The Occurrence of Psammoma Bodies in Papillary Adenocarcinoma of the Lung

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1 The Occurrence of Psammoma Bodies in Papillary Adenocarcinoma of the Lung DAVID H. UNTERMAN, M.D., AND I. M. REINGOLD, M.D. Laboratory Service, Veterans Administration Hospital, Long Beach, California 90801, and UCLA School of Medicine, Los Angeles, California ABSTRACT Unterman, David H., and Reingold, I. M.: The occurrence of psammoma bodies in papillary adenocarcinoma of the lung. Am. J. Clin. Pathol. 57: , In a series of 56 consecutive necropsies of patients with primary adenocarcinoma of the lung, nine of the lesions contained psammoma bodies. Three similar cases not from this series are included in the study. The 12 adenocarcinomas contained papillary formations, with the psammoma bodies easily recognizable within the glands and papillary processes of the primary tumor and, in several instances, in their metastatic foci. The psammoma bodies were laminated and nonlaminated types and contained various amounts of mucopolysaccharides, iron, and calcium. The differentiation of these tumors from other papillary adenocarcinomas with psammoma bodies, especially of the thyroid gland, is important because of the prognostic and therapeutic implications. In two recent surgical cases, metastatic papillary adenocarcinomas with psammoma bodies were found in cervical and mediastinal lymph nodes with the primary sites of the tumors in the lungs. PSAMMOMA BODIES are most frequently ob- to whether it arose in the lung or thyroid served in tumors of the thyroid gland, ova- gland, and the prognostic evaluation of ries, and meninges, and their recognition is the patient would be considerably different, an aid in the identification of these tumors. A perusal of the literature disclosed very We have observed these bodies in cases of few references concerning psammoma bodpapillary adenocarcinoma of the lung and ies in general and calcification or psamin their metastases in lymph nodes and moma bodies with carcinoma of the lung. 8 ' T parenchymatous organs. Since the micro- This prompted us to re-examine our nescopic characteristics of papillary adeno- cropsies of patients with adenocarcinoma carcinomas of the lung, thyroid gland, and of the lungs in an attempt to identify psamovary are similar in both primary and meta- moma bodies, static tumors, with minor variations, proper identification of the primary tumor be- Material and Methods comes significant. Thus, a metastatic papil- A series of 56 necropsies of patients with lary adenocarcinoma with psammoma bod- adenocarcinoma of the lungs was studied ies would be treated differently according at the Long Beach Veterans Administration Hospital during a 5-year period from 1963 Received April 26, 1971; accepted for publication, _...., May 18, to All microscopic sections from these Address reprint requests to: D. H Unterman, n e c r o p sj e s were re-examined to identify M.D., Laboratory Service, Veterans Administration r Hospital. Long Beach, California psammoma bodies in the primary tumors 297

2 298 UNTERMAN AND RE1NGOLD A.J.C.P. Vol. 57 and their metastases. In nine cases psammoma bodies were readily recognized. Macroscopic and microscopic characteristics of the tumors and their metastases were studied, and the locations and characteristics of the psammoma bodies were evaluated by hematoxylin and eosin and by special stains, including the Von Kossa for calcium salts, periodic acid-schiff (PAS) for mucin, and Prussian blue stain for iron. An analysis of symptomatology, therapy, and prognosis was made. In addition, this report includes three additional recent necropsies of adenocarcinoma of the lungs with psammoma bodies which were not included in the above five-year period. The 12 cases from our autopsy material were the source of this study. We have also found two cases in our recent surgical material in which scalene lymph nodes and tissue removed from the mediastinum contained adenocarcinoma with psammoma bodies and in which the lungs were identified as the primary site by both clinical and pathologic evidence. Report of Cases Clinical Aspects The patients were Caucasian men and ranged in age from 20 to 80 years, with a median age of 61 years. Eleven of 12 patients were more than 53 years of age. The most common symptoms, in