Anaplastic lymphoma kinase expression in a recurrent primary cutaneous anaplastic large cell lymphoma with eventual systemic involvement

Anaplastic lymphoma kinase expression in a recurrent primary cutaneous anaplastic large cell lymphoma with eventual systemic involvement

J AM ACAD DERMATOL Letters 671 VOLUME 65, NUMBER 3 REFERENCES 1. Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: ...

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Letters 671


REFERENCES 1. Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000;42:217-24. 2. Baudraz-Rosselet F, Ruffieux C, Lurati M, Bontems O, Monod M. Onychomycosis insensitive to systemic terbinafine and azole treatments reveals non-dermatophyte moulds as infectious agents. Dermatology 2010;220:164-8. 3. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum. J Am Acad Dermatol 2008;59:S75-76. 4. Scher RK, Tavakkol A, Sigurgeirsson B, Hay RJ, Joseph WS, Tosti A, et al. Onychomycosis: diagnosis and definition of cure. J Am Acad Dermatol 2007;56:939-44. 5. Donnelly RF, McCarron PA, Lightowler JM, Woolfson AD. Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis. J Control Release 2005;103:381-92. 6. Watanabe D, Kawamura C, Masuda Y, Akita Y, Tamada Y, Matsumoto Y. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol 2008;144:19-21. 7. Sotiriou E, Koussidou-Ermonti T, Chaidemenos G, Apalla Z, Ioannides D. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum: preliminary results of a single-center open trial. Acta Derm Venereol 2010;90:216-7. doi:10.1016/j.jaad.2010.06.008

Anaplastic lymphoma kinase expression in a recurrent primary cutaneous anaplastic large cell lymphoma with eventual systemic involvement To the Editor: Distinction between primary cutaneous anaplastic large cell lymphoma (PCALCL) and systemic anaplastic large cell lymphoma (ALCL) is important because of differences in clinical behavior, treatment, and prognosis.1 PCALCL is defined as the absence of extracutaneous disease at the time of diagnosis.1 Translocations involving the anaplastic lymphoma kinase (ALK) gene detected by immunohistochemistry as positive staining with antibodies against ALK or fluorescent in situ hybridization are observed in 50% to 80% of systemic ALCL cases but are rare in PCALCL.2,3 Therefore, ALK positivity in ALCL suggests the probability of systemic involvement, ie, systemic ALCL. We present a case of ALK-positive PCALCL with eventual systemic involvement. A 33-year-old man presented with a 2.5-cm right postauricular and smaller right axillary and lower leg nodules. Biopsy specimens were consistent with ALCL (Fig 1). Immunohistochemistry revealed

Fig 1. A and B, Sections show pleomorphic cells with enlarged nuclei, medium nucleoli, hyperchromasia, and moderate cytoplasm. A, Box denotes approximate location of highpowered field magnifications in B to D; overlying epidermis (e) is also depicted. (A and B, Hematoxylin-eosin stain; original objective magnifications: A, 310; B, 340.) C, Cells stain strongly with antibodies against CD30. D, Atypical cells also stain strongly with antibodies against anaplastic lymphoma kinase-1.

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Fig 2. A 1.0- 3 1.4- 3 0.4-cm erythematous nodule on left aspect of patient’s back.

nuclear and cytoplasmic ALK staining. Fluorescent in situ hybridization confirmed an ALK translocation. T-cell receptor gene rearrangement studies revealed monoclonality. A bone-marrow biopsy specimen and computed tomography scan revealed unremarkable findings. He received 6 cycles of cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone during a 5-month period resulting in complete response. Four months later, he developed a biopsy-proven ALCL nodule on the upper aspect of his left arm, which responded completely to 4 cycles of ifosfamide, carboplatin, and etoposide and localized radiation therapy. One year later, he presented with another biopsy-proven ALCL nodule on the lower aspect of his back (Fig 2), which was excised without recurrence. Two months later, biopsy specimen of a 5.8- 3 4.5-cm painful, necrotic, left lower intra-abdominal mass confirmed systemic ALCL. He received 3 additional cycles of ifosfamide, carboplatin, and etoposide chemotherapy, consolidative radiation therapy, and autologous stem cell transplantation with reduction in the mass’s size. He again underwent radiation treatment to the same area 3 months later for positron emission tomography (PET)-positive uptake. He has been in complete remission for at least 7 months. PCALCL has a 97.5% 5-year survival, whereas systemic spread decreases survival to 58.3%.2 Our patient developed systemic lesions approximately 2 years after diagnosis, suggesting that ALK-positive PCALCL follows a more aggressive course. Limited early systemic disease and initial chemotherapy may have masked early systemic involvement. The most common ALK mutation in ALCL results from a t(2;5)( p23;q35), fusing the ALK domain coding region with the N-terminal portion of the nucleophosmin gene, resulting in the constitutively expressed fusion protein nucleophosmin-ALK.3 Our patient had both nuclear and cytoplasmic ALK



