© Borgis - New Medicine 4/2004, s. 94-96
Paweł Krawczyk1, Beata Gryglicka1, Robert Kieszko1, Elżbieta Korobowicz2, Sebastian Sojczuk1, Janusz Milanowski1
Malignant neoplasms and pulmonary sarcoidosis – A case report
1Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Poland
Head: Prof. Janusz Milanowski MD, PhD
2Department of Pathomorphology, Medical University of Lublin, Poland
Head: Prof. Elżbieta Korobowicz MD, PhD
Most researchers believe that patients with pulmonary sarcoidosis are predisposed to develop malignancies, but others presume that malignancies lead to sarcoidosis. The case of a 52-year-old female patient with histopathologically diagnosed pulmonary sarcoidosis is reported. Computed tomography revealed an abnormal mass in the liver hilus. Histopathological examination indicated mucocellular carcinoma of unknown cause. An increased level of CA 125 (3641 U/ml) and normal values of CEA and CA 19-9 were suggestive of the onset of gynaecological neoplasia. The case report presented confirms that an association between sarcoidosis and malignancy is highly probable.
Little is known about cancer risk following sarcoidosis; some authors even hypothesise that malignancy gives rise to sarcoidosis (1). In 1974, Brincker et al. found out that lymphoma and pulmonary carcinoma occurred eleven and three times more frequently in patients with than those without sarcoidosis (2). The problem is further complicated when a sarcoid-like reaction in the course of neoplasia is considered in the lymph nodes, spleen or liver. The reaction may not indicate metastatic disease and does not necessarily suggest sarcoidosis, but may signify a local response or resistance to cancer cells. Therefore, some malignancies may be initially misdiagnosed as sarcoidosis and reversely, which in both situations require biopsy (3, 4).
The cause of a high risk of malignant neoplasms in patients with pulmonary sarcoidosis remains obscure. However, an increased incidence of lymphoma may result from immune defects often found in patients with sarcoidosis. Alterations in the function of cells con-trolling inflammatory response give rise to sarcoidosis. An increase in Th1-lymphocyte proliferation with abnormal cytokine secretion can be found in the airway and local lymph nodes. Cytokines, chemotactic agents and growth factors promote granuloma formation followed by destruction and fibrosis of the lung parenchyma with its permanent disorganization, which may produce the so-called "scar cancer” of the lung. Immunomodulatory activity also causes immunological abnormalities in the peripheral blood leading not only to an increased risk of lymphoma but also to a dec-reased anti-cancer response efficacy. Moreover, genetic alterations determined at the microsatellite DNA level (microsatellite instability) and a loss of heterozygosity have been detected in patients with sarcoidosis, and this may influence the co-existence of sarcoidosis and malignancies (5, 6, 7).
In October 2002, a 52-year-old female patient with histopathologically confirmed sarcoidosis originating from the mediastinal lymph node was admitted to the Pulmonary Department, Medical University of Lublin, in order to diagnose the cause of mediastinal and abdominal lymph node enlargement. Chest X-ray and abdominal ultrasonography revealed the presence of lesions but the patient complained only of weakness, thoracalgia and abdominal pain. In May 2002, the patient was admitted to hospital for pericarditis, and in June 2002, for gastric ulceration confirmed histo-pathologically following a gastroscopy.
Results of routine serum biochemical and haema-tological tests were within the normal range. The immunological parameters demonstrated a high level of gammaglobulins (28.7% of total proteins; reference ranges: 9-22%) resulting from an increased IgG concentration (3022 mg/dl; norm: 800-1700 mg/dL). Cytometry of peripheral blood lymphocytes showed the prevalence of cellular response; 80.4% of all lymphocytes were of a T-cell phenotype, and the CD4:CD8 ratio value was 1.05. The surface IL-2 (CD25 antigen) receptor was found on 33.5% of T-helper cells.
Bronchoscopy demonstrated a vascular network in the bronchial mucosa. 45% of the bronchoalveolar lavage fluid (BALF) cells were T-cell phenotype lymphocytes. The CD4:CD8 ratio was 4.7; 72.9% of T-lymphocytes had the HLA DR antigen on the surface and 18.6% of T-helper cells were CD25-positive. Histopathology of endobronchial biopsy specimens revealed the presence of giant and epithelial cell granulomas, which confirmed the diagnosis of pulmonary sarcoidosis.
The patient´s condition progressively deteriorated. Serum biochemistry showed an increased level of bilirubin of 5.2 mg/dL with direct-reacting bilirubin of 3.9 mg/dL. The serum levels of AsPAT, AlAT, diastase, lipase, alkaline phosphatase and GGTP were signi-ficantly increased. Abdominal CT revealed an abnormal mass of 6 to 7 cm in diameter with packets of lymph nodes in the liver hilus, close to the head of the pancreas and in the pyloric region of the stomach. The presence of lesions resulted in an occluded bile tract, disturbed venous circulation and deformed duodenum.
