Case Report

Paraneoplastic vasculitis associated with esophageal carcinoma

Toshihiro Mita,1 Yukihiro Nakanishi,2 Atsushi Ochiai,2 Tadakazu Shimoda,1 Hoichi Kato,3

Hajime Yamaguchi4 and Gotaro Toda5

1Clinical Laboratory, 3Surgery and 4Internal Medicine, National Cancer Center Hospital, and 2Pathology Division,National Cancer Center Research Institute, and 5Department of Internal Medicine, School of Medicine, Tokyo JikeiUniversity, Tokyo, Japan

malignancy.1–3 Vasculitis can be idiopathic or associated witha variety of underlying conditions, such as autoimmune syn-dromes, infections, allergic disorders and malignant neo-plasms.4 The majority of patients with malignant neoplasm-associated vasculitis who have been described had hema-tologic neoplasms.5 We describe here a patient who devel-oped mild but continuous fever and numbness prior to thediagnosis of esophageal and gastric carcinomas. Thesesymptoms subsided soon after removal of the esophagealcarcinoma, and histologic examination revealed vasculitis inthe esophagus, stomach and serratus anterior muscles. Thevasculitis was most pronounced in the esophagus. This is thefirst detailed case report of esophageal carcinoma asso-ciated with paraneoplastic vasculitis.

CLINICAL SUMMARY

A 69-year-old man had mild fever and numbness for 5months. His body temperature was approximately 37.5°Cduring that period. There was no history of arthralgia, skineruption or Raynaud’s phenomenon suggesting collagendisease. His numbness was localized in the lower limbs, andwas pronounced on the left side. No history of weakness,muscle pain or autonomic dysfunction was reported. Hevisited his physician and an upper gastrointestinal endoscopyrevealed both esophageal and gastric carcinomas. He wasadmitted to the National Cancer Center Hospital for surgicaltreatment. He smoked 20 cigarettes per day and had drunk 1 L beer/day for 50 years. There was a past history of fattyliver 20 years earlier. He used no medications.

On physical examination, he appeared well but histemperature was 37.4°C. No lymphadenopathy or skin lesionwas found. The lung, heart and abdomen were physicallynormal. Sensory impairment to touch, pain and vibration wasfound in the lower limbs and was more pronounced on the left

Pathology International 1999; 49: 643–647

We report a case of esophageal carcinoma associated withparaneoplastic vasculitis. A 69-year-old man suffered fromlow-grade fever and numbness of the lower limbs for 3months before esophageal and gastric carcinomas weredetected. Concurrent infection or collagen disease wasruled out following clinical and laboratory examinations. InApril 1996, the gastric carcinoma was completely removedby endoscopic mucosal resection, but the symptomsremained. Three weeks later esophagectomy was per-formed for esophageal carcinoma after which time the feverand numbness disappeared. The esophageal carcinomawas a well-differentiated squamous cell carcinoma invadinginto the submucosal layer. Twenty-two lymph node metas-tases were found in 68 resected lymph nodes. Latent thyroidcancer was found. Histologically, vasculitis was detected inthe esophagus, stomach and serratus anterior muscle. Thedistribution and degree of vasculitis were most pronouncedin the esophagus. The concurrent onset and spontaneousresolution of fever and numbness after the removal of the esophageal carcinoma suggested a paraneoplasticorigin. The majority of patients with malignant neoplasm-associated vasculitis had hematologic neoplasms. Cases ofesophageal carcinoma associated with paraneoplasticvasculitis are extremely rare.