order of frequency at the time of admission, were pain (chest, back, shoulder, neck, and arm), cough (productive and nonproductive), hemoptysis, dyspnea, anorexia, and hoarseness. Five patients had symptoms indicative of metastatic lesions: three patients had lytic lesions in bones and two had evidence of cerebral metastases. One patient had left-sided hemiparesis, and at necropsy an unexpected carcinoma of the right lower lobe with many cerebral metastases was found. Another patient had a past history of bronchial asthma of two years' duration; at necropsy, the bronchi of the upper, middle, and lower lobes of the right lung were invaded by tumor. Symptoms had been present for 1 to 24 months prior to admission. In every case the clinical course was that of rapid deterioration, with death occurring 1 to 8 months after admission. Essential Laboratory Findings Serum calcium levels were within normal limits in nine of ten patients for whom this test was performed; one had mild hypocalcemia (8.2 and 8.9 mg. per 100 ml.). None had hypercalcemia. Mild elevations in serum alkaline phosphatase (as high as 50 King-Armstrong units) occurred in five patients with hepatic or osseous metastases. Lactate dehydrogenase was moderately elevated (as high as 750 Wroblewski units) in eight patients with widespread metastases. Uric acid levels were elevated in two patients (6.7 and 8.2 mg. per 100 ml.). Ten of twelve patients had lesions which were visible on roentgenograms of the chest at the time of admission. Sputum cytology demonstrated malignant cells in seven of nine patients, and in two of these patients distinct psammoma bodies were also seen. Pleural fluid was positive in the four patients examined. Bronchial biopsies in five of six patients and scalene lymph nodes in three of four patients were positive for tumor. Eleven patients were confirmed as having tumor prior to autopsy, and all tumors were considered to be inoperable. Treatment Nine patients were treated with a chemotherapeutic agent and two of these received additional radiation therapy. Chemotherapeutic drugs consisted of Streptonigrin, used in five patients, and Velban, Cytoxan, hydroxyurea, and imidazole-4-carboxamide, each given to a single patient. Necropsy Findings Macroscopic Features. Seven of the primary pulmonary tumors were in the right lung and five in the left lung; neither upper nor lower lobes predominated. The tumors ranged from 3 to 15 cm. in diam-

3 March 1972 PULMONARY CARCINOMA WITH PSAMMOMA BODIES Fie. 1 (upper, left). A nest of papillary adenocarcinoma in a dilated alveolus, showing multiple concentrically laminated psammoma bodies. Hematoxylin and eosin. x 200. FIG. 2 (upper, right). Intimate association of adenocarcinoma and psammoma bodies which are of the non-laminated, crystalline, and fractured form. Other psammoma bodies present in this primary tumor did contain concentric laminations and were positive for iron, calcium salts, and mucin. Hematoxylin and eosin. X 400. FIG. 3 (lower, left). Lymphatic channel within parenchyma of the lung, containing papillary adenocarcinoma with psammoma bodies. Laminations can be seen. Hematoxylin and eosin. X105. FIG. 4 (lower, right). An adenoid cystic pattern was seen in association with papillary adenocarcinoma in this primary tumor in the lung. Psammoma bodies in this case were chiefly nonlaminated, more eosinophilic, and contained iron, calcium salts, and mucin. Hematoxylin and eosin. X

4 300 UNTERMAN AND REINGOLD A.J.C.P. Vol. 57 eter, varied from tannish-white to dark gray, and were firm to hard, with an occasional area of necrosis. The affected lung weighed as much as three times normal. In six patients significant amounts of anthracotic pigment were present throughout the lung. In all patients, metastases to lymph nodes and viscera were found; the organs most often involved, in order of frequency, were the liver, adrenal glands, kidneys, spleen, brain, and pancreas. In 11 of 12 patients the thyroid gland was grossly and microscopically free of tumor. In one patient in whom the thyroid gland and lung contained papillary adenocarcinoma, metastases were also present in the mediastinal lymph nodes, adrenal glands, and both lungs. A large mass of the pulmonary tumor was a poorly differentiated adenocarcinoma containing droplets of mucin and psammoma bodies; the tumor in the thyroid gland was a microscopic focus of well differentiated papillary adenocarcinoma without evidence of psammoma bodies. It is probable that both organs were primary sites. Although it is not unusual to find a small papillary adenocarcinoma of the thyroid gland associated with extensive metastases, it is also not uncommon to find a second primary site with carcinoma of the thyroid gland. 