- Email: [email protected]
Rapidly progressive malignant melanoma in a patient treated with tocilizumab
J AM ACAD DERMATOL
e78 Letters
AUGUST 2012
Prof. Dr. T€ urkan Saylan Dermatology and Leprosy Clinic, I_ stanbul, Turkey E-mail: [email protected] REFERENCES 1. Aydogan I, Kavak A, Parlak AH, Alper M, Annakkaya AN, Erbas M. Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel. J Eur Acad Dermatol Venereol 2005;19:345-7. 2. Mukherjee A, Girdhar BK, Desikan KV. Leprous phlebitis. Int J Lepr Other Mycobact Dis 1980;48:48-50. 3. Mukherjee A, Girdhar BK, Malviya GN, Ramu G, Desikan KV. Involvement of subcutaneous veins in lepromatous leprosy. Int J Lepr Other Mycobact Dis 1983;51:1-6. 4. White NW. Venous thrombosis and rifampicin. Lancet 1989;2:434-5.
Fig 1. Case 1. Persistent serpentine supravenous hyperpigmented eruption.
They also hypothesized that lower temperature in the subcutaneous fat around veins of lower extremities may be advantageous for the multiplication of the organisms.2 In another study, 29 of 31 patients with LL who underwent biopsy of the subcutaneous vein from the forearm showed histologic evidence of lepromatous phlebitis.3 Drugs employed in the treatment of leprosy could be considered as a probable cause in the pathogenesis of PSSHE. It is notable that rifampicin has been associated with the development of thrombophlebitis.4 Our observation in 6 LL patients and literature review suggests that PSSHE may result from a subclinical/clinical thrombophlebitis and subsequent postinflammatory hyperpigmentation. All our patients were treated for leprosy many years ago and Doppler ultrasound (US) showed no abnormalities, except in patient 6 in whom there was superficial thrombophlebitis by Doppler US. There were no current signs of leprosy in our patients and PSSHE was most likely secondary to prior treatment or thrombophlebitis. us¸ra Karahacıoglu, Ays¸e Kavak, MD,a,b Fatma B€ ul, Leprosy Nurse,b M. Koray MD,b I_ lgin G€ Tas¸malı, MD,c Tan Cimilli, MD,c and Fırat Baytekin, MDd
http://dx.doi.org/10.1016/j.jaad.2011.09.001
Rapidly progressive malignant melanoma in a patient treated with tocilizumab To the Editor: We report a 59-year-old Caucasian woman with a melanoma on her left knee. Eleven months earlier she had started tocilizumab for uncontrolled rheumatoid arthritis which was being treated with methotrexate and leflunomide. Tocilizumab was stopped shortly after the melanoma diagnosis. At the time of diagnosis the melanoma was ulcerated and had a Breslow thickness of 2.5 mm ( pT3b) (Fig 1). BRAF mutation status was negative. A sentinel node biopsy was positive and a complete lymphadenectomy showed one additional affected node. There was no evidence of distant metastases ( pT3bN2aM0, stage IIIB). During the following months rapid progression occurred, first locoregional (Fig 2) and later with distant metastases. The patient did not respond to multiple treatments (isolated limb perfusion, dacarbazine [DTIC], ipilimumab). The patient died 10 months after diagnosis. Tocilizumab is a humanized anti-interleukin 6 (IL-6) receptor IgG1 antibody that inhibits IL-6 from binding both its soluble and membrane-bound receptor, thus inhibiting IL-6 signal transduction.1 IL-6 is a proinflammatory cytokine with pleiotropic
Department of Dermatology, D€ uzce University, oy Dr. Sadi Konuk Training and D€ uzcea; Bakırk€ Research Hospital, Prof. Dr. T€ urkan Saylan Dermatology and Leprosy Clinic,b Radiodiagnostic Clinic,c and Pathology Clinic,d I_ stanbul, Turkey Funding sources: None. Conflicts of interest: None declared. Correspondence to: Ays¸e Kavak, MD, Bakırk€oy Dr. Sadi Konuk Training and Research Hospital,
Fig 1. Melanoma at time of diagnosis.
