Classification of tumors is a pillar of diagnosis and management in oncology. The significance of classification of tumors is widely accepted and different approaches have been suggested. While older attempts were based on clinical features, mainstream classification schemes are centered on microscopic features of cells, their arrangements and relationships to adjacent normal tissues — that is, the light microscopic features of the individual tumors. Over the years such morphological phenotypes have been described in detail for various types of tumors as it is felt that we must firstly learn to recognize a tumor accurately before we can treat it effectively. The resulting histological classifications were intended to facilitate comparison of results in various fields of oncology; be useful to pathologists, clinicians and epidemiologists; and to ensure precise communication between specialists worldwide. Nevertheless the efforts of overenthusiastic pathologists and the hunt for new entities occasionally resulted in unnecessary and unwanted ‘splitting’. It is now increasingly appreciated that inventing new names for lesions that are merely morphological variations or stages in the life history of an established entity should be avoided. The fibrosing/hyalinized variants of soft tissue or odontogenic tumors are two examples that come to mind and might be cited in an argument supporting ‘lumping’ (as opposed to splitting) classifications. The modern attitude is that any meaningful classification – that is, any classification that is to be of value in the ideal management of the patients – should depend on strong links between neoplastic morphological phenotypes and a particular biological behavior/prognosis.
To provide internationally acceptable criteria for the histological diagnosis of the tumors, the World Health Organization (WHO) published in 2005 its International Classification of Head and Neck Tumours (including also the larynx) .
A histological classification of neoplasms is not only extremely important for a reliable prognosis to be established, as the construction of such a reliable prognosis lies at the heart of a superior plan for clinical management of tumor patients — but such a classification must also be able to facilitate reliable communication between pathologists all over the world.
The WHO fully endorsed this principle and the series of volumes on the classification of human tumors published under its auspices is based on it. The aforementioned links are more obvious in the case of tumors of hematopoietic and lymphoid tissues. Other regions of the human body, including larynx, also provide valid examples. For instance, proponents of ‘lumping’ classifications would have difficulties in reproaching the distinction of laryngeal neuroendocrine carcinoma and verrucous squamous cell carcinoma as the former metastasizes more frequently than conventional squamous cell carcinoma and the latter has a less aggressive behavior than conventional squamous cell carcinoma . It is also noted that the 5-year survival rates for laryngeal verrucous squamous cell carcinoma and small cell neuroendocrine carcinoma are 95% and 5%, respectively . Exact identification of neoplastic morphological phenotypes enables clinicians to plan specific and individual tumor staging . Together, they are regarded as the “gold standard” for defining appropriate treatment, though factors such as the presence of another malignancy, comorbidities, environmental aspects, and previous treatment can be influential as well .
The WHO classification of laryngeal tumors is considered satisfactory, but there is room for improvement. For example, the classification lists 4 types of neuroendocrine carcinomas: a) typical carcinoid, b) atypical carcinoid, c) small cell carcinoma, neuroendocrine type and d) combined small cell carcinoma, neuroendocrine type with non-small cell carcinoma . A criticism of this may be that the list does not adequately define the entire clinicopathologic spectrum of these tumors. Specifically, the most notable deficiency of this four-tiered scheme is the absence of a category for large cell neuroendocrine carcinoma . Currently a large consensus is building that the classification of neuroendocrine carcinomas of the larynx encompasses the following categories :
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Neuroendocrine carcinoma, grade 1 (carcinoid tumor or well differentiated neuroendocrine carcinoma).
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Neuroendocrine carcinoma, grade 2 (atypical carcinoid tumor or moderately differentiated neuroendocrine carcinoma).
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Neuroendocrine carcinoma, grade 3 large cell type.
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Neuroendocrine carcinoma, grade 3 small cell type.
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Combined neuroendocrine carcinoma with non-neuroendocrine carcinoma (squamous cell carcinoma, adenocarcinoma, etc.).
