Fred R. Hirsch

Staging and prognostic factors in small cell lung cancer: a consensus report

‘Division of Oncology, Department of Medicine, University Hospital, Zitrich (Switzerland); 2Department of Surgery, Mt. Sinai Hospital, Toronto (Canada); 3Divi 4Department of Internal Medicine, Birpebjerg Hospital, Copenhagen (Denmark); ‘NCI-Navy Medical Oncology Branch, Bethesda, MD (U.S.A.); 6Department OfRadiothcrapy, Medical Academy, Gdansk (Poland); ‘lnstiiut for Cancer Research, Vienna (A@&); ‘Section ofHematologylOncology, Department of Medicine, Dartmouth-HitchcockMedical Center, Hanover.NH (U.S.A.); ‘Department OfMedicine, Central Sygehusel. Hillerod {Denrrmk); and ‘ODepartment of Radiotherapy, Inrtitut Jules Bordet. Brwsels (Belgium)

Prophylactic irradiation in bronchogenic small cell anaplastic carcinoma. A comparative trial of localized versus extensive radiotherapy including prophylactic brain irradiation in patients receiving combination chemotherapy

A total of 114 patients with bronchogenic small cell anaplastic carcinoma and staged as having regional disease all underwent combination chemotherapy consisting of CCNU, cyclophosphamide, and methotrexate. They were randomized to receive either radiotherapy to the primary tumor and regional lymph nodes (4000 rad) or extensive radiotherapy, which included the brain, adrenals, and upper retroperitoneal lymph nodes. Fifteen patients were free of disease after 18 months of chemotherapy and the treatment was discontinued. Only 3 patients subsequently relapsed. No difference was observed between the two groups of patients in median survival time, response rate, duration of response, or relapse pattern, including the frequency of brain metastasis.

Bone-marrow examination in the staging of small-cell anaplastic carcinoma of the lung with special reference to subtyping. An evaluation of 203 consecutive patients.

Histologic examination of bone‐marrow from the posterior iliac crest was routinely done as a pretreatment staging procedure in 203 consecutive patients with small‐cell anaplastic carcinoma of the lung. Subtyping of the patients according to the WHO classification included 27.8% with “fusiform” cell type (WHO II,1), 28.3% with “polygonal” cell type (WHO II,2), 42.8% with “lymphocyte‐like” cell type (WHO II,3), and 1.1% with mixed types (WHO II,4). Bone‐marrow involvement was found in 17.2%. No significant difference was observed among the histological subtypes with regard to bone‐marrow involvement. A comparison of bone‐marrow biopsy and aspiration in patients investigated with both procedures showed that aspiration alone was diagnostic in nine of 24 (38%) positive patients as compared with two of 24 (8%) with biopsy alone, while in the remaining 13 patients (54%) both procedures were positive. Of the 35 patients with positive bone‐marrow examination, 77% had no other evidence of distant metastatic disease if liver metastases identified by peritoneoscopy and liver biopsy are excluded as a staging procedure. With the exception of thrombocytopenia which was observed in six patients, with bone‐marrow metastases, hematological findings were of little value in detecting bone‐marrow involvement.

Hormonal polypeptides and amine metabolites in small cell carcinoma of the lung, with special reference to stage and subtypes.

To elucidate the ectopic hormonal pattern in patients with small cell carcinoma of the lung, plasma ACTH, serum calcitonin, serum gastrin, plasma glucagon, serum insulin, plasma secretin, plasma VIP, serum growth hormone, serum hCG/LH, the total of serum hCG and hCG‐β‐subunit, serum α‐subunit, serum human placental lactogen, urine ADH, urine 5‐HIAA, urine VMA, urine HVA, and urine hCG‐LH were measured prior to therapy in 75 patients. Twenty‐two patients (29%) had elevated plasma ACTH, and 18 of these had concomitant increased values of corticosteroids in a 24‐hour urine sample. Forty‐eight patients (64%) were found to have elevated serum calcitonin, and one‐third of the patients were diagnosed as having the ectopic ADH syndrome. Serum gastrin concentrations were increased in 20% of the patients, but the elevations were marginal in almost all cases. None of the remaining substances was found to be significantly elevated. Concentrations of plasma ACTH, serum calcitonin, and urine ADH were not found to be correlated with the stage of the disease, and no correlation of these substances with the histological subtypes of small cell carcinoma was disclosed.