J AM ACAD DERMATOL
Letters e79
VOLUME 67, NUMBER 2
Department of Dermatology, University Hospital, Ghenta; Department of Medical Oncology, OLV van Lourdes Hospital, Waregemb; Departments of Medical Oncologyc and Dermatology,d AZ Groeninge Hospital, Kortrijk; Dr Suys also has a private practice in Kortrijk, Belgium Funding sources: None. Fig 2. Extensive locoregional progression.
effects on different cell types.2 Tocilizumab has been used for rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, Castleman disease, and Crohn’s disease.1 Several studies have reported that tocilizumab therapy is generally well tolerated. Adverse reactions are quite common, up to 90%, but these are mostly low-grade reactions. The most common adverse events are infections and infestations (mostly upper respiratory tract infections), gastrointestinal disorders (nausea, vomiting, diarrhea, perforation), infusion reactions and hypersensitivity reactions, hematological abnormalities, altered lipid profile, and liver function disorders. All these adverse events seem to be equally prevalent with tocilizumab therapy as with classic disease modifying antirheumatic drugs as methotrexate.3 Regarding the risk of malignancy, one could suppose that the immunosuppressive properties of tocilizumab may be a concern. However, the available data do not show an increased malignancy risk with tocilizumab compared with placebo or disease-modifying antirheumatic drugs.2,3 With regard to malignant melanoma, IL-6 has been found to be a potent inhibitor of melanoma cell adhesion and proliferation. Treatment with the IL-6/sIL-6R complex showed growth inhibition of melanoma cells.4 Thus, it could be hypothesized that blocking the IL-6 signal can result in uncontrolled growth of melanoma, as occurred in our patient. It could be argued whether the melanoma was already present before tocilizumab was started. IL-6 is particularly important in inhibiting growth of early-stage melanoma.5 Blocking IL-6 could lead to rapid progression of melanoma. This case focuses attention on the mid- to longterm side effects of the relatively new class of biological treatments. Postmarketing surveillance is an important tool to learn about long-term side effects. This case also emphasizes the importance of a dermatological check-up before starting those medications. Michiel Bonny, MD,a Veronique Buyse, MD,b,c and Erwin Suys, MDd
Conflicts of interest: None declared. Correspondence to: Michiel Bonny, MD, De Pintelaan 185, 9000 Ghent, Belgium E-mail: [email protected] REFERENCES 1. Venkiteshwaran A. Tocilizumab. MAbs 2009;1:432-8. 2. Bannwarth B, Richez C. Clinical safety of tocilizumab in rheumatoid arthtritis. Expert Opin Drug Saf 2011;10:123-31. 3. Patel A, Moreland L. Interleukin-6 inhibition for treatment of theumatoid arthritis: A review of tocilizumab therapy. Drug Des Devel Ther 2010;4:263-78. 4. Wagley Y, Yoo Y-C, Seo HG, Rhee MH, Kim TH, Kang KW, et al. The IL-6/sIL-6R treatment of a malignant melanoma cell line enhances susceptibility to TNF-a-induced apoptosis. Biochem Biophys Res Commun 2007;354:985-91. 5. Lu C, Vickers M, Kerbel R. Interleukin 6: A fibroblast-derived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression. Proc Natl Acad Sci U S A 1992;89:9215-9. http://dx.doi.org/10.1016/j.jaad.2011.08.033
Cutaneous metastasis of thyroid carcinoma mimicking Mondor disease To the Editor: Mondor disease, typified by superficial thrombophlebitis, has been previously reported in association with breast carcinoma1,2 and metastatic lung cancer.3 We report a case of biopsy-confirmed cutaneous metastasis of insular thyroid carcinoma mimicking Mondor disease. A 77-year-old woman, with a history of recurrent insular thyroid carcinoma treated with radioactive iodine, radiation, and multiple resections, presented with a progressively enlarging right-sided neck mass that was later found to be recurrent thyroid carcinoma and a plaque on the superior lateral left breast, which prompted dermatologic evaluation. The patient reported a history of chronic left arm and breast lymphedema of unknown etiology. The lesion on the left breast developed 2 months prior to this hospital admission and was intermittently painful. A breast biopsy had been performed 6 months earlier, adjacent to the lesion, which showed the lesion to be benign; therefore the patient was given a clinical diagnosis of Mondor disease and was advised that the superficial thrombophlebitis may have resulted as a complication of the biopsy procedure. Warm
e78 Letters
AUGUST 2012
Prof. Dr. T€ urkan Saylan Dermatology and Leprosy Clinic, I_ stanbul, Turkey E-mail: [email protected] REFERENCES 1. Aydogan I, Kavak A, Parlak AH, Alper M, Annakkaya AN, Erbas M. Persistent serpentine supravenous hyperpigmented eruption associated with docetaxel. J Eur Acad Dermatol Venereol 2005;19:345-7. 2. Mukherjee A, Girdhar BK, Desikan KV. Leprous phlebitis. Int J Lepr Other Mycobact Dis 1980;48:48-50. 3. Mukherjee A, Girdhar BK, Malviya GN, Ramu G, Desikan KV. Involvement of subcutaneous veins in lepromatous leprosy. Int J Lepr Other Mycobact Dis 1983;51:1-6. 4. White NW. Venous thrombosis and rifampicin. Lancet 1989;2:434-5.
