Sarcomatoid neoplasms of the lung and pleura

Sarcomatoid neoplasms of the lung and pleura are rare tumors that present a complex differential diagnosis, making them challenging for surgical pathologists. In the lung, the main tumors are the sarcomatoid carcinomas, including pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. They are characterized by histologic heterogeneity; molecular data support their origin from a pluripotent stem cell that undergoes neoplastic transformation with divergent epithelial and sarcomatous differentiation. Diagnosis is difficult in small biopsy specimens and typically requires a resection specimen. Despite the presence of sarcomatoid features, these tumors are classified as lung carcinomas. Pulmonary blastomas must be distinguished from pleuropulmonary blastomas, which are a unique type of thoracic sarcoma typically occurring in young children. In the pleura, the main tumors to consider are the sarcomatoid and desmoplastic types of malignant mesothelioma, solitary fibrous tumor, and desmoid tumor. While light microscopy is sufficient to diagnose most of these tumors, immunohistochemistry can be useful in selected settings. In particular, it can aid to confirm epithelial differentiation in spindle cell carcinomas and the presence of rhabdomyosarcoma in sarcomatoid carcinomas, mesotheliomas, or pleuropulmonary blastomas. For sarcomatoid and desmoplastic mesothelioma, keratin is the most useful stain because it can highlight invasive growth and mesothelial markers are positive in only the minority of cases. Clinical and radiologic correlation is needed to separate some pleomorphic carcinomas with pleural involvement from sarcomatoid malignant mesothelioma, since these poorly differentiated tumors may not express the usual immunohistochemical markers for carcinoma or mesothelioma.     

Spindle basaloid squamous carcinoma of the upper aerodigestive tract: immunohistochemical and clinicopathological study of three cases

We describe the clinicopathological and immunohistochemical features of three spindle (sarcomatoid) basaloid squamous carcinomas in three men aged 73, 69, and 59 years with a history of tobacco and alcohol abuse. Two tumors were located in the hypopharynx and one was located in the nasal cavity. The three tumors have a pedunculated polypoid appearance. Histologically, they were composed of conventional basaloid squamous carcinomas with extensive malignant spindle cell proliferation, comprising more than 50% of the tumor. The sarcomatoid component demonstrated immunoreactivity with one or more epithelial markers. One case in addition expressed CD99 and Bcl-2 and was originally diagnosed as monophasic synovial sarcoma; however, a subsequent biopsy disclosed basaloid squamous cell carcinoma with sarcomatoid stroma. Two patients were treated with surgery and radiation whereas one refused therapy. The patients were alive 14 (case patient 1), 10 (case patient 2), and 8 (case patient 3) months after diagnosis. In the absence of evidence from immunohistochemical or electron microscopy studies, a polypoid malignant spindle cell tumor of a mucosal surface of the upper aerodigestive tract should be considered a sarcomatoid carcinoma until proven otherwise. The type of epithelial component would determine the subtype of sarcomatoid carcinoma.     

Sarcomatoid carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical analysis of 14 patients

Sarcomatoid carcinoma of the urinary bladder is a rare entity, in which both the histogenesis and biological behavior remain controversial. We herein describe the clinicopathologic and immunohistochemical profiles of sarcomatoid carcinomas and discuss the significance of cell adhesion molecules in the development of this peculiar neoplasm. The authors examined formalin-fixed and paraffin-embedded tissue samples from 14 patients with sarcomatoid carcinoma of the urinary bladder. An immunohistochemical analysis was performed by using antibodies against epithelial and mesenchymal antigens as well as adhesion molecules. Most patients suffered from an advanced stage of the tumor, extending to the muscular layer (7 cases) or to the perivesical tissues (5 cases). Microscopically, all 14 tumors were composed predominantly of a carcomatoid component and an obviously carcinomatous component. The sarcomatoid component was composed of a mixture of spindle cells, round cells, and pleomorphic giant cells. The carcinomatous components consisted of papillary or nonpapillary high-grade transitional cell carcinoma (TCC). The zones of gradual transition between the carcinomatous and the sarcomatous elements were focally apparent in each tumor. The findings of an immunohistochemical examination indicated that both carcinomatous and sarcomatoid components expressed epithelial antigens (pankeratin or EMA), even though the staining pattern varied from case to case. As for cell adhesion molecules, the carcinomatous components were positive for E-cadherin (8 of 12), CD44s (8 of 12), and CD44v6 (6 of 12). Although the sarcomatoid components were also positive for E-cadherin (5 of 12), CD44s (4 of 12), and CD44v6 (3 of 12), these rates were lower than those in the carcinomatous components. Six patients died of their disease between 5 and 36 months after the diagnosis was made. The recognition of sarcomatoid carcinomas has important therapeutic and prognostic implications. It seems appropriate to treat these neoplasms in the same manner as conventional high-grade TCCs with similar degrees of invasion. We consider that sarcomatoid carcinomas should be regarded as a high-grade carcinoma that shows a prominent pseudosarcomatous dedifferentiation. The sarcomatoid component of sarcomatoid carcinomas may result from either anaplastic changes or dedifferentiation related to the process of losing cell adhesion molecules.     

