Heterogeneity of so-called neuroendocrine lung tumors.

The diagnosis of neuroendocrine (NE) lung tumor is dependent on a number of observations: organoid structure, dense core granules, and various molecular components, including chromogranin A, neurosecretory enolase, synaptophysin, neural cell adhesion molecules, and others. None of these is specific for lung tumors. The Kulchitsky cell, which has these characteristics, forms a carcinoid, which exemplifies the NE tumor. It is euploid, has few mitoses, no necrosis and a 5- to 10-year survival of over 90%. When carcinoids show malignant characteristics, i.e., increased mitoses and necrosis, they have been labeled atypical and have a survival of 50%. Because all other non-small cell lung tumors, especially large cell tumors, may show one or more of these things because of the inherent heterogeneity of lung tumors, the term NE has been applied to them without real evidence that this affects survival with or without chemotherapy. This is expensive and without clinical significance.

A century of pathology at Yale: personal reflections.

This history is largely about the players on the stage of the Yale Pathology Department acting out their roles as observed by the author in over a half century as a member of the department and as associate dean of the medical school.

Minimum prostate-specific antigen (PSA) level diagnostic of prostate cancer.

The PSA levels in benign prostatic hyperplasia (BPH) and prostate adenocarcinoma (PA) overlap, both below and above 4 to 10 ng/mL. There is no known PSA level diagnostic of PA. In this study, data were obtained in 160 consecutive men aged 58 to 87. Prebiopsy PSA levels (PSA-1) were obtained prior to "sextant" gun biopsies in 97 cases diagnosed as noncarcinoma, and in 56 cases diagnosed as PA. Multiple hematoxylin and eosin sections were made of each biopsy, and Gleason scores given the PAs. Cases were followed up to 30 months with repeated PSA levels and additional biopsies. The highest PSA level in NPA in this series was 54.6 ng/mL.

Pathogenesis and pathology.

Pathogenesis consists of a discussion of the role of oncogenes and suppressor genes on small-cell lung cancer and non-small-cell lung cancer as well as the external factors of smoking (active and passive), asbestos, and radon. Pathology consists of discussion of squamous cell lung cancer, adenocarcinoma and bronchoalveolar carcinoma, large cell carcinoma (including giant cell and clear cell variants), and neuroendocrine tumors. Mesotheliomas are discussed as is the role of monoclonal antibodies in diagnosis.

Prognostic significance of histopathologic subtype and stage in small cell lung cancer.

A study of 149 light microscopic tissue slides from 147 patients with recorded initial diagnoses of small cell lung cancer (SCLC) (114 cases) and undifferentiated carcinoma (35 cases) was undertaken to test the reproducibility and prognostic impact of a new histopathologic subclassification of SCLC proposed by the Pathology Panel of the International Association for the Study of Lung Cancer (IASLC). This study was further designed to test the impact of clinical stage, age, sex, and race on survival. The tissue slides were blindly reclassified as SCLC or non-SCLC by a panel of five pathologists with no knowledge of the initial diagnosis. The SCLCs were divided into the three subtypes outlined by the IASLC pathology panel: small (classic or pure), mixed (small cell/large cell), and combined (small cell/squamous carcinoma or small cell/adenocarcinoma). Small cell lung cancer was clinically staged as local, regional, or distant. Consensus diagnosis (defined as agreement by at least three of the five pathologists) was achieved in 144 (96.6%) of the 149 cases. Of these 144 cases, 124 were reclassified as SCLC (115 [92.8%] small, five [4.0%] mixed, and four [3.2%] combined) and 20 were classified as non-SCLC. The median lengths of survival for the small, mixed, and combined subtypes were 225, 1,110, and 203 days, respectively (P = .025). Adequate staging data were available in 123 of the 124 SCLC cases. Of the 123 SCLC cases, 27 (21.9%) were local, 22 (17.9%) were regional, and 74 (60.2%) were distant stage. The median lengths of survival for the local, regional, and distant stages were 428, 251, and 111 days, respectively. This association was highly significant (P = .0001). We conclude that stage is the major determinant of survival in SCLC. Mixed subtypes had significantly longer survival times than the small or combined subtypes (P = .025). Survival times were longer for women than for men, and the survival time difference between men and women was significant (P = .0028). We found no significant differences in survival according to age or race.

Biopsies of non-small cell lung cancer: central review in cooperative studies of the Radiation Therapy Oncology Group.

Cooperative trials involving many institutions have long been recognized as a major means of gaining enough experience in a reasonably short period of time to determine the effectiveness of new approaches in cancer therapy. In order to make such multiinstitutional trials meaningful, it is necessary to have uniform and objective diagnostic standards in histopathology. Large cooperative therapeutic trials, such as the Radiation Therapy Oncology Group (RTOG) constructs, must rely on the histopathologic diagnoses of many pathologists from varied institutions or subject them to central review, which is a longer and costlier process. This study is an assay of the need for central review in cooperative studies on non-small cell lung cancer, which includes squamous cell, large cell, adenocarcinomas, and combined squamous cell and adenocarcinomas.

