293

0 1992 The Japanese Society of Pathology

Vasculitis and Pyrexia Associated with Superficial Spreading Gastric Carcinoma

Bunshiro Akikusa', Yasushi Harihara2, Yoshinobu Nagatol, and Masakazu Nobori'

A case of low-grade fever developjng about a month before the discovery of gastric carcinoma is reported. No findings of infection or collagen disease were revealed. The fever continued for about 3 months, but promptly disappeared after surgical removal of the tumor. A superficial spread- ing mucosal carcinoma with minimal invasion to the sub- mucosa was seen in the antrum, showing the features of poorly differentiated adenocarcinoma. In addition, unique venous inflammation was recognized beneath and around the neoplasm. Arteries and lymph vessels did not exhibit any inflammatory changes. It was presumed that the gas- tric carcinoma had induced phlebitis, which subsequently brought about the fever. As to the pathogenetic mecha- nism, it was suggested that a substance produced by the carcinoma cells flowed into nearby veins to induce the phlebitis. Acta Pathol Jpn 42 : 293-297, 1992.

Key words : Pyrexia, Gastric cancer, Vasculitis, Paraneoplas- tic syndrome

Neoplasms affect their hosts in a variety of ways. Although the outcome is often catastrophic, tumor-host interactions are a two-way process, since the host exerts effects on the tumor as well. Various kinds of neoplastic disease have been described in association with vasculitis as examples of tumor effects on the host (1, 2). How- ever, to our knowledge, gastric cancer has not been reported to be accompanied by vasculitis. We describe here a patient who developed a mild but continuous fever prior to diagnosis of gastric carcinoma. The fever sub- sided soon after gastrectomy and histologic examination

Received September 10, 1991. Accepted for publication December 3, 1991. 'Department of Pathology, School of Medicine, Chiba Univer- sity, Chiba. *Department of Surgery, Asahi General Hospital, Chiba. Mailing address : Bunshiro Akikusa, M.D., Department of Pathology, School of Medicine, Chiba University, lnohana 1- 8-1, Chuo-ku Chiba 260, Japan.

revealed vasculitis. Although a variety of paraneoplas- tic vasculitides have been reported, angiitis involving only the veins near the neoplasm as seen in the present case has not been reported so far.

CASEREPORT

A 71-year-old woman visited her physician late in September, 1988, with a complaint of low-grade pyrexia, loss of appetite, and upper abdominal discomfort. Anti- biotics were ineffective for the fever and she was referred to Asahi General Hospital at the end of October. Upper gastrointestinal endoscopy revealed a flat lesion in the antrum. This was diagnosed as adenocarcinoma from biopsy material obtained at the time. She was admitted for treatment of gastric carcinoma and further investiga- tion of the low-grade fever. She had lost about 5 k g body weight in one month.

Hemoglobin was 9.6 g/dL, erythrocyte count 364 x 1 04/mm3, leukocyte count 5,300/mm3, and platelet count 51.1x104/mm3. The levels of serum trans- aminases were not elevated and neither HBs antigen nor HBs antibody was positive. Serum total protein was 6.7 g/dL and albumin 3.2 g/dL. The IgG level was 1903.0 mg/dL, IgA 322.6mg/dl, IgM 133.9mg/dL, and IgE 214.8 IU/ml: The level of serum complement, C3, was 97.5 mg/dL (normal, 46.5-67.2) and that of C4 60.4 mg/dL (normal, 15.8-30.5). The level of C-reactive protein (CRP) was 16.2 mg/dL (normal, 0.3 or less). Results of RA test and Coombs test, and tests for antinuclear antibody and anti-DNA antibody were all negative. Results of serologic testing for syphilis and tuberculin skin test were negative. Urinalysis showed no abnormalities. Chest X-ray films and an electro- cardiogram exhibited no abnormalities. Blood cultures showed no growth.

The fever was elevated to 38°C and continued to appear almost every day. Although the origin of the

294 Gastric Carcinoma with Vasculitis (Akikusa et a/.)

fever was still undetermined, subtotal gastrectomy was performed on December 15, 1988, because concurrent infection or collagen disease had been ruled out by extensive clinical and laboratory examinations. After the operation, the fever subsided in a few days, the level of CRP decreased to 0.3mg/dL, and the patient was discharged on December 29. Since then she has been clear of gastric carcinoma and fever up to June, 1991.

PATHOLOGIC FINDINGS

A superficial spreading flat carcinoma, type Ilb accord- ing to the Japanese classification of early gastric car- cinoma (3), measuring 6.9 by 4.5 cm, was located in the area from the lesser curvature to the anterior wall of the antrum. Besides this lesion, no particular alterations were grossly recognizable.

Histologically, the neoplasm was a poorly differentiated adenocarcinoma (Fig. l), sometimes show- ing a vague tubular pattern, and was mostly situated in the mucosa except for a limited area about 0 .5cm in diameter near the lesser curvature where the carcinoma had invaded into the submucosa slightly. Invasion of lymphatic vessels by the carcinoma cells was sometimes seen in the submucosa, but blood vessel invasion was not recognized. The cytoplasm of the carcinoma cells was usually periodic acid-Schiff (PAS) positive, and the

positivity was mostly maintained after amylase diges- tion. Some carcinoma cells had alcian blue-positive material in the cytoplasm. No metastases were seen in the resected regional lymph nodes.

