Pseudomesotheliomatous Carcinoma of the Lung

Pseudomesotheliomatous Carcinoma of the Lung A Variant of Peripheral Lung Cancer T. R. HARWOOD, M.D., D. R. GRACEY, M.D., AND H. YOKOO, M.D. From the Departments of Pathology, and Pulmonary Section of the Department of Medicine, V.A. Research Hospital and Northwestern University Medical School, Chicago, Illinois 60611 ABSTRACT Harwood, T. R., Gracey, D. R., and Yokoo, H.: Pseudomesotheliomatous carcinoma of the lung. A variant of peripheral lung cancer. Am J Clin Pathol 65: 159-167, 1976. Six cases of primary lung cancer that closely mimic malignant pleural mesothelioma clinically and anatomically are compared with four proven cases of malignant pleural mesothelioma. Findings on roentgenograms of the chest, clinical history, and gross examination of the lung specimens are not helpful in distinguishing between these two neoplasms. Microscopic examination of the hematoxylin and eosin-stained tissues is often inconclusive. Tissues were stained with hematoxylin and eosin, PAS with and without diastase treatment (DPAS), mucicarmine, alcian blue, toluidine blue, and colloidal iron with and without digestion by testicular hyaluronidase. Among these histochemical methods, DPAS was found to be particularly useful in distinguishing the primary lung cancers from the mesotheliomas. All primary lung cancers except one showed DPAS-positive material (mucin) in both the cytoplasm of the cancer cells and within the lumina of neoplastic glands. In contrast, none of the mesotheliomas showed the presence of DPAS-positive material. Histologically, all lung cancers were glandular. Five were classified as bronchiolar carcinoma, the remaining one as poorly differentiated adenocarcinoma. In two of the bronchiolar carcinomas, a small subpleural primary focus was demonstrated. This finding suggests a possible origin of these cancers as a small subpleural tumor that became widely disseminated via the subpleural lymphatics. This form of primary lung cancer possesses sufficient gross and microscopic characteristics that recognition should be given to it as a variant of primary lung cancer, with emphasis on differentiating it from pleural mesothelioma. (Key words: Pseudomesotheliomatous carcinoma; Peripheral lung cancer; Mesothelioma; Adenocarcinoma of lung; adenocarcinoma.) THERE IS A TYPE of primary lung cancer justify its recognition as a separate entity, possessing a characteristic clinical presenta- Although its existence is mentioned occation and distinct morphologic features that sionally in the literature,',4,5 the standard textbooks and the monographs 3 on lung Received May 1, 1975; accepted for publication May cancer do not recognize it. 14, 1975. Because of its close resemblance to Address reprint requests to Dr. Yokoo: Laboratory Service, V.A. Research Hospital, 333 E. Huron Street, _. i: nanf nl Pllra ] mesothelioma on PTOSS malignant pleural mesotneiioma On gross Chicago, Illinois 60611. examination, and often on microscopic 159

160 HARWOOD, GRACEY, AND YOKOO A.J.C.P.Vol. 65 examination as well, we prefer to call it "carcinoma of the pseudomesotheliomatous type." Six cases of this type of lung cancer have been observed in our laboratory. The clinical, gross and microscopic features are presented in this report. Material and Method Six cases of primary lung cancer simulating malignant pleural mesothelioma were analyzed from the standpoint of their clinical presentation. The gross and microscopic features of the specimens were studied in detail. Multiple sections were available from each case. They were stained with hematoxylin and eosin, periodic acid-schiff reagent (PAS), PAS after diastase treatment (DPAS), mucicarmine, colloidal iron, and metachromatic stains. In addition, four cases of malignant pleural mesothelioma were studied for comparison, particularly from the standpoint of gross and microscopic appearances. Report of Six Cases Case 1. A 50-year-old white man was first admitted in July 1967, three months after a diagnosis of malignant mesothelioma was made at another hospital. There is no record of his smoking history. The patient had worked in a shipyard in WW II and had been indirectly exposed to asbestos in his work. On physical examination, the patient appeared well-developed and wellnourished, in no acute distress. The only positive physical findings were consistent with a left pleural effusion. Chest x-ray showed a density in the left costophrenic angle. His terminal admission was prompted by progressive deterioration. He died February 2, 1968. At autopsy the right and left lungs weighed 440 and 550 Gm., respectively. The left lung was atelectatic. Both lungs had to be removed by sharp dissection. The left lung was completely covered with a thick layer of grey-white fibrous tissue 0.8 to 2.0 cm. in thickness. The right lung had multiple grey-white plaques, strongly suggestive grossly of a malignant pleural mesothelioma. The visceral and parietal pleurae were completely fused. The tumor grossly appeared confined to the pleurae. Metastatic tumor was found in multiple lymph nodes, pericardium, diaphragm, left adrenal gland, liver, spleen and brain. No clear-cut primary tumor nodule was recognized grossly or microscopically. Microscopic examination revealed a bronchiolar carcinoma (see Table 1). Case 2. The patient, a 55-year-old white man, was first admitted on September 21, 1967 complaining of progressive hoarseness for one year. He had smoked one pack of cigarettes per day for the prior 27 years. He had lost 5.5 kg. in weight during the preceding month. On physical examination, he was well-developed and wellnourished, in no acute distress. Direct laryngoscopy, using local anesthesia, revealed an extensive lesion of the right true vocal cord. The right cord was fixed. Biopsies revealed well-differentiated squamous-cell carcinoma. On October 6, 1967 the patient underwent laryngectomy, radical neck dissection, and tracheostomy. The preoperative chest x-ray was unremarkable. On November 3, 1967, the patient complained of marked dyspnea at rest, and had findings of a left pleural effusion. Chest x-ray showed complete opacification of the left lung with a marked shift of the mediastinum to the right. A chest tube was placed for relief of symptoms and 4,200 ml. of serosanguineous pleural fluid were removed via the tube. Needle biopsy of the pleura revealed adenocarcinoma. Our impression was that the pleural carcinoma was from a second primary source, probably in the lung. On February 26, 1968, physical examination revealed findings consistent with a left