Prognostic indicators for survival in stage I carcinoma of the lung: a histologic study of 47 surgically resected cases.

In a previous study of 91 consecutive lung cancer cases, we reported that tumor stage was the only significant predictor of survival, with all 5-yr survivors having Stage I disease. Approximately half of the 47 Stage I cases survived 5 yr, so the present study was initiated to determine which histologic features were predictive of survival for Stage I cases. An average of 10 slides per case was evaluated independently by three pathologists, and each slide was subjectively scored using previously agreed criteria for the following parameters: vascular or lymphatic invasion; anaplasia; mitotic rate; inflammatory host response; and the presence or absence of necrosis, tumor giant cells, a central scar, mucin production, benign giant cell reaction, or desmoplasia. Survival was also correlated with patient's age, sex, tumor (T) and nodal (N) status, tumor cell type, and histologic heterogeneity. All three observers found the extent of tumor necrosis to be a significant negative predictor of survival (P less than 0.05). One observer found tumor giant cells to be an adverse factor, another observer found scar carcinomas to have worse survival, and a third observer found lymphocytic inflammatory host response to be a positive predictor and venous invasion to be a negative predictor of survival (P less than 0.05). All other parameters showed no significant correlation with survival. The finding of some parameters which correlated with survival according to one but not the other two observers indicates that the results of studies of histologic prognostic indicators by a single observer may not be valid for other pathologists attempting to use the same subjective criteria.

Post-operative thoracic irradiation with or without levamisole in non-small cell lung cancer: results of a Radiation Therapy Oncology Group Study.

The Radiation Therapy Oncology Group conducted a Phase III single blind trial to evaluate the addition of Levamisole to post-operative thoracic irradiation (200 cGy five times weekly to a total of 5000 cGy plus 1000 cGy boost) in patients with resected RTOG Stage II-III non-small cell lung cancer with positive nodes. Between February 1980 and February 1983, 74 patients from 18 RTOG institutions were randomized; accrual to this study was prematurely terminated due to poor accrual and the inferior survival observed in the levamisole-treated patients on another RTOG trial. Sixty-four patients were evaluable; 32 assigned to levamisole and 32 were assigned to placebo. Over 95% of the patients have been followed for a minimum of 4 years or to death. Two patients on placebo and 5 on levamisole experienced Grade 3 pneumonitis or esophagitis; 1 patient on placebo and 2 on levamisole experienced Grade 3 pulmonary fibrosis. Three patients on levamisole experienced other Grade 3 or 4 toxicity: 1 case of intractable nausea and vomiting and 2 with Grade 4 neutropenia (less than 500 per mm3). There were no fatal complications. Median disease-free survival was 13 months in the placebo group and 9 months for the levamisole group. Median time to distant metastases was 18 and 12 months, and median survival was 20 and 13 months, respectively. We concluded that this study failed to demonstrate an advantage for levamisole.

Lung cancer heterogeneity. Prognostic implications.

Although histologic heterogeneity of lung cancer is well recognized, little information is available related to possible effects of this heterogeneity on prognosis. We collected 100 consecutive lung cancer cases, including 35 autopsies and 65 surgical resections, which were extensively sampled (average, ten blocks per case) and analyzed for histologic heterogeneity. Slides were randomized and classified by five pathologists using the 1981 World Health Organization (WHO) classification scheme. Five-year follow-up data were obtained for the surgical cases, and detailed information on staging and survival from time of diagnosis was available in 91 cases. Survival time was analyzed with respect to the patient's age, sex, stage, predominant histologic pattern, and presence or absence of major heterogeneity. The latter is defined as the presence on at least one slide of a major histologic pattern different from that of the remaining slides for that case. The only statistically significant predictor of survival was tumor stage (P less than 0.0001). Heterogeneous tumors appeared to have a worse survival, but this did not reach statistical significance. There was no relationship between survival and predominant histologic pattern (cell type), sex, or age.

Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy.

Over the past decade, improvement in survival has developed for patients with small cell lung carcinoma (SCLC) due to treatment strategies that include: cyclic combination chemotherapy, thoracic irradiation, and prophylactic cranial irradiation. In this study, we assess the outcome of treatment with initial cyclic combination chemotherapy including: cyclophosphamide, VP 16-123 and methotrexate combined with radiotherapy (RT), 6000 cGY [corrected] to the thorax for patients with limited disease and 3000 cGy [corrected] for patients with extensive disease. Forty-six patients are evaluated: 26 patients with limited disease and 20 with extensive disease. In patients who received 6000 cGy [corrected], to thoracic lesions, in combination with chemotherapy, administered for 3 courses prior to and following RT, the rate of clinically detected failure in the thorax was 3.8%. Morbidity was considered acceptable, although the occurrence of encephalopathy in 6 of 19 cases who received cranial irradiation, 3000 cGy [corrected], and concomitant chemotherapy was a serious consequence. Control of the primary tumor achieved by the use of higher dose RT is shown to be superior to that observed at lower doses of RT. This suggests that for the small cohort of patients whose disease is truly limited at the time of diagnosis, therapeutic regimens, which include higher dose RT, could increase the number of long term survivors of SCLC.