The veins in the submucosa exhibited varying degrees of inflammatory cell infiltration throughout the vessel walls (Figs. l a , 2), but fibrinoid or other necrotic changes were not evident. The infiltrated inflammatory cells consisted of mononuclear cells, including a few plasma cells, occasional neutrophils, and eosinophils, but multinucleated giant cells were not recognized. The affected veins often showed mild to moderate intimal thickening, but intraluminal thrombosis was absent. The angiitis was evident in numerous veins, being local- ized mainly in the submucosa. In fact, similar inflammatory changes were seen in only a few veins in the external muscular layers and serosa. The phlebitis was present irrespective of the depth of the submucosa, and the inflammatory changes did not seem to be en- hanced around the areas of neoplastic submucosal inva- sion. Arteries and lymph vessels showed no vasculitic changes.

All of the resected material was subjected to step- sectioning for microscopic examination. The distribu- tion of phlebitis and carcinoma, illustrated in Fig. 3, shows that the vasculitis lay beneath and around the carcinoma. It was noteworthy that an area along the

Figure 1. a : Gastric carcinoma in the mucosa and a vein with inflammatory changes in the submucosa. HE. b : Higher-magnification view showing poorly differentiated adenocarcinoma with a vague tubular pattern. HE.

Acta Pathologica Japonica 42 (4) : 1992 295

greater curvature in the gastric body showed no vas- culi t ic changes.

For immunohistochemistry, the sections were deparaffinized and then stained using the avidin-biotin- peroxidase complex method. The primary antibodies used were those against MT1, MB1 (4), lysozyme(5), chromogranin A and gastrin (DAKO, Kyoto, Japan). I t was revealed that the majority of mononuclear inflammatory cells in the areas of phlebitis were M T I - positive T cells, some were MB1-positive B cells, and a

Figure 2. a : A submucosal vein showing conspicuous infiltration of mononuclear cells and an artery without changes in the lesser curvature of the gastric body. No carcinoma cells are present. HE. b: An adjacent section stained with elastica van Gieson exhibiting a thin internal elastic membrane indicated by arrows.

few were lysozyme-positive macrophages. No im- munoreactivity for chromogranin A or gastrin was detected in the tumor cells.

A study using indirect immunofluorescence was also performed on the paraffin sections, but no deposition of IgG, IgA, IgM, C1, C3 or fibrinogen was demonstrated in the inflamed veins and carcinoma cells. In addition, the patient’s serum did not react with these tissues.

296 Gastric Carcinoma with Vasculitis (Akikusa et a/.)

Submucosal invasion Figure3. Distribution of angiitis and carcinoma in the subtotally resected stomach.

DISCUSSION

The patient presented here began to develop mild but almost constant fever about a month before the discov- ery of gastric carcinoma. The fever abated soon after gastrectomy. Disappearance of the symptoms and signs of vasculitis following surgical removal of a tumor has been described in only a few cases(6-8). This, as well as the almost concurrent onset of neoplasm and vasculitis, indicate a close relationship between the two disorders. These two criteria (concurrent onset and parallel course) postulated by Callen(8) may be useful when considering whether the association of one disorder with a neoplasm is more than coincidental. The present case fulfilled these criteria, even though, in a strict sense, the neoplasm seemed to have developed prior to the vasculitis.

Tumor fever is known to occur occasionally in patients with cancer showing disseminated metastases with ne- crosis (9) or concurrent infections (lo), but not in those with early carcinoma without metastasis. Therefore, it would have seemed unreasonable to assume that the fever in our patient was caused by the neoplasm itself. However, concurrent infection was not revealed in the present case.

The highly elevated level of CRP dropped to normal after gastrectomy. This seemed to indicate that an inflammatory lesion did exist, and that the inflammation was cured by the removal of the carcinoma.

Although the phlebitis was distributed beneath and around the carcinoma, it might have extended beyond the surgical margins. It was noteworthy that the vascular changes were not recognized along the greater curvature near the oral surgical margin, suggesting that the vas- culitis had not occurred systemically but developed only near the carcinoma. Such a unique distribution of vas- culitis has not been described in previous cases.

Considering these clinical, laboratory and histologic findings, it was assumed that the gastric carcinoma had induced phlebitis, which subsequently brought about the fever.

Angiitis has occasionally been reported to occur in association with various kinds of neoplasm, although in some cases the relationship between these two disorders is obscure. Malignancies of the hematopoietic, lym- phatic and mononuclear phagocytic systems, such as various kinds of leukemia and lymphoma including hairy cell leukemia, are the most frequently described neo- plasms accompanied by vasculitides (1, 2, 11). As to solid tumors, vasculitides have been described occasion- ally in association with various neoplasms (12-14). However, tumors of the gastrointestinal tract have rarely been reported to be associated with vasculitides except for one case of cutaneous leukocytoclastic vasculitis accompanying adenocarcinoma of the colon (8).

