OAT CELL CARCINOMA OF THE URINARY BLADDER WITH ECTOPIC ADRENOCORTICOTROPIC HORMONE PRODUCTION
SEPPO PARTANEN AND ULLA ASIKAINEN
A case of primary oat cell carcinoma of the urinary bladder with ectopic adrenocorticotropic hormone (ACTH) secretion in a 55- year-old woman is reported. Cystoscopy revealed a large necrotic tumor in the bladder; the tumor was partially electroresected. At autopsy, a large residual tumor infiltrating the wall of the bladder was found. It had metastasized to the lymph nodes, left ovary, liver, spinal canal, bone marrow, and hypophysis. Bilateral adrenocor- lical hyperplasia was found. Microscopically, the tumor was iden- tical morphologically to oat cell carcinoma, and the cells contained argyrophilic hormone granules and immunohistochemically demon- strable ACTH. Apparently, oat cell carcinomas with endocrinologic activity have not been reported previously in the urinary bladder. HUM PATHOL 16:313-315, 1985.
Among urinary bladder carcinomas, undifferentiated carcinomas composed of small cells are rarely observed; the microscopic features of these tumors have been reported to resemble those of oat cell carcinoma of the bronchus.1,2 Oat cell carcinomas in various locations are often associated with ectopic production of polypeptide or protein hor- mones, of which adrenocorticotropic hormone (ACTH) is probably the most common.3-5 Hormone storage granules have been demonstrated in oat cell carcinomas by electron microscopy and argyrophilic staining.6,7 Oat cell carcinoma can lead rapidly to death, because the ectopic hormone secretion can cause serious life-threatening electrolyte dis- turbances.8
REPORT OF A CASE
A 55-year-old woman was admitted to Jorvi Hospital in January 1981 with symptoms of left hemiplegia, re- garded as a complication of elevated blood pressure. An- tihypertensive therapy with a beta-blocker (Atenol) had been instituted one year previously. The patient recovered fairly well, but the creatinine level was 200 umol/l (normal range, 50 to 115 pmol/l). Urography showed bilaterally contracted kidneys. The patient had taken large quantities of analgesics for migraine for long periods and chronic interstitial nephritis was therefore suspected. The patient’s medical history revealed several urinary tract infections during the preceding 17 years.
The patient was readmitted in November 1982 for evaluation of hematuria. The creatinine level at that time was 407 pmol/l. Cystoscopy revealed a large necrotic tumor at the trigonal region of the bladder, almost completely filling it. The surface of the tumor was partially necrotic. The diagnosis, based on cystoscopic examination, was car- cinoma of the bladder, stage II.I to IV. Electroresection was performed, but the surgery was not radical. The primary histologic diagnosis was anaplastic carcinoma. Ultrasound examination revealed connection of the tumor to the ovary. It was suspected that the ovarian tumor was the primary tumor.
At the end of December 1982 paresis of the lower ex-
tremities, which later became total paraparesis, developed. Myelography showed signs of an extradural process at the level of T10 to T11, suspected to be a metastasis. Because of the malignant primary disease, decompression was not performed. The blood glucose level was slightly elevated (5.8 mmol/l; normal range, 3.1 to 5.0 mmol/l). The hemo- globin level was 85 g/l. Urine analysis showed hematuria and proteinuria. The patient had metabolic acidosis, con- sidered a result of renal dysfunction. Serum electrolyte levels were normal. The plasma cortisol level was not de- termined. The patient died in January 1983. Excluding surgery, no therapy had been used. Autopsy was per- formed.
Pathologic Findings
Autopsy findings. A large tumor was found in the uri- nary bladder. The surface was necrotic, and the margins were slightly elevated. It had infiltrated the bladder wall and formed a tumor nodulus on the serosa on the left side of the uterus (fig. I). In each ovary a smooth-walled cyst, containing yellowish clear fluid and measuring about 5 cm in diameter, was found. In the left ovary a yellowish ne- crotic metastasis measuring about 1 cm was seen on the cut surface, adjacent to the cyst but not bulging into the lumen. Metastases were found in one common iliac node, in one node above the pancreas head, in the liver, and in the ex- tradural space of the lower thoracic spinal canal. Tracheal, bronchial tree, and pulmonary parenchyma was normal. The hypophysis weighed 0.9 g, and a yellowish softening was found in the right lateral area of the anterior lobe. Both adrenal glands were enlarged; the right adrenal weighed 10.5 g and the left 8.5 g; the aggregate weight was 0.3 g/ kg of body weight. Both the surface and the cut surface of the adrenal cortex were mottled yellow-brown. Mild gen- eral atherosclerosis was present, but old infarcts were found in the left cerebral frontal cortex and in the left lower sur- face of the cerebellum. In the heart old infarcts were found in the septum and posteriorly in the left ventricle.