Different criteria (morphologic, immunohistochemical and/or electron microscopic) are useful for the diagnosis of these various neuroendocrine carcinomas . The histogenesis of combined non-neuroendocrine carcinoma with neuroendocrine carcinoma is most likely linked to transdifferentiation of respiratory mucinous gland ductal epithelium to intestinal-type and squamous phenotype. Interestingly, similar morphologies and phenotypes have been reported in other head and neck sites with or partially lined by respiratory epithelium and seromucinous glands (sinonasal mucosa, middle ear and eustachian tube, base of tongue).
As mentioned, specific histologic types exhibit different degrees of aggressiveness giving rise to different survival rates. Establishing the phenotype gives us a qualitative snapshot of the disease. Different light microscopic tumor types have different biological behaviors, suggesting that only similar types can be roughly equated for their prognostic implications.
For the sake of completion we are providing a table with a series of unusual laryngeal tumors reported since 1969, though we acknowledge that many are case reports for which interpretations may differ or for which a distinct clinicopathological correlation cannot be established. This variability of histological types underscores the fundamental utility of WHO classification for uniformly reporting each tumor.
We must first learn to recognize different tumor phenotypes, then develop classifications to group them appropriately into relevant prognostic categories, and then establish treatment algorithms that align with the prognostic categories. At the same time that we are striving for better and better classification systems, we also need to be wary of unnecessary splitting of categories or inventing new names for lesions that are merely morphological variations of a single entity. Although there is a long list of variants of different tumor types that have been described in the larynx (see Table ), we are not suggesting that each of these deserves a category within new classification schemes. Indeed, most of these lesions are well described and better understood in their biology from other organ sites and anatomical locations. New classifications should only be adopted when there is substantial literature and a body of work that illustrates the prognosis based on histological classification, as we have seen in the neuroendocrine tumor spectrum. Utilizing the more specific histological subtyping for neuroendocrine tumors of the larynx which we have described above will give rise to better data on prognosis and survival rates. Consistent application of such a classification will also give us a better understanding of the spectrum of this disease.
| Histologic types | Authors | Years |
|---|---|---|
| Moderately differentiated neuroendocrine carcinoma | Goldman et al. | 1969 |
| Small cell neuroendocrine carcinoma | Olofsson and Van Nostrand | 1972 |
| Acinic cell carcinoma | Montes Noriega | 1974 |
| Synovial sarcoma | Miller et al. | 1975 |
| Clear cell carcinoma | Ferlito | 1976 |
| Giant cell carcinoma | Ferlito | 1976 |
| Combined small cell carcinoma and squamous cell carcinoma | Eusebi et al. | 1978 |
| Mycosis fungoides (presenting initially as a laryngeal lesion) | Hood et al. | 1979 |
| Well differentiated neuroendocrine carcinoma | Gehanno et al. | 1980 |
| Salivary duct carcinoma | Ferlito et al. | 1981 |
| Benign myoepithelioma | Batsakis et al. | 1983 |
| Ewing sarcoma | Abramowsky and Witt | 1983 |
| Alveolar soft part sarcoma | Michaels | 1984 |
| Burkitt lymphoma (presenting initially as a laryngeal lesion) | Michaels | 1984 |
| Laryngeal blastoma | Eble et al. | 1985 |
| Junctional nevus | Seals et al. | 1986 |
| Mast cell sarcoma (presenting initially as a laryngeal lesion) | Horny et al. | 1986 |
| Epithelial-myoepithelial carcinoma | Mikaelian et al. | 1986 |
| Basaloid squamous cell carcinoma | Wain et al. | 1986 |
| Malignant myoepithelioma (myoepithelial carcinoma) | Ibrahim et al. | 1991 |
| Mucinous adenocarcinoma | Tsang et al. | 1991 |
| Leiomyoblastoma | Mori et al. | 1992 |
| Granulocytic sarcoma (presenting initially as a laryngeal lesion) | Vassallo et al. | 1993 |
| Solitary fibrous tumor | Safneck et al. | 1993 |
| Neuroectodermal tumor | Ohlms et al. | 1994 |
| NUT midline carcinoma | Vargas et al. | 2001 |
| Large cell neuroendocrine carcinoma | Greene et al. | 2005 |
| Intestinal-type adenocarcinoma | Bell et al. | 2014 |
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