Primary cutaneous large cell lymphoma CD30+: a case-based review
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1 Case-based review Primary cutaneous large cell lymphoma CD30+: a case-based review Anna Campanati 1 Katia Giuliodori 1 Emanuela Martina 1 Luca Conocchiari 1 Giulia Ganzetti 1 Gaia Goteri 2 Annamaria Offidani 1 1 Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy 2 Anatomic Pathology, Department of Neurosciences, Polytechnic Marche University, Ancona, Italy Address for correspondence: Emanuela Martina Dermatological Clinic, Department of Clinical and Molecular Sciences Polytechnic Marche University Ancona, Italy ema.martina@gmail.com Summary CD30+ primary cutaneous lymphoproliferative disorders (LPD) are clinically and pathologically heterogeneous entities. They include primary cutaneous anaplastic large-cell lymphoma (PC-ALCL), borderline cases and lymphomatoid papulosis (LyP). In PCALCL > 75% of the tumor cells express CD30 antigen; it is the second most common form of cutaneous T-cell lymphoma (CTCL) and more often affects older males. We report a case of 85-year-old man with a 2-month history of severe itching, eczematous lesions of the trunk and an asymptomatic, ulcerated lesion of at least 7 cm diameter of the scalp. A biopsy of this neoplasm revealed the CD30+ T-cell lymphoproliferative nature, but further studies were needed to reach a definitive diagnosis of PC-ALCL. This report, with a review of the latest Literature, emphasizes the relevance of a strong clinicopathological correlation for the correct diagnosis and management of PC-ALCL. KEY WORDS: cutaneous lymphoma; CD30; ALK; anaplastic lymphoma. Introduction Primary cutaneous lymphomas (PCL) are a wide group of neoplasms with a variety of clinical, histological and immunophenotypical features (1). A lymphoma is defined primary when arises in the skin and often remains isolated to the skin for a long time. Cutaneous lymphomas are recognize as a separate entity for their biological behavior and prognosis and their histological-immunophenotypical peculiarities since 2005, when The World Health Organization- European Organization for Research and Treatment of Cancer (WHO/EORTC) classification was released (2). In 2008, the WHO classification has adopted the WHO/EORTC criteria. Cutaneous T cell lymphoma (CTCL) accounts for 65% of primary CL (1, 3); the most common form of CTCL is mycosis fungoides (approximately 40%). The second most common CTCL are the primary cutaneous CD30+ lymphoproliferative disorders (LPD), a group that include lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PC-ALCL) and borderline cases that have overlapping features. The diagnosis requires a biopsy specimen of suspected skin lesions and immunophenotypic/molecular analysis. However, the spectrum of CL is complex and in many cases it is impossible to achieve a final diagnosis without a strong clinicopathological correlation. We report a case in which this correlation was essential in order to establish an appropriate clinical and therapeutic management. Case report A 85-year-old man referred to our Dermatological Department with 2-month history of severe itching and several eczematous patches, mainly localized at the trunk, unresponsive to topical application of steroids (Figure 1 a). Blood parameters showed neutrophilic leukocytosis and IgE increase; chest radiography, thyroid and abdomen ultrasonography showed no pathological findings. Physical examination revealed an asymptomatic ulcerated lesion of at least 7 cm diameter localized at right parietal region of the scalp, behind the ear (Figure 1 b).there was no cervical, axillary, or inguinal lymphadenopathy, neither hepatosplenomegaly. Then, a skin biopsy was performed. It revealed a dermal infiltrate composed of anaplastic large cells, with- 60 Clinical Dermatology 2016; 4 (2):60-64
