- Email: [email protected]
Sarcoidosis–lymphoma syndrome
Letters to the Editor / Med Clin (Barc). 2015;145(6):273–278
the development of new lymphadenopathies and involvement of the spleen during a chronic course of sarcoidosis should be investigated early to rule out the concomitant onset of lymphoma, since lymphadenopathy is present in more than 60% of cases of lymphoma and involvement of bone marrow and splenomegaly is present in 30%–70% of cases. By contrast, splenomegaly occurs in only 7% of cases of sarcoidosis, and asymptomatic involvement is more common.8 References 1. Drent M, Costabel U. European respiratory monograph 32: sarcoidosis. Plymouth: European Respiratory Society; 2005. p. 233–50. 2. Giovinale M, Fonnesu C, Soriano A, Cerquaglia C, Curigliano V, Verrecchia E, et al. Atypical sarcoidosis: case reports and review of the literature. Eur Rev Med Pharmacol Sci. 2009;13:37–44. 3. Nakamura S, Jaffe ES, Swerdlow SH. EBV-positive diffuse large B-cell lymphoma of the elderly. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al., editors. WHO classification of tumors of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008. p. 243–5. 4. Friedberg JW, Fisher RI. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008;22 Suppl. 5:941–52.
Sarcoidosis–lymphoma syndrome夽 Síndrome sarcoidosis-linfoma Dear Editor, Systemic sarcoidosis is a granulomatous inflammatory disease of unknown aetiology with pulmonary and extra-pulmonary manifestations. The presence of granulomas is not exclusive to sarcoidosis and these may occur in diseases of different aetiologies.1 We present a case of diagnosis of Hodgkin lymphoma in a patient with a prior history of sarcoidosis that illustrates the challenge of diagnosis of this disease in certain scenarios. The case was that of a 43-year-old woman, with no prior history of interest, diagnosed with systemic sarcoidosis at another centre in 1999. She had widespread involvement of the lymph nodes and spleen. In addition, multiple pulmonary nodules were observed. A splenectomy was performed, and the pathology study showed non-necrotising granulomas, sarcoids, in which Ziehl–Neelsen stains were negative. Her post-operative course was good, and her angiotensin converting enzyme (ACE) levels reduced from 132 to 85 g/l. In addition, radiological improvement, but not disappearance, of her lymphadenopathy and pulmonary lesions was observed. The patient remained asymptomatic without treatment, with annual check-ups at our centre until 2009. Ten years after her splenectomy, she mentioned having discomfort in her neck area. Although no lymphadenopathies were palpated, respiratory function tests, including lung diffusion testing, were performed. These turned out to be normal, and no increased ACE was observed. Despite this, given the suspicion of recurrence of sarcoidosis, a chest–abdomen–pelvis computed tomography scan was requested. Lymphadenopathies of insignificant size and imaging of a nodule measuring a millimetre in the upper lobe of the right lung, with non-specific characteristics, which were linked to residual lesions, were observed in the imaging test. Thirteen years after her initial diagnosis of sarcoidosis, the patient had pain in her neck
夽 Please cite this article as: González-Munera A, García-Fernández ME, Ríos-Blanco JJ. Síndrome sarcoidosis-linfoma. Med Clin (Barc). 2015;145:277–278.
277
5. Cohen PR, Kurzrock R. Sarcoidosis and malignancy. Clin Dermatol. 2007;25 Suppl. 3:326–33. 6. Bichel J, Brincker H. Treatment of pruritus in Hodgkin’s disease and in reticulum cell sarcoma. Scand J Haematol. 1965;2:85–90. 7. Brincker H. The sarcoidosis-lymphoma syndrome. Br J Cancer. 1986;54:467–73. 8. Goswami T, Siddique S, Cohen P, Cheson BD. The sarcoid lymphoma syndrome. Clin Lymphoma Myeloma Leuk. 2010;10 Suppl. 4:241–7.
Laia Giralt a , Albert Sánchez-Font a,∗ , Blanca Sánchez-González b , Eva Balcells a a
Servei de Pneumologia, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Barcelona, Spain b Servei d’Hematologia, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Barcelona, Spain ∗ Corresponding
author. E-mail address: [email protected] (A. Sánchez-Font).