Microscopic findings. The specimens were fixed in phosphate-buffered 10 per cent neutral formalin or in Bouin’s fluid and thereafter processed routinely. Argyro- philic staining was done according to the method of Gri- melius.9 Adrenocorticotropic hormone-immunoreactivity was studied by the peroxidase-antiperoxidase method.10 The primary antiserum was rabbit antihuman whole ACTH serum (Wellcome Laboratories, England), at a di- lution of 1:200. Adsorption control was done with purified porcine whole ACTH (Sigma, St. Louis, Missouri), 10 µg/ ml of diluted anti-ACTH serum. Incubation was per- formed overnight at 4℃. The nuclei were lightly counter- stained with hematoxylin.
All samples of the bladder tumor obtained at surgery indicated a necrotic malignant tumor. The surface was also necrotic, and the tumor had infiltrated the wall. The growth patterns differed slightly in various parts of the tumor. In some areas the tumor was composed of spindle cells forming ribbons, in which the cell axes were perpen- dicular to the long axes of the ribbons (fig. 2). In other areas round cells formed solid sheets or rounded groups. The histologic features were compatible with undifferen- tiated carcinoma of the urinary bladder and also with oat cell carcinoma of the bronchus. In specimens from metas-
Received April 29, 1983, from the Department of Pathology, Jorvi Hospital, Espoo, Finland. Revision accepted for publication July 14, 1983.
Address correspondence and reprint requests to Dr. Partanen: Staff Pathologist, Department of Pathology, Jorvi Hospital, SF- 02740 Espoo 74, Finland.
tases obtained at autopsy, similar areas of oat cell carcinoma was seen. In addition, in an iliac lymph node metastasis carcinoma cells formed tubular structures, and multinu- cleated carcinoma cells were numerous. Microscopy re- vealed oat cell carcinoma cells in the posterior lobe of the
hypophysis, in the dura above the hypophysis, and in the bone marrow of the thoracic vertebrae. The lateral portion of the right anterior lobe of the hypophysis was necrotic. No signs of Crooke’s hyalinization were found. Grimelius staining demonstrated numerous carcinoma cells con-
taining cytoplasmic hormone granules both in formalin- fixed samples obtained at surgery and in Bouin’s fluid- fixed samples obtained at autopsy (fig. 2). Immunohisto- chemical staining for ACTH revealed a normal number of morphologically normal hypophyseal corticotrophs. Im- munohistochemical staining for ACTH was also positive in some cells of the bladder carcinoma (fig. 2). After adsorp- tion of anti-ACTH serum with purified ACTH, no reaction was seen in the hypophysis or in the carcinoma cells.
The thickness of both adrenal cortices was increased to 3 to 4 mm, and acidophilic cells forming compact groups were seen in the widened zona fasciculata. In the kidneys moderate interstitial nonspecific chronic nephritis was present. The cysts in the ovaries were lined with a single layer of flattened epithelium.
DISCUSSION
In the urinary bladder undifferentiated carcinomas composed of small cells are rarely found. Microscopically, these tumors have been reported to be similar to oat cell carcinoma of the bronchus.12 This type of urinary bladder carcinoma is infrequent; in a large series of bladder carci- nomas reported by Kunze et al.,11 the incidence of undif- ferentiated carcinoma was 1.2 per cent. Oat cell carcinoma of the bronchus has unique, well-known microscopic fea- tures.12 Typically, in addition to the characteristic micro- scopic features, oat cell carcinomas have been shown to synthesize and secrete various polypeptide and protein hor- mones, occasionally leading to clinical manifestations, the best known being ectopic ACTH production.3,4,3,8 After the special properties of oat cell carcinoma of the bronchus had been recognized, similar carcinomas with evidence of en- docrinologic differentiation and hormone synthesis were found in other locations, e.g., the esophagus, 13 prostate, 14 and larynx. 13 The present case of so-called undifferentiated carcinoma of the urinary bladder appears morphologically, histochemically, and biologically similar to oat cell carci- noma of the bronchus and of other locations. Evidence of ACTH production was obtained both by the immunohis- tochemical demonstration of ACTHI in carcinoma cells and by the finding of bilaterally diffuse adrenocortical hyper- plasia at autopsy. However, the electrolyte changes of blood found in hypercorticism+ were not observed in the present case, either because production of corticosteroids was only slightly elevated or because the time was too short for the changes to be seen. In addition, concomitant renal insuf- ficiency could mask electrolyte changes.
