Ann Hematol DOI 10.1007/s00277-014-2202-1
LETTER TO THE EDITOR
Paraneoplastic pemphigus occurring after bendamustine and rituximab therapy for relapsed follicular lymphoma Takashi Higo & Tomomitsu Miyagaki & Fumihiko Nakamura & Akihito Shinohara & Hiroki Asano & Hiroyuki Abe & Naoyuki Senda & Ayumi Yoshizaki & Masashi Fukayama & Mineo Kurokawa
Received: 22 August 2014 / Accepted: 26 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Dear Editor, Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous disorder which is predominantly associated with lymphoproliferative disorders including non-Hodgkin lymphoma, B-chronic lymphocytic leukemia, Castleman disease, and Waldenström macroglobulinemia [1]. PNP is characterized by painful mucosal erosion with frequent skin eruption, histological changes of acantholysis or lichenoid/interface dermatitis, and serum autoantibodies against plakin family proteins [2, 3]. Although the cause of PNP is not identified in most cases, previous literatures have indicated that PNP may be triggered by specific treatment modalities for lym-
T. Higo : F. Nakamura : A. Shinohara : H. Asano : M. Kurokawa (*) Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: [email protected] T. Miyagaki : N. Senda : A. Yoshizaki Department of Dermatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan H. Abe : M. Fukayama Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan M. Kurokawa Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
phoid neoplasms. Patients with lymphoid malignancies were recurrently affected by PNP within several cycles of fludarabine-containing therapy [4–7] or after local radiotherapy [8–10]. Here, we describe the first case of PNP occurring after bendamustine and rituximab therapy for follicular lymphoma. A 77-year-old Japanese woman was diagnosed with follicular lymphoma and achieved complete remission after six cycles of rituximab, cyclophosphamide, vincristine, and prednisolone therapy. A follow-up computed tomography scan detected recurrence of lymphadenopathy at 16 months after completion of the immunochemotherapy. At the age of 80 years, salvage therapy was commenced with bendamustine (60 mg/ m2, days 1–2) and rituximab (375 mg/m2, day 1) of a 28-day cycle, which led to salient regression of lymphadenopathy. On day 23 of the second cycle, the patient noticed painful stomatitis and skin lesions with fever. Physical examination detected hemorrhagic crusts on the lips, oral erosions, blistering of the eyelids, and eruptions on the trunk (Fig. 1a). Repeated blood cultures did not show any evidence of bacterial infections. Initial diagnosis of cytomegalovirus (CMV) infection was made on the basis of a positive CMV pp65 antigenemia test result. While fever was improved by ganciclovir administration, stomatitis and skin rash remained almost stable. A skin biopsy from the trunk was therefore performed, and histopathological examination revealed suprabasal clefts with scattered necrotic keratinocytes (Fig. 1b). The Nikolsky sign (i.e., blistering after manual rubbing of the skin) was positive. Serum autoantibodies against desmoglein 3 were detected by chemiluminescent enzyme immunoassay. Taken together, the patient was diagnosed with PNP.
Ann Hematol Fig. 1 Paraneoplastic pemphigus. a The patient presenting with hemorrhagic blistering of the eyelids (upper left), crusts and erosions on the lips and erosions on the tongue (lower left), and eruptions on the trunk (right); b histopathological evaluation of the skin showing suprabasal clefts and infiltration of neutrophils and eosinophils (HE stain, ×400)
Methylprednisolone at 1 g daily was administered for three consecutive days, which was followed by prednisolone at 1 mg/kg daily. This treatment resulted in immediate alleviation of the skin lesions, but the recovery of mucosal eruptions was modest. PNP may be triggered by treatment with bendamustine and rituximab for lymphoid neoplasms. Because fludarabine and bendamustine share the properties of purine analogue, we surmise that bendamustine rather than rituximab was associated with the pathogenesis of PNP in our case. It is plausible that we have overlooked PNP because skin toxicities are a well-known adverse event of bendamustine. We should carefully evaluate histopathology and serum autoantibodies against plakin family proteins in search of PNP especially when the skin lesions are persistent. Informed consent was obtained from the patient for being included in this case study.
Conflict of interest The authors have no conflict of interest directly relevant to the content of this article. F.N., A.S., and M.K. were given lecture fees, and M.K. was funded from Chugai Pharmaceutical Co., Ltd., for research outside this work. A.S. and M.K. were funded, and M.K. was given lecture fees from Eisai Co., Ltd., for research outside this work.
