Anaplastic Carcinoma of the Lung with Metastasis to the Anus: Report

of a Case*

S. KANHOUWA, M.D.,~ ~V. BURNS, ?~,I.D.,+ M. ~r


R. CHISHOLN[, M.D. 82 Washington, D. C.

R e p o r t of a Case

CARCINOMAS of the lung, particularly tile anaplastic and undifferentiated types, have a tendency to early and widespread metastases. Although the metastatic patterns may differ according to cell type, the most frequent sites of metastases inchtde lymph nodes, liver, adrenals, bone, and brain. 6 Solitary and multiple metastases to the mucosa and submucosa of the gastrointestinal tract are u n c o m m o n but have been described in medical literature. 1-4, 7, s Metastases to the anus are extremely rare; a few cases of anal metastases from carcin o m a of the rectum and colon have been described.S T h i s report describes an anaplastic large-cell carcinoma of the lung metastatic to the anus, the diagnostic problem encountered in differentiating the primary site, and the resolution of the problem by ultrastructural studies.

A 45-year-old Negro man was admitted to an area hospital in January 1972, with the complaint of pain of three months' duration in the right shoulder. Past medical history revealed heavy cigarette smoking and alcoholic intake. Chest x-rays demonstrated a lesion in the right upper lobe. Bronchoscopy and biopsies of right scalene lymph nodes were negative. Thoracotomy on February 20, 1972, revealed an unresectable tumor of the right upper lobe, infiltrating the mediastinum and encircling the right innominate vein. T h e tumor was biopsied. T h e patient was transferred to the Veterans Administration Hospital, Washington, D. C., on March 9, 1972, with complaints of swelling of the right arm and edema of the legs of three weeks' duration. On physical examination the patient was welldeveloped and alert, and in no acute distress. Significant physical findings included dullness to percussion over the right upper chest, a 10-cm liver span, 3 + edema of the right upper extremity and legs, and a right Horner's syndrome. T h e heart, the remainder of the abdomen, anus, rectum, and prostate were normal. Chest x-ray revealed a density in the right upper lobe. Electrocardiogram was within normal limits. Urinalysis, electrolytes, blood urea nitrogen, and serum folic acid and vitamin B12 were also within normal limits. Total protein was 5.9 g/100 ml, serum albumin 2.0 g/ 100 ml, alkaline phosphatase 200 m u / m l , SGOT 72 mu/ml, hemoglobin 9.4 mg/100 ml, and prothrombin time was prolonged by four seconds. Intravenous pyelogram was normal. Biopsy of the tumor was interpreted at this hospital as an anaplastic large-cell carcinoma, compatible with a primary pulmonary tumor. During hospitalization, the patient had episodes of diarrhea. Stool examination was negative for occult blood. Results of upper gastrointestinal and small-bowel series, barium-enema examination, and sigmoidoscopy were within normal limits. Liver biopsy and small-bowel biopsy were not performed because of the abnormal p r o t h r o m b i n time, which

* Received for publication May 17, 1974. -[-National Cancer Institute, Veterans Administration Medical Oncology Branch, VA Hospital, Washington, D. C.; NCI, Bethesda, Maryland. ++Associate Pathologist, VA Hospital, Washington, D.C.; Associate Professor, Department of Pathology, George Washington University and Medical Center, Washington, D. C. w National Cancer Institute, Veterans Administration Medical Oncology Branch, VA Hospital, Washington, D. C.; NCI--Bethesda, Maryland; Professor, Department of Pathology, George Washington University and Medical Center, Washington, D.C. 82Department of Medical Ontology, Freedman's Hospital, Washington, D. C. Address reprint requests to Dr. S. Kanhouwa, St. Elizabeth's Hospital, Black Burn Laboratory, Washington, D. C. 20032.

42 Dis. Col. & Rect. Jam-Feb. 1975

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FIo. 1. Anaplastic largecell carcinoma (surgical biopsy, right upper lobe of the lung; hematoxylin and eosin; •

was not correctable by vitamin K administration. Bone marrow aspirate and biopsy showed megaloblastoid erythroid changes but no evidence of metastatic disease. 99roTe--sulfur colloid liver scan showed enlargement of the liver and a questionable borderline defect posteriorly. Strontium-87 bone

scan showed spotty areas of uptake in the ribs overlying the right upper lobe. The patient was treated with cobalt irradiation (5,000 fads) to the right upper lobe, over a period of five weeks, and with nitrogen mustard and methotrexate. There was a noticeable decrease in the size of the lesion in the

FIG, 2. Anaplastic large-cell carcinoma with_ giant-cell component, surgical biopsy of the anus. T h e tumor was mostly submucosaI in location (hematoxylin and eosin; •