February 1976 PSEUDOMESOTHELIOMATOUS CARCINOMA 161 Table 1. Staining Reactions, Showing Difference between Pseudomesotheliomatous Carcinomas and True Mesotheliomas Intracytoplasmic Intraluminal Case No. Tumor Type (WHO) PAS DPAS Alcian Blue PAS DPAS Mucicarmine Mucicarmine Alcian Blue 68 A 42 WHO 111.2 68 A 112 WHO III.2 ± ± ± 70 A 7 WHO III.2 71 A 60 WHO III.2 ~~ 71 A 246 Poorly diff.? WHO III.2 71 A 339 WHO III.2 67 A 156 Mesothelioma WHO XII.2 68 A 277 Mesothelioma WHO XII.2 NS* NS* 71 A 310 Mesothelioma WHO XII.2 72 A 53 Mesothelioma WHO XII.2 ± K NS = not adequate stain (control negative). pleural effusion and marked ascites. The patient was readmitted for the last time with progressive ascites and increasing dyspnea. His condition deteriorated rapidly and he died on April 20, 1968. Autopsy revealed carcinoma covering the left lung with metastases to the mediastinal lymph nodes and involvement of the entire left pleura. The right lung weighed 1,050 Gm., the left 1,500 Gm. The left lung was entirely encased by a layer of grey-white tumor tissue slightly more than. 1 cm. in thickness. The microscopic diagnosis was bronchiolar adenocarcinoma. It was PAS-positive (see Table 1). Case 3. The patient, a 59-year-old white man, was admitted September 10, 1969, because of progressive pain and weakness of the right arm and leg. He had walked with a limp for two months prior to admission. He denied any sensory disturbance other than pain. He had lost 16 kg. in weight since being operated on for a stomach ulcer at another hospital 3J4