8 Microscopic Features. Of the 56 adenocarcinomas of the lungs, nine contained psammoma bodies within the tumor. In all nine tumors, papillary features were prominent, and as a result all the tumors were classified as papillary adenocarcinoma with the presence of psammoma bodies. The three additional recent necropsies showed similar findings. The tumors consisted of anaplastic glands which showed all degrees of differentiation and frequently formed papillary excrescences or fronds and deposits of psammoma bodies (Figs. 1 and 2). The tumor filled alveoli or replaced parenchyma with dysplastic glands, usually lined by cuboidal cells with moderately pleomorphic and hyperchromatic nuclei and moderately vacuolated eosinophilic cytoplasm. Bizarre, nucleated, giant tumor cells were frequently encountered. Tumor was frequently observed in lymphatic channels within the lung (Fig. 3). There were focal areas of necrosis, inflammation, and fibrosis. In one tumor, the major microscopic feature was that of an adenoid cystic carcinoma (Fig. 4). Mucous secretions were identified in tumor nests when stained with hematoxylin and eosin preparations in eight cases and were identified in all tumors when stained with PAS mucin stain. All 12 tumors in our necropsy series showed the presence of variable numbers of psammoma bodies within the primary tumors, and in some instances in their metastases, in the kidney in two instances, and in the heart in one (Fig. 5). The psammoma bodies ranged in size from 25 to 150 ju. and were usually seen in papillary fronds of tumor, in tumor glands, and in alveoli adjacent to tumor. Frequently they occurred as single or multiple, dense, calcified, ovoid deposits with distinct concentric laminations (Fig. 6). They also appeared as calcified, non-laminated, dark basophilic or rounded cystalline deposits. In addition, in one tumor there was a more amorphous and fragmented form of calcification within tumor nests (Fig. 7). The psammoma bodies contained various amounts of calcium salts (Von Kossa stain), mucopolysaccharides (PAS mucin stain), and iron (Prussian blue stain). Discussion Psammoma bodies can be considered to be similar to calcospherites or microliths, except that the former have been used to describe calcifications intimately related to tumors. Concentric laminations are usually described with psammoma bodies, but their absence is not unusual, and variable forms of calcifications associated with tumor have been called psammoma bodies. Several theories pertaining to the origin of psammoma bodies in relation to carci-

5 March 1972 PULMONARY CARCINOMA W I T H PSAMMOMA BODIES 301 FIG. 5 (left). Myocardium and epicardium with metastases from the primary tumor of the lung seen in Figure 2. Many psammoma bodies were present in the numerous metastatic foci in the heart. Hematoxylin and eosin. x 105. Fie. 6 (right). Psammoma body containing distinct concentric laminations in an area of more poorly differentiated, primary adenocarcinoma of the lung. Hematoxylin and eosin. x 400. noma of the thyroid gland were reviewed by Klinck and Winship. 2 Psammoma bodies are believed to arise from degenerating or dead tumor epithelium, secretions of epithelial tumor cells, or a composite of both. Our material appears to substantiate these findings. The concentric laminated form of psammoma body appears to arise from a degenerating cell or secretion nidus, whereas the non-laminated form, which has a distinct crystalline appearance, may be derived mainly or entirely from secretions. Mineralogic studies indicate that psammoma bodies are composed of calcium phosphate containing some combined carbonate and belong to the apatite group of minerals. 2 The psammoma bodies that we have found intimately associated with papillary adenocarcinoma of the lungs are of two types: those calcifications with concentric laminations and those without laminations. The former are more common and resemble the classical psammoma bodies associ- FIG. 7. Papillary adenocarcinoma containing centrally located, fragmented, and amorphous calcifications of various sizes within tumor nests in the primary tumor. Hematoxylin and eosin. X 105'