References 1. Zhu X, Zhang B (2007) Paraneoplastic pemphigus. J Dermatol 34(8): 503–511 2. Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H, Mutasim D, Ariss-Abdo L (1990) Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 323(25):1729–1735 3. Anhalt GJ (2004) Paraneoplastic pemphigus. J Investig Dermatol Symp Proc 9(1):29–33 4. Bazarbachi A, Bachelez H, Dehen L, Delmer A, Zittoun R, Dubertret L (1995) Lethal paraneoplastic pemphigus following treatment of
Ann Hematol chronic lymphocytic leukaemia with fludarabine. Ann Oncol 6(7): 730–731 5. Braess J, Reich K, Willert S, Strutz F, Neumann C, Hiddemann W, Wörmann B (1997) Mucocutaneous autoimmune syndrome following fludarabine therapy for low-grade non-Hodgkin’s lymphoma of B-cell type (B-NHL). Ann Hematol 75(5–6):227–230 6. Reich K, Brinck U, Letschert M, Blaschke V, Dames K, Braess J, Wörmann B, Rünger TM, Neumann C (1999) Graft-versus-host disease-like immunophenotype and apoptotic keratinocyte death in paraneoplastic pemphigus. Br J Dermatol 141(4):739–746 7. Gooptu C, Littlewood TJ, Frith P, Lyon CC, Carmichael AJ, Oliwiecki S, MacWhannell A, Amagai M, Hashimoto T,
Dean D, Allen J, Wojnarowska F (2001) Paraneoplastic pemphigus: an association with fludarabine? Br J Dermatol 144(6):1255–1261 8. Fried R, Lynfield Y, Vitale P, Anhalt G (1993) Paraneoplastic pemphigus appearing as bullous pemphigoid-like eruption after palliative radiation therapy. J Am Acad Dermatol 29(5 Pt 2): 815–817 9. Lee MS, Kossard S, Ho KK, Barnetson RS, Ravich RB (1995) Paraneoplastic pemphigus triggered by radiotherapy. Australas J Dermatol 36(4):206–210 10. Plumb R, Doolittle GC (1996) Paraneoplastic pemphigus in a patient with non-Hodgkin’s lymphoma. Am J Hematol 52(1):58–59
LETTER TO THE EDITOR
Paraneoplastic pemphigus occurring after bendamustine and rituximab therapy for relapsed follicular lymphoma Takashi Higo & Tomomitsu Miyagaki & Fumihiko Nakamura & Akihito Shinohara & Hiroki Asano & Hiroyuki Abe & Naoyuki Senda & Ayumi Yoshizaki & Masashi Fukayama & Mineo Kurokawa
Received: 22 August 2014 / Accepted: 26 August 2014 # Springer-Verlag Berlin Heidelberg 2014
Dear Editor, Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous disorder which is predominantly associated with lymphoproliferative disorders including non-Hodgkin lymphoma, B-chronic lymphocytic leukemia, Castleman disease, and Waldenström macroglobulinemia [1]. PNP is characterized by painful mucosal erosion with frequent skin eruption, histological changes of acantholysis or lichenoid/interface dermatitis, and serum autoantibodies against plakin family proteins [2, 3]. Although the cause of PNP is not identified in most cases, previous literatures have indicated that PNP may be triggered by specific treatment modalities for lym-
T. Higo : F. Nakamura : A. Shinohara : H. Asano : M. Kurokawa (*) Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: [email protected] T. Miyagaki : N. Senda : A. Yoshizaki Department of Dermatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan H. Abe : M. Fukayama Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan M. Kurokawa Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
phoid neoplasms. Patients with lymphoid malignancies were recurrently affected by PNP within several cycles of fludarabine-containing therapy [4–7] or after local radiotherapy [8–10]. Here, we describe the first case of PNP occurring after bendamustine and rituximab therapy for follicular lymphoma. A 77-year-old Japanese woman was diagnosed with follicular lymphoma and achieved complete remission after six cycles of rituximab, cyclophosphamide, vincristine, and prednisolone therapy. A follow-up computed tomography scan detected recurrence of lymphadenopathy at 16 months after completion of the immunochemotherapy. At the age of 80 years, salvage therapy was commenced with bendamustine (60 mg/ m2, days 1–2) and rituximab (375 mg/m2, day 1) of a 28-day cycle, which led to salient regression of lymphadenopathy. On day 23 of the second cycle, the patient noticed painful stomatitis and skin lesions with fever. Physical examination detected hemorrhagic crusts on the lips, oral erosions, blistering of the eyelids, and eruptions on the trunk (Fig. 1a). Repeated blood cultures did not show any evidence of bacterial infections. Initial diagnosis of cytomegalovirus (CMV) infection was made on the basis of a positive CMV pp65 antigenemia test result. While fever was improved by ganciclovir administration, stomatitis and skin rash remained almost stable. A skin biopsy from the trunk was therefore performed, and histopathological examination revealed suprabasal clefts with scattered necrotic keratinocytes (Fig. 1b). The Nikolsky sign (i.e., blistering after manual rubbing of the skin) was positive. Serum autoantibodies against desmoglein 3 were detected by chemiluminescent enzyme immunoassay. Taken together, the patient was diagnosed with PNP.
