[1] Aside from the great heterogeneity seen in lung cancers (especially those occurring among tobacco smokers), the considerable variability in diagnostic and sampling techniques used in medical practice, the high relative proportion of individuals with suspected GCCL who do not undergo complete surgical resection, and the near-universal lack of complete sectioning and pathological examination of resected tumor specimens prevent high levels of quantitative accuracy.
[1] These variants are increasingly appreciated as having different genetic, biological, and clinical properties, including prognoses and responses to treatment regimens, and therefore, that correct and consistent histological classification of lung cancers are necessary to validate and implement optimum management strategies.
Carcinomas are tumors composed of transformed, abnormal cells with epithelial tissue architecture and/or molecular characteristics, and which derive from embryonic endoderm.
[1] The current rules for classifying lung cancers under WHO-2004, while useful and improved, remain to some extent fairly complex, ambiguous, arbitrary, and incomplete.
[9] Subcellular characteristics often noted in the malignant giant cells of GCCL cases include abundant mitochondria, concentric whorls of tonofilament-like fibrils, and aggregates of several pairs of centrioles.
[citation needed] In one early case series, abundant production of loose malignant giant cells were noted to fill the alveoli of patients without destroying, infiltrating, or disturbing the normal underlying architecture, a pathologic behavior that bears some resemblance to the pneumonic variant of bronchioloalveolar carcinoma.
[14] However, in one study where a giant-cell carcinoma tumor that had been completely excised was sectioned and examined, no qualitative or quantitative abnormalities in tissue vascularization were noted.
[9] GCCL have been noted to be encapsulated, and to be divided via septa into "pseudolobules", by a highly fibrous stroma, suggested to be produced commensurately with tumor growth.
[25] GCCLs are particularly notable among lung cancers for their extremely unusual tendency to metastasize to the small intestine, occasionally causing obstruction, severe bleeding, and/or intussusception.
[18] Several studies, both in giant-cell tumor specimens and in cell lines, have identified rearrangement and amplification of the c-myc oncogene, sometimes in combination with mutations of the K-ras gene.
[28][29] Overexpression of vascular endothelial growth factor (VEGF) has been shown to occur in GCCL and is thought to be related to the high metastatic potential of this lung cancer variant.
[14] Malignant giant cells identical to those found in GCCL commonly occur in lung cancer cases with a prominent major or minor clear-cell carcinoma pattern (for a discussion about this variant, see for example[30]).
[18] Malignant giant cells are commonly found — and vary in relative proportion to a greater or lesser degree — in both primary tumors and metastatases of many different variants of lung carcinomas.
[35] GCCL have been long known[36] for secretion of the beta subunit of human chorionic gonadotropin (beta-HCG), often in large amounts, which can lead to very high levels of estrogen and painful gynecomastia (breast enlargement) in males as paraneoplastic signs.
[9] Because of its rarity, there have been no randomized clinical trials of treatment of GCCL, and all information available derives from small retrospective institutional series or multicenter metadata.
[5] However, in the latter report the 11.8% figure was based on data that included spindle cell carcinoma, a variant which is generally considered to have a less dismal prognosis than GCCL.
In the large 1995 database review by Travis and colleagues, giant-cell carcinoma has the third-worst prognosis among 18 histological forms of lung cancer.
[15] The true incidence, prevalence, and mortality of GCCL is generally unknown due to a lack of accurate cancer data on a national level.
In an American study of a database of over 60,000 lung cancers, GCCL comprised between 0.3% and 0.4% of primary pulmonary malignancies, with an age-adjusted incidence rate of about 3 new cases per million persons per year.
[5][45] However, in a more recent series of 4,212 consecutive lung cancer cases, only one (0.024%) lesion was determined to be a "pure" giant-cell carcinoma after complete sectioning of all available tumor tissue.
[35] While some evidence suggests GCCL may have been considerably more common several decades ago, with one series identifying 3.4% of all lung carcinomas as giant-cell malignancies,[46] it is possible that this number reflect Most published case series and reports on giant cell-containing lung cancers show that they are diagnosed much more frequently in men than they are in women,[16][42] with some studies showing extremely high male-to-female ratios (12:1 or more).
[16][40] Like nearly all lung carcinomas, however, GCCs are exceedingly rare in very young people: in the US SEER program, only 2 cases were recorded to occur in persons younger than 30 years of age between 1983 and 1987.
[16] Most sources credit Nash and Stout with publishing the first detailed report in the medical literature recognizing GCCL as a distinct clinicopathological entity in 1958.