162 HARWOOD, GRACEY, AND YOKOO A.J.C.P. Vol. 65 months prior to admission. In 1959 the patient had been treated for tuberculosis. The history of this was vague. The patient had smoked one to two packs of cigarettes a day for more than 40 years. Physical examination revealed that the patient was emaciated. There was an operative scar in the midline of the abdomen. His mental status was difficult to evaluate. He did not know dates and was not able to do simple calculations. He manifested many neurologic abnormalities. The VDRL was positive to four dilutions. A liver scan revealed hepatomegaly with a large defect in the right lobe compatible with a space-occupying lesion. The chest x-ray revealed pleural thickening in the right base and the suggestion of some encapsulated fluid. A bone marrow examination revealed metastatic carcinoma. The patient's condition deteriorated progressively and he died four months after admission. Autopsy revealed adenocarcinoma of the right lung with extension and/or metastases covering the entire visceral and parietal pleura, with nodules in liver, vertebral bones, and spleen. In some areas the pleura was markedly fibrosed and thickened, but no other primary tumor tissue was identified. (See Table 1 for histology.) Case 4. A 76-year-old white man was admitted December 12, 1970, with chronic obstructive pulmonary disease, known for many years. Five months prior to admission the patient had been evaluated at another hospital for an 18-kg. weight loss and progressive dyspnea. At that time a thoracentesis had been performed. We were unable to obtain any information as to the nature of the fluid removed. The patient had smoked more than a pack of cigarettes a day for 40 years. On admission the patient was a welloriented and cachectic, with a right pleural effusion. Serum chemistries revealed progressive elevation of the serum alkaline phosphatase to 111 units (our normals, 30-85 mil. per ml.). Thoracentesis revealed a yellowish-green, clear fluid. The specific gravity was 1.015 and protein, 3.5 mg. per 100 ml. Cultures of the pleural fluid and biopsies were negative for mycobacteria and fungi. Multiple cytologic examinations of the pleural fluid were negative. The patient suddenly went into coma on February 25, 1971, his condition deteriorated rapidly, and he died. At autopsy the lower lobe of the right lung was fused to the underlying diaphragm by abundant grey-white fibrous tissue. The visceral and parietal pleurae in this area were diffusely matted together, forming a thick layer of grey tissue that encircled the lower lobe. It was as much as 0.3 cm. in thickness. There was a nodule 0.7 cm. in diameter in the pulmonary parenchyma immediately beneath the pleura which appeared continuous with the overlying thick pleural tissue. Elsewhere the right and left lungs showed marked emphysematous changes with focal areas of fibrosis. The bronchial tree was not remarkable. Metastatic deposits were found in the left adrenal gland and pericardium. Histologic sections showed a bronchiolar carcinoma (see Table 1). Case 5. A 51-year-old black man was admitted July 6, 1971, complaining of intermittent pleuritic chest pain over the left posterior chest. The patient had lost 7.8 kg. in weight over the prior three months. He had smoked one pack of cigarettes per day for 36 years. His mother had died of cancer of unknown origin at the age of 48. Physical examination was not remarkable except for localized tenderness to pressure in the left posterior rib cage and a pleural friction rub in the left lower axillary area. The admission chest x-ray showed a left lower lobe infiltrate with a left pleural effusion. There was a 2 cm. questionably nodular lesion in the left midlung field peripherally, and two nodular lesions were seen in the left lower lobe. On July 19, 1971, a pleural biopsy was non-diagnostic, and

February 1976 PSEUDOMESOTHELIOMATOUS CARCINOMA 163 '«* '&%..-\;4 /" # * *~*»^ I-A-246 FIG. 1. Half of bisected lung, demonstrating pleural involvement with encasement of the lung by tumor. the patient refused to undergo any further studies. He left against medical advice on July 27, 1971, returning August 23, 1971, with left chest pain of a pleuritic nature. On readmission the patient had had a 10.5 kg. weight loss over four months. He weighed 44 kg. and was cachectic and in chronic respiratory distress. His attention span was short, but he was oriented and cooperative. The physical findings were again consistent with a left pleural effusion, and again there was a pleural friction rub in the left axilla. The chest x-ray showed progression of the left pleural effusion. Brain scan showed a suspicious area of uptake in the right parietofrontal area. A pleural biopsy revealed adenocarcinoma in the pleura. During hospitalization a spinal-cord lesion with rapidly progressive flaccid paraplegia and a sensory level at T6 developed. The patient's condition progressively deteriorated and he died on September 3, 1971. Autopsy revealed complete obliteration of the left pleural cavity due to fusion of the visceral and parietal pleurae. The left lung was covered by a thick layer of grey-white hard tissue averaging 0.5 cm. in thickness (Fig. 1). There was a grey tumor nodule 1.5 cm. in diameter over the lateral aspect of the lower lobe immediately below the thickened pleura and continuous with the thickened pleura. Elsewhere, the pulmonary parenchyma was free of tumor tissue. Metastatic lesions were found in the left adrenal gland and kidney. The tumor invaded the spine at the levels of the sixth, seventh, and eighth thoracic vertebrae and resulted in compression of the spinal cord at these levels. The right lung was not involved by the tumor, but there was a localized tuberculous granuloma in the upper lobe. Tissue sections confirmed the presence of PAS-positive adenocarcinoma (see Table 1 and Figs. 2 and 3). Case 6. A 49-year-old white man was admitted November 18, 1971, with complaints of chronic weight loss, cough,