area and swelling was observed in that area, so another tomography scan was performed. Multiple lymphadenopathies were observed in her neck, chest and abdomen. The largest in size measured 2 cm. The possibility of recurrence of sarcoidosis was suggested. As the patient did not have involvement of the internal organs or lungs, starting treatment was ruled out and it was decided to assess her clinical evolution. A year later, it was decided to perform a PET-CT scan. The scan showed uptake in supra- and infradiaphragmatic lymphadenopathies with no uptake in other areas. When the patient went in to the following check-up, she had palpable supraclavicular lymphadenopathy with a diameter of around 5 cm, and an excisional biopsy of this was performed. In the pathology study, 15 years after the patient had been diagnosed with sarcoidosis, she was diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma. Currently, she is in chemotherapy treatment with a good clinical course. The association of sarcoidosis with malignant processes was initially reported in 1974 by Brincker and Wilbek,2 and subsequently in 1986 by Brincker, who identified sarcoidosis–lymphoma syndrome3 and reported its main characteristics: (1) the lymphoproliferative processes is normally diagnosed after sarcoidosis; (2) median age at the time of diagnosis of sarcoidosis is 41 years, 10 years older than in normal cases of sarcoidosis; and (3) Hodgkin disease appears more commonly than expected in the general population. Recently, London et al. reported a series of 14 cases of diagnosis of sarcoidosis subsequent to a diagnosis of lymphoma.4 The case that we have presented corresponded to a typical sarcoidosis–lymphoma syndrome patient as described by Brincker.3 Regarding the aetiology of the association, although in some cases immunosuppressant treatment has been suggested as a predisposing factor for the development of lymphoproliferative disease, our patient had not received any treatment for sarcoidosis, and therefore her lymphoma could have been directly related to her prior history of granulomatous disease. Sarcoidosis is considered to be a local immune-mediated response induced by unknown antigens that results in activation of CD4+ T lymphocytes accompanied by decreased CD8+ T lymphocytes. This environment of cytotoxic T cell depletion would lead to the development of lymphoproliferative processes.5 In addition, B cell system hyperactivity has been observed in sarcoidosis in
278
Letters to the Editor / Med Clin (Barc). 2015;145(6):273–278
connection with Epstein–Barr virus infection.6 This involves increased lymphocyte mitotic activity, which increases the risk of malignant transformation. Several authors have attempted to report effective methods for differential diagnosis of the presentation of recurrence of sarcoidosis and lymphoproliferative disease in the form of lymphadenopathies. In a laboratory study, hypercalcaemia and increased ACE levels are associated with sarcoidosis, but cases in patients with isolated lymphoma have also been reported.7 In addition, Kis et al.8 described the usefulness of PET to distinguish between these processes in a patient with recurrence of sarcoidosis concomitant with bronchus-associated lymphoid tissue lymphoma. Even so, the authors themselves affirmed that PET cannot replace the need to complete the study with a histological diagnosis. Sarcoidosis–lymphoma syndrome is rare, but it is necessary to be aware of this relationship for a differential diagnosis in cases of suspected recurrence of sarcoidosis and to complete its analysis with a pathology study. References 1. Rose CD, Neven B, Wouters C. Granulomatous inflammation: the overlap of immune deficiency and inflammation. Best Pract Res Clin Rheumatol. 2014;28:191–212. 2. Brincker H, Wilbek E. The incidence of malignant tumours in patients with respiratory sarcoidosis. Br J Cancer. 1974;29:247–51. 3. Brincker H. The sarcoidosis–lymphoma syndrome. Br J Cancer. 1986;54:467–73.
4. London J, Grados A, Fermé C, Charmillon A, Maurier F, Deau B, et al. Sarcoidosis occurring after lymphoma: report of 14 patients and review of the literature. Medicine (Baltimore). 2014;93:e121. 5. Karakantza M, Matutes E, MacLennan K, O’Connor NT, Srivastava PC, Catovsky D. Association between sarcoidosis and lymphoma revisited. J Clin Pathol. 1996;49:208–12. 6. Linnenberg HS, Medici TC, Rhyner K. The sarcoidosis–lymphoma syndrome – a lymphocyte dysregulation? Pneumologie. 1992;46:229–35. 7. DeRemee RA, Banks PM. Non-Hodgkin’s lymphoma associated with hypercalcemia and increased activity of serum angiotensin-converting enzyme. Mayo Clin Proc. 1986;61:714–8. 8. Kis A, Eszes N, Tamasi L, Losonczy G, Csekeo A, Csomor J, et al. Sarcoidosis lymphoma syndrome – the value of PET-CT in the diagnosis. World J Surg Oncol. 2013;11:235.