Dis. Col. &Rect. Jam-Feb. 1975


right upper lobe on repeated chest x-ray. T h e edema of the right arm and legs subsided, and the patient appeared clinically improved. Two months after treatment was initiated, an indurated firm lesion appeared on the left lateral wall of the anus, and subsequently ulcerated. T h e lesion was biopsied. T h e patient was considered to have pro~essive disease and chemotherapy was changed to CCNU and hydroxyurea. T h e anal lesion was irradiated to a total of B,000 rads. Pancytopenia subsequently developed, and the patient was treated by blood transfusions. His condition worsened and massive inguinal lymph node and lower abdominal skin metastases developed. T h e patient died on October 4, 1972. Materials



Tissues from the open lung biopsy, the anal lesion, and material obtained at aut o p s y w e r e f i x e d i n 10 p e r c e n t f o r m a l d e Fro. 3. Necrotic, ulcerated mass involving the anus and perianal skin (~oss, autopsy).

hyde and examined by light microscopy. Tumors obtained from the anus and at

FIG. 4. Poorly differentiated tumor cells with giant-cell component, carcinoma of the right upper lobe of the lung (autopsy; •

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FIG. 5. Anal rumor showing large anaplastic and multinucleated giant cells (hematoxylin and eosin; autopsy: X360).

autopsy were stained with hematoxylin and eosin, mucicarmine and Masson Fontana's silver stain. Tissue from the premortem anal biopsy and postmortem hmg tumor and anaI mass were examined by electron microscopy. Tissues were minced to I-2 mm square pieces and fixed in 2.5 per cent glutaraldehyde (biologic grade), buffered with 0.15 M phosphate (Millonig's), pH 7.5, for an hour. After rinsing overnight in the phosphate buffer, specimens were postfixed for two hours in 1 per cent osmium tetroxide, buffered with 0.2 M barbital (Veronal) acetate at p H 7.5. T h e complete fixation took place at 0 C. After dehydration with alcohol and placing in propylene oxide, the tissues were embedded in Epon 813. " T h i c k " sections, 1 to 2 microns, were stained with toluidine blue. Sections 300400 A were made on an LKB ultramicrotome, mounted on uncoated copper mesh grids, and stained with uranyl acetate and lead citrate. T h i n sections were examined and photographed with an AEI 801 electron microscope.


Biopsies: T h e open lung biopsy contained sheets and nests of large anaplastic cells with a marked giant cell component (Fig. 1). No squamous or glandular differentiation was identified. Premortem biopsy of the anus revealed a focally ulcerated but otherwise intact stratified epithelial lining. T h e underlying tissues were infiltrated by large neoplastic cells and many multinucleated giant cells (Fig. 2). Special stains for melanin and mucin were negative. T h e lesion was considered metastatic, although the possibility of a primary anal tumor, possibly a malignant melanoma, could not be ruled out. Autopsy: T h e r e was a 3 • 3 X 2-cm firm white mass in the apex of the upper lobe of tile right hmg. Multiple small metastatic nodules were found throughout both right and left lungs. In the left lateral perianal skin and anal canal, there was 5 • 4 • 3-cm ulcerated mass which extended into the submucosa of the distal rectum (Fig. 5). T h e r e were metastases



Dis. Col. & Rect. J'an.-Feb. 1975

Fro. 6. T u m o r cells forming acini with microvilli (•

to the interventricular septum of the myocardium; the liver; hilar, abdominal, retroperitoneal, left axillary, inguinal and pelvic lymph nodes; the periprostatic soft tissues, cul-de-sac; iliopsoas muscle; rib; lumbar vertebrae, and skin of the lower abdomen. Sections of autopsy material showed an anaplastic tumor, similar to that described above, except that rare giant cells contained mucicarmine-positive vacuoles, particularly in the anal lesion (Figs. 4 and 5). Electron Microscopy: Tissue from the premortem anal biopsy was technically of poor quality but was essentially similar to tissues obtained postmortem from the lung and anal tumors. The electron micrographs are described together.

The usual postmortem artifactual changes in cellular organelles were present. Low-power electron micrographs demonstrated marked pleomorphism of nuclei, with tortuous infolded nuclear membranes, prominent invaginations, and the formation in some cells of "pseudoinclusions," probably due to entrapped portions of cytoplasm. Nucleoli were prominent. Some cells contained double nucleoli. Neoplastic cells demonstrated prominent microvillus formation on multiple cell surfaces. A striking pattern identified on electron microscopy was the formation os microacinar spaces into which numerous microvilli of various sizes and shapes projected (Fig. 6). These structures contained a small amount of debris and appeared to be