164 HARWOOD, GRACEY, AND YOKOO A.J.C.P. Vol. 65 anorexia, and malaise. The patient had begun to lose weight approximately a year prior to admission. His usual weight was 59 kg., but on admission he weighed 47 kg. He had smoked 1 to 1!4 packs of cigarettes per day for 30 years and stated that he'd had a chronic cigarette cough for many years. The patient weighed 47 kg. and was 170 cm. tall. He appeared cachectic and chronically ill. Examination of the chest revealed a mild scoliosis. The diaphragm moved on the right, but there was no apparent diaphragmatic movement on the left. There were decreased vocal fremitus and decreased breath sounds accompanied by dullness to percussion at the left base. Vesicular breath sounds were heard above the area of dullness, and there were diffuse rhonchi with occasional wheezing and a few coarse rales over the left anterior chest. Radiologic studies revealed bilateral pleural effusions. Three pleural biopsies were obtained using a Cope needle. The first two biopsies were not specific. The third biopsy showed adenocarcinoma. The patient's condition deteriorated rapidly and on December 14, 1971, he died. At autopsy the left lung was completely encircled by a thick layer of grey-white hard tissue as much as 0.4 cm. in thickness. The parenchyma of the left and right lungs was not remarkable. The bronchial tree showed no evidence of gross abnormalities. Metastatic deposits were found in the regional lymph nodes, left adrenal gland, mesenteric lymph nodes, and the serosa of the stomach, small and large intestines (see Table 1 for microscopic findings). Summary of Clinical Data The average age of the patients was 57 years. The total duration of illness related to the cancer was less than 8 months after the onset of clinical symptoms referable to the disease. Dyspnea, chest pain and weight loss were most frequently mentioned as the presenting symptoms. All patients smoked cigarettes, with the possible exception of the patient in Case 1, where no smoking history was available. Chest x-ray films were indicative of either pleural thickening or effusion. Although the nature of the disease was suspected in every case, it was uncertain in the absence of histologic confirmation in two cases, and in another a diagnosis of malignant mesothelioma was entertained. Pleural biopsies were often negative, showing only fibrous tissue. Cytologic study of pleural fluid was likewise unrewarding. Sputum cytology was uniformly negative. Gross and Microscopic Appearance The left lung was involved three times, the right lung twice, and both lungs in one case, although in the last case the left lung seemed to be surrounded by the most tumor. The involved lungs were increased in weight due to the large amounts of tumor tissue surrounding the pulmonary parenchyma. With the exception of one case in which only the lower lobe was primarily involved, the lungs were completely encased by a thick layer of grey neoplastic tissue which was infiltrating the fused and thickened visceral and parietal pleurae. The thicknesses of this neoplastic tissue ranged from 0.3 to 2.0 cm. (Fig. 1). Lung that was completely encased by thickened pleura was often atelectatic. The opposite lung was usually free of metastatic tumor but often was involved by chronic pulmonary disease such as fibrosis with pleural adhesions, emphysema, and/or old tuberculosis. Asbestos bodies were not found in any of the cases. Metastases were frequently found in regional lymph nodes, adrenal glands, vertebral bones, pericardium and livera pattern reminiscent of peripheral lung cancers. Primary tumor was demonstrated in two cases, but in the remaining four no primary site was identified. In the latter cases the

PSEUDOMESOTHELIOMATOUS CARCINOMA 165 'i* FIG. 2 (upper). Overall pattern of adenocarcinoma of pseudomesotheliomatous type, W H O classification III.2. Hematoxylin and eosin. x200. Fie. 3 (lower). High-power photomicrograph to show detail of cuboidal to columnar epithelium of pseudomesotheliomatous carcinomas. Hematoxylin and eosin. X450. primary site was thought to be small, subpleural in location, and probably obliterated by the overlying tumor tissue in the earlier stage of cancer development. This assumption is supported by the findings in the two cases where a small subpleural nodule (0.7 and 1.5 cm. in diameter, respectively) having identical morphology

