VOLUME 33 䡠 NUMBER 26 䡠 SEPTEMBER 10 2015

JOURNAL OF CLINICAL ONCOLOGY

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not included in the WHO-EORTC classification for cutaneous lymphomas.1 We report a rare case of PCMCL and, to the best of our knowledge, the only reported case to include treatment with autologous hematopoietic stem-cell transplantation (ASCT) and the longest follow-up period in the literature of 3 years.

Primary Cutaneous Mantle-Cell Lymphoma: A Case Report and Literature Review Introduction Mantle-cell lymphoma (MCL) represents 3% to 10% of all nonHodgkin lymphomas. It shows a male predominance and occurs at a median age of 60 years. Patients presenting with MCL usually present with stage III or IV disease with lymphadenopathy, hepatosplenomegaly and bone marrow involvement and only rarely with localized disease. Extranodal involvement is common, typically involving the GI tract and the Waldeyer ring. MCL is characterized by a monomorphic lymphoid proliferation with a diffuse, vaguely nodular or, in rare cases, follicular growth pattern. It is characterized by specific pathologic, immunophenotypic, and molecular genetic features as well as by small B cells (positive for CD19, CD20, and CD22) coexpressing surface immunoglobulin, CD5, and CD43 and lacking CD23 and CD10. Almost all cases of MCL are positive for cyclin D1, which represents the characteristic cytogenetic abnormality t(11;14)(q13; q32) between the [email protected] and CCND1 genes.1 MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of 3-7 years with only a small subset of patients presenting with an indolent clinical course.2,3 Extranodal involvement is usually a manifestation of disseminated disease.3,4 Skin involvement is rare, occurring in only 2% to 6% of cases of MCL but seen in 17% of patients with stage IV disease.4,5 Cutaneous disease arising as a primary tumor of the skin is extremely rare, with only a few cases reported in the literature.4-8 According to the European Organisation for Research and Treatment of Cancer (EORTC), B-cell lymphoma is considered a primary cutaneous tumor if there is no extracutaneous disease at the time of diagnosis and during the first 6 months of follow-up.9 However, primary cutaneous MCL (PCMCL) is

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Case Report A 68-year-old woman with chronic idiopathic lymphedema of the legs diagnosed early in her second decade presented with rapidly growing skin lesions. Three violaceous nodular lesions with irregular borders arising from her edematous skin were distributed circumferentially around the right calf. The largest lesion measured 4 ⫻ 3 cm (Fig 1A) and was associated with two smaller adjacent lesions measuring 2 ⫻ 2 cm each (Figs 1B and 1C). She was otherwise well and had no B symptoms. Biopsy of the lesions showed a dense infiltrate extending from the epidermal/dermal junction to the subcutis with monomorphic lymphocytes in a diffuse pattern. The lymphocytes were mostly intermediate to large in size, with irregular nuclear membranes and prominent nucleoli and displayed a characteristic MCL immunophenotype. Immunohistochemistry was positive for CD20, CD5, cyclin D1, Bcl-2, Bcl-6 and negative for CD10, CD23, and CD3. Ki67 was positive in 90% to 95% of tumor cells indicating a high proliferation index (Fig 2). Flow cytometry detected a kappa light chain restricted B-cell population expressing CD45, CD20, CD22, CD19, and CD5. Fluorescent in situ hybridization (FISH) was positive for the characteristic CCND1/IGH gene rearrangement associated with t(11;14) (Fig 3; arrows point to areas [in yellow] that highlight FISH positivity). The results were consistent with a diagnosis of pleomorphic variant MCL, which has been reported to be a poor prognostic feature particularly in the context of a high proliferation index.1

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Fig 2.

Her staging investigations showed no disease elsewhere to suggest that this was a manifestation of disseminated disease. Computer tomography (CT) of her neck, chest, abdomen, and pelvis showed no masses or lymphadenopathy. Positron emission tomography (PET) showed intense fluorodeoxyglucose uptake by the skin lesions only (Fig 4). Her full blood count, peripheral blood film, and serum lactate dehydrogenase were normal. She had no bone marrow involvement on the basis of bone marrow aspirate, trephine, and FISH. Cytogenetics showed a normal 46,XX karyotype. As a result of the circumferential distribution of the lesions it was not possible to target them with radiotherapy. The patient received six 14-day cycles of rituximab, cyclophosphamide, doxorubicin, vincris-