Treatment of small cell anaplastic carcinoma of the lung with the oral solution of VP‐16‐213 (NSC 141540, 4′‐demethylepipodophyllotoxin 9‐(4,6‐0‐ethylidene‐β‐D‐glucopyranoside)

The semisynthetic podophyllotoxin derivative VP‐16‐213 (NSC 141540) has been evaluated in a phase II study in patients with small cell anaplastic carcinoma of the lung. The drug was administered as an oral solution, the drinking ampoule, in doses of 100 mg twice a day for 4 days in 30 patients previously treated with intensive combination chemotherapy and for 5 days in 10 untreated patients. The courses were repeated every third week with dose modifications according to individual tolerance. All patients had measurable disease and objective responses were obtained in 20 patients (50%), 15 previously treated (50%) and 5 untreated patients (50%). The median time for response after the start of treatment was 15 days (range 6–42) and the median duration of response was 56 days (range 16–147). Dose‐limiting toxicity was principally hematologic, consisting of leukopenia, but gastrointestinal toxicity and alopecia were also observed. The study demonstrated that VP‐16‐213 administered as an oral solution is highly effective against small cell anaplastic carcinoma of the lung without clinical cross‐resistance to CCNU, cyclophosphamide, methotrexate, or vincristine. Cancer 40:633–637, 1977.

Peritoneoscopy in the staging of 190 patients with small‐cell anaplastic carcinoma of the lung with special reference to subtyping

Peritoneoscopy with liver biopsy was routinely done as a pretreatment staging procedure in 190 patients with small‐cell anaplastic carcinoma of the lung. Subtyping of the patients according to the WHO classification included 28.3% with fusiform cell type (WHO II,1), 28.9% with polygonal cell type (WHO II, 2), 41.5% with lymphocytelike cell type (WHO II, 3) and 1.3% with mixed types (WHO II, 4). Liver metastases were found in 21% of the patients with adequate liver biopsy. In addition macroscopic signs of liver metastases were observed in 9%. No significant differences were observed among the histological subtypes. Liver function tests, such as alkaline phosphatase, LDH and GOT, were of little value in excluding liver metastases. On the other hand, 2 of 3 abnormal liver function tests were highly indicative of liver metastases. In patients with positive liver biopsy, 41% had liver metastases alone and 76% had no other evidence of distant metastatic disease if bone‐marrow involvement identified with bone marrow examination is excluded as a staging procedure.

Tumor heterogeneity in lung cancer based on light microscopic features

In order to study the problem of morphological tumor heterogeneity in lung cancer, 200 consecutive patients who had undergone surgery for a malignant lung tumor, were evaluated retrospectively with regard to morphological type. The tumor was classified morphologically in 187 patients, and 163 (87%) had a morphologically homogeneous tumor, based on light microscopic features and using the criteria recommended by the World Health Organization. The remaining 24 patients (13%) had a tumor with morphologic features of more than one cell type. It is concluded that morphological heterogeneity is a considerable problem in the classification of malignant lung tumors. This heterogeneity has been regarded as evidence of an endodermal origin of all major types of lung cancer. Future prospective studies will have to determine whether it has any therapeutic significance.