Abdominal abnormalities required histopathological examination. Laparoscopy revealed mucocellular car-cinoma but of an unknown origin. The malignant cells demonstrated anti-cytokeratin and anti-mucus reactivity. An increased level of CA 125 (3641 U/ml) and normal values of CEA and CA 19-9 might have been suggestive of the onset of gynaecological neoplasia.
In view of a high bilirubin level (17.3 mg/dL), transcutaneous drainage of the bile tract was performed. The patient was treated with Endoxan and received two courses of chemotherapy with Cisplatin, Adriamycine and Vincristine. Since the therapy was ineffective, palliative treatment was instituted.
Association between sarcoidosis and malignancy has been addressed in several studies with contradictory results. Some researchers have reported a high incidence of lung cancer in patients with idiopathic pulmonary fibrosis but the trends described for other entities, i.e. sarcoidosis, systemic sclerosis and occupational diseases, are unclear. In a retrospective cohort study of 474 patients with sarcoidosis, the risk of lung cancer doubled in the first decade of follow-up, to decrease significantly thereafter (7). The association between sarcoidosis and malignant lymphoproliferative disease was considered to be so constant that the authors seemed to be convinced of the existence of sarcoidosis-lymphoma syndrome (2). Askling et al. also considered that patients with sarcoidosis seem to be at an increased cancer risk of the stomach, small intestine and liver, as well as melanoma and non-melanoma skin cancers, non-Hodgkin´s lymphoma and leukaemia (5). Seersholm et al., who assessed 254 patients with sarcoidosis for a mean period of 25 years, did not support the theory of sarcoidosis-lymphoma syndrome but their results suggested a highly probable association between sarcoidosis and lung cancer. At the same time, the authors reported only single cases of colonic and pancreatic malignancies, two cases of gastric and ovarian neoplasms and three cases of cervical cancer, which denied the co-existence of these malignancies with sarcoidosis (6).
The issue of predisposition to the development of sarcoidosis in patients with malignancies is still open. Suen et al reported six patients (four with lymphomas, one with ovarian cancer and one with breast cancer) with sarcoidosis diagnosed within the mean period of nine months after chemotherapy or bone marrow transplantation that would suggest the presence of the malignancy-sarcoidosis syndrome (1). Pandha et al. found 48 reports of cases in which sarcoidosis was recognised on or after diagnosing testicular cancer (8).
Contrary to the literature data, we report a rare co-existence of cancer localised in the abdomen, and pulmonary sarcoidosis. The assessment of immune systemic disturbances did not contribute to the recognition which disease leads to those abnormalities. It is also not clear whether immune abnormalities resulting from one disease influence the development of another one. Hypergammaglobulinaemia and a high percentage of T CD8+ cells and CD4+ lymphocytes with IL-2 receptor found in the peripheral blood may relate to the natural anti-cancer response. However, the presented case report may confirm a likely association between sarcoidosis and neoplasia different than lung cancer and lymphoma.
Moreover, the co-development of these diseases poses a new diagnostic problem. Extrapulmonary sarcoidosis is found primarily in the abdominal lymph nodes, liver, kidneys and spleen; particularly, liver granulomas may lead to hepatitis, which is a well-known risk factor in hepatocellular cancer. White et al. described a case of systemic and ovarian sarcoidosis with mucinous cystadenoma concomitant in the same ovary (9). Gastric sarcoidosis manifested as polypoid lesions in the antral stomach region was also reported (10). However, epithelioid cell granulomas identical to those in systemic sarcoidosis, are occasionally seen in malignant neoplasms, particularly in the lymphatic vessels draining the primary tumour. Lymph node enlargement and parenchymal nodules in cancer patients may not indicate metastatic disease. Several authors described individual cases of sarcoid-like reaction in the regional lymph nodes, spleen and liver in the course of gastric and colonic carcinomas (11, 15).
From histopathological diagnosis of sarcoidosis based on samples from the mediastinal lymph nodes and bronchial mucosa, as well as the results of the BALF examination, recognition of sarcoid aetiology of abdominal lesions might have been established in our patient. The correct diagnosis and adequate treatment were, however, delayed, which resulted in exacerbation of biochemical parameters. The patient´s cancer was misdiagnosed as sarcoidosis, which may be justified in view of that in spite of earlier confirmation of sarcoidosis, the biopsy was performed on atypical extrapulmonary lesions.
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