Fig 3. www.jco.org

tine, and prednisolone (R-CHOP). After the second cycle there was complete resolution of the skin lesions (Fig 5), and a PET scan after the third cycle showed a complete metabolic response. Her treatment was complicated by one episode of febrile neutropenia from which she recovered quickly. She presented 15 months later with recurrence of the skin lesions in the same area. Biopsy and restaging using the modalities described in this Case Report indicated recurrence of PCMCL with no evidence of systemic disease. She was treated with three cycles of dexamethasone, doxorubicin, cytarabine, and carboplatin (DHAC) and had autologous stem cells collected after the second cycle. She received an ASCT after the third cycle with no complications. Her PET scan after chemotherapy showed a complete metabolic response (Fig 6). She had an episode of herpes zoster reactivation and remained well during a 16-month remission, after which she developed another skin lesion consistent with PCMCL. Discussion PCMCL is difficult to diagnose because in the rare reported cases it is often associated with systemic disease,4 and it is not included in the WHO-EORTC classification for cutaneous lymphomas.1 Of the 23 reported cases of cutaneous MCL4-8,10-16 only six were thought to possibly be PCMCL.4-8 These are summarized in Table 1. The cases reported by Bertero et al6 were based on histologic and immunohistochemical features without the use of cyclin D1 or cytogenetic investigations now considered standard diagnostic techniques, and the staging modalities to exclude systemic involvement were not reported. The case reported by Lynch et al7 had CT and PET findings that were thought less likely to represent systemic disease but were suspicious, and the patient underwent treatment for presumed systemic disease and extensive dermal involvement.7 © 2014 by American Society of Clinical Oncology

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Fig 4.

Of the six cases, only three seem to be clear cases of PCMCL.4,5,8 Sen et al4 reported a case in which a 76-year-old man presented with a single thigh nodule with pathologic, immunophenotypic, and cytogenetic investigations consistent with MCL. Bone marrow biopsy (BMB) and CT, but not PET, were used to exclude systemic involvement. The lesion was initially responsive to cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine (hyper-CVAD) but the patient had recurrent skin lesions treated with paclitaxel and topotecan, and he was reported alive 30 months after diagnosis with disease confined to the

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skin. Estrozi et al5 reported a case in which a 72-year-old man presented with a rapidly growing cutaneous nodule in the right temporal region with pathologic, immunophenotypic, and cytogenetic features consistent with MCL. BMB, CT, and PET excluded systemic involvement. The lesion was excised but recurred within 15 days. It was treated with local radiotherapy, and the patient was reported as well with no lesions at 6 months. Zattra et al8 reported a case in which a 77-year-old man presented with diffuse erythematous nodules and plaques involving all body areas with pathologic and immunophenotypic investigations consistent with MCL. FISH was not reported, but

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Fig 5.

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77

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83

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M

M

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Sex

Nodules

Nodules and plaques

Nodule

Nodule

Nodules

Nodules

Clinical Presentation

Both thighs

All body areas

Temporal

Thigh

Breast

Breast and back

Location

BM, CT of head, neck, thorax, abdomen, pelvis (mild mediastinal lymphadenopathy improved from 10 months prior and periaortic and pericaval slightly increased from 4.5 months prior). PET showed skin lesions as well as hypermetabolic cervical nodes. WCC normal.

BM biopsy, CT of head, neck, thorax, abdomen, and pelvis and PET negative. BM biopsy, CT of head, neck, thorax, abdomen, and pelvis and PET negative. WCC normal.

BM biopsy and CT of head, thorax, abdomen, pelvis negative. WCC normal.

Not reported

Not reported

Investigations Excluding Systemic Involvement

Cytogenetics by FISH

Cyclin D1⫹, CD20⫹, CD79a⫹, Bcl-2⫹, CD5⫹, CD3⫺, CD10⫺, CD23⫺, CD30⫺, and Ki67 high

Cyclin D1⫹, CD20⫹, CD5⫹, CD3⫺, CD10⫺, CD23⫺, Bcl-6⫺, and Ki67 (80%) Cyclin D1⫹, CD20⫹, CD22⫹, CD79a⫹, Bcl-2⫹, CD5⫹, CD3⫺, CD10⫺

Treatment

Hyper-CVAD; recurrent lesions treated with paclitaxel and topotecan Surgical resection and radiotherapy for recurrence Etoposide 100 mg per day and prednisone 25 mg per day for 5 days per month for 11 months then maintained on 5 mg prednisone daily