6 302 UNTERMAN AND REINGOLD A.J.CP. Vol. 57 ated with tumors of the thyroid gland and ovaries. The non-laminated forms are, in many instances, fractured, fragmented, or diffusely granular, and resemble crystalline deposits. The latter small, non-laminated and irregular calcifications have been previously described as occurring only rarely in papillary adenocarcinoma of the lung. 8 Microliths are diffusely present within the alveoli in the condition known as "pulmonary alveolar microlithiasis." The lungs in this condition, when it is severe, are stony-hard, and the cut sections may resemble coarse sandpaper. 8 The alveoli are filled with concentric laminated spherules which stain intensely with hematoxylin and eosin, PAS, and colloidal iron stains. These calcospherites may incite little reaction or, when severe, a marked interstitial fibroblastic, histiocytic, and lymphocytic response. When microlithiasis is associated with chronic pulmonary congestion, pneumonia, or pneumoconiosis, corpora amylacea may be found in association with microliths, and they differ in that they attain a larger size and are not calcified. 1 Occasionally, both corpora amylacea and microliths are diffusely present throughout the affected lung; in these circumstances, it may be difficult to differentiate the two. Corpora amylacea are usually associated with persistent pulmonary edema and are larger ovoid structures, concentrically laminated, with radial striation between the rings, and having a central core of black pigment. They have little or no calcification and no iron, whereas psammoma bodies associated with tumors of the lung and microliths in pulmonary alveolar microlithiasis contain moderate amounts of both calcium salts and iron. 5 Papillary carcinoma of the thyroid gland can be differentiated from similar tumors of the lung in most instances by clinical means, by their course, and by their response to therapy. These tumors are usually first noticed as nodular lesions in the thyroid gland; they grow slowly, so patients may live for many years after recognition of the tumors, 4 and usually they metastasize to cervical lymph nodes and bones. These tumors usually occur in women between the ages of 20 and 50 years, and frequently respond to radioisotopes. In our series of papillary carcinomas of the lungs, the tumors appeared first in the lungs or in one of their metastatic sites; all were in men (mean age 61 years), and the patients had symptoms mainly referable to the respiratory tract. These tumors grew rapidly once the diagnosis had been made; the patients usually died within 2 years of the onset of symptoms or recognition of the tumor and had distant lymph nodal and visceral metastases. In a scalene lymph node removed as a surgical specimen, a focus of papillary adenocarcinoma with psammoma bodies was found. The patient had evidence of a primary tumor of the lung which included a mass in the upper lobe of the right lung and malignant cells in the sputum. Thus, the lung should be considered along with the thyroid gland and, more rarely, the ovary, as a possible primary site when papillary adenocarcinoma with psammoma bodies is found in lymph node biopsies. Acknowledgment. Mr. Timothy Dodge, Chief, Medical Illustration Service, and his associates prepared the photomicrographs. References 1. Baar HS, Ferguson FF: Microlithiasis alveolaris pulmonum. Arch Pathol 76: , Klinck GH, Winship T: Psammoma bodies and thyroid cancer. Cancer 12: , Liebow AA: Tumors of the lower respiratory tract, Atlas of Tumor Pathology, Section V, Fascicle 17. Washington, D. C, AFIP, Lindsay S: Carcinoma of the Thyroid Gland. Springfield, 111., Charles C Thomas, 1960, pp Michaels L, Levine C: Pulmonary corpora amylacea. J Pathol Bact 74:49-56, Spencer H: Pathology of the Lung. Second edition. Edited by H Spencer. London W.l, Pergamon Press Ltd., 1968, pp Watson WL: Lung Cancer, A Study of 5,000 Memorial Hospital Cases. St. Louis, The CV Mosby Co., 1968, pp Wyse EP, Hill CS, Ibaney ML, el ah Other malignant neoplasms associated with carcinoma of the thyroid: Thyroid carcinoma multiplex. Cancer 24: , 1969