Two cases of sarcoidosis-lymphoma syndrome

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Med Oncol (2007) 24:469–471 DOI 10.1007/s12032-007-0026-8


Two cases of sarcoidosis-lymphoma syndrome Nada Suvajdzic Æ Branislava Milenkovic Æ Maja Perunicic Æ Jelena Stojsic Æ Snezana Jankovic

Received: 22 March 2007 / Accepted: 12 April 2007 / Published online: 17 May 2007  Humana Press Inc. 2007

Abstract An association between sarcoidosis and lymphoproliferative diseases (LD), the sarcoidosis-lymphoma syndrome, has been previously described, and may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. We report two patients who developed Hodgkin’s disease and diffuse large B-cell non-Hodgkin’s lymphoma (NHL) subsequent to their diagnosis of sarcoidosis after latency periods of 6 years and 18 years respectively. Both patients developed histologically-proven sarcoidosis late in life, at 46 years and 58 years, and had differing clinical courses. The first had radiographically staged II chronic progressive respiratory sarcoidosis (RS) and required longterm methotrexate to control the disease, while the second achieved a spontaneous remission of her stage I intrathoracic RS. After treatment, the patient with Hodgkin’s disease remains in remission 2.5 years following six cycles of ABVD protocol chemotherapy and involved-field radiotherapy, while the NHL patient remains in remission at 3 years following six cycles of R-COP protocol chemotherapy. Clinicians should be aware of the potential risks of malignancy, and especially of LD in sarcoidosis patients. They should be alerted to the possibility of additional pathology by any atypical clinical features, and should biopsy new lesions and adenopathy to exclude any coexistent neoplasm. N. Suvajdzic (&)  M. Perunicic  S. Jankovic Institute of Hematology, Clinical Center of Serbia, 2, Koste Todorovic Str., 11000 Belgrade, Serbia and Montenegro e-mail: [email protected] B. Milenkovic  J. Stojsic Institute for Pulmonary Diseases and TB, Clinical Center of Serbia, Belgrade, Serbia and Montenegro


Sarcoidosis  Lymphoma

Introduction An association between sarcoidosis and lymphoproliferative diseases (LD) has been previously described [1–3]. Brincker and Wilbeck noted a far greater than expected incidence of LD in those patients with previous respiratory sarcoidosis (RS) [1], and first coined the term ‘‘sarcoidosislymphoma syndrome’’ (SLS) [4] to describe this apparent sequence in events. An analysis of 17 such patients in their series revealed that eight had developed Hodgkin’s disease, and nine patients had non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia or multiple myeloma [4]. Some authors have described cases of simultaneous sarcoidosis and LD [5], and others of sarcoidosis appearing after chemotherapy for LD [6–8]. We report two patients who developed Hodgkin’s disease and diffuse large B-cell NHL subsequent to their diagnosis of sarcoidosis.

Case reports Case 1 A 52-year-old male was diagnosed with stage IIIA Hodgkin’s disease, with a mixed cellularity subtype, in May 2004. He had involvement of the left axillary (up to 4.7 cm) and mediastinal lymph nodes, spleen (17 · 7.5 cm), and two suspected lymph nodes in the external iliac arterial chain (measuring 2 cm and 3 cm respectively). He was treated with six cycles of the ABVD protocol (doxorubicin, bleomycin, vincristine, deticene)


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and had involved-field radiotherapy; and remains in hematological remission 2.5 years later. His past medical history included RS diagnosed in April 1998, which was histologically confirmed with mediastinoscopy, and classified radiographically as stage II intrathoracic sarcoidosis. When he originally presented with RS he had had no constitutional symptoms or internal organ involvement, and laboratory analyses revealed normocalcemia and an elevated serum level of angiotensin-converting enzyme (ACE). He was initially treated with 20 mg of daily prednisolone with a good clinical response, and medication was gradually tailed off. However in April 2003 he relapsed, with progression on chest radiography, worsening lung function and a rise in serum ACE levels. He was commenced on 10 mg of daily methotrexate, once more with a good clinical response, and the sarcoidosis remains stable with maintenance therapy of 25 mg of weekly methotrexate. At the time the Hodgkin’s disease was diagnosed, his RS had been in remission (Fig. 1).

of >80% cells Ki 67+) analyses of a scalene lymph node. She received six cycles of the R-COP protocol (rituximab, cyclophosphamide, vincristine, and prednisolone) and remains in complete remission at 3 years. Her past medical history included RS in 1985, which was histologically confirmed by biopsy of a left-sided cervical lymph node. At the time she was radiographically classified as having stage I intrathoracic disease, and had had no constitutional symptoms or internal organ involvement; no data is known about her serum calcium or ACE levels. She achieved a continued spontaneous remission within a year of presentation, and at latest review has a normal chest X-ray and serum ACE levels. The histological diagnosis of sarcoidosis was once more confirmed on the 2003 lymph node biopsy. At the time of NHL diagnosis her sarcoidosis had also been in remission.