Key words: esophagus, paraneoplastic syndrome, squamouscell carcinoma, vasculitis

Tumors can produce signs and symptoms at a distance fromthe tumor or its metastasis.1 These are collectively referred toas paraneoplastic syndromes or remote effects of malig-nancy.1 In these cases, the course of the paraneoplasticsyndrome runs parallel to the course of the underlying

Correspondence: Yukihiro Nakanishi, MD, Pathology Division,National Cancer Center Research Institute, 1-1, Tsukiji 5-chome,Chuo-ku, Tokyo 104-0045, Japan. Email: yknakani@gan2.ncc.go.jp

Received 12 January 1999. Accepted for publication 13 March1999.

side. No weakness of the lower limbs was noted. Mentalstatus testing, optic fundi and other cranial nerve functionswere normal. Examination of his blood disclosed a whiteblood cell count of 13 400/mm3. The erythrocyte sedimen-tation rate was elevated at 101 mm/h. Renal function testsand liver function tests were within the normal range. Theserum levels of immunoglobulins (Ig) and complement werewithin the normal range. The level of C-reactive protein(CRP) was 7.8 mg/dL. Hepatitis B and C tests were negative.Results of rheumatoid arthritis (RA) test, antinuclear anti-body, anti-DNA antibody, and anti-neutrophil cytoplasmicantibody were all negative.

In April 1996, gastric carcinoma at tumour node metastasis(TNM) stage I (pT1pNxpM0) was removed by endoscopicmucosal resection (EMR), but the fever and numbnessremained. The gastric neoplasm was located on the gastricbody and showed an intramucosal well-differentiated tubularadenocarcinoma. Three weeks later concurrent infection andcollagen disease were ruled out following extensive clinicaland laboratory examinations. Esophageal carcinoma atstage II (pT1pN1M0) was surgically removed. After theoperation, the fever subsided within a few days. Gradualclinical improvement of numbness was also noted and hisCRP level decreased to the normal range 14 days after theesophageal operation. In June 1997, he developed local re-currence and systemic metastases. He received chemother-apy for recurrent disease. He died in October 1997. Anautopsy was not performed.

PATHOLOGICAL FINDINGS

Macroscopic examination of the resected esophagusrevealed a protruding lesion along with a superficial spread-ing area, measuring 8.0 3 6.0 cm, in the middle third of the thoracic esophagus. Histologic examination of theesophageal cancer revealed a well-differentiated squamouscell carcinoma invading into the submucosal layer (Figs 1,2).Lymphatic and blood vessel invasions were seen in thesubmucosa. Twenty-two lymph node metastases were foundin 68 resected lymph nodes. Some small arteries beneathand near the tumor exhibited varying degrees of inflam-matory cell infiltration consisting of lymphocytes, eosinophilsand plasma cells throughout the vessel walls (Figs 1,3,4). Noleukocytoclasis was seen. Fibrinoid necrosis and intraluminalthromboses were recognized in some of the affected arteries.Vasculitis similar to that seen in the esophagus was sparselyobserved in the stomach resected by EMR (Fig. 5). Serratusanterior muscle, which had been biopsied at the esophagec-tomy because of the investigation for systemic vasculitis,showed similar vasculitis (Fig. 6). Histologic examination ofthe left lobe of the thyroid, resected at the esophagectomy tofacilitate the digestive tract reconnection, revealed a latentpapillary carcinoma measuring 1 mm. No vasculitis was seenin the thyroid or the surrounding muscle.

Esophageal carcinoma was immunohistochemically neg-ative for chromogranin A. Most of the mononuclear inflam-matory cells in the affected arteries were UCHL-1-positive T

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Figure 1 Histologic appearance oftumor invading the submucosa of theesophagus. Arrowhead indicates thevasculitis (HE).

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Figure 2 High magnification view ofesophageal carcinoma. Tumor nestshows zonal differentiation andkeratinization (HE).

Figure 3 High magnification view of Fig. 1. Marked lymphocytes,eosinophils and plasma cells infiltratethrough the small arteriole withfibrinoid necrosis (HE).

Figure 4 Distribution of vasculitis in theesophagus. , Carcinoma; d, vasculitis.

cells, some were L-26 positive B cells and a few lysozyme-positive macrophages were noted. No deposition of IgG, IgAor IgM was demonstrated in the affected arteries.