staining, which is unusual in PCALCL.3 Other reported cases of ALK-positive PCALCL had only cytoplasmic staining, no nucleophosmin-ALK translocation, and were more indolent.4 This suggests that different types of ALK mutations confer different prognoses in PCALCL. For ALK-positive PCALCL cases, we recommend baseline computed tomography and PET scans followed by a history, physical examination, and, for PET-avid disease (94% of lymphomas), PET scans, every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter in accordance with recommendations of National Cancer Instituteesponsored international workshops.5 For PET-negative ALCL, more judicious use of computed tomography scans as clinically indicated may be used. Derek V. Chan, MD, PhD,a,b Pamela Summers, MD,b Marie Tuttle, MD,b Kevin D. Cooper, MD,b,d Brenda Cooper, MD,a,c Henry Koon, MD,a,c and Kord Honda, MDb Departments of Medicinea and Dermatology,b and Seidman Cancer Center,c University Hospitals Case Medical Center/Case Western Reserve University; and Louis Stokes Veterans Affairs Medical Center,d Cleveland, Ohio The first two authors contributed equally to this work. Supported in part by National Institutes of Health T32 grant No. AR007569 (Dr Chan; Program Director: Dr Cooper) and by a Dermatology Foundation Dermatologist Investigator Research Fellowship (Dr Tuttle). Conflicts of interest: None declared. Correspondence to: Derek V. Chan, MD, PhD, Division of Dermatology, Department of Medicine, Ohio State University, 2012 Kenny Road, Columbus, OH 43221 E-mail: [email protected] REFERENCES 1. Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. 2. Vergier B, Beylot-Barry M, Pulford K, Michel P, Bosq J, de Muret A, et al. Statistical evaluation of diagnostic and prognostic features of CD301 cutaneous lymphoproliferative disorders: a clinicopathologic study of 65 cases. Am J Surg Pathol 1998;22:1192-202. 3. Medeiros LJ, Elenitoba-Johnson KS. Anaplastic large cell lymphoma. Am J Clin Pathol 2007;127:707-22. 4. Kadin ME, Pinkus JL, Pinkus GS, Duran IH, Fuller CE, Onciu M, et al. Primary cutaneous ALCL with phosphorylated/activated cytoplasmic ALK and novel phenotype: EMA/MUC11,


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cutaneous lymphocyte antigen negative. Am J Surg Pathol 2008;32:1421-6. 5. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-86. doi:10.1016/j.jaad.2010.06.016

Development of myelodysplastic syndrome evolving to acute myeloid leukemia in a patient receiving etanercept for psoriasis To the Editor: Etanercept has been associated with the development of acute myeloid leukemia (AML) in 3 previously reported cases.1-3 We present another case in which etanercept was temporally associated with the development of a myelodysplastic syndrome (MDS), culminating in AML and death. The sequence of events is summarized in Table I. A 43-year-old man with a history of limited chronic plaque psoriasis (involving z10% of the skin) began taking etanercept for psoriasis in September 2006. He had a pre-existing unexplained mild thrombocytopenia first noted the month before initiation of etanercept. One year later (September 2007), symptomatic anemia developed, and etanercept was discontinued. Workup led to a diagnosis (in

December 2007) of MDS and refractory anemia with excess blasts. Subsequent diagnoses included chronic myelomonocytic leukemia (February 2008) and then AML (August 2009), which culminated in death 3 months later. This case raises the question of whether etanercept promoted the development of MDS, with ultimate progression of MDS to AML. The poor prognosis observed in our patient is consistent with therapy-related MDS, in which the prognosis is known to be poor regardless of International Prognostic Scoring System score. Therefore, it is difficult to know whether this indicates that the disease may have progressed without treatment with etanercept. The association, however, does raise the possibility that etanercept accelerated the evolution of myelodysplasia into AML. Three similar cases have been reported previously (Table II). Taken together, these 4 cases suggest a temporal association between the administration of etanercept and the development of AML. It is notable that in one of the 3 previously reported cases (Table II), the patient had a pre-existing leukopenia before initiation of etanercept.1 Importantly, our patient had a pre-existing mild thrombocytopenia before initiation of etanercept. Whether this is coincidence,

Table I. Timeline of disease progression in case patient Date

August 2006 September 2006 September 2007 November 2007

December 2007

February 2008 September 2008 June 2009 August 2009

August through October 2009 November 4, 2009 November 15, 2009 November 19, 2009


Mild thrombocytopenia: platelet count, 107-126 3 109/L (reference range, 150-450 3 109/L) Etanercept started for limited psoriasis (z10% skin involvement; elbows, knees, trunk) Onset of fatigue and shortness of breath Hemoglobin value, 8.6 g/dL (reference range, 13.5-17.5 g/dL); platelet count, 195 3 109/L (reference range, 150-450 3 109/L) Etanercept discontinued Bone-marrow biopsy result consistent with myelodysplastic syndrome, refractory anemia with excess blasts Cytogenetics: 46, XY (5 metaphases) Repeated bone-marrow biopsy result consistent with chronic myelomonocytic leukemia Cytogenetics: each metaphase has t(3;5)(q21;q31) Begin imatinib 400 mg daily Stabilization of leukocytosis and monocytosis Increase in peripheral blood blasts Transfusion support necessary Bone-marrow biopsy result consistent with acute myeloid leukemia with 27% myeloblasts Cytogenetics: each metaphase has t(3;5)(q21;q31) Imatinib discontinued Two cycles of decitabine Induction chemotherapy with cytarabine plus daunorubicin Plan for consolidation with HLA-identical sibling donor allogeneic bone-marrow transplant Development of fevers and a left-sided pulmonary infiltrate Chemotherapy discontinued Multiorgan system failure associated with H1N1 influenza Death