Not reported

Observation

Not reported but clonal population found using molecular investigation for IgH rearrangement t(11;14) Bortezomib and rituximab for presumed systemic disease

t(11;14)

CDI9⫹, CD20⫹, CD22⫹, CD5⫹, Not reported HLA⫺ DR⫹, Leu-8⫹, IgM⫹ IgD⫹ with restriction for the ␭ light chain, and Leu-8⫹. CD30⫺, CD71⫺ and CALLA⫺ CDI9⫹, CD20⫹, CD22⫹, CD5⫹, Not reported HLA⫺ DR⫹, Leu-8⫹, IgM⫹ IgD⫹ with restriction for the ␭ light chain, Leu-8⫹, CD30⫺, CD71⫺ and CALLA⫺ Cyclin D1⫹, CD20⫹, CD5⫹, t(11;14) CD3⫺, CD10⫺, CD23⫺, ⫺ CLA , and Ki67 (51.6%)

Immunophenotype on Immunohistochemistry

Table 1. Summary of Cases Reported of Primary Cutaneous MCL in the English Literature Outcome

Disseminated herpes zoster within 2 mo of diagnosis, palliated and died

28 mo later in remission of the cutaneous disease

Alive and free of disease at 6 mo

Alive after 30 mo with disease confined to skin

Systemic disease after 2 yr

Died 3 yr later of unrelated causes

Abbreviations: BM, bone marrow; CT, computed tomography; hyper-CVAD, cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine; MCL, mantle-cell lymphoma; mo, months; PET, positron emission tomography; WCC, white cell count; yr, years.

6

72

4

Estrozi et al 20095 Zattra et al 20108

Lynch et al 20127

76

3

Sen et al 20024

22

2

Bertero et al 19946

78

1

Age (years)

Bertero et al 19946

Reference

Patient No.

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there was a clonal B-cell population on molecular testing for IgH gene rearrangement. BMB, CT, and PET excluded systemic involvement. The patient was treated 1 year after the appearance of the first lesion with oral etoposide (100 mg per day) and prednisone 25 mg per day on five consecutive days per month for 11 months followed by maintenance therapy with prednisone 5 mg per day. This resulted in almost complete remission of skin lesions after 28 months of follow-up. In systemic MCL, a watch-and-wait approach in indolent cases is an option.17 However, in the majority of cases, MCL has an aggressive course characterized by inevitable relapse. On the basis of the most recent data, the standard of care in younger, fit patients is an induction regimen containing rituximab and high-dose cytarabine followed by ASCT.2,18,19 The European MCL network trial has shown that highdose cytarabine in addition to R-CHOP significantly increases complete response rates, time to treatment failure, and overall survival.19 In older patients not fit for ASCT, the standard of care is R-CHOP followed by rituximab maintenance.2 In addition, ASCT in first remission leads to better outcomes than ASCT used as a salvage strategy.20 It is difficult to determine the therapy of choice in PCMCL, given that PCMCL is rarely reported and it is unclear whether the standard of care in systemic disease applies in this localized presentation. The clinical course of the skin lesions needs to be considered, given that the more rapidly growing lesions likely represent more aggressive disease. For localized disease, radiotherapy followed by close observation can be an attractive option, particularly for elderly patients, but the evidence for this is limited.21,22 Furthermore, as seen in our case and others reported, there can be multiple skin lesions that may be difficult to target with radiotherapy. Chemotherapy as reported in our case report, by Sen et al4, and by Zattra et al8 can be effective. Nevertheless, relapse, which is characteristic of MCL, was seen in all but one of the reported cases; that one case had a short follow-up period of only 6 months. This highlights that aggressive therapy, including ASCT as part of first-line therapy, if possible, is likely needed and that close follow-up of these patients is crucial not only to treat relapsed cutaneous disease but also to monitor for possible systemic disease.