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FIG. 7. Tumor ceils with acinus (upper right corner), showing cilia projecting into lumen ( X 4,000). formed by two or more ceils, with desmosomal attachments in a n u m b e r of areas. A few cells contained cilia which projected into the lumina (Fig. 7). Tile cells showed various degenerative changes, and some contained prominent lipid vacuoles. Rare cells contained crystalline formations which were usually paranuclear in location. A few cells contained prominent myelin-like figures. Scattered throughout the tumor were cells with masses of glycogen particles in their cytoplasm. Occasional inflammatory cells, including macrophages, were scattered throughout the tumor. Collagen bundles surrounded and were interspersed between clumps of cells. T h e nuclear pleomorphism appeared to be more prominent

in the tissue from the anus, but otherwise the electron micrographs of lung and anal tumors were identical. No premelanosomes or melanosomes were identified in any of the tissues examined. Discussion A h h o u g h metastases to the gastrointestinal tract from primary tumors in the lung occur more frequently than might be anticipated from a review of medical literature, metastases to the anus and perianal skin are most unusual. T h e esophagus is usually invaded by direct extension. T h e mucosa and submucosa of the remainder of the gastrointestinal tract may be involved by single or multiple metastases#, 4, 6 Me-


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K A N H O U W A , E T AL.

tastases to these sites are p r o b a b l y the result of spread t h r o u g h the l y m p h a t i c n e t w o r k that connects the lung, mediastinal a n d a b d o m i n a l l y m p h nodes, retrograde l y m p h a t i c invasion, a n d / o r h e m a t o g e n o u s dissemination. Anaplastic carcinomas a n d p o o r l y differentiated e p i d e r m o i d carcinomas of the l u n g have a particular p r o p e n sity to metastasize to the gastrointestinal tract as m u l t i p l e p o l y p o i d or button-like u m b i l i c a t e d a n d superficially ulcerated mucosal a n d submucosal nodules. I n a series of ten consecutive cases of metastatic tumors to the small bowel, five were anaplastic carcinomas, with p r i m a r y lesions in the l u n g ) I n a series os 35 patients with e p i d e r m o i d carcinoma of the lung, eight (23 per cent) h a d lesions that metastasized to the gastrointestinal tract, excluding the esophagus. Five of the eight carcinomas were p o o r l y differentiated in character. 6 I n a series of 18 patients with anaplastic carc i n o m a of the lung, nine (50 per cent) metastasized to the gastrointestinal tract (excluding the esophagus). Eight of these nine h a d p r o m i n e n t gi.ant-cell components. 6 O t h e r tumors t h a t sometimes metastasize to the gastrointestinal tract include malign a n t m e l a n o m a s a n d carcinomas of the breast a n d ovary. TM Metastasis to the anus f r o m a p r i m a r y cancer in the lung, to o u r knowledge, has n o t been described in medical literature. I n this case, clinically, the p a t i e n t was considered to have an u n d o u b t e d anaplastic large-cell carcinoma of the lung. T h e a p p e a r a n c e of the anal mass raised the question w h e t h e r it represented an unrecognized p r i m a r y anal malignancy, possibly

Jam-Feb. 1975

a malignant melanoma, with pulmonary metastases. T h e anal lesion was n o t identified until almost eight m o n t h s after the onset of p u l m o n a r y symptoms. T h e promin e n t microvillus and m i c r o a c i n a r formations, as well as occasional cilia production, identified on electron microscopy, and the absence of m e l a n i n precursors w o u l d confirm the clinical a n d light microscopic impression that this t u m o r was derived from b r o n c h o p u l m o n a r y e p i t h e l i u m a n d that the anal lesion represented a metastatic r a t h e r t h a n a p r i m a r y tumor. Electron microscopy is an i n v a l u a b l e aid in diagnosing selected neoplastic diseases, and its use in such cases is strongly encouraged.

References 1. Asch IvIJ, W i e d e l PD, H a b i f DV: Gastrointestinal metastases fiom carcinoma of the

2. 3. 4. 5. 6.



breast: Autopsy study and 18 cases requiring operative intervention. Arch Surg 96: 840, 1968 Backman H: Metastases of malignant melanoma in the gastrointestinal tract. Geriatrics 24:112 (Aug) 1969 Burns WA, Matthews MJ: Metastatic mucosal tumors of the small intestine. Med Ann DC 39: 8, 1970 de Castro CA, Dockerty MB, Mayo CW: Meta. static tumors of the small intestines. Surg Gynecol O bstet 105: 159, 1957 Killingback M, Wilson E, Hughes ES: Anal metastases from carcinoma of the rectum and colon. Aust NZ J Surg 34: 178, 1965 Matthews MJ: Problems in morphology and behavior of bronchopulmonary malignancy, Lung Cancer, Facts, Concepts and Strategies. Chapter 2. Edited by L Isreal. New York and Basel, S Karger, 1975 Morgan MW, Sigel B, Wolcott MW: Perforation of a metastatic carcinoma of the jejunum after cancer chemotherapy. Surgery 49: 687, 1961 Wootton DG, Morgan SC, Hughes RK: Perforation of a metastatic bronchogenic carcinoma to the jejunum. Ann Thorac Surg 3: 57, 1967

Anaplastic carcinoma of the lung with metastasis to the anus: report of a case.

Anaplastic Carcinoma of the Lung with Metastasis to the Anus: Report of a Case* S. KANHOUWA, M.D.,~ ~V. BURNS, ?~,I.D.,+ M. ~r M.D.,w R. CHISHOLN[...
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