Organización del plan de estudios A) Flexibilidad

The World Health Organization (WHO) defines six major types of lung cancer:

adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma, sarcomatoid carcinoma, and adenosquamous carcinoma. (2, 3)

4

The histological classification of lung cancer, especially adenocarcinoma, has undergone substantial revision in recent years, in part driven by clinical studies showing remarkable responses among cancers with certain molecular profiles to specific chemotherapeutic agents. (4) Although histological classification may be most accurately applied to resection specimens with generous sam-plings of tumor, guidelines have been published for the classification of lung cancers in small biopsy specimens. (5, 6)

In the author’s experience (VLR) of the 1051 lung cancer specimens for which smoking history was available, the distribution of the six histological types was as follows: adenocarcinoma – 39.4%; squamous cell carcinoma – 27.5%; small cell carcinoma – 12.4%; large cell carcinoma – 12.4%; sarcomatoid carcinoma – 6.2%; and adenosquamous carcinoma – 2.2%. Over 90% of these cancers occurred in smokers or ex-smokers, ranging from about 90% of adenocarcino-mas, to 98% of squamous cell carcinoadenocarcino-mas, and 100% of small cell carcinomas.

The histological types are described below in more detail.

Adenocarcinoma: The WHO recognizes several patterns of adenocarcinoma of the lung, including acinar, papillary, bronchioloalveolar cell carcinoma and solid variants with mucous production. (2, 3) More recent studies have indi-cated that the micropapillary pattern should be considered a specific variant, as this pattern often implies a poor prognosis clinically. (4) Furthermore, the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society have recommended that the term bronchioloalveolar cell carcinoma be dropped, because in the literature, this term has been applied to lung cancers with vastly different clinical behav-iors and outcomes. (4) Most mucinous bronchiloalveolar cell carcinomas have been reclassified as invasive mucinous adenocarcinoma, since there is nearly always an invasive component in adequately sampled tumors. Some variants with nearly 100% five-year disease-free survival have also been recognized, in-cluding adenocarcinoma in situ and minimally invasive adenocarcinoma. Most non-mucinous bronchioloalveolar cell carcinomas have been reclassified into one of these two categories. (4) Less common variants of pulmonary adenocar-cinoma recognized by the WHO include fetal adenocaradenocar-cinoma and colloid ad-enocarcinoma. (2, 3) Pulmonary adenocarcinomas with enteric differentiation have also been recognized more recently. (4, 7)

Squamous cell carcinoma: The second most common of the histologic pat-terns recognized by WHO, squamous cell carcinoma, is characterized by tumor growth as sheets or nests which demonstrate one or more of the following:

keratin pearl formation, intercellular bridges, and individual cell keratinization.

(2, 3) Basaloid carcinoma and lymphoepithelioma-like carcinoma are recog-nized variants. Some cases may also occur with an endobronchial papillary growth pattern. One should use caution not to confuse apoptotic cells with hypereosinophilic cytoplasm, and pyknotic nuclei with individual cell keratini-zation.

Small cell carcinoma: This variant is considered a high grade neuroendocrine carcinoma, which is frequently widespread at the time of diagnosis, often manifested by bulky mediastinal lymph node metastases. Small cell carcinoma is characterized by cells with a high nuclear to cytoplasmic ratio, scant cyto-plasm, and frequent nuclear molding. Mitotic figures are frequent and nucleoli inconspicuous. Chromatin is described as showing a salt and pepper distribu-tion. Rosettes may be present and focal necrosis is a frequent finding. Crush artifact is often seen in small biopsy specimens. When a small cell carcinoma pattern is present in a tumor that also displays large cell, squamous or ade-nocarcinoma differentiation, the tumor is referred to as combined small cell carcinoma. (2, 3)

Large cell carcinoma: With the advent of sensitive and specific immunohis-tochemical markers for adenocarcinoma and squamous cell carcinoma, this category continues to shrink as a percentage of lung cancers in general. These tumors form sheets and nests of cells with large nuclei and typically prominent nucleoli; mitotic figures are usually readily identified. (2, 3) The term large cell carcinoma should probably only be used on resection specimens where the tumor is extensively sampled and no evidence of adeno- or squamous differ-entiation is apparent. Recognized variants include large cell neuroendocrine carcinoma and rhabdoid phenotype. (3)

Sarcomatoid carcinoma: This category was newly proposed after the original 1997 Helsinki document and includes variants that were previously included in the squamous, large cell or adenocarcinoma categories. (1, 3) Variants of sar-comatoid carcinoma include pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma and pulmonary blastoma. These tumors typically include a spindle cell or mesenchymal element that may be confused with soft tissue sarcomas. Carcinomas including sarcomatoid, giant cell, ade-nocarcinoma or squamous cell carcinoma mixtures are referred to as pleomor-phic carcinoma. If the sarcomatoid component includes heterologous elements (osteosarcomatoid, chondrosarcomatoid or rhabdomyosarcomatoid differenti-ation) the term carcinosarcoma is preferred.

Adenosquamous carcinoma: Lung carcinomas that contain both adenocarcino-ma and squamous cell carcinoadenocarcino-ma components are referred to as adenosqua-mous carcinoma. Conventionally, at least 10% of each component should be present in the tumor. This diagnosis is difficult or impossible to make on small biopsy specimens and should be reserved for resection specimens. (5, 6) One of the authors (VLR) has studied 76 primary lung cancers in patients with asbestosis as defined by the recent 2010 classification (8) who also underwent fiber analyses. (9) The distribution of histological types using the recent WHO classification is shown in Table 1. The distribution of histological types is similar for patients with asbestosis, pleural plaques without asbestosis, and

lung cancer patients with neither plaques nor asbestosis. Hence, the histolog-ical type of a lung cancer has no value in either proving or disproving a rela-tionship with asbestos. Any of the six major histological categories mentioned above may occur as a consequence of asbestos exposure.

Table 1. Histological Typing of Lung Cancer in 76 Cases of Asbestosis with Fiber Analysis

Histological Type Number Percentage

Adenocarcinoma 31 40.8

Squamous cell carcinoma 17 22.4

Small cell carcinoma^* 12 15.8

Large cell carcinoma** 5 6.6

Sarcomatoid carcinoma 5 6.6

Adenosquamous carcinoma 6 7.9

TOTAL 76 100

*Includes two combined small cell carcinomas (one squamous, one large cell)

**Includes one large cell neuroendocrine carcinoma

A number of far less common primary lung malignancies are recognized by WHO, including primary pulmonary sarcomas, lymphomas, salivary gland-like carcinomas, melanomas, intrapulmonary thymomas, teratomas, clear cell tumors, and carcinoid tumors. (2, 3) Clin et al. have reported that there is an association between pulmonary carcinoid tumors and asbestos exposure. (10) For the remaining tumors, there is no evidence that these primary pulmonary malignancies are asbestos related. The same is true for pulmonary blastoma, a rare variant of sarcomatoid carcinoma.

There is no major difference in the proportion of peripheral versus central cancers in patients who were exposed to asbestos in comparison to those who were not. Thus the central versus peripheral distribution of lung cancer among asbestos workers is similar to that of lung cancer patients with no background of asbestos exposure. (9, 11)

Some studies have recorded a predominance of lower lobe carcinomas among asbestos-exposed workers (12–20), whereas others have not. (9, 21–24) Never-theless, the overlap is great enough that the lobar distribution is hardly suffi-cient to assign attribution to asbestos exposure in an individual case. (11)