Immunohistochemical Biomarkers of Mesenchymal Neoplasms in Endocrine Organs: Diagnostic Pitfalls and Recent Discoveries

Mesenchymal neoplasms rarely present in or adjacent to endocrine organs. In this context, the recognition of these rare tumor types can be challenging, with significant potential for misdiagnosis as sarcomatoid carcinomas (i.e., anaplastic thyroid carcinoma and sarcomatoid adrenal cortical carcinoma) or neuroendocrine carcinomas, depending upon the dominant histologic patterns. In this review, we address potential pitfalls in diagnosing selected mesenchymal neoplasms arising within or near endocrine organs, including dedifferentiated liposarcoma, synovial sarcoma, angiosarcoma, PEComa, proximal-type epithelioid sarcoma, Ewing sarcoma, and neuroblastoma. For each of these tumor types, we review clinical and pathologic features, histologic clues to distinguish them from endocrine neoplasms, and recently developed immunohistochemical markers that can be particularly useful for establishing the correct diagnosis.     

Immunohistochemical detection of Fas and Fas ligand in sarcomatoid renal cell carcinoma

Sarcomatoid renal cell carcinomas (SRC) are rare neoplasms associated with a very poor prognosis. The aim of this study was to evaluate biomarker expression and clinical significance in this uncommon renal cancer. Cytokeratin, epithelial membrane antigen, vimentin, desmin, smooth muscle actin, CD34, S-100 protein, MIB 1, p53, Fas and Fas ligand immunohistochemical expression was investigated in seven renal cell carcinomas with sarcomatoid changes. No significant difference between sarcomatoid and nonsarcomatoid areas was observed with the different biomarkers, excepted for Fas ligand. Fas expression was diffuse in sarcomatoid and nonsarcomatoid areas. However, Fas ligand had a higher expression in sarcomatoid in comparison to nonsarcomatoid areas. Our results showed that Fas and Fas ligand are both expressed in renal cancer. We suggest that the aggressive behavior of sarcomatoid carcinoma may be related to a higher expression of Fas ligand by tumor sarcomatoid cells. These findings may indicate that Fas ligand is a possible therapeutic molecular target for treatment of SRC.     

Chromosomal gains in the sarcomatoid transformation of chromophobe renal cell carcinoma.

The hallmark of chromophobe renal cell carcinoma is multiple chromosomal losses from among chromosomes 1, 2, 6, 10 and 17. Chromophobe renal cell carcinoma with distant metastases or sarcomatoid transformation are uncommon and little is known about their chromosomal abnormalities. We collected six sarcomatoid chromophobe renal cell carcinomas and three primary chromophobe renal cell carcinomas with distant metastases. A cytogenetic analysis by fluorescent in situ hybridization on paraffin-embedded tissue was performed using centromeric probes for chromosomes 1, 2, 6, 10 and 17. We found more than one signal in four of six (66%) sarcomatoid chromophobe renal cell carcinomas, in both sarcomatoid and adjacent epithelial components. Both primary chromophobe renal cell carcinomas and matched metastases showed single signals for all chromosomes studied in two cases and no abnormalities in the remaining case. We concluded that: (1) both epithelial and sarcomatoid components of sarcomatoid chromophobe renal cell carcinoma show different genetic abnormalities from those characteristic of chromophobe renal cell carcinoma; (2) sarcomatoid chromophobe renal cell carcinomas frequently have multiple gains (polysomy) of chromosomes 1, 2, 6, 10 and 17; (3) distant metastases show the same genetic patterns, usually chromosomal losses (monosomy), found in the primary tumors.     

Spindle cell tumours of the breast: practical approach to diagnosis

Spindle cell tumours of the breast are uncommon and often present diagnostic challenges. The most important is the sarcomatoid/metaplastic carcinoma, which has monophasic and biphasic variants. Each of these groups presents special diagnostic difficulties. In the monophasic variant the mesenchymal component predominates and the epithelial element forms a minor component often detected only after immunohistochemical study. The spindle cell areas may be bland and therefore under-diagnosed as nodular fasciitis or fibromatosis. Alternatively they may be highly malignant with a pattern that is misinterpreted as primary sarcoma of the breast. In the biphasic variant, the difficulty is in distinguishing between sarcomatoid carcinoma, myoepithelial carcinoma or malignant phyllodes tumour. Other spindle cell lesions of the breast include the various myofibroblastic tumours, the spindle cell variant of adenomyoepithelioma, the varied primary breast sarcomas, metastatic tumours with spindle cell morphology and, finally, the very rare follicular dendritic cell tumour. A simple practical approach to the diagnosis of spindle cell lesions is presented to help the general surgical pathologist to compile a differential diagnosis and to arrive at the correct conclusion     

A spindle cell tumour in the bladder

Spindle cell lesions in the bladder can be challenging and present a wide differential diagnosis. We report a case of one of these diagnoses - sarcomatoid variant of urothelial carcinoma. We also describe how to differentiate between benign and malignant mimics and discuss the molecular features of sarcomatoid variant of urothelial carcinoma.     

Uncommon tumours in the adult bladder: rare entities with recognized diagnostic pitfalls

Non-urothelial neoplasms and masses in the bladder such as myofibroblastic and smooth muscle proliferations, paraganglioma and lymphoma are uncommon. Nonetheless, pathologists must correctly classify these lesions to ensure optimal patient management. It is also recognized that particular entities in each of the aforementioned categories can be misconstrued as urothelial carcinoma or a spindle cell variant of urothelial carcinoma. This review will cover the clinicopathological features of selected lesions in the adult bladder including; myofibroblastic proliferations (occurring with antecedent trauma or spontaneously), smooth muscle neoplasms, sarcomatoid carcinoma, paraganglioma and lymphoma. The morphologic, immunohistochemical and, where appropriate, molecular/cytogenetic features described herein should help pathologists correctly classify these uncommon lesions.     

Diagnostic Controversies in Vascular Proliferations of the Thyroid Gland

Vascular lesions are one of the most controversial issues in thyroid pathology. The differential diagnosis includes benign lesions on one side, i.e., endothelial reactive hyperplasia (Masson’s “hemangioma”) in goiter and hemangioma, and malignant tumors on the other, i.e., angiosarcomas and undifferentiated (angio)sarcomatoid carcinomas. Benign reactive endothelial hyperplasia with atypias mimicking malignant tumors may occur in long-standing nodular goiter, as a result of spontaneous hemorrhage followed by granulation tissue and fibrous organization. Alternatively, it may follow a fine-needle aspiration biopsy (FNAB) procedure. Angiosarcoma is a rare primary malignant thyroid tumor, mainly observed in endemic goiter areas displaying morphologic and phenotypical similar to those typical of angiosarcomas in other locations (including focal cytokeratin expression). The distinction between angiosarcoma and (angio)sarcomatoid anaplastic carcinoma is difficult and the true existence of angiosarcoma has been challenged. Other extremely rare vascular lesions or mimics in the thyroid include benign hemangioma and pseudo-angiosarcomatous variant of medullary carcinoma. The differential diagnosis between benign and malignant vascular conditions in FNAB material is extremely challenging, and the cytopathology report should be remarkably cautious, especially in poorly cellular and highly hemorrhagic cases: atypias in endothelial cells are not per se indicative of malignancy, being a common feature of reactive endothelial hyperplasia in infracted goiter nodules as well.     

Morphological features useful in the differential diagnosis between undifferentiated carcinoma and gastrointestinal stromal tumor

Undifferentiated (sarcomatoid) carcinomas may closely mimic gastrointestinal stromal tumors (GISTs) due to possible histological and immunohistochemical overlap between these two entities. To avoid unnecessary employment of a wide spectrum of immunohistochemical stainings and molecular genetics and thus decrease costs, finding simple morphological features to target further investigation of such neoplasms of the gastrointestinal tract would be helpful.Five cases classified as undifferentiated (sarcomatoid) carcinomas with a definite proof of the diagnosis, i. e. the presence of a differentiated carcinomatous component, were retrieved from archives of several institutions. For comparison, 84 cases of GIST mutated in KIT or PDGFRA genes served as the control group. Hematoxylin and eosin stained slides were evaluated for the presence of patterns which might discriminate between sarcomatoid carcinoma and GIST.Lymphatic invasion and entrapment of fat tissue strongly favor the diagnosis of undifferentiated carcinoma, as it was found in all or almost all cases of undifferentiated carcinoma, but in no GIST. Alternation of low- and high- grade areas, formation of angiosarcomatous-like spaces, and the presence of yolk sac-like areas were also detected in all cases of undifferentiated carcinoma, but only in 1.2%, 2.4% and 7.2% of the GISTs, respectively. Furthermore, DOG1 was negative in all cases of undifferentiated carcinoma.According to this study, the presence of the histological findings listed above should prompt extensive tumor sampling in order to find a differentiated carcinomatous component. However, due to the small number of cases of undifferentiated carcinoma available for the study, a larger multi-institutional study is warranted.     

Inflammatory sarcomatoid carcinoma: a case report and discussion of a malignant tumor with benign appearance

Inflammatory sarcomatoid carcinoma is an aggressive tumor with an unusually benign appearance. We report the case of a 65-year-old man with a history of inoperable poorly differentiated carcinoma of the right lung, for which he had received chemoradiotherapy. A new solitary mass was discovered 4 years later in the left lung on surveillance computed tomography. The patient underwent thoracotomy with a wedge biopsy on which frozen section was performed. The nodule was vaguely granulomatous and associated with a mixed inflammatory infiltrate and a deceptively bland spindle cell proliferation. Results of immunoperoxidase studies, however, showed that the nodule contained neoplastic cells with an epithelial phenotype that were invading the pulmonary vessels. These are features of the rare inflammatory sarcomatoid carcinoma. In contrast to sarcomatoid carcinomas, this case highlights the deceptively benign appearance of inflammatory sarcomatoid carcinoma. This leads us to concur with the recommendation to exercise caution when attempting the diagnosis of apparently benign lesions on intraoperative frozen section in patients with high clinical suspicion of malignancy.     

Immunohistochemistry and lectin histochemistry in sarcomatoid renal cell carcinoma: a comparison with classical renal cell carcinoma

We investigated the expression of various cell markers in renal cell carcinoma, concentrating particularly on the sarcomatoid variety, using lectin and immunohistochemical techniques. The sarcomatoid variant showed stronger staining in a higher proportion of cases for vimentin and reduced positivity for epithelial membrane antigen, in comparison with classical renal cell carcinoma. All sarcomatoid tumours reacted with at least one cytokeratin, enabling them to be distinguished from true renal sarcomas; this is of diagnostic value when a panel of markers is used. Overall a similar pattern of markers is seen in sarcomatoid and classical renal cell carcinoma using lectin and immunohistochemistry, suggesting that the sarcomatoid variant arises as a metaplastic change rather than having a different histogenesis.     

Non-small cell lung carcinomas with a minor sarcomatoid component and pleomorphic carcinomas are associated with high expression of programmed death ligand 1

Pleomorphic carcinomas are known to be highly programmed death ligand 1 (PD-L1) positive non-small cell lung cancer (NSCLC) types. However, the level of PD-L1 expression in lung carcinomas with a minor sarcomatoid component, comprising less than 10 % of the tumor mass, has not been determined yet. We hypothesized that NSCLC with a minor sarcomatoid component is more closely related to pleomorphic carcinomas in terms of PD-L1 expression than to NSCLC types without sarcomatoid features. The surgical resections from 690 lung carcinoma patients were retrospectively analyzed for the presence of PD-L1 by means of immunohistochemistry using the 22C3 PharmDx assay. The tumor proportion score system was applied to quantify the level of PD-L1 expression. Membranous staining present in ≥ 1 % of tumor cells was chosen as the cut-off to define a positive result for PD-L1 expression. Tumors were allocated into one of four subgroups: “adenocarcinoma”, “squamous cell carcinoma”, “pleomorphic carcinoma”, or “NSCLC with a minor sarcomatoid component”. PD-L1 expression in pleomorphic carcinomas (26/32, 81.3 %) and in the subgroup of NSCLC with a minor sarcomatoid component (35/46, 76.1 %) was identified in a comparable proportion of cases. Pleomorphic carcinomas were significantly more often PD-L1 positive than adenocarcinomas (p < 0.001) or squamous cell carcinomas (p = 0.0015). Accordingly, the proportion of PD-L1 expressing NSCLC with a minor sarcomatoid component was significantly higher than that of the adenocarcinoma (p < 0.001) or squamous cell carcinoma (p = 0.002) subgroup. In summary, we identified a presumable new subgroup of highly PD-L1 positive neoplasms within the NSCLC spectrum that is related to pleomorphic carcinomas in terms of PD-L1 expression. Further investigation regarding genetic relation and mechanism of PD-L1 expression in these two NSCLC categories is recommended.     