2 Clin.Derm b XP11.qxp_. 20/09/16 14:47 Pagina 61 Primary cutaneous large cell lymphoma CD30+: a case-based review Figure 1 - (a) Eczematous patches localized at the trunk; (b) ulcerated lesion localized at right parietal region, behind the ear. out involvement of the hair follicles. These cells exhibited T phenotype CD45-, CD3+, CD2-, CD5-, CD4+, CD8-, CD20-, CD30+++, CD15-, CD56-, MUM1+++, TIA1+/-, ALK-, granzyme+/-, perforin- (Figure 2). All of these histological features raised three different diagnostic hypotheses: 1. skin involvement by a systemic anaplastic large cell lymphoma ALK negative; 2. primary cutaneous anaplastic large cell lymphoma CD30+; 3. large cell transformation identified during the progression of mycosis fungoides (MF). Therefore skin biopsy of an eczematous patch was performed. It showed a superficial, dermal infiltrate composed of small cells, without epidermotropism, with T phenotype CD3, CD2, CD5 and CD7 positive, without co-expression of cytotoxic molecules (granzyme, perforin, TIA1) or CD30; the molecular study didn t shown a monoclonal rearrangement of TCR. This allowed us to exclude the hypothesis of a MF progression. Bone marrow cytomorphologic examination and total body CT-scan was performed in order to exclude extra-cutaneous involvement. A diagnosis of primary cutaneous anaplastic large cell lymphoma CD30+ was carried out, according to WHO-EORTC criteria (2). The lesion was surgically excised and then treated with radiotherapy (Figure 3). Clinical Dermatology 2016; 4 (2):60-64 The skin itching was treated with systemic corticosteroid and antihistaminic therapy, and with a daily use of moisturizing cream. This therapeutic strategy led to a significant improvement and the patient remains under follow-up. Discussion Mycosis fungoides, a cutaneous T-cell lymphoma, is a subgroup of non-hodgkin s lymphomas, characterized by skin infiltration and occasionally systemic involvement (4). CD30+ large transformation of MF is well described in literature (5, 6). Primary cutaneous anaplastic large-cell lymphomas (PC-ALCL) belong to the CD30+ T-cell lymphoproliferative disorders and they usually affects older patients (2, 7). Male:female ratio is 3:1, with a median age of 55 years at the time of diagnosis (7, 8). PC-ALCL often appears with a solitary or grouped, rapidly growing and ulcerating large tumors or thick plaques. Rarely, the disease occurs with multifocal lesions. Spontaneous complete or partial regression of the tumor is reported in up to 44% of the patients (9). Histological examination is the first step in the diagnostic work-up of clinically suspected CD30+ lympho- 61
3 Clin.Derm b XP11.qxp_. 20/09/16 14:47 Pagina 62 A. Campanati et al. Figure 2 - Low- and high- power view of histology and immuno histology: the tumor appeared as an ulcerated lesion with a «V» shape (a, H&E,1X), constituted by a diffuse infiltrate of atypical lymphoid reactive for CD3 (b, d) and CD30 (c, e). Figure 3 - Parietal region after surgery and radiotherapy. proliferative disorders. The histopathology of CTCLs consists of diffuse non-epidermotropic infiltrates with cohesive sheets of large CD30+ tumor cells. Typically, the tumor cells show a typical aspect, with round, oval, 62 or irregularly shaped nuclei and prominent and eosinophilic nucleoli as well as abundant cytoplasm (2). Immunohistochemistry plays a pivotal role by revealing the presence of CD30+ large pleomorphic or Clinical Dermatology 2016; 4 (2):60-64
4 Primary cutaneous large cell lymphoma CD30+: a case-based review anaplastic T cells. PC-ALCL is defined by CD30 ex - pression of at least 75% of the tumor cells (10). With respect to the immunophenotype, the tumor cells generally express a CD4+ T-cell phenotype with variable loss of pan-t-cell antigens, such as CD2, CD3, and CD5. CD15 is usually negative, but the cutaneous lymphocyte antigen is positive. In contrast to the primary nodal CD30-positive lymphoma, C-ALCL generally does not express the epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK) (11). Systemic lymphomas frequently express ALK+ cells (12), but some ALK+ primary cutaneous ALCL cases have been reported (13). PC-ALCL prognosis is good; the neoplasm has an indolent behavior with five-years survival rates range of 76-96%, but cutaneous relapse is frequent (39%) (7, 14). A presentation with multifocal skin lesions, extensive single limb involvement and head or neck lesions are recognized as unfavorable prognostic factors in PC- ALCL (14-18). Lee et al. have recently suggested that the extent of the lesion is a prognostic factor and it also correlates with relapse rate. Finally, the extent was more important than other features such as anatomical site or number of skin lesions (19). The treatment of PC-ALCL with diffuse skin lesions or extracutaneous spread often needs chemotherapy, with frequent relapses. The CD30 directed antibodydrug