The patterns of vasculitides reported previously in patients with neoplasm have not been uniform. Most of them have been angiitis involving arteries, arterioles or capillaries (1). To our knowledge, however, among vas- culitides with neoplasm, vasculitis involving only veins like that seen in the present case has not been described in the literature.

Since the vasculitis was seen only in the veins near the carcinoma, it appeared that a substance produced by the carcinoma cells flowed into nearby veins and induced the phlebitis. Furthermore, it can be postulated that this unknown substance acquired antigenicity to induce anti- body production, subsequently resulting in the formation of immune complexes in veins near the carcinoma. Although the presence of antigen and/or antibody depo- sition in the inflamed veins could not be demonstrated in the present case, this hypothesis cannot be rejected because such deposition has not always been demon- strated even in angiitis that is generally considered to be caused by immune complexes (1 5, 16).

lmmunoperoxidase analysis revealed that the majority of infiltrating cells in the present case were T- lymphocytes. Therefore, a T-cell-dependent cell-

Acta Pathologica Japonica 42 (4) : 1992 29 7

mediated process, which has recently been considered by some investigators to operate in the pathogenesis of systemic vasculitides (1 7, 18), could have played a role in the development of the present vasculitis.

Whatever the pathogenetic mechanisms responsible, the occurrence of angiitis in association wi th carcinoma should be given much more attention when examining surgical materials in order to develop an understanding of tumor-induced vasculitis and other tumor-host inter- actions.

Acknowledgements : The authors are indebted to Prof. Yo- ichiro Kondo for his useful suggestions in the preparation of this manuscript.

REFERENCES 1.

2.

3.

4.

5.

6.

Cupps TR and Fauci AS: Vasculitis and neoplasm. Major Prob Intern Med 21 : 116-122, 1981. Greer JM, Longley S, Edwards NL, Elfenbein GJ, and Panush RS. Vasculitis associated with malignancy : Experience with 13 patients and literature review. Medicine (Baltimore) 67 : 220-230, 1988. Kay S. The stomach. In Silverberg SG, ed. Princi- ples and Practice of Surgical Pathology. Churchill Livingstone, New York, 1988 : 81 9-843. Poppema S, Hollema H, Visser L, and Vos H. Mono- clonal antibodies (MT1, MT2, MB1, MB2, MB3) reactive with leukocyte subsets in paraffin-embedded tissue sections. Meister P, Huhn D, and Nathrath W. Malignant his- tiocytosis. lmmunohistochemical characterization on paraffin embedded tissue. Virchows Arch [A ] 385:

Andrasch RH, Bardana EJ Jr, Porter JM, and Pirofsky B. Digital ischemia and gangrene preceding renal neoplasm : An association with sarcomatoid adenocar- cinoma of the kidney. Arch Intern Med 136: 486- 488, 1976.

Am J Pathol 127: 418-429, 1987.

233-246, 1980.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Susman BR, Levin FC, Barland P, and Fromowitz F. Vasculitis associated with renal oncocytoma. NY State J Med 81 : 1501-1503, 1981. Callen JP. Cutaneous leukocytoclastic vasculitis in a patient with an adenocarcinoma of the colon. J Rheumatol 14: 386-389, 1987. Warshaw AL, Carey RW, and Robinson DR. Control of fever associated with visceral cancers by indomethacin. Surgery 89: 414-416, 1981. Anonymous. Fever in malignant disease. Br Med J 1 : 591-592, 1974 (editorial). Spann CR, Callen JP, Yam LT, et a/. Cutaneous leu kocytoclastic vasculitis complicating hairy cell leuke- mia (leukemic reticuloendotheliosis). Arch Dermatol

Johnson PC, Rolak LA, Hamilton RH, and Laguna JF. Paraneoplastic vasculitis of nerve: A remote effect of cancer. Ann Neurol 5 : 437-444, 1979. Vincent D, Dubas F, Hauw JJ, et a/. Nerve and muscle microvasculitis in peripheral neuropathy : A remote effect of cancer? J Neurol Neurosurg Psychiatry 49:

Hoag GN. Renal cell carcinoma and vasculitis: Report of two cases. J Surg Oncol 35 : 35-38, 1987. Paronetto F. Systemic nonsuppurative necrotizing angiitis. In Miescher PA and Muller-Eberhard HJ, eds. Textbook of Immunopathology. Grune h Stratton, New York, 1976 : 101 3-1 024. Fauci AS, Haynes BF, and Katz P. The spectrum of vasculitis : Clinical, pathologic, immunologic, and ther- apeutic consideration. Ann Intern Med 89: 660-676, 1978. Gephardt GN, Ahmad M, and Tubbs RR. Pulmonary vasculitis (Wegener's granulomatosis) : Immunohisto- chemical study of T and B cell markers. Am J Med

Kissel JT, Riethman JL, Omerza J, Rammohan KW, and Mendell JR. Peripheral nerve vasculitis : Immune characterization of the vascular lesions. Ann Neurol

122 : 1057-1 059, 1986.

1007-1010, 1986.

74: 700-704, 1983.

25: 291-297, 1989.