DISCUSSION

Symptom complexes in cancer-bearing patients that cannotreadily be explained either by the local or distant spread ofthe tumor or by the elaboration of hormones indigenous to thetissue from which the tumor arise are known as paraneo-plastic syndromes.1 Diverse signs and symptoms are foundin paraneoplastic syndromes and include hypercalcemia,endocrinopathies, neuromyopathic paraneoplastic syndromeand vasculitis.1

Pathologic examination of the resected specimen revealedsystemic vasculitis that was more pronounced in the esoph-agus than in the stomach and serratus anterior muscle. Novasculitis was seen in the thyroid and the surroundingmuscle. The patient had esophageal, gastric and latentthyroid carcinomas which were discovered after the onset oflow-grade fever and numbness in the lower limbs. Thesesymptoms remained after removal of the gastric carcinomabut subsided after surgical removal of the esophagealcarcinoma. The highly elevated level of CRP also dropped tonormal after removal of the esophageal carcinoma. Theseindicate that an inflammatory lesion did exist and that the inflammation disappeared after the removal of theesophageal carcinoma. Fever is known to occur occasionallyin patients with cancer showing necrosis or concurrent

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Figure 5 Vasculitis similar to that seen in the esophagus wassparsely observed in the endoscopically resected stomach (HE).

Figure 6 Biopsied serratus anteriormuscle showed similar vasculitisobserved in the esophagus (HE).

infection6 but, in this case, necrosis and concurrent infectionwere ruled out following extensive clinical and pathologicexaminations. Meanwhile, neuromuscular disease and col-lagen disease, that also cause numbness, were excludedfollowing clinical examinations.

Curth has defined the criteria for paraneoplastic syn-dromes.5 First, the malignancy should be discovered almostat the same time as the paraneoplastic sign occurs. Second,if the tumor is removed, the neoplastic changes shouldimprove. Third, if the paraneoplastic lesion is always asso-ciated with a particular tumor site, one might suspect arelationship between them. In the present case, the temporalrelationship between both conditions, spontaneous reso-lution after tumor removal and distribution of vasculitissuggest a paraneoplastic origin of the systemic vasculitis.Therefore, esophageal carcinoma could be concerned invasculitis and continuous vasculitis-related symptoms, butthis remains to be verified. Diverse subtypes of inflammatoryblood vessel diseases have been reported in patients withsolid tumors.7 The present case seems to display some of theprominent features that characterize the syndrome of musclemicrovasculitis: asymmetrical sensory-motor disorder, highsedimentation rate and microvasculitis.4,7–9 Denervationmuscle atrophy was not seen in the muscle tissue near thethyroid and serratus anterior muscle.

Although the association between vasculitis syndrome anda variety of neoplastic diseases is widely recognized, mostoccurred in patients with hematologic malignant neo-plasms.8–10 Fewer than 90 cases of vasculitis in patients withsolid tumors are documented in the literature. Among them,four cases have been reported to have vasculitis in theadjacent tissue of the solid tumor.11–14 Cutaneous leuko-cytoclastic vasculitis and nerve and muscle microvasculitiswere the most frequently observed vasculitic subtypes.15 Theunique distribution of vasculitis in this case is uncommon.The vasculitis was seen not only in the tumor-distant tissuebut also in the tumor-adjacent tissue. Therefore, it can bepostulated that circulating immune complexes or tumor-associated antigens operated at a distant and at a local level.The pathogenesis of vasculitis in the tumor-adjacent tissueseems to be different from that of vasculitis in the tumor-distant tissue. It is possible that local factors may pre-dominate in the pathogenesis of vasculitis in the tumor-adjacent tissue. However, further studies of paraneoplasticvasculitis are required to elucidate the mechanism of vas-culitis. The commonest malignant solid neoplasms accom-panied by paraneoplastic vasculitis were renal, lung,prostate, colon and breast cancer. One case of vasculitis in apatient with esophageal cancer was listed in the table of acase report and review,3 but this report lacks detailed

clinicopathologic descriptions of the patient with esophagealcancer. Therefore, our present case is the first detailed reportof esophageal carcinoma associated with paraneoplasticvasculitis.

Although the present case possessed synchronous, triple,solid tumors, it demonstrated a typical clinical course of paraneoplastic syndrome with esophageal cancer. Cer-tainly, paraneoplastic vasculitis is rare, but if a patient with vasculitis-related symptoms that resists conventionaltherapy, the possibility of a concurrent malignant neoplasmshould be considered.

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