Tereza Takagaki

Nuclear/cytoplasmic ratio correlates strongly with survival in non-disseminated neuroendocrine carcinoma of the lung

In order to verify whether quantitative morphological indices of neuroendocrine carcinoma of the lung may help to predict survival, 47 biopsies (from 37 males and 10 females; 16–82 years of age) were studied by light microscopy. Areal fractions of nuclei, cytoplasm, stroma, and blood vessels were determined using a standard point counting method. The counts were made in six non‐coincident microscopic fields in each case, and the areal fractions of nuclei, of the entire tumour cell, stroma, blood vessels and the nuclear/cytoplasmic ratio were computed. In a multivariate linear regression analysis, survival in months after biopsy was considered the dependent variable of age and of all morphometric parameters listed above. The significance level was set at 5%. For all patients (disregarding staging) survival was negatively correlated (P< 0.001, multiple r=0.5435) with age and nuclear/cytoplasmic ratio. When only patients with disease confined to the thorax (stages I. II and III) were taken into account, the accuracy of the Function predicting survival increased considerably (P=0.004, multiple r=0.7957). The use of simple stereological methods therefore, proved to be of value in predicting survival in patients with neuroendocrine carcinomas of the lung.

Stereological estimates of the nuclear/cytoplasmic ratio and star volume on fibreoptic biopsies are of prognostic value for survival in a preliminary study of advanced squamous cell carcinoma of the lung.

This study evaluated the role of morphometric and clinical parameters in establishing the prognosis of patients submitted to radiotherapy for advanced squamous cell carcinoma of the lung.

Refractory remodeling of the microenvironment by abnormal type V collagen, apoptosis, and immune response in non-small cell lung cancer ☆

Collagen V shows promise as an inducer of the death response via caspases. Remodeling of the microenvironment by collagen V, tumoral/vascular apoptosis, and the immune response were evaluated, based on the prognosis of 65 patients with surgically excised non-small cell lung cancer. Immunofluorescence, immunohistochemistry, morphometry, tridimensional reconstruction, and a real-time polymerase chain reaction were used to evaluate the amount, structure, and molecular chains of collagen V, tumoral and vascular apoptosis, immune cells, and microvessel density. The impact of these markers was tested on follow-up until death from recurrent lung cancer occurred. A decreased and abnormal synthesis of collagen V was found to lead to increased angiogenesis due to a low endothelial death rate and a low immune response. A Cox model analysis, controlled for the lymph node stage, demonstrated that only collagen V and vascular apoptosis variables were significantly associated with survival time. A point at the median for collagen V and vascular apoptosis divided patients into 2 groups, each with a distinctive prognosis. Those with a collagen V higher than 9.40% and vascular apoptosis higher than 1.09% had a low risk of death (0.27 and 0.41, respectively) compared to those with a collagen V lower than 9.40% and vascular apoptosis lower than 1.09%. Collagen V and vascular apoptosis in resected non-small cell lung cancer was strongly related to the prognosis, suggesting that strategies aimed at preventing low collagen V synthesis, or local responses to low vascular apoptosis may have a greater impact in lung cancer treatment.

Different morphology, stage and treatment affect immune cell infiltration and long‐term outcome in patients with non‐small‐cell lung carcinoma

da Costa Souza P, Parra E R, Atanazio M J, da Silva O B, Noleto G S, Ab’Saber A M, de Morais Fernezlian S, Takagaki T & Capelozzi V L 
(2012) Histopathology 61, 587–596

Mutational Profile and New IASLC/ATS/ERS Classification Provide Additional Prognostic Information about Lung Adenocarcinoma: A Study of 125 Patients from Brazil

Aim: To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatments. Methods: In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). Results:EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (<72 packs/year), clinical stage I/II, and acinar histologic subtype presented better survival than women aged ≤71 years, with a history of smoking (>72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. Conclusions: These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC.

Marcadores morfológicos de prognóstico no mesotelioma maligno: um estudo de 58 casos

OBJECTIVE: Various markers have shown promise as diagnostic markers and prognostic predictors in malignant mesothelioma (MM). METHODS: Through morphometric and immunological studies of markers in stromal components (calretinin, CEA, Leu-M1 and thrombomodulin) and nuclear components (p53 and Ki-67), we evaluated post-diagnosis survival in 58 patients with MM. RESULTS: The histologic pattern of the MM was typical in 50 cases and atypical in 8. Through immunohistochemistry, we confirmed 40 cases of mesothelioma and 11 cases of adenocarcinoma, although we were unable to classify 7 of the 8 cases presenting atypical histologic patterns. Cox multivariate analysis revealed that the risk factor for death was higher (476.2) among patients of advanced age, presenting the biphasic subtype and testing positive for components expressed at the nuclear level. CONCLUSION: The most useful immunohistochemical markers were was calretinin (for mesothelioma) and CEA (for adenocarcinoma). Immunohistochemical quantification of thrombomodulin facilitated the diagnosis of mesothelioma in patients testing positive for both calretinin and CEA. The most useful prognostic information was that provided by the routine histopathological analysis of the tumor type. It is of note that the combination of a mean age of 55 years and 30.5% immunohistochemical markers in nuclear components created a natural dividing point between patients in which survival was shorter than expected and those in which it was longer than expected. Therefore, histopathological analysis offers a powerful weapon with great potential to inform decisions regarding the use of adjuvant chemotherapy after surgical excision of a mesothelioma.