Differentiation of adenocarcinoma of the lung and malignant mesothelioma : predictive value and reproducibility of immunoreactive antibodies

A panel of antibodies against keratins, epithelial membrane antigen (EMA), epithelial antigen (Ber‐EP4), carcinoembryonic antigen (CEA), tumour‐associated glycoprotein (B72.3), vimentin and LeuM1 was applied to sections of adenocarcinoma of the lung and malignant mesothelioma in a randomized design. The proportion of stained tumour cells within each section was estimated independently in five categories by three pathologists (no positive tumour cells, 1–10%, 11–33%, 34–66% and more than 67% positive tumour cells). The kappa values representing the chance corrected interobserver agreement for the different antibodies in such a five group assessment were between 0.38 and 0.72. In two group assessment the kappa values were between 0.53 and 0.94. Nosological sensitivity and nosological specificity were calculated for all antibodies, and diagnostic sensitivity and diagnostic specificity (predictive values) were calculated for the Ber‐EP4, CEA, B72.3, LeuM1 and vimentin. The difference between nosological sensitivity and nosologic specificity and the clinically relevant predictive values of positive and negative tests were demonstrated. In respect of the reproducibility and the diagnostic power defined by the predictive values, we demonstrated that a panel of antibodies, including CEA, Ber‐EP4 and B72.3 and, to a lesser degree, LeuM1 and vimentin is applicable for the histopathological distinction between adenocarcinoma of the lung and malignant mesotheliomas. Before introduction of new diagnostic tests, including new antibodies, the prevalence of the tested tumours should be estimated. Nosological sensitivity and nosological specificity should be converted to predictive values.

The histopathological diagnosis of malignant mesothelioma v. pulmonary adenocarcinoma: reproducibility of the histopathological diagnosis

In a randomized design we examined the interobserver variation in the histopathological diagnosis of adenocarcinoma of the lung and malignant mesothelioma. In three rounds, three pathologists assessed slides from 42 tumours originally diagnosed as adenocarcinomas, malignant mesotheliomas or benign lesions in the pleura. In the first round the assessments were made on haematoxylin and eosin (H & E) stained sections; in the second, on H & E sections plus sections stained with histochemical mucin stains; and in the final round, the diagnoses were made on H & E sections and sections stained with a panel of antibodies against various antigens (cytokeratin, EMA, CEA, Ber‐EP4, B72.3, Leu‐M1, vimentin and S‐100 protein) said to be of value in the differential diagnosis. The overall interobserver agreements for the three rounds were 0.659, 0.802 and 0.817; the kappa values were 0.461, 0.681 and 0.690. It is concluded that differentiation between adenocarcinoma of the lung and malignant mesothelioma should be made on sections stained with H & E and mucin and/or immunohistochemical staining reactions, including antibodies against B72.3. Ber‐EP4 and CEA.

ME1-Antibody labelling of primary bronchogenic tumours and extrapulmonary malignancies

ME1 is a monoclonal antibody which is generated by the use of a mesothelioma cell line (SPCIII). The antibody has a preferential reaction to antigens on mesothelial and mesothelioma cells. In a prospective study we determined the reactivity in frozen sections from malignant mesotheliomas (two cases, positive controls), lung tumours (115 cases) and other malignant tumours (23 cases). The two malignant mesotheliomas were immunoreactive in most of the tumour cells. The reaction was strong, often with a diffuse staining of the cytoplasm and in some tumour cells there was heavy staining of the cell membrane. Five adenocarcinomas of the lung (9%), one large cell carcinoma (10%) and 18 squamous cell carcinomas of the lung (41%) were positive (defined as tumours containing more than 10% positive tumour cells with a strong reaction). The same was true for seven out of 23 (30%) extrapulmonary malignancies. The overall nosologic specificity of ME1 was 76%. Twenty out of the 26 ME1-positive lung tumours and six out of seven ME1-positive extrapulmonary malignancies were also positive for one or more markers, which is considered characteristic of carcinomas. The six negative lung tumours were squamous cells carcinomas and the negative extrapulmonary tumour was a meningeoma; all of them with a morphology different to malignant mesothelioma. In conclusion, when frozen sections are available, ME1 might be useful in the differential diagnosis of malignant tumours. However, a positive reaction is not specific for malignant mesothelioma.