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Primary cutaneous DLBCL, leg type

Written2017-09Ding-Bao Chen
Department of Pathology, Peking University People's Hospital, Beijing 100044, People's Republic of China;

Abstract Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) leg type is an aggressive type of CBCL, characterized by skin lesions mainly on the legs and a predominance of diffuse sheets of centroblasts and immunoblasts. Given the poor prognosis, old age at onset, frequent relapses, and extracutaneous spread, PCDLBCL, leg type is a distinct type of cutaneous lyphoma. Here the clinicopathology of extranodal lymphomas will be discussed.

Keywords Diffuse large B-cell lymphoma; Cutaneous lymphoma; Primary cutaneous, leg type

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ICD-Topo C420,C421,C424
ICD-Morpho 9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
Atlas_Id 1245

Clinics and Pathology

Disease PCDLBCL, leg type is composed exclusively of large transformed B-cells, most commonly arising in the leg. PCDLBCL, leg type was first reported as a subgroup of PCFCL in 1987 based on its particular histological feature and more aggressive behavior. In 1996, the term "primary cutaneous large B-cell lymphoma of the leg" was proposed, which was used to classify it as a distinctive subgroup in the EORTC classification. In the last WHO-EORTC classification, this entity was finally defined PCDLBCL, leg type to reflect the predominant but not exclusive anatomic location of the lesions (Swerdlow, et al ,2008. Selva, et al, 2017).
Phenotype / cell stem origin Tumor cells express B-cell markers (CD20, CD79a, and PAX5). Cytoplasmic IgM expression seems to be a sensitive marker of PCDLBCL, leg type. BCL-2, MUM1/IRF4, and FOX-P1 are strongly expressed regardless of the location of the skin lesions. A study suggests that cell-of origin is germinal center experienced and superantigen driven selected B-cell, in a stage between germinal center B-cell and plasma cell (Swerdlow, et al , 2008. Selva, et al, 2017).
Epidemiology PCDLBCL, LT represents 5%-10% of all PCBCLs commonly presenting in elderly females (male:female 1:3-4), with a peak incidence in the seventh decade of life (Swerdlow, et al , 2008. Selva, et al, 2017).
Clinics Patients present solitary or multiple, rapidly growing, red to bluish-red firm tumors on one or both legs, usually below the knee. In 10%-15% of cases, the lesions are localized at other sites such as the trunk, head-neck, and upper arms. Multiple lesions may be disseminated or aggregated. Extracutaneous sites are often disseminated, most commonly in lymph nodes, bone marrow, and nervous system (Swerdlow, et al , 2008. Selva, et al, 2017).
Pathology Histologically, there is a diffuse and dense infiltrate throughout the dermis that often involves the subcutis but is separated from the epidermis by a Grenz zone. The infiltrate mainly consists of confluent sheets of large B-cells with roundish nuclei, prominent nucleoli, and open chromatin resembling centroblasts and immunoblasts. Anaplastic cells are occasionally seen. Mