Basaloid Carcinoma, Lung
A poorly differentiated malignant epithelial tumor that is considered a variant of squamous cell carcinoma. It has features (small cells, lobular architecture with peripheral palisading, high mitotic rate) shared with basal cell or basaloid carcinomas in other organs, e.g., skin and anal canal. Fully formed squamous features are absent, but the immunophenotype is consistently of squamous type. Tumors showing 50% of more of this histology, but with areas of typical squamous cell carcinoma, are still regarded as basaloid carcinoma. The term used in the WHO 2015 classification is basaloid squamous cell carcinoma.
This is a rare tumor, perhaps accounting for 3–6% of cases in surgically resected series, but published data are confounded by variations in definition since the lesion was first described by Brambilla and colleagues in 1992. Until the publication of the WHO 2015 classification, this tumor was considered a variant of large cell carcinoma but the consistent immunohistochemical (IHC) and molecular features shared with squamous cell carcinoma justified the move in classification. Furthermore, the position was confused by the coexistence, in older WHO classifications, of a basaloid squamous cell carcinoma, separate from basaloid carcinoma, where more classical squamous cell carcinoma was allowed. Consequently, the effective merging of these two descriptions may suggest the proportion of cases now meeting the diagnostic criteria may be a little higher than 6%. Here tumors are strongly associated with tobacco smoking.
Lesions are mostly described in a population ranging from 60 to 80 years, a typical cohort, not different from other non-small cell carcinomas.
There may be a male predominance, but this is not clear and is not a strong or consistent finding.
These lesions may be found in any location in the lung, although there is a definite predilection for a more central location. This is in keeping with a bronchogenic origin. The tumors arise from hyperplasia and dysplasia within bronchial epithelium and retain a more definite expression of their parent, basal cell phenotype.
Treatment is no different from other NSCLC of squamous type and depends on the stage and extent of disease spread at the time of diagnosis. A confident diagnosis of basaloid (squamous cell) carcinoma is generally only rendered in surgically resected cases.
The original description of basaloid carcinoma inferred a poor prognosis, with a much lower 5-year postoperative survival, when allowing for stage, when compared to resected NSCLC in general. Although this has not been a universal finding in all reported studies, it is probably, in general, correct. Once again, these data need to be treated with some caution, given the variation in criteria used and the confusion that existed around the diagnosis. It is likely that there would be considerable variation in the cases included under this diagnostic category.
In most ways, these tumors do not differ in gross appearance from other NSCLC. They tend to be bulky central masses, often showing involvement of a large bronchus. Necrosis may be marked and may be visible as spots, lines, or serpiginous cords of yellowish tissue admixed with a rather homogeneous greyish-white tumor, representing the viable tissue. An endobronchial component is described in up to 85% of cases. Invasion of mediastinal fat and pleura is seen in about 15% of surgically resected cases. There may be tumor hemorrhage. The tumor margin is often lobulated. In some cases, the solid tumor is hard and sclerotic.
The central, bronchogenic character of these lesions means that distal, obstructive pneumonia is common in resection specimens.
The microscopic features are very similar to those found in basaloid or basal cell carcinomas in other sites. These tumors are high grade, epithelial malignant tumors comprising masses, nodules, and trabeculae of relatively small cuboidal or fusiform cells with irregular nuclei with granular or clumped chromatin. Nucleoli and nuclear molding are not generally seen. Mitotic and apoptotic figures are numerous. Cytoplasm is scanty and indistinct. Typical features of squamous cell carcinoma are not encountered in basaloid carcinoma, but occasional foci of rather abrupt, small keratin pearl formation may be seen, immediately surrounded by basaloid cells, rather than the usual large cells with abundant eosinophilic cytoplasm and variably expression of intercellular bridges, as seen in typical squamous cell carcinoma. As indicated in the definition, if the dominant component of a tumor (>50%) is basaloid, and the remainder is typical squamous cell carcinoma, then a diagnosis of basaloid squamous cell carcinoma can still be given.
Peripheral palisading around the edges of the tumor masses is always present. Comedo-type necrosis is also very common, and these foci may coalesce to create large geographic areas in some cases, corresponding to the macroscopic features described above. Less often, the tumor cells separate and small, irregular cystic spaces develop. Small indistinct rosettes may be seen. The stroma of basaloid carcinomas may show interesting features; it may be loose and myxoid, or dense and sclerotic; very occasionally there may be osseous or chondroid metaplasia. A distinctive feature is the deposition of basement membrane-like material among the tumor cells. Usually this is quite limited in extent and normally is a linear, cord-like deposit but can be present in small clumps or nodules. Occasionally the deposition is extensive, to the exclusion of tumor cells in some areas.
Consistent with the origin from bronchial epithelium, there is commonly squamous dysplasia or carcinoma in situ in the adjacent bronchi.
More or less by definition, these tumors show a squamous phenotype. There is strong and diffuse staining with all squamous-associated markers such as p40, p63, and cytokeratins 5 and 6. Other markers such as cytokeratins 10 and 14 and the high molecular weight cytokeratin combo markers (keratins 1, 5, 10, and 14) 34βE12 are also usually widely expressed. TTF1 is negative. Occasional cases, around 10%, may show patchy weak staining for a neuroendocrine marker, mostly CD56. SOX4 and IVL (involucrin) may be preferentially expressed in basaloid as opposed to classical squamous cell carcinoma.
Molecular data on this relatively rare tumor are few, but the general finding is that they share genetic features with classical squamous cell carcinomas. This finding, combined with the IHC data, was the main justification for moving these basaloid carcinomas from the large cell carcinoma into the squamous cell carcinoma category.
Studies of mRNA expression show upregulation of genes controlling cell cycle, transcription, and chromatin remodeling and splicing, all consistent with a highly proliferative tumor with strong links to tobacco carcinogens. Genes associated with squamous differentiation are downregulated, which initially might appear counterintuitive but, in fact, is commensurate with the morphological phenotype described above. Furthermore, gene expression patterns were found, which are associated with aggressive tumor behavior and poor tumor differentiation (upregulation of ectopic male germ cell/placenta-specific signatures, genes related to the testis and embryonic stem cells, and poorly differentiated tumor-associated genes such as NANOG, OCT4, SOX2, and MYC, downregulation of the Polycomb gene silencing system).
TP53 gene mutations are the commonest mutations found.
The differential diagnosis of basaloid (squamous cell) carcinoma of the lung is important given the nature of the tumor and its aggressive phenotype. Depending on the particular features present, the differential diagnoses, in the context of a surgically resected case, include squamous cell carcinoma (non-basaloid), small cell carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC). Adenoid cystic carcinoma and other undifferentiated tumors including a basaloid carcinoma associated with NUT gene (NUTM1) translocation may also be considered.
In a case where there are classical and basaloid squamous cell carcinoma features admixed, the dominant pattern determines the diagnosis. This rule cannot apply to small biopsy or cytology diagnosis where a diagnosis of squamous cell carcinoma will be given but basaloid features may be described. This is generally not an issue since, apart from possible prognostication, there are no therapeutic decisions predicated on the distinction.
Cell size may lead to some confusion with small cell carcinoma, especially if the sample is poorly fixed or traumatized. This is much more likely to be an issue in small biopsy or cytology samples. Attention to the nuclear features (fine speckled or featureless chromatin and nuclear molding favor small cell carcinoma) and the immunophenotype should secure the correct diagnosis. Nuclear p40 or p63 and widespread cytoplasmic 34βE12 are not found in SCLC.
Distinction between basaloid squamous cell carcinoma and LCNEC is a regular issue, and it has been recommended that neuroendocrine markers be employed whenever a basaloid tumor is encountered. Both tumors may have an insular growth pattern, with high mitotic and apoptotic rate, comedo-type necrosis, and peripheral nuclear palisading. Rosettes are common in LCNEC but not uncommon in basaloid squamous cell carcinoma. IHC is essential in this differential and should be clear-cut. The strong squamous phenotype indicated basaloid squamous cell carcinoma, while two or more convincing neuroendocrine markers secure a LCNEC diagnosis. Occasionally pathologists will encounter a tumor with the above morphology, but which lacks either convincing immunophenotype. In these circumstances a diagnosis of large cell carcinoma may be made, but basaloid or neuroendocrine morphology may be described as appropriate.
Prominent rosettes and/or hyaline stroma may give a tumor an adenoid cystic appearance, but distinction should be assisted by IHC since the pure squamous immunophenotype is not seen in adenoid cystic carcinoma which also demonstrates myoepithelial cells.
NUT carcinoma is extremely rare and is more often a mediastinal tumor, but has features which can be morphologically and immunohistochemically indistinguishable from each other. NUT carcinoma patients tend to be younger but this is not absolute. IHC using a specific anti-NUT antibody will identify NUT carcinoma, which also shows a translocation involving the NUTM1 gene at 15q14 and a number of potential partners.
References and Further Reading
- Travis, W. D., Brambilla, E., Burke, A. P., Marx, A., & Nicholson, A. N. (Eds.). (2015). WHO classification of tumours of the lung, pleura, thymus and heart. Geneva: WHO Press.Google Scholar