Fig 1. Case 1. Persistent serpentine supravenous hyperpigmented eruption.
They also hypothesized that lower temperature in the subcutaneous fat around veins of lower extremities may be advantageous for the multiplication of the organisms.2 In another study, 29 of 31 patients with LL who underwent biopsy of the subcutaneous vein from the forearm showed histologic evidence of lepromatous phlebitis.3 Drugs employed in the treatment of leprosy could be considered as a probable cause in the pathogenesis of PSSHE. It is notable that rifampicin has been associated with the development of thrombophlebitis.4 Our observation in 6 LL patients and literature review suggests that PSSHE may result from a subclinical/clinical thrombophlebitis and subsequent postinflammatory hyperpigmentation. All our patients were treated for leprosy many years ago and Doppler ultrasound (US) showed no abnormalities, except in patient 6 in whom there was superficial thrombophlebitis by Doppler US. There were no current signs of leprosy in our patients and PSSHE was most likely secondary to prior treatment or thrombophlebitis. us¸ra Karahacıoglu, Ays¸e Kavak, MD,a,b Fatma B€ ul, Leprosy Nurse,b M. Koray MD,b I_ lgin G€ Tas¸malı, MD,c Tan Cimilli, MD,c and Fırat Baytekin, MDd
http://dx.doi.org/10.1016/j.jaad.2011.09.001
Rapidly progressive malignant melanoma in a patient treated with tocilizumab To the Editor: We report a 59-year-old Caucasian woman with a melanoma on her left knee. Eleven months earlier she had started tocilizumab for uncontrolled rheumatoid arthritis which was being treated with methotrexate and leflunomide. Tocilizumab was stopped shortly after the melanoma diagnosis. At the time of diagnosis the melanoma was ulcerated and had a Breslow thickness of 2.5 mm ( pT3b) (Fig 1). BRAF mutation status was negative. A sentinel node biopsy was positive and a complete lymphadenectomy showed one additional affected node. There was no evidence of distant metastases ( pT3bN2aM0, stage IIIB). During the following months rapid progression occurred, first locoregional (Fig 2) and later with distant metastases. The patient did not respond to multiple treatments (isolated limb perfusion, dacarbazine [DTIC], ipilimumab). The patient died 10 months after diagnosis. Tocilizumab is a humanized anti-interleukin 6 (IL-6) receptor IgG1 antibody that inhibits IL-6 from binding both its soluble and membrane-bound receptor, thus inhibiting IL-6 signal transduction.1 IL-6 is a proinflammatory cytokine with pleiotropic
Department of Dermatology, D€ uzce University, oy Dr. Sadi Konuk Training and D€ uzcea; Bakırk€ Research Hospital, Prof. Dr. T€ urkan Saylan Dermatology and Leprosy Clinic,b Radiodiagnostic Clinic,c and Pathology Clinic,d I_ stanbul, Turkey Funding sources: None. Conflicts of interest: None declared. Correspondence to: Ays¸e Kavak, MD, Bakırk€oy Dr. Sadi Konuk Training and Research Hospital,
Fig 1. Melanoma at time of diagnosis.
