- Email: [email protected]
Zoledronic acid–induced cutaneous B-cell pseudolymphoma
1238 Letters
J AM ACAD DERMATOL
DECEMBER 2011
Fig 2. A and B, Perivascular and interstitial dermatitis in the papillary and superficial dermis. C, Neutrophils predominate in the inflammatory infiltrate. D, Nuclear dust between inflammatory cells. There is no evidence of vasculitis. (Hematoxylineeosin stain; original magnification: A, 325; B, 350; C, 3100; D, 3200.)
Antonio Martorell-Calatayud, MD,a Celia Requena, MD, PhD,a Onofre Sanmartin, MD, PhD,a Nicole Balmer, MD,b and Carlos Guillen-Barona, MD, PhDa Department of Dermatology,a Instituto Valenciano de Oncologia, Valencia, Spain, and the Department of Pathology,b Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina Funding sources: None. Conflicts of interest: None declared. Correspondence to: Antonio Martorell-Calatayud, MD, Department of Dermatology, Instituto Valenciano Oncologia, San Jose de la Monta~ na, 14, Valencia 46009, Spain E-mail: [email protected]
REFERENCES 1. Crino L, Scagliotti G, Marangolo M, Figoli F, Clerici M, De Marinis F, et al. Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1997;15:297-303. 2. Larson BJ, Waples JM, Pusateri A, Mendenhall NP. Lynch JW Jr. A phase II study of gemcitabine in patients with relapsed or
refractory low-grade non-Hodgkin lymphoma. Am J Clin Oncol 2005;28:165-8. 3. Brandes A, Reichmann U, Plasswilm L, Bamberg M. Time- and dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabine—a report of three cases. Anticancer Drugs 2000;11:15-7. 4. Marucci G, Sgarbanti E, Maestri A, Calandri C, Collina G. Gemcitabine-associated CD81 CD301 pseudolymphoma. Br J Dermatol 2001;145:650-2. 5. Bessis D, Guillot B, Legouffe E, Guilhou JJ. Gemcitabine-associated scleroderma-like changes of the lower extremities. J Am Acad Dermatol 2004;51:S73-6. doi:10.1016/j.jaad.2009.04.003
Zoledronic acideinduced cutaneous B-cell pseudolymphoma To the Editor: A 57-year-old white female with a history of breast cancer and positive lymph nodes underwent surgery followed by chemotherapy and radiation without complications in 2002. Three years later, metastatic disease to the spine and adrenal glands was discovered, and she was started on letrozole tablets and a bisphosphonate, zoledronic acid, intravenously. Nine months after starting the medications, she presented to our dermatology clinic with a 1-month history of mildly pruritic and
J AM ACAD DERMATOL
Letters 1239
VOLUME 65, NUMBER 6
edematous papules and plaques 4 mm to 1.2 cm in diameter located primarily on the right arm (Fig 1) but also on other extremities. Three skin biopsy specimens showed nodular lymphoid hyperplasia with no evidence of a lymphoproliferative disorder (Fig 2). Immunohistochemical stains were positive for CD20, CD23, BCL2, and MUM1. Immunoglobulin heavy chain gene rearrangement studies were polyclonal and a fluorescence in situ hybridization study for BCL2 and MALT1 was negative. Routine blood work was normal. Pseudolymphoma, possibly secondary to medications, was diagnosed. Subjectively, the patient noticed worsening after zoledronic acid infusions. Four months later, the patient stopped the zoledronic acid for 8 months because of a dental procedure and experienced complete clearing of her skin. Given the spinal metastases, her oncologist restarted the zoledronic acid infusions and within 2 weeks the lesions recurred. She is currently adequately treated with topical corticosteroids and diphenhydramine cream. Cutaneous pseudolymphoma (CPL) was first described in 1891 by Kaposi1 and represents a benign lymphoproliferative process that should be differentiated from cutaneous lymphomas. CPL generally displays benign biologic behavior, although one study showed that 4% of patients may progress to lymphoma.2 CPL can be subdivided into cutaneous T-cell pseudolymphomas (CTPL) and cutaneous Bcell pseudolymphomas (CBPL).1 Causes of pseudolymphoma include drugs, tattoos, insect bites, trauma, hyposensitization injections, gold pierced earrings, vaccinations, acupuncture, Borrelia burgdorferi infection, varicella zoster infection, HIV infection, photosensitivity-associated, and idiopathic.1 The cause of CTPL can usually be identified, whereas CBPL is often idiopathic.1 Drugs are an important inciting agent in CPL and tend to be more common in CTPL, although several cases of CBPL have been reported. Phenytoin is the most common drug associated with CPL. Other broad categories of drugs that have been associated with CPL are anticonvulsants, antipsychotics, antihypertensives, cytotoxics, antirheumatics, antibiotics, antidepressants, anxiolytics, antihistamines, antiarrhythmics, sex steroids, and lipid lowering agents.1 More recently described drug-induced cases of pseudolymphoma include etanercept, methylphenidate, and lornoxicam.3-5 Drugs specifically associated with CBPL include antidepressants, neuroleptics, allopurinol, and vaccines (eg, hepatitis A and hepatitis B).1,6 Initially, the pathogenesis of drug-induced pseudolymphoma was thought to be a hypersensitivity reaction. However, recent evidence suggests that these drugs
Fig 1. Erythematous papules on the right arm.
