CASE REPORT

Sarcoid Reaction in Primary T\imor of Bronchogenic LargeCell Carcinoma Accompanied with Massive Necrosis

Kosuke Kashiwabara, Masakazu Toyonaga*, Yuji Yamaguchi*,Hiroyuki Nakamura**, Seigo Hirayama*** and Ryo-ichi Kurano****

Abstract

A 49-year-old womanconsulted our hospital for evalua-tion of a tumor with cavitation in the S6 segment of the rightlung. She was given a diagnosis of pulmonary tuberculomabecause percutaneous needle aspiration cytology revealedepithelioid cells with a background of necrosis. However, adiagnosis of large cell carcinoma with central necrosis (p-T2N0M0) was established by thoracoscopic lung biopsy sixmonths later. Pathological findings of surgical resectionspecimens showed that epithelioid cell granulomas adja-cent to the neoplasm had a sarcoid reaction and the necro-sis was related to the rapidly growing tumor because therewas no clinical evidence of systemic sarcoidosis and pul-monary mycobacterial or fungal infection. This is the firstreport in which sarcoid reactions were recognized in a pri-mary large cell carcinoma.(Internal Medicine 40: 127-130, 2001)

Key words: epithelioid cell granulomas, systemic sarcoidosis,fungal infections, pulmonary tuberculoma, percu-taneous needle aspiration cytology, coexistence

Introduction

It has been reported that non-caseating epithelioid cell granu-lomas are occasionally found in lymph nodes draining a re-gion containing the malignant tumor in patients with malig-nant diseases ( 1-4). Such tumor-associated histologic changeshave been termed "sarcoid reaction", but this is not indicativeof systemic sarcoidosis. Howeverthere have been a few re-ports in which sarcoid reaction existed within the primary tu-mor in patients with lung cancer (5-7) and the histological typeof all reported cases was adenocarcinoma (6). The present re-port describes a case of bronchogeniclarge cell carcinomaac-

companied by noncaseating epithelioid cell granulomas withinthe primary tumor.

Case ReportA 47-year-old asymptomatic non-smoking womanpresentedfor evaluation of an abnormal shadowin the right middle lungfield in October 1998 (Fig. 1A). A computed tomogram (CT)of the chest revealed a tumor (28x26 mm)with a cavity in theright S6 and no presence of calcification or satellite nodules(Fig. IB). Transbronchial lung biopsy failed to obtain diagnos-tic material, only necrotic tissue and percutaneous needle aspi-ration cytology of the lung (NAC) was performed. Pulmonarytuberculoma was diagnosed based on epithelioid cells with abackground of necrosis in the obtained specimen (Fig. 2), al-though smear culture and polymerase chain reaction (PCR) ofMycobacteriumtuberculosis were negative. She was givenorally 400 mg of isoniazid, 450 mg of rifampicin and 1,000mg of ethambutol hydrochloride for 6 months, but no improve-ment of the nodular shadowcould be seen. Chest CTafter thecompletion of the treatment of antituberculosis drugs showeda dumb-bell like enlargement of the tumor (Fig. 3).She was admitted to our hospital for pathological evalua-tion of the tumor by thoracoscopic lung biopsy in May 1999.On admission, her body temperature was 36.8°C, heart rate 68beat/min, respiratory rate 15/min, and blood pressure 1 10/50mmHg.Analysis of arterial blood gas was normal (pH 7.42,PaO2 86.2 Torr, PaCO2 41.0 Torr, HCO3" 26.2 mmol/Z). Labo-ratory data revealed a white blood cell count of 6,500/mm3,red blood cell count 390x104/mm3, hemoglobin 1 1.9 g/dl, plate-let count 24.8x lO4/mm3, aspartate aminotransferase 1 9 U//, ala-nine aminotransferase 21 U//, lactate dehydrogenase 147 U//,alkaline phosphatase 8 1 U//, C-reactive protein 0.70 mg/dl. AnIgE antibody to aspergillus and a soluble cryptococcal polysac-charide antigen in serumwerenegative. Tumormarker levelsincluding cytokeratin 19 fragment (CYFRA 21-1),

carcinoembryonic antigen (CEA) and neuron-specific enolaseFrom the Respiratory Department, *the Surgical Department, the Taragi Municipal Hospital, Kumamoto, * *the Fifth Department of Internal Medicine, Tokyo

Medical University, Tokyo, ***the First Department of Internal Medicine, KumamotoUniversity, Kumamotoand ****the Division of Pathology,KumamotoRegional Medical Center, Kumamoto

Received for publication March 3 1 , 2000; Accepted for publication August 7, 2000Reprint requests should be addressed to Dr. Kosuke Kashiwabara, the Respiratory Department, Taragi Municipal Hospital, 42 10 Taragi, Taragi-machi, Kuma-

gun, Kumamoto 868-0501

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Kashiwabara et al

A

B

Figure 1. A roentgenogram (A) and computed tomogram (B) ofthe chest revealed a tumor with a cavity in right S6.

Figure 2. A percutaneous needle aspiration cytology of the lungobtained epithelioid cells (arrow) with a background of necrosis

(arrowhead) (x400).

Figure 3. A chest computed tomogramafter te completion ofthe treatment of antituberculosis drugs showed a dumb-bell likeenlargement of the tumor.