Adriana González-Munera a,∗ , María Eugenia García-Fernández b , Juan José Ríos-Blanco c a
Servicio de Medicina Interna, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain b Servicio de Anatomía Patológica, Hospital Universitario La Paz, Madrid, Spain c Servicio de Medicina Interna, Hospital Universitario La Paz, Madrid, Spain ∗ Corresponding
author. E-mail address: [email protected] (A. González-Munera).
the development of new lymphadenopathies and involvement of the spleen during a chronic course of sarcoidosis should be investigated early to rule out the concomitant onset of lymphoma, since lymphadenopathy is present in more than 60% of cases of lymphoma and involvement of bone marrow and splenomegaly is present in 30%–70% of cases. By contrast, splenomegaly occurs in only 7% of cases of sarcoidosis, and asymptomatic involvement is more common.8 References 1. Drent M, Costabel U. European respiratory monograph 32: sarcoidosis. Plymouth: European Respiratory Society; 2005. p. 233–50. 2. Giovinale M, Fonnesu C, Soriano A, Cerquaglia C, Curigliano V, Verrecchia E, et al. Atypical sarcoidosis: case reports and review of the literature. Eur Rev Med Pharmacol Sci. 2009;13:37–44. 3. Nakamura S, Jaffe ES, Swerdlow SH. EBV-positive diffuse large B-cell lymphoma of the elderly. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al., editors. WHO classification of tumors of haematopoietic and lymphoid tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008. p. 243–5. 4. Friedberg JW, Fisher RI. Diffuse large B-cell lymphoma. Hematol Oncol Clin North Am. 2008;22 Suppl. 5:941–52.
Sarcoidosis–lymphoma syndrome夽 Síndrome sarcoidosis-linfoma Dear Editor, Systemic sarcoidosis is a granulomatous inflammatory disease of unknown aetiology with pulmonary and extra-pulmonary manifestations. The presence of granulomas is not exclusive to sarcoidosis and these may occur in diseases of different aetiologies.1 We present a case of diagnosis of Hodgkin lymphoma in a patient with a prior history of sarcoidosis that illustrates the challenge of diagnosis of this disease in certain scenarios. The case was that of a 43-year-old woman, with no prior history of interest, diagnosed with systemic sarcoidosis at another centre in 1999. She had widespread involvement of the lymph nodes and spleen. In addition, multiple pulmonary nodules were observed. A splenectomy was performed, and the pathology study showed non-necrotising granulomas, sarcoids, in which Ziehl–Neelsen stains were negative. Her post-operative course was good, and her angiotensin converting enzyme (ACE) levels reduced from 132 to 85 g/l. In addition, radiological improvement, but not disappearance, of her lymphadenopathy and pulmonary lesions was observed. The patient remained asymptomatic without treatment, with annual check-ups at our centre until 2009. Ten years after her splenectomy, she mentioned having discomfort in her neck area. Although no lymphadenopathies were palpated, respiratory function tests, including lung diffusion testing, were performed. These turned out to be normal, and no increased ACE was observed. Despite this, given the suspicion of recurrence of sarcoidosis, a chest–abdomen–pelvis computed tomography scan was requested. Lymphadenopathies of insignificant size and imaging of a nodule measuring a millimetre in the upper lobe of the right lung, with non-specific characteristics, which were linked to residual lesions, were observed in the imaging test. Thirteen years after her initial diagnosis of sarcoidosis, the patient had pain in her neck
夽 Please cite this article as: González-Munera A, García-Fernández ME, Ríos-Blanco JJ. Síndrome sarcoidosis-linfoma. Med Clin (Barc). 2015;145:277–278.
277
5. Cohen PR, Kurzrock R. Sarcoidosis and malignancy. Clin Dermatol. 2007;25 Suppl. 3:326–33. 6. Bichel J, Brincker H. Treatment of pruritus in Hodgkin’s disease and in reticulum cell sarcoma. Scand J Haematol. 1965;2:85–90. 7. Brincker H. The sarcoidosis-lymphoma syndrome. Br J Cancer. 1986;54:467–73. 8. Goswami T, Siddique S, Cohen P, Cheson BD. The sarcoid lymphoma syndrome. Clin Lymphoma Myeloma Leuk. 2010;10 Suppl. 4:241–7.
Laia Giralt a , Albert Sánchez-Font a,∗ , Blanca Sánchez-González b , Eva Balcells a a
Servei de Pneumologia, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Barcelona, Spain b Servei d’Hematologia, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Universitat Pompeu Fabra, Barcelona, Spain ∗ Corresponding
author. E-mail address: [email protected] (A. Sánchez-Font).