may impair immunologic function as evidenced by drug-induced stimulation of blastic transformation of lymphocytes and impaired ability of T-suppressor lymphocytes to suppress B-cell differentiation and immunoglobulin production.1 A literature review has not yielded any cases of CPL with bisphosphonates. Zoledronic acid is a bisphosphonate used in metatstatic disease to the bone, hypercalcemia of malignancy, multiple myeloma, Paget disease, and postmenopausal osteoporosis. The mechanism of action includes inhibition of osteoclast activity and reduction of bone resorption and turnover. Uncommon but serious side effects recently reported include osteonecrosis of the jaw in patients with dental procedures and orbital inflammatory disease.7 In our patient, the skin lesions developed several months after initiation of zoledronic acid, which is typical for CPL. Moreover, she cleared upon discontinuing the drug, and flared upon restarting infusions. An additional biopsy of new lesions following the reinfusion of zoledronic acid would provide stronger evidence that this is the same process. However, the patient declined another biopsy, and the new lesions appear clinically similar to the old lesions. We propose adding zoledronic acid to the list of medications associated with CBPL. Kory H. Kitagawa, MD, and Marcelle Grassi, MD Department of Dermatology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York Funding sources: None. Conflicts of interest: None declared. Correspondence to: Kory H. Kitagawa, MD, Dermatology Resident, State University of New York at Buffalo, 13A Elk Terminal, Buffalo, NY 14204 E-mail: [email protected]
1240 Letters
J AM ACAD DERMATOL
DECEMBER 2011
Fig 2. A, Perivascular and diffuse mononuclear cell infiltrate in the superficial and mid dermis with relative sparing of the deeper reticular dermal collagen. B, A discrete germinal center in the superficial dermis with a well developed mantle zone. No epidermotropism is seen. C, A germinal center showing a polymorphous mononuclear cell population with small- and medium-sized lymphocytes admixed with immunoblasts and macrophages. (Hematoxyline eosin stain; original magnification: A, 34; B, 310; C, 340.) REFERENCES 1. Ploysangam T, Breneman DL, Mutasim DF. Cutaneous pseudolymphomas. J Am Acad Dermatol 1998;38(6 part 1):877-95. 2. Nihal M, Mikkola D, Horvath N, Gilliam AC, Stevens SR, Spiro TP, et al. Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential. Hum Pathol 2003;34:617-22. 3. Guis S, Schiano de Colella JM, Bonnet N, Andrac-Meyer L, Balandraud N, Mattei JP, et al. Cutaneous pseudolymphoma associated with a TNF-alpha inhibitor treatment: etanercept. Eur J Dermatol 2008;18:474-6. 4. Stavrianeas NG, Katoulis AC, Bozi E, Toumbis-Ioannou E, Kanelleas AI, Makris M, et al. Cutaneous pseudolymphoma
following administration of lornoxicam. Acta Derm Venereol 2007;87:453-5. 5. Welsh JP, Ko C, Hsu WT. Lymphomatoid drug reaction secondary to methylphenidate hydrochloride. Cutis 2008;81: 61-4. 6. Maubec E, Pinquier L, Viguier M, Caux F, Amsler E, Aractingi S, et al. Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol 2005;52:623-9. 7. Sharma NS, Masselos K, Hooper MJ, Francis IC. Zoledronic acid infusion and orbital inflammatory disease. N Engl J Med 2008;359:1410-1. doi:10.1016/j.jaad.2009.04.015
J AM ACAD DERMATOL
DECEMBER 2011
Fig 2. A and B, Perivascular and interstitial dermatitis in the papillary and superficial dermis. C, Neutrophils predominate in the inflammatory infiltrate. D, Nuclear dust between inflammatory cells. There is no evidence of vasculitis. (Hematoxylineeosin stain; original magnification: A, 325; B, 350; C, 3100; D, 3200.)