166 HARWOOD, GRACEY, AND YOKOO A.J.C.P. Vol. 65 and appearing to be continuous with the overlying pleural tumor was found. Histologically, the tumor consisted of dense collagenous stroma and glandular structures lined by cuboidal to columnar neoplastic epithelial cells (Figs. 2 and 3). In all cases glandular architecture was uniformly evident. In one case the architecture was papillary and in two, the tumor cells formed some solid aggregates of neoplastic cells with areas of loosely arranged glands. Pleomorphism varied widely. In one case the tumor cells were rather uniform and no mitotic figures were observed, while in another, pleomorphism was marked with numerous mitotic figures. The collagenous stroma was often hyalinized, and in two cases there were areas in which the thickened pleura did not contain neoplastic cells. Histochemically, intracytoplasmic and/or intraluminal mucin was identified in every case. Except in one case (Case 5), all cancers had the microscopic appearance consistent with terminal bronchiolar carcinoma (WHO classification III.2). In case 5, while much of the tumor was poorly differentiated adenocarcinoma, some areas were consistent with bronchiolar carcinoma. The results of gross and microscopic examinations of the bronchial tree were not remarkable in any of the cases, thus excluding the possibility of bronchial origin of these cancers. In one case (Case 3), the pleura may have been previously diseased by a chronic fibrosing process that preceded the development of the cancer. So far, squamous-cell carcinoma, oat-cell carcinoma, and undifferentiated large-cell carcinoma have not been seen in association with the pseudomesotheliomatous carcinoma in our laboratory, although they are known to occur peripherally. 7 Criteria for Diagnosis Diagnosis of this neoplasm on a clinical basis is difficult. Pleural effusion, chest pain, dyspnea, absence of an intrapulmonary nodule and thickened pleura on chest x-ray, along with general signs and symptoms of malignancy, together suggest this entity. Findings on pleural biopsy may not be diagnostic. Because the gross and microscopic appearances of pseudomesotheliomatous carcinoma are often similar to those of malignant pleural mesothelioma and metastatic carcinoma, exclusion of primary tumors elsewhere both in and outside the lung is the most important criterion in establishing the diagnosis. Since this can be done only by postmortem examination, definitive diagnosis of this tumor before death is virtually impossible on a clinical basis alone. A major problem in diagnosis is to differentiate pseudomesotheliomatous carcinomas from malignant pleural mesothelioma. Gross examination of lung specimens is not always helpful since the two lesions appear identical grossly. 4,5 The definitive diagnosis should rest upon microscopic examination, taking the following considerations into account. If the biphasic or sarcomatous feature seen in some of the malignant pleural mesotheliomas is pressent, the diagnosis of pseudomesotheliomatous carcinoma can readily be excluded. The presence or absence of intracytoplasmic and intraluminal mucin is perhaps the most useful feature in differentiating the two lesions. 1,2 ' 6 Histogenesis The histogenesis of this tumor is not clear. However, there are two findings that suggest its histogenesis. The first is the presence of a small subpleural nodule continuous with the pleural tumor in two of the cases. The gross and microscopic features of these subpleural nodules are consistent with terminal bronchiolar carcinoma associated with a healed subpleural scar. The second finding is the lack of tumor tissue in the thickened fibrosed pleura in one of the cases. This finding suggests that

February 1976 PSEUDOMESOTHELIOMATOUS CARCINOMA 167 the fibrous thickening of the pleura might not all be due to the presence of tumor. The fibrous thickening may have existed prior to the development of the tumor. It is postulated that the following sequence of events might have been operative. In the early stage of disease the pleura is chronically diseased and fibrosed. In the next stage the diseased pleura and the pulmonary parenchyma immediately beneath the pleura contribute to the development of a carcinoma in a manner similar to scar carcinoma. 7 In the third and last stage the tumor spreads rapidly across a thickened pleura in a manner similar to a malignant mesothelioma. The findings of chronic disease, including adhesive pleuritis, severe pulmonary emphysema, and tuberculous granuloma, in this series lend support to this hypothesis. Conclusion Six cases of primary lung cancers of the pseudomesotheliomatous type are briefly described. The clinical, gross and microscopic features of this type of carcinoma closely resemble those of malignant pleural mesothelioma. Microscopically, five of the six cases were bronchiolar carcinomas, while one was poorly differentiated adenocarcinoma, and in every case intracytoplasmic mucin was demonstrated in the tumor cells. The histogenesis of this cancer is postulated based on the histologic observations. Because of its highly characteristic gross and microscopic features, its recognition as a unique form of peripheral lung cancer appears justified. References 1. Churg J, Selikoff I: Geographic pathology of pleural mesothelioma, The Lung, International Academy of Pathology Monograph. Baltimore, Williams and Wilkins, 1968, pp 284-297 2. Churg J, Rosen SH, Moolten S: Histological characteristics of mesothelioma associated with asbestos. Ann NY Acad Sci 132:614-622, 1965 3. Kreyberg L, Liebow AA, Uehlinger EA, et al: Histological typing of lung tumors, International Histological Classification of Tumours, No. 1, World Health Organization, Geneva, 1967 4. McCaughey WTE: Criteria for diagnosis of diffuse mesothelial tumors. Ann NY Acad Sci 132:603-613, 1965 5. Webster I: Mesotheliomatous tumors in South Africa: Pathology and experimental pathology. Ann NY Acad Sci 132:623-646, 1965 6. Winslow DJ, Taylor HB: Malignant peritoneal mesothelioma: A clinico-pathological analysis of 12 cases. Cancer 13:127-136, 1960 7. Yokoo H, Suckow EE: Peripheral lung cancers arising in scars. Cancer 14:1205-1215, 1961