Nada Hamad Royal North Shore Hospital; University of Sydney, Sydney, Australia

Tasman Armytage Royal North Shore Hospital, Sydney, Australia

Kirsty McIlroy and Nisha Singh Pathology Laboratory Medicine Services, Sydney, Australia

Christopher Ward Royal North Shore Hospital, Northern Blood Research Centre, Kolling Institute; University of Sydney, Sydney, Australia

ACKNOWLEDGMENT

Presented in abstract form as an oral presentation at the 2010 Annual Scientific Meeting of the HAA (Haematology Society of Australia and New Zealand [HSANZ], the Australian and New Zealand Society of Blood Transfusion [ANZSBT], and the Australasian Society of Thrombosis and Haemostasis [ASTH]). AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES 1. Swerdlow SH, Harris NL, Jaffe ES, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, in Bosman FT, Lakhani SR, Ohgaki H (eds): World Health Organization Classification of Tumours. Lyon, France, International Agency for Research on Cancer, 2008 2. Witzens-Harig M, Hess G, Atta J, et al: Current treatment of mantle cell lymphoma: Results of a national survey and consensus meeting. Ann Hematol 91:1765-1772, 2012 3. Sorror ML, Sandmaier BM, Storer BE, et al: Comorbidity and disease status based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 25:4246-4254, 2007 4. Sen F, Medeiros LJ, Lu D, et al: Mantle cell lymphoma involving skin: Cutaneous lesions may be the first manifestation of disease and tumors often have blastoid cytologic features. Am J Surg Pathol 26:1312-1318, 2002 5. Estrozi B, Sanches JA Jr, Varela PC, et al: Primary cutaneous blastoid mantle cell lymphoma: Case report. Am J Dermatopathol 31:398-400, 2009 6. Bertero M, Novelli M, Fierro MT, et al: Mantle zone lymphoma: An immunohistologic study of skin lesions. J Am Acad Dermatol 30:23-30, 1994 7. Lynch DW, Verma R, Larson E, et al: Primary cutaneous mantle cell lymphoma with blastic features: Report of a rare case with special reference to staging and effectiveness of chemotherapy. J Cutan Pathol 39:449-453, 2012 8. Zattra E, Zambello R, Marino F, et al: Primary cutaneous mantle cell lymphoma. Acta Derm Venereol 91:474-475, 2011 9. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005 10. Bogle MA, Riddle CC, Triana EM, et al: Primary cutaneous B-cell lymphoma. J Am Acad Dermatol 53:479-484, 2005 11. Canpolat F, Tas¸ E, Albayrak So¨nmez A, et al: Cutaneous presentation of mantle cell lymphoma. Acta Derm Venereol 90:548-550, 2010 12. Dubus P, Young P, Beylot-Barry M, et al: Value of interphase FISH for the diagnosis of t(11:14)(q13;q32) on skin lesions of mantle cell lymphoma. Am J Clin Pathol 118:832-841, 2002 13. Ellison DJ, Turner RR, Van Antwerp R, et al: High-grade mantle zone lymphoma. Cancer 60:2717-2720, 1987 14. Geerts ML, Busschots AM: Mantle-cell lymphomas of the skin. Dermatol Clin 12:409-417, 1994 15. Ishibashi M, Yamamoto K, Kudo S, et al: Mantle cell lymphoma with skin invasion characterized by the common variant in the subcutis and blastoid transformation in the overlying dermis. Am J Dermatopathol 32:180-182, 2010 16. Motegi S, Okada E, Nagai Y, et al: Skin manifestation of mantle cell lymphoma. Eur J Dermatol 16:435-438, 2006 17. Martin P, Chadburn A, Christos P, et al: Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27:1209-1213, 2009 18. Delarue R, Haioun C, Ribrag V, et al: CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: A phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood 121:48-53, 2013 19. Hermine O, Hoster E, Walewski J, et al: Alternating courses of 3x CHOP and 3x DHAP plus rituximab followed by a high dose Ara-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) increases overall survival when compared to 6 courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: Final analysis of the MCL younger trial of the European Mantle Cell Lymphoma Network (MCL net). 54th American Society of Hematology Annual Meeting and Exposition, Atlanta, GA, December 8-11, 2012 (abstr 151) 20. Geisler CH: Autologous transplantation and management of younger patients with mantle cell lymphoma. Best Pract Res Clin Haematol 25:211-220, 2012 21. Lowry L, Smith P, Qian W, et al: Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: A randomised phase III trial. Radiother Oncol 100:86-92, 2011 22. Leitch HA, Gascoyne RD, Chhanabhai M, et al: Limited-stage mantle-cell lymphoma. Ann Oncol 14:1555-1561, 2003

DOI: 10.1200/JCO.2012.47.2829; published online ahead of print at www.jco.org on April 14, 2014 ■ ■ ■

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Primary Cutaneous Mantle-Cell Lymphoma: A Case Report and Literature Review.

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