Case 2

An association between sarcoidosis and malignancy, and in particular with lymphoma (SLS), has been previously described, however, the evidence favoring this association is mostly based on case reports and statistical or observational epidemiological analyses from cross registry studies [1–10], and it remains controversial. Brincker and Wilbeck reported that lymphoma occurred 11 times more frequently in patients with sarcoidosis, especially in the chronic active disease type [1]. Askling also found that chronic active sarcoidosis was associated with a doubled risk of subsequent lymphoma of both the Hodgkin’s and non-Hodgkin’s types during the first decade of follow-up, though this risk normalised thereafter [10]. It has been postulated that the occurrence of lymphoma during the natural course of sarcoidosis may be attributed to the underlying immunological abnormalities that occur in the disease process [1], such as a decrease in CD-8 positive T-cell suppressor/cytotoxic cells, an activation of CD4-positive T-cell helper/ inducer cells, abnormal cytokine production, cutaneous anergy to particular antigens, and hypergammaglobulinemia [11]. In contrast, others have not found any association between sarcoidosis and malignancy (including LD) and have suggested instead that the previous associations may have been due to disease misclassifications [12–14]. For example, a mass on a chest radiograph and CT scan in a patient with sarcoidosis may have been attributed to malignancy, when in fact it was due to sarcoidosis; similarly mediastinal lymphadenopathy in a patient with malignancy may have be attributed to the underlying tumor, when in fact it could have actually represented sarcoidosis [15]. In addition, non-caseating epitheloid granulomata can occur in patients

A 76-year-old woman was diagnosed with stage IIA diffuse large B-cell NHL in September 2003. She had involvement of the right scalene lymph nodes (up to 4 cm) and bilateral paratracheal lymphadenopathy (up to 1.5 cm). The diagnosis was made after histopathological (showing a diffuse infiltrate of large round and oval cells resembling centroblasts) and immunohistochemical (showing large neoplastic cells strongly positive for CD20 and CD79a, slightly positive for IgM+, negative for CD3, CD43, CD45Ro, bcl2 and cytokeratin, and expressing a high proliferative index

Fig. 1 Bilateral hilar adenopathy accompanied by small parenchymal infiltrations (arrows) on chest X-ray (May 2004)


Med Oncol (2007) 24:469–471

with neoplastic disease, a so-called ‘‘sarcoid-like’’ reaction (quoted as occurring in 4.4% of carcinomas, 13.8% of Hodgkin’s disease patients, and in 7.3% of NHL cases) without any clinical evidence of sarcoidosis [16]. This phenomenon can be localized to the neoplastic tissue itself, to the regional lymph nodes and to other organs, and thus can also lead to a misdiagnosis of sarcoidosis. Our two patients both developed their RS at an advanced age (46 years and 58 years) [4], and their diagnoses were made based on their clinical presentations, radiographic findings, and the histological appearance of non-caseating epitheloid granulomata with the exclusion of other granulomatous diseases [17]. They both developed lymphoma after long latency periods (of 6 years and 18 years) following RS, similar to Brincker’s SLS patients, who developed LD at a median interval of 95 months (range 3–377 months)[4]. Though the true risk of lymphoma following sarcoidosis is not known, further investigation may help to clarify the possible underlying molecular mechanisms. We believe that clinicians should be aware of the potential risks of malignancy, and especially of LD in sarcoidosis patients. They should be alerted to the possibility of additional pathology by any atypical clinical features, and should biopsy new lesions and adenopathy to exclude any coexistent neoplasm. Acknowledgments We would very much like to thank Dr Henry Dushan Edward Atkinson, Imperial College Medical School, St Mary’s Hospital, Praed Street, London W2 1NY, UK for his critical review and assistance in the writing of this article.

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