Ann Hematol Fig. 1 Paraneoplastic pemphigus. a The patient presenting with hemorrhagic blistering of the eyelids (upper left), crusts and erosions on the lips and erosions on the tongue (lower left), and eruptions on the trunk (right); b histopathological evaluation of the skin showing suprabasal clefts and infiltration of neutrophils and eosinophils (HE stain, ×400)
Methylprednisolone at 1 g daily was administered for three consecutive days, which was followed by prednisolone at 1 mg/kg daily. This treatment resulted in immediate alleviation of the skin lesions, but the recovery of mucosal eruptions was modest. PNP may be triggered by treatment with bendamustine and rituximab for lymphoid neoplasms. Because fludarabine and bendamustine share the properties of purine analogue, we surmise that bendamustine rather than rituximab was associated with the pathogenesis of PNP in our case. It is plausible that we have overlooked PNP because skin toxicities are a well-known adverse event of bendamustine. We should carefully evaluate histopathology and serum autoantibodies against plakin family proteins in search of PNP especially when the skin lesions are persistent. Informed consent was obtained from the patient for being included in this case study.
Conflict of interest The authors have no conflict of interest directly relevant to the content of this article. F.N., A.S., and M.K. were given lecture fees, and M.K. was funded from Chugai Pharmaceutical Co., Ltd., for research outside this work. A.S. and M.K. were funded, and M.K. was given lecture fees from Eisai Co., Ltd., for research outside this work.
References 1. Zhu X, Zhang B (2007) Paraneoplastic pemphigus. J Dermatol 34(8): 503–511 2. Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H, Mutasim D, Ariss-Abdo L (1990) Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 323(25):1729–1735 3. Anhalt GJ (2004) Paraneoplastic pemphigus. J Investig Dermatol Symp Proc 9(1):29–33 4. Bazarbachi A, Bachelez H, Dehen L, Delmer A, Zittoun R, Dubertret L (1995) Lethal paraneoplastic pemphigus following treatment of
Ann Hematol chronic lymphocytic leukaemia with fludarabine. Ann Oncol 6(7): 730–731 5. Braess J, Reich K, Willert S, Strutz F, Neumann C, Hiddemann W, Wörmann B (1997) Mucocutaneous autoimmune syndrome following fludarabine therapy for low-grade non-Hodgkin’s lymphoma of B-cell type (B-NHL). Ann Hematol 75(5–6):227–230 6. Reich K, Brinck U, Letschert M, Blaschke V, Dames K, Braess J, Wörmann B, Rünger TM, Neumann C (1999) Graft-versus-host disease-like immunophenotype and apoptotic keratinocyte death in paraneoplastic pemphigus. Br J Dermatol 141(4):739–746 7. Gooptu C, Littlewood TJ, Frith P, Lyon CC, Carmichael AJ, Oliwiecki S, MacWhannell A, Amagai M, Hashimoto T,
Dean D, Allen J, Wojnarowska F (2001) Paraneoplastic pemphigus: an association with fludarabine? Br J Dermatol 144(6):1255–1261 8. Fried R, Lynfield Y, Vitale P, Anhalt G (1993) Paraneoplastic pemphigus appearing as bullous pemphigoid-like eruption after palliative radiation therapy. J Am Acad Dermatol 29(5 Pt 2): 815–817 9. Lee MS, Kossard S, Ho KK, Barnetson RS, Ravich RB (1995) Paraneoplastic pemphigus triggered by radiotherapy. Australas J Dermatol 36(4):206–210 10. Plumb R, Doolittle GC (1996) Paraneoplastic pemphigus in a patient with non-Hodgkin’s lymphoma. Am J Hematol 52(1):58–59