Oat cell carcinomas have been thought to be derived from mucosal endocrine cells.6,13 Endocrine cells have also been demonstrated in the transitional epithelium of the genitourinary tract, 16 and two cases of carcinoid tumor of the bladder have been reported.17,18 It seems that highly malignant oat cell carcinoma can develop from mucosal endocrine cells of the urinary bladder as well. The number of undifferentiated carcinomas of the urinary bladder that are oat cell carcinomas remains to be determined. The rec- ognition of a carcinoma of this type in the urinary bladder might also be of value with respect to the institution of proper management.
References
1. Mostofi FK, Sobin LI, Torloni H: Histological typing of urinary bladder tumours. In International Histological Classification of Tu- mours, 10. Geneva, World Health Organization, 1973
2. Koss LG: Tumors of the urinary bladder. In Atlas of Tumor Pathology, series 2, fascicle 11. Washington, DC, Armed Forces Institute of Pa- thology, 1975
3. Azzopardi JG, Williams ED: Pathology of “nonendocrine” tumors as- sociated with Cushing’s syndrome. Cancer 22:274, 1968
4. Rees I.H, Ratcliffe JG: Ectopic hormone production by non-endocrine tumours. Clin Endocrinol 3:263, 1974
5. Imura H: Ectopic hormone syndromes. In Abe K (cd): Clinics in En- docrinology and Metabolism. Philadelphia, WB Saunders Co, 1980, pp 235-260
6. Bensch KG, Corrin B, Pariente R, et al: Oat-cell carcinoma of the lung. Its origin and relationship to bronchial carcinoid. Cancer 22:1163, 1968
7. Partanen S, Syrjanen KJ, Hjelt LH: Light microscopical and fluores- cence histochemical observations on the endocrinological activity of human pulmonary neoplasia. Arch Geschwulstforsch 50:97, 1980
8. Singer W, Kovacs K, Ryan N, et al: Ectopic ACTH syndrome: clinico- pathological correlations. J Clin Pathol 31:591, 1978
9. Grimelius L .: A silver nitrate stain for a2-cells in human pancreatic islets. Acta Soc Med Upsal 73:243, 1968
10. Sternberger LA: Immunocytochemistry. Englewood Cliffs, New Jersey, Prentice-Hall, 1974
11. Kunze E, Schauer A, Schmitt M: Histology and histogenesis of two dif- ferent types of inverted urothelial papillomas. Cancer 51:348, 1983
12. Azzopardi JG: Oat cell carcinoma of the bronchus. J Pathol Bact 78:513, 1959
13. Tatcishi R, Taniguchi K, Horai T, et al: Argyrophil cell carcinoma (apu- doma) of the esophagus. A histopathologic entity. Virchows Arch [A] 371:291, 1976
14. Wenk RE, Bhagavan BS, Levy R, et al: Ectopic ACTH, prostatic oat cell carcinoma and marked hypernatraemia. Cancer 40:773, 1977
15. Mills SE, Cooper PH, Garland TA, et al: Small cell undifferentiated carcinoma of the larynx. Report of two patients and review of 13 additional cases. Cancer 51:116, 1983
16. Feyrter F: Ueber das urogenitale Helle-Zellen-System des Menschen. Zeitschrift Mikrosk Anat Forsch 57:324, 1951
17. Feyrter F: Zur Pathologie des urogenitalen Helle-Zellen-Systems. Vir- chows Arch 320:564, 1951
18. Colby TV: Carcinoid tumor of the bladder. Arch Pathol Lab Med 104:199, 1980
NON-HODGKIN’S LYMPHOMA PRESENTING AS MALIGNANT PERICARDIAL EFFUSION AND CARDIAC TAMPONADE
URIAS A. ALMAGRO, MD, AND EUDOKIA REMENIUK, MD
A case of malignant lymphoma, Rappaport histiocytic type, in which the initial clinical presentation was malignant pericardial
Received March 30, 1983, from the Department of Pathology, Veterans Administration Medical Center, Wood (Milwaukee), and the Medical College of Wisconsin, Milwaukee, Wisconsin. Revision accepted for publication July 23, 1983.
Address correspondence and reprint requests to Dr. Almagro: Department of Pathology, V.A. Medical Center, 5000 West Na- tional Avenue, Wood (Milwaukee), WI 53193.
effusion with cardiac tamponade is presented. The pathogenesis of malignant pericardial effusion is discussed, and the value of cy- tology in the diagnosis of malignant pericardial effusion is em- phasized. HUM PATHOL 16:315-317, 1985.
Cardiac and/or pericardial involvement by malignant lymphoma usually occurs as part of disseminated disease, often without attendant cardiac dysfunction. In most cases the lymphomatous involvement is seen only at autopsy, and, in some cases, it may be apparent only microscopically.