J AM ACAD DERMATOL
Letters e79
VOLUME 67, NUMBER 2
Department of Dermatology, University Hospital, Ghenta; Department of Medical Oncology, OLV van Lourdes Hospital, Waregemb; Departments of Medical Oncologyc and Dermatology,d AZ Groeninge Hospital, Kortrijk; Dr Suys also has a private practice in Kortrijk, Belgium Funding sources: None. Fig 2. Extensive locoregional progression.
effects on different cell types.2 Tocilizumab has been used for rheumatoid arthritis, systemic onset juvenile idiopathic arthritis, Castleman disease, and Crohn’s disease.1 Several studies have reported that tocilizumab therapy is generally well tolerated. Adverse reactions are quite common, up to 90%, but these are mostly low-grade reactions. The most common adverse events are infections and infestations (mostly upper respiratory tract infections), gastrointestinal disorders (nausea, vomiting, diarrhea, perforation), infusion reactions and hypersensitivity reactions, hematological abnormalities, altered lipid profile, and liver function disorders. All these adverse events seem to be equally prevalent with tocilizumab therapy as with classic disease modifying antirheumatic drugs as methotrexate.3 Regarding the risk of malignancy, one could suppose that the immunosuppressive properties of tocilizumab may be a concern. However, the available data do not show an increased malignancy risk with tocilizumab compared with placebo or disease-modifying antirheumatic drugs.2,3 With regard to malignant melanoma, IL-6 has been found to be a potent inhibitor of melanoma cell adhesion and proliferation. Treatment with the IL-6/sIL-6R complex showed growth inhibition of melanoma cells.4 Thus, it could be hypothesized that blocking the IL-6 signal can result in uncontrolled growth of melanoma, as occurred in our patient. It could be argued whether the melanoma was already present before tocilizumab was started. IL-6 is particularly important in inhibiting growth of early-stage melanoma.5 Blocking IL-6 could lead to rapid progression of melanoma. This case focuses attention on the mid- to longterm side effects of the relatively new class of biological treatments. Postmarketing surveillance is an important tool to learn about long-term side effects. This case also emphasizes the importance of a dermatological check-up before starting those medications. Michiel Bonny, MD,a Veronique Buyse, MD,b,c and Erwin Suys, MDd
Conflicts of interest: None declared. Correspondence to: Michiel Bonny, MD, De Pintelaan 185, 9000 Ghent, Belgium E-mail: [email protected] REFERENCES 1. Venkiteshwaran A. Tocilizumab. MAbs 2009;1:432-8. 2. Bannwarth B, Richez C. Clinical safety of tocilizumab in rheumatoid arthtritis. Expert Opin Drug Saf 2011;10:123-31. 3. Patel A, Moreland L. Interleukin-6 inhibition for treatment of theumatoid arthritis: A review of tocilizumab therapy. Drug Des Devel Ther 2010;4:263-78. 4. Wagley Y, Yoo Y-C, Seo HG, Rhee MH, Kim TH, Kang KW, et al. The IL-6/sIL-6R treatment of a malignant melanoma cell line enhances susceptibility to TNF-a-induced apoptosis. Biochem Biophys Res Commun 2007;354:985-91. 5. Lu C, Vickers M, Kerbel R. Interleukin 6: A fibroblast-derived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression. Proc Natl Acad Sci U S A 1992;89:9215-9. http://dx.doi.org/10.1016/j.jaad.2011.08.033
Cutaneous metastasis of thyroid carcinoma mimicking Mondor disease To the Editor: Mondor disease, typified by superficial thrombophlebitis, has been previously reported in association with breast carcinoma1,2 and metastatic lung cancer.3 We report a case of biopsy-confirmed cutaneous metastasis of insular thyroid carcinoma mimicking Mondor disease. A 77-year-old woman, with a history of recurrent insular thyroid carcinoma treated with radioactive iodine, radiation, and multiple resections, presented with a progressively enlarging right-sided neck mass that was later found to be recurrent thyroid carcinoma and a plaque on the superior lateral left breast, which prompted dermatologic evaluation. The patient reported a history of chronic left arm and breast lymphedema of unknown etiology. The lesion on the left breast developed 2 months prior to this hospital admission and was intermittently painful. A breast biopsy had been performed 6 months earlier, adjacent to the lesion, which showed the lesion to be benign; therefore the patient was given a clinical diagnosis of Mondor disease and was advised that the superficial thrombophlebitis may have resulted as a complication of the biopsy procedure. Warm