Antonio Martorell-Calatayud, MD,a Celia Requena, MD, PhD,a Onofre Sanmartin, MD, PhD,a Nicole Balmer, MD,b and Carlos Guillen-Barona, MD, PhDa Department of Dermatology,a Instituto Valenciano de Oncologia, Valencia, Spain, and the Department of Pathology,b Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina Funding sources: None. Conflicts of interest: None declared. Correspondence to: Antonio Martorell-Calatayud, MD, Department of Dermatology, Instituto Valenciano Oncologia, San Jose de la Monta~ na, 14, Valencia 46009, Spain E-mail: [email protected]
REFERENCES 1. Crino L, Scagliotti G, Marangolo M, Figoli F, Clerici M, De Marinis F, et al. Cisplatin-gemcitabine combination in advanced non-small-cell lung cancer: a phase II study. J Clin Oncol 1997;15:297-303. 2. Larson BJ, Waples JM, Pusateri A, Mendenhall NP. Lynch JW Jr. A phase II study of gemcitabine in patients with relapsed or
refractory low-grade non-Hodgkin lymphoma. Am J Clin Oncol 2005;28:165-8. 3. Brandes A, Reichmann U, Plasswilm L, Bamberg M. Time- and dose-limiting erysipeloid rash confined to areas of lymphedema following treatment with gemcitabine—a report of three cases. Anticancer Drugs 2000;11:15-7. 4. Marucci G, Sgarbanti E, Maestri A, Calandri C, Collina G. Gemcitabine-associated CD81 CD301 pseudolymphoma. Br J Dermatol 2001;145:650-2. 5. Bessis D, Guillot B, Legouffe E, Guilhou JJ. Gemcitabine-associated scleroderma-like changes of the lower extremities. J Am Acad Dermatol 2004;51:S73-6. doi:10.1016/j.jaad.2009.04.003
Zoledronic acideinduced cutaneous B-cell pseudolymphoma To the Editor: A 57-year-old white female with a history of breast cancer and positive lymph nodes underwent surgery followed by chemotherapy and radiation without complications in 2002. Three years later, metastatic disease to the spine and adrenal glands was discovered, and she was started on letrozole tablets and a bisphosphonate, zoledronic acid, intravenously. Nine months after starting the medications, she presented to our dermatology clinic with a 1-month history of mildly pruritic and
J AM ACAD DERMATOL
Letters 1239
VOLUME 65, NUMBER 6
edematous papules and plaques 4 mm to 1.2 cm in diameter located primarily on the right arm (Fig 1) but also on other extremities. Three skin biopsy specimens showed nodular lymphoid hyperplasia with no evidence of a lymphoproliferative disorder (Fig 2). Immunohistochemical stains were positive for CD20, CD23, BCL2, and MUM1. Immunoglobulin heavy chain gene rearrangement studies were polyclonal and a fluorescence in situ hybridization study for BCL2 and MALT1 was negative. Routine blood work was normal. Pseudolymphoma, possibly secondary to medications, was diagnosed. Subjectively, the patient noticed worsening after zoledronic acid infusions. Four months later, the patient stopped the zoledronic acid for 8 months because of a dental procedure and experienced complete clearing of her skin. Given the spinal metastases, her oncologist restarted the zoledronic acid infusions and within 2 weeks the lesions recurred. She is currently adequately treated with topical corticosteroids and diphenhydramine cream. Cutaneous pseudolymphoma (CPL) was first described in 1891 by Kaposi1 and represents a benign lymphoproliferative process that should be differentiated from cutaneous lymphomas. CPL generally displays benign biologic behavior, although one study showed that 4% of patients may progress to lymphoma.2 CPL can be subdivided into cutaneous T-cell pseudolymphomas (CTPL) and cutaneous Bcell pseudolymphomas (CBPL).1 Causes of pseudolymphoma include drugs, tattoos, insect bites, trauma, hyposensitization injections, gold pierced earrings, vaccinations, acupuncture, Borrelia burgdorferi infection, varicella zoster infection, HIV infection, photosensitivity-associated, and idiopathic.1 The cause of CTPL can usually be identified, whereas CBPL is often idiopathic.1 Drugs are an important inciting agent in CPL and tend to be more common in CTPL, although several cases of CBPL have been reported. Phenytoin is the most common drug associated with CPL. Other broad categories of drugs that have been associated with CPL are anticonvulsants, antipsychotics, antihypertensives, cytotoxics, antirheumatics, antibiotics, antidepressants, anxiolytics, antihistamines, antiarrhythmics, sex steroids, and lipid lowering agents.1 More recently described drug-induced cases of pseudolymphoma include etanercept, methylphenidate, and lornoxicam.3-5 Drugs specifically associated with CBPL include antidepressants, neuroleptics, allopurinol, and vaccines (eg, hepatitis A and hepatitis B).1,6 Initially, the pathogenesis of drug-induced pseudolymphoma was thought to be a hypersensitivity reaction. However, recent evidence suggests that these drugs
Fig 1. Erythematous papules on the right arm.
