonary squamous cell carcinoma. After radiotherapy, there was rapid increase in size of the tumor, and a sarcomatoid change with predominant sarcomatous component was observed. These sarcomatoid foci showed weak immunoreactivity to cytokeratin and strong immunoreactivity to vimentin 3 .

Mesenchymal
(sarcomatoid) differentiation in mesothelioma is seen in 5-10% of cases and about twothirds of these cases are associated with distant metastases, while in typical epithelioid mesotheliomas only one third of the cases are associated with metastases 4 .

Sarcomatoid transformation in Breast cancer
Sarcomatoid transformation in breast cancer is a rare occurrence. The carcinosarcomas of the breast present as well circumscribed, hypoechoic mass 23 . These tumors are usually Her-2/neu negative and behave similar to triple negative adenocarcinomas with early metastases and overall poor survival 24 . With fine needle aspiration, the sarcomatoid component can be underdiagnosed due to its focality. It is always important to keep a carcinosarcoma in differential when the tumor is rapidly growing, shows early metastases and has radiologic features suggestive of a sarcomatous component.

Sarcomatoid transformation in Genitourinary cancers
Presence of sarcomatoid change is seen in 5% of renal cancers and can be seen in up to 20% of cases with advanced disease. The sarcomatoid change is associated with extreme nuclear pleomorphism and multinucleated giant cells and is categorized by World Health Organization (WHO) as Grade IV according to WHO/ International society of Urologic Pathology grading for clear cell and papillary renal cell carcinoma 25 . It has also been reported in chromophobe renal cell carcinoma and is associated with poor prognosis 26 . Sarcomatoid renal cell cancer are usually large and associated with poor prognosis with median survival of 6 months and higher percentage of sarcomatoid components confers worse prognosis in these patients 27 .
The hypoxia inducible pathway markers were expressed in sarcomatoid clear cell renal cell cancer, supporting a common origin of the epithelioid and sarcomatoid components. However the mechanism underlying non-clear cell sarcomatoid renal cell carcinoma appears to be different 28,29 . Overexpression of vascular endothelial growth factor (VEGF) was observed in majority of the clear cell and non-clear cell sarcomatoid renal cell cancers and a VEGF targeted therapy might play a promising role in treatment of these tumors 28,29 .
In a study done by Bi et al, twenty-nine cases of sarcomatoid renal cancers were selected. The carcinomatous and sarcomatoid elements were separated and whole exome sequencing was independently performed. The study revealed that the carcinomatous and sarcomatoid elements shared 41.7% of somatic single nucleotide variants (SSNVs), providing a strong evidence that both components arise from a single cell of origin that might undergo stepwise somatic mutations 30 . The frequency of TP53 mutations was higher in the sarcomatous component (31.6%) when compared to that in carcinomatous components (0%) 30 . The sarcomatoid renal cell cancers express programmed death-1 (PD-1) and programmed death ligand-1 (PDL-1) at a higher rate than their non sarcomatoid counterparts 31 . Expression of PD-1/ PDL-1 is also associated with higher tumor grade, necrosis and worse clinical outcomes 32 . Expression of these ligands may confer responsiveness to anti PD-1/ PDL-1 therapy in these tumors 31 . Sarcomatoid transformation has also been observed in a mature cystic teratoma of ovary 33 and urinary bladder 34,35 .

Sarcomatoid transformation in Gastrointestinal cancers
Sarcomatoid transformation is rare in gastrointestinal tract cancers. In 1989, a study described anaplastic sarcomatoid morphology in the carcinoma of small intestine in six cases, and indicated poor prognosis with the presence of sarcomatoid morphology 36 . A case of duodenal sarcomatoid carcinoma showed predominant pleomorphic cells without glandular differentiation which were positive for cytokeratin and vimentin 37 . It has also been reported in the jejunum, where the patient presented with acute abdominal pain and small bowel perforation. This case had favorable prognosis likely due to low Ki-67 proliferation index of the tumor, and the patient was recurrence free at 7 months of follow up. 13 Another case with similar presentation in jejunum had an aggressive tumor showing immunoreactivity to cytokeratin, vimentin, and focal positivity for epithelial membrane antigen. Electron microscopy of the sarcomatoid component revealed irregular nuclei with prominent nucleoli, stacks of rough endoplasmic reticulum and intermediate filaments in the cytoplasm [38][39][40] . The intestinal sarcomatoid carcinoma is similar in morphology to the pleomorphic giant cell carcinomas of the lung with alveolar growth pattern and discohesive cells 39 . The sarcomatoid carcinoma of the small intestine is commonly present at an advanced stage with distant metastases 41 , and it is necessary to distinguish sarcomatoid tumors from other spindle cell tumors of the GI tract such as gastrointestinal stromal tumor, schwannoma and leiomyosarcoma. There are reports of sarcomatoid transformation in the hepatocellular carcinoma and combined hepatocellular cholangiocarcinoma 42,43 . This change could present after radiofrequency ablation 44 . Accumulation of mutated p53 protein might be responsible for this transformation and the associated aggressive behavior of these tumors 45 .

Role of precision medicine
Predictive, preventive, and personalized medicine (PPPM) is a promising and emerging field in the cancer management. PPPM, including the next generation sequencing (NGS), has provided a rapid and accurate platform for diagnosing cancer and tailoring cancer treatment to the individual characteristics of a patient 47 . Cancer development frequently involves specific genetic alterations. Identifying the mutations involved in sarcomatoid transformation and a personalized approach to each patient might be a better approach in treating these cancers as they are resistant to conventional chemotherapy and radiation therapies. The use of "omics", a combination of genomics, transcriptomics, proteomics, metabolomics and radiomics, with the application of NGS, high performance liquid chromatography (HPLC), Mass spectrometry (MS) and nuclear magnetic resonance technology might be the answer to the challenges faced in the treatment of these cancers 48 . Cancer is associated with chronic inflammation and detection of biomarkers of chronic inflammation in various types of cancer might help in prevention and early diagnosis of cancer 49 . Identifying the specific biomarker panel for a type of cancer through liquid biopsy and combining this with multi-omic approach might help in better patient stratification and personalized therapy for each patient 50 . Furthermore, a multiomic approach using machine learning may serve as an ideal tool for patient stratification and identifying the individuals at high risk 51 .

Conclusion
Sarcomatoid transformation could occur in many cancer types, and is associated with stepwise gene mutation leading to aggressive clinical behavior. Etiologic agents include ionizing radiation and chemotherapeutic agents, but the sarcomatoid transformation has also been reported to arise de novo. TGF-β appears to play an important role in this transformation. The transformed cancers share many mutations with the original epithelial cancers (up to 41%) supporting the monoclonal origin. The involvement of tyrosine kinase pathway in this transformation might lead to targeted therapy. Sarcomatoid transformation in a carcinoma should always be in the differential when there is a sudden increase in size of the tumor, and an effective treatment plan is extremely important. Use of agents that interfere with the tyrosine kinase pathway might be the new potential addition to the chemotherapy regimen in these cases. Precision medicine is a promising emerging field which might help in the treatment of these tumors and further exploration of this field in Sarcomatoid carcinomas is warranted.

Conflicts of Interest
Juwairiya Arshi, MD and Feng Yin MD, PhD have no disclosures.

Funding Information
None