(NSE) were normal.Thoracoscopic lung biopsy specimens yielded a diagnosis

of lung cancer with central necrosis. The patient underwentright lower lobectomy and lymphadenectomy in July 1999.Pathological findings of surgically resected specimens showeda bronchogenic large cell carcinoma (p-T2N0M0)composedof undifferentiated tumor cells with a moderateamountof cy-

toplasm and nuclei, consisting of coarse chromatin clumpingand prominent nucleoli (Fig. 4A) and the bulk of the dumb-bell like tumor was made up of massive necrosis. In addition,epithelioid cell granulomas with giant cells existed adjacent tothe neoplasm and the necrosis (Fig. 4B), but not in the otherplaces of the specimen. There was no pathological finding sug-gestive of pulmonary tuberculoma adjacent to the large cellcarcinoma in the dumb-bell like tumor. Mycobacterium tuber-culosis, aspergillus and cryptococcus in the necrosis were nega-tive by Ziehl-Neelsen, periodic acid-Schiff (PAS) and Giemsastain. A culture of mycobacterium tuberculosis was also nega-tive, but cultures of aspergillus and cryptococcus were not done.The epithelioid cell granulomas adjacent to the tumor werediagnosed as sarcoid reaction and the necrosis was related tothe rapidly growing tumor of large cell carcinoma. Specimens

128 Internal Medicine Vol. 40, No. 2 (February 2001)

Sarcoid Reaction in Large Cell Carcinoma

A

B

Figure 4. Pathological findings of surgical resection specimensshowed a large cell carcinoma composed of undifferentiated tu-mor cells with a moderateamountof cytoplasm and nuclei whichhad coarse chromatin clumping and prominent nucleoli (x200)(A) and epithelioid cell granulomas (arrow) with giant cells (ar-rowhead) adjacent to the neoplasm and necrosis (xlOO) (B).

obtained by lymphadenectomy showed no presence of lymphnode metastasis or epithelioid cell granulomas.

Discussion

This is the first report in which sarcoid reactions existedwithin the primary tumor of bronchogenic large cell carcinoma.Sarcoid reactions have been reported to occur in a variety ofmalignant diseases and have a high incidence in lymphopro-liferative disorders such as Hodgkin's disease or non-Hodgkin'slymphoma.The overall incidence of this reaction in patientswith carcinoma has been reported to be 4.4% (3). With regardto lung cancer patients, Laurberg et al (4) reported that 20 outof 630 patients (3.2%) had sarcoid reactions in the mediastinallymph nodes. In addition, they were found not only in lymph

nodes draining a region containing the malignant tumor, butalso in the tumor itself or in nonregional tissues. Somestudieshave shownthat sarcoid reactions are observed within the pri-mary tumor in patients with lung cancer (5-7), similar to in thepresent case. Aoki et al (6) mentioned that the histologic typeof all reported cases was adenocarcinoma. On the other hand,it has been reported that patients with sarcoid reactions in theregional lymph nodes of the lung very often have squamouscell carcinoma because this carcinoma grows moreslowly thanother types of carcinomaand regional lymphnodes are ex-posed to the lymph flow from lung cancers for a longer period(7,8).

The pathogenesis of sarcoid reactions has remained unclear.Brincker (3) reported that tumor-associated sarcoid reactionsdo not contribute to a direct interaction between tumor cellsand lymph nodes, since this reaction commonlyoccurred inlymph nodes without metastasis. Therefore sarcoid reactionsmay be caused by soluble antigenic factors derived from tu-mor cells. In addition, this reaction might be a marker of animmunologically mediated anti-tumor response of macro-phages activated by T-lymphocytes and may be associated withlonger survival because Hodgkin's disease patients with a sar-coid reaction have been reported to have a significantly longerrelapse-free survival period (8). Our patients had no metastasisof mediastinal lymph node in the surgical resection specimensin spite of the fact that surgical treatment was delayed for sixmonths.

In the present case, the initial diagnosis was pulmonary tu-berculoma because the cytological findings of the specimenobtained by NACshowed epithelioid cells with a backgroundof necrosis. Epithelioid cell granuloma in the neoplasm wasfinally diagnosed as sarcoid reaction, but no systemic sarcoid-osis was recognized because there was no presence of hilarlymphadenopathy or extrathoracic lesions of sarcoidosis. Pul-monary tuberculoma, bronchocentric granulomatosis (whichusually represents a type of allergic bronchopulmonary as-pergillosis) and cryptococcosis were also excluded becausesmears of mycobacteriumtuberculosis, aspergillus and cryp-tococcus in the necrosis were negative and because IgE anti-body to aspergillus and soluble cryptococcal polysaccharideantigen in serum were negative. Wesuspect that the massivenecrosis coexisting with epithelioid cell granuloma in the NACspecimens was caused by the rapid enlargement of large cellcarcinoma. Althoughthe diagnostic rate for smear culture ofmycobacterium tuberculosis in NACspecimens is not high,the presence of epithelioid cells and necrosis in the specimensis useful for the diagnosis of pulmonary tuberculomas (9, 10).We reported that 5 1% of pulmonary tuberculomas were diag-nosed by only NAC, but not by a transbronchial approach (9).Howeverwhenepithelioid cells and necrosis were due to sepa-rate diseases with different underlying pathogenic mechanismssuch as sarcoid reaction and lung cancer, the coexistence ofepithelioid cells and necrosis in the NACspecimens may bemisdiagnosed as pulmonary tuberculoma.Wereported a rare case in which sarcoid reaction was presentwithin the primary tumor of large cell carcinoma with massive

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necrosis. The coexistence of sarcoid reaction and necrosis madeit difficult to diagnose by NAC.Our findings also suggest thatit is important to consider the presence of neoplasm in caseswith tuberculoma when antituberculosis drugs are ineffective.

Acknowledgements: The authors are indebted to Prof. J. Patrick Barronand Ms. T. Kojima of the International Medical Communications Center ofTokyo Medical University for their review of this manuscript.

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