Muzinöses, tubuläres und spindelzelliges Nierenkarzinom

The new WHO-classification of renal tumors includes new subtypes, one of which is the mucinous, tubular, and spindle cell carcinoma. Many of these tumors had been previously diagnosed as sarcomatoid carcinoma. There are areas of cord-like growth and spindle cell configuration, sometimes with a clear cell appearance. The cells have low-grade nuclear features. It has been postulated that these tumors are related to the loop of Henle. In this study, 21 tumors were immunohistochemically and genetically analyzed. The analysis showed complex genomic aberrations, but no chromosome 3p losses. Fluorescence in situ hybridization detected no von Hippel-Lindau gene deletions on chromosome 3p25, which are characteristic for clear cell renal carcinomas. These findings show that there is no genetic relationship to clear cell renal carcinomas. The results of the immunohistochemical analyses showed a complex immunophenotype, but could not prove a derivation from the loop of Henle. The prognosis of these tumors seems to be favorable.     

Challenges in surgical pathology of adrenocortical tumours

Adrenocortical carcinomas are rare tumours that can be diagnostically challenging. Numerous multiparametric scoring systems and diagnostic algorithms have been proposed to differentiate adrenocortical adenoma from adrenocortical carcinoma. Adrenocortical neoplasms must also be differentiated from other primary adrenal tumours, such as phaeochromocytoma and unusual primary adrenal tumours, as well as metastases to the adrenal gland. Myxoid, oncocytic and sarcomatoid variants of adrenocortical tumours must be recognized so that they are not confused with other tumours. The diagnostic criteria for oncocytic adrenocortical carcinoma are different from those for conventional adrenocortical carcinomas. Adrenocortical neoplasms in children are particularly challenging to diagnose, as histological features of malignancy in adrenocortical neoplasms in adults may not be associated with aggressive disease in the tumours of children. Recent histological and immunohistochemical studies and more comprehensive and integrated genomic characterizations continue to advance our understanding of the tumorigenesis of these aggressive neoplasms, and may provide additional diagnostic and prognostic utility and guide the development of therapeutic targets.     

Analysis by comparative genomic hybridization of epithelial and spindle cell components in sarcomatoid carcinoma and carcinosarcoma: histogenetic aspects.

Sarcomatoid carcinomas and carcinosarcomas are histologically malignant biphasic neoplasms with an epithelial and a spindle cell component. Both a polyclonal and a monoclonal origin have been postulated for these tumours, but the latter has been favoured. For carcinosarcoma, the stem cell from which the epithelial and mesenchymal components are derived is expected to be more immature than the epithelial stem cell from which different components of sarcomatoid carcinoma originate, since in the latter, immunohistochemical or ultrastructural epithelial characteristics are still detectable. In the present study, comparative genomic hybridization was used to test the hypothesis that both tumour components in sarcomatoid carcinoma have more chromosomal aberrations in common than those in carcinosarcoma. From three sarcomatoid carcinomas originating from the urinary bladder and two carcinosarcomas from the pharynx, the epithelial and spindle cell components were microdissected and analysed for their respective chromosomal aberrations, using comparative genomic hybridization. High-level homology was seen in chromosomal aberrations between the different components in each tumour. This level of homology was even higher in the carcinosarcomas (65 and 91 per cent) than in both sarcomatoid carcinomas (21-51 per cent). The different phenotypic components of both sarcomatoid carcinoma and carcinosarcoma show a large overlap of chromosomal aberrations, strongly suggesting a monoclonal origin for all of these tumours. These findings do not support the hypothesis that the divergence between epithelial and spindle cell components occurs at an earlier stage in carcinosarcomas than in sarcomatoid carcinoma.     

Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics

Conventional urothelial carcinoma accounts for most carcinomas of the urinary tract lining. However, neoplastic urothelium has the capacity to demonstrate enormous plasticity. A variety of unusual architectural patterns of urothelial carcinoma, such as the nested, microcystic and inverted variants, can be mistaken for reactive processes or benign tumours. Others such as the micropapillary, plasmacytoid and discohesive variants, can mimic metastatic tumour from other sites. The micropapillary variant in particular is more aggressive. In addition, urothelial carcinoma has a propensity to demonstrate divergent differentiation with glandular, squamous, small cell neuroendocrine, lymphoepithelioma-like, sarcomatoid or other elements. Pure squamous carcinoma or adenocarcinoma (the latter in particular) can be difficult to distinguish from contiguous or metastatic spread. Some variants have prognostic and potential therapeutic implications. Molecular genetic evidence has emerged recently supporting a close relationship between urothelial carcinoma and various divergent elements. Sarcomatoid carcinoma and its differential diagnosis with other spindle cell lesions of urinary tract will be covered in a separate review.