may impair immunologic function as evidenced by drug-induced stimulation of blastic transformation of lymphocytes and impaired ability of T-suppressor lymphocytes to suppress B-cell differentiation and immunoglobulin production.1 A literature review has not yielded any cases of CPL with bisphosphonates. Zoledronic acid is a bisphosphonate used in metatstatic disease to the bone, hypercalcemia of malignancy, multiple myeloma, Paget disease, and postmenopausal osteoporosis. The mechanism of action includes inhibition of osteoclast activity and reduction of bone resorption and turnover. Uncommon but serious side effects recently reported include osteonecrosis of the jaw in patients with dental procedures and orbital inflammatory disease.7 In our patient, the skin lesions developed several months after initiation of zoledronic acid, which is typical for CPL. Moreover, she cleared upon discontinuing the drug, and flared upon restarting infusions. An additional biopsy of new lesions following the reinfusion of zoledronic acid would provide stronger evidence that this is the same process. However, the patient declined another biopsy, and the new lesions appear clinically similar to the old lesions. We propose adding zoledronic acid to the list of medications associated with CBPL. Kory H. Kitagawa, MD, and Marcelle Grassi, MD Department of Dermatology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York Funding sources: None. Conflicts of interest: None declared. Correspondence to: Kory H. Kitagawa, MD, Dermatology Resident, State University of New York at Buffalo, 13A Elk Terminal, Buffalo, NY 14204 E-mail: [email protected]
1240 Letters
J AM ACAD DERMATOL
DECEMBER 2011
Fig 2. A, Perivascular and diffuse mononuclear cell infiltrate in the superficial and mid dermis with relative sparing of the deeper reticular dermal collagen. B, A discrete germinal center in the superficial dermis with a well developed mantle zone. No epidermotropism is seen. C, A germinal center showing a polymorphous mononuclear cell population with small- and medium-sized lymphocytes admixed with immunoblasts and macrophages. (Hematoxyline eosin stain; original magnification: A, 34; B, 310; C, 340.) REFERENCES 1. Ploysangam T, Breneman DL, Mutasim DF. Cutaneous pseudolymphomas. J Am Acad Dermatol 1998;38(6 part 1):877-95. 2. Nihal M, Mikkola D, Horvath N, Gilliam AC, Stevens SR, Spiro TP, et al. Cutaneous lymphoid hyperplasia: a lymphoproliferative continuum with lymphomatous potential. Hum Pathol 2003;34:617-22. 3. Guis S, Schiano de Colella JM, Bonnet N, Andrac-Meyer L, Balandraud N, Mattei JP, et al. Cutaneous pseudolymphoma associated with a TNF-alpha inhibitor treatment: etanercept. Eur J Dermatol 2008;18:474-6. 4. Stavrianeas NG, Katoulis AC, Bozi E, Toumbis-Ioannou E, Kanelleas AI, Makris M, et al. Cutaneous pseudolymphoma
following administration of lornoxicam. Acta Derm Venereol 2007;87:453-5. 5. Welsh JP, Ko C, Hsu WT. Lymphomatoid drug reaction secondary to methylphenidate hydrochloride. Cutis 2008;81: 61-4. 6. Maubec E, Pinquier L, Viguier M, Caux F, Amsler E, Aractingi S, et al. Vaccination-induced cutaneous pseudolymphoma. J Am Acad Dermatol 2005;52:623-9. 7. Sharma NS, Masselos K, Hooper MJ, Francis IC. Zoledronic acid infusion and orbital inflammatory disease. N Engl J Med 2008;359:1410-1. doi:10.1016/j.jaad.2009.04.015