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Histologic Subtype in NSCLC: Does It Matter?

Histologic Subtype in NSCLC: Does It Matter?

ABSTRACT: ABSTRACT: Platinum-based doublet chemotherapy remains the cornerstone of therapy in the first-line setting in advanced non–small-cell lung cancer (NSCLC) for patients with good performance status. However, this paradigm has recently been challenged by the results of a study that showed a survival benefit with the addition of bevacizumab to carboplatin and paclitaxel in bevacizumab-eligible patients and by the superior efficacy of gefitinib and erlotinib compared to chemotherapy in epidermal growth factor receptor (EGFR) gene mutation–positive tumors (mainly adenocarcinomas). In addition, histology has been recently recognized as a potential predictive factor in advanced NSCLC patients treated with chemotherapy. Prospective data from a preplanned subgroup analysis of a phase III study and retrospective reviews consistently reported a significant interaction between treatment by histology and response/survival in nonsquamous NSCLCs treated with pemetrexed, compared to squamous cell carcinoma (SCC). Thymidylate synthase, the main target of pemetrexed, was found to be differentially expressed among the histotypes of lung cancer, being lower in adenocarcinoma and higher in SCC and small-cell lung cancer. Thus, the availability of adequate amounts of tissue from biopsies to allow accurate pathologic subclassifications at diagnosis will be critical to help the oncologist select the most appropriate chemotherapy regimen as we move toward an individualized molecularly based approach.

Since the publication of a meta-analysis in 1995 that demonstrated a modest survival benefit compared to best supportive care, platinum-based chemotherapy became the cornerstone of therapy in the first-line setting in advanced-stage non–small-cell lung cancer (NSCLC) for patients with good performance status.[1] A recent meta-analysis of 16 randomized trials including 2,714 patients demonstrated an advantage of chemotherapy over best supportive care with an absolute improvement in survival of 9% at 12 months.[2]

Therapeutic guidelines indicate doublets of cisplatin or carboplatin with either gemcitabine (Gemzar), taxanes (paclitaxel or docetaxel [Taxotere]), or vinorelbine as reference regimens.[3,4] These guidelines are based on randomized phase III studies that compared these chemotherapy combinations “head to head” without detecting relevant differences in efficacy.[5-7] However, evidence from several randomized clinical trials and systematic reviews suggest that cytotoxic chemotherapy has reached an efficacy plateau.[8,9]

Currently the optimal therapeutic strategy for the individual patient diagnosed with stage IIIB or IV NSCLC is quite difficult to define since the decision-making process is shifting very quickly toward an individualized approach. Emerging evidence suggests that aside from the effects of well-known clinical parameters such as stage of disease and patient performance status, lung cancer behaves differently in different patients as the result of a variety of molecular profiles. The impact of histology in this context has been overlooked in the past.

The role of histology in addition to tumor-node-metastasis (TNM) stage was assessed in surgically managed stage I–IIIA NSCLC cases from the database of the International Association for the Study of Lung Cancer (IASLC), in the process of defining the new TNM staging system for lung cancer in the recently released 7th edition of the International Union Against Cancer and American Joint Committee on Cancer’s TNM Classification of Malignant Tumors. In 12,428 cases of NSCLC, age, gender, and performance status—but not histology—were found to be prognostic for survival after adjustment for stage of disease. Adenocarcinoma was more frequent than squamous cell carcinoma (SCC) in women (55% vs 25%), while the opposite was true in men (30% vs 57%). In a model including histology, pathologic stage, gender, and age, SCC patients had a significant survival advantage over those with adenocarcinoma or large-cell carcinoma (LCC), with no significant difference between LCC and adenocarcinoma. Cases designated as bronchioloalveolar carcinoma (BAC) had a superior prognosis compared with other histotypes. The better prognosis for SCC compared with other histotypes could not be demonstrated in women.[10]

In the same way, the Japanese Joint Committee of Lung Cancer Registry reported over 13,000 lung cancer cases that underwent surgery in 2002. They found a better prognosis for women and adenocarcinoma, with a 67% 5-year survival for adenocarcinoma vs 53% for SCC. In this study, the analysis of prognostic factors (including histology) was not adjusted for stage or gender; such adjustments could have led to different results.[11] In fact, by adjusting for stage and gender, any effect of imbalance that would favor adenocarcinoma is diminished, thus revealing a possible survival advantage for SCC.

Histology of Lung Cancer

Currently, the World Health Organization (WHO) classification of lung tumors should remain the common ground by which to compare results of studies potentially aimed at identifying a differential activity of any cytotoxic regimen according to histology.

In the past, oncologists dealing with lung cancer routinely distinguished only between small-cell lung cancer (SCLC) and NSCLC to select for the appropriate therapeutic management. NSCLC encompasses several subtypes with different morphologic features that are often treated according to similar strategies, so in everyday practice a clear-cut distinction among such histotypes was not considered mandatory.[12] Conversely, the WHO classifications of lung cancer have always kept the different histologic types separated, with individual categories for SCC, adenocarcinoma, and LCC.[13] Over the past few decades, the changing habits of cigarette smoking and enviromental pollution have contributed to changes in the relative frequency of these histologic subtypes. Adenocarcinoma shows a growing incidence, particularly in younger nonsmoking females, whereas SCC and SCLC are on the decline.[14]

The histologic recognition of classical SCC is generally straightforward, with distinctive areas of keratinization and an associated inflammatory component, especially in cases undergoing cavitation. Less differentiated forms of SCC, without keratinization and with smaller cells, may resemble basal cell layers of the squamous epithelium. In these cases, immunohistochemistry (IHC) may be required to detect specific types of cytokeratins, and neuroendocrine markers may also be helpful.

Adenocarcinoma includes a morphologically heterogeneous group of tumors that are less frequently associated with tobacco smoking than SCC. Adenocarcinomas are made of glands with papillary structures, or solid growth with mucin production.

BAC is still classified as an adenocarcinoma, although its pathologic definition has undergone major changes in recent years. Indeed, newly proposed strict criteria for the diagnosis of BAC are not correctly applied across all institutions, and when these criteria are followed, pure BAC cases become quite rare. The diagnosis of BAC is now restricted to tumors that have a lepidic growth along pulmonary septa in the absence of parenchymal invasion,[15] with further division into mucinous and nonmucinous forms. In clinical practice, however, the most common finding is adenocarcinoma showing a combined pattern of growth, with conventional acinar or papillary adenocarcinoma associated with mixed areas of BAC in the same tumor. Such tumors are classified as a mixed subtype of adenocarcinoma.

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