brentuximab vedotin has appeared as a promising alternative treatment for advanced PC-ALCL (20). PC-ALCL must be distinguished from the potentially malignant or progressive entities that occur with overlapping clinical and pathological features. In our patient, histopathological examination revealed the CD30+ T-cell lymphoproliferative nature, but further biopsies and imaging techniques were needed to exclude other CD30+ cutaneous lesions and a systemic involvement. In conclusion, the diagnosis of PC-ALCL could be difficult without a multidisciplinary approach; the correlation of clinical findings with histopathology and immunopathology is essential for the correct management (21). References 1. Kempf W, Sander CA. Classification of cutaneous lymphomas an update. Histopathology. 2010;56: Willemze R, Jaffe ES, Burg G, Cerroni L, et al. WHO- EORTC classification for cutaneous lymphomas. Blood. 2005;105(10): Burg G, Kempf W. Epidemiology. In Burg G, Kempf W eds. Cutaneous lymphomas. New York: Taylor& Francis. 2005; Campanati A, Giangiacomi M, Goteri G, Penna L, Turtù S, Offidani AM. A case of follicular mycosis fungoides with follicular mucinosis: a rare association. Am J Dermatopathol. 2002;24(5): Ohtani T, Kikuchi K, Koizumi H, Kunii T, Aiba S. A case of CD30+ large-cell transformation in a patient with unilesional patch-stage mycosis fungoides. Int J Dermatol. 2009;48(6): Naeini FF, Najafian J, Nilforoushzadeh M. CD30+ large transformation of mycosis fungoides during pregnancy. Indian J Dermatol Mar;58(2): Bekkenk MW, Geelen FA, van Voorst Vader PC, Heule F, Geerts ML, van Vloten WA, Meijer CJ Willemze R. Primary and secondary cutaneous CD30(+) lymphoproliferative disorders; a report from the Dutch Cutaneous Lymphoma Group on the longterm follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood. 2000;95(12): Savage KJ, Harris NL, Vose JM, et al. International Peripheral T-cell Lymphoma project. ALK-anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-cell Lymphoma Project. Blood. 2008;111: Kadin ME. Current management of primary cutaneous CD30+ T-cell lymphoproliferative disorders. Oncology (Williston Park). 2009;23(13): Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein J, Thiele J, Vardiman JW. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. World Health Organization; de Bruin PC, Beljaards RC, van Heerde P, Van Der Valk P, Noorduyn LA, Van Krieken JH, Kluin-Nelemans JC, Willemze R, Meijer CJ. Differences in clinical behaviour and immunophenotype between primary cutaneous and primary nodal anaplastic large cell lymphoma of T-cell or null cell phenotype. Histopathology. 1993;23(2): Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology. 2009;2009: Falini B, Bigerna B, Fizzotti M, et al. ALK expression defines a distinct group of T/null lymphomas ( ALK lymphomas ) with a wide morphological spectrum. Am J Pathol. 1998;153: Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49: Vergier B, Beylot-Barry M, Pulford K, et al. Statistical evaluation of diagnostic and prognostic features of CD30 cutaneous lymphoproliferative disorders: a clinicopathologic study of 65 cases. Am J Surg Pathol. 1998;22: Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis: a European multicenter study of 47 patients. Cancer. 1993;329: Paulli M, Berti E, Rosso R, et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin: clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Clinical Dermatology 2016; 4 (2):
5 A. Campanati et al. Cutaneous Lymphoma Project Group. J Clin Oncol. 1995;13: Sugaya M, Fujita H, Izutsu K, et al. Primary cutaneous anaplastic large cell lymphoma with leg involvement: a case report and review of 11 cases. J Dermatol. 2011;38: Lee WJ, Moon IJ, Lee SH, Won CH, Chang SE, Choi JH, Chan Moon K, Park CS, Huh J, Lee MW. Cutaneous anaplastic large-cell lymphoma (ALCL): A comparative clinical feature and survival outcome analysis of 52 cases according to primary tumor site. J Am Acad Dermatol Feb Oregel KZ, Everett E, Zhang X, Nagaraj G. Complete response in a critically ill patient with ALK-negative anaplastic large cell lymphoma treated with single agent brentuximab-vedotin. Expert Rev Anticancer Ther Mar;16(3): Potenza C, Calvieri S. Dermatologist in health care system. Dermatologia Clinica. 2003;vol 23, 2003: Clinical Dermatology 2016; 4 (2):60-64
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