area and swelling was observed in that area, so another tomography scan was performed. Multiple lymphadenopathies were observed in her neck, chest and abdomen. The largest in size measured 2 cm. The possibility of recurrence of sarcoidosis was suggested. As the patient did not have involvement of the internal organs or lungs, starting treatment was ruled out and it was decided to assess her clinical evolution. A year later, it was decided to perform a PET-CT scan. The scan showed uptake in supra- and infradiaphragmatic lymphadenopathies with no uptake in other areas. When the patient went in to the following check-up, she had palpable supraclavicular lymphadenopathy with a diameter of around 5 cm, and an excisional biopsy of this was performed. In the pathology study, 15 years after the patient had been diagnosed with sarcoidosis, she was diagnosed with nodular lymphocyte-predominant Hodgkin lymphoma. Currently, she is in chemotherapy treatment with a good clinical course. The association of sarcoidosis with malignant processes was initially reported in 1974 by Brincker and Wilbek,2 and subsequently in 1986 by Brincker, who identified sarcoidosis–lymphoma syndrome3 and reported its main characteristics: (1) the lymphoproliferative processes is normally diagnosed after sarcoidosis; (2) median age at the time of diagnosis of sarcoidosis is 41 years, 10 years older than in normal cases of sarcoidosis; and (3) Hodgkin disease appears more commonly than expected in the general population. Recently, London et al. reported a series of 14 cases of diagnosis of sarcoidosis subsequent to a diagnosis of lymphoma.4 The case that we have presented corresponded to a typical sarcoidosis–lymphoma syndrome patient as described by Brincker.3 Regarding the aetiology of the association, although in some cases immunosuppressant treatment has been suggested as a predisposing factor for the development of lymphoproliferative disease, our patient had not received any treatment for sarcoidosis, and therefore her lymphoma could have been directly related to her prior history of granulomatous disease. Sarcoidosis is considered to be a local immune-mediated response induced by unknown antigens that results in activation of CD4+ T lymphocytes accompanied by decreased CD8+ T lymphocytes. This environment of cytotoxic T cell depletion would lead to the development of lymphoproliferative processes.5 In addition, B cell system hyperactivity has been observed in sarcoidosis in
278
Letters to the Editor / Med Clin (Barc). 2015;145(6):273–278
connection with Epstein–Barr virus infection.6 This involves increased lymphocyte mitotic activity, which increases the risk of malignant transformation. Several authors have attempted to report effective methods for differential diagnosis of the presentation of recurrence of sarcoidosis and lymphoproliferative disease in the form of lymphadenopathies. In a laboratory study, hypercalcaemia and increased ACE levels are associated with sarcoidosis, but cases in patients with isolated lymphoma have also been reported.7 In addition, Kis et al.8 described the usefulness of PET to distinguish between these processes in a patient with recurrence of sarcoidosis concomitant with bronchus-associated lymphoid tissue lymphoma. Even so, the authors themselves affirmed that PET cannot replace the need to complete the study with a histological diagnosis. Sarcoidosis–lymphoma syndrome is rare, but it is necessary to be aware of this relationship for a differential diagnosis in cases of suspected recurrence of sarcoidosis and to complete its analysis with a pathology study. References 1. Rose CD, Neven B, Wouters C. Granulomatous inflammation: the overlap of immune deficiency and inflammation. Best Pract Res Clin Rheumatol. 2014;28:191–212. 2. Brincker H, Wilbek E. The incidence of malignant tumours in patients with respiratory sarcoidosis. Br J Cancer. 1974;29:247–51. 3. Brincker H. The sarcoidosis–lymphoma syndrome. Br J Cancer. 1986;54:467–73.
4. London J, Grados A, Fermé C, Charmillon A, Maurier F, Deau B, et al. Sarcoidosis occurring after lymphoma: report of 14 patients and review of the literature. Medicine (Baltimore). 2014;93:e121. 5. Karakantza M, Matutes E, MacLennan K, O’Connor NT, Srivastava PC, Catovsky D. Association between sarcoidosis and lymphoma revisited. J Clin Pathol. 1996;49:208–12. 6. Linnenberg HS, Medici TC, Rhyner K. The sarcoidosis–lymphoma syndrome – a lymphocyte dysregulation? Pneumologie. 1992;46:229–35. 7. DeRemee RA, Banks PM. Non-Hodgkin’s lymphoma associated with hypercalcemia and increased activity of serum angiotensin-converting enzyme. Mayo Clin Proc. 1986;61:714–8. 8. Kis A, Eszes N, Tamasi L, Losonczy G, Csekeo A, Csomor J, et al. Sarcoidosis lymphoma syndrome – the value of PET-CT in the diagnosis. World J Surg Oncol. 2013;11:235.
Adriana González-Munera a,∗ , María Eugenia García-Fernández b , Juan José Ríos-Blanco c a
Servicio de Medicina Interna, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain b Servicio de Anatomía Patológica, Hospital Universitario La Paz, Madrid, Spain c Servicio de Medicina Interna, Hospital Universitario La Paz, Madrid, Spain ∗ Corresponding
author. E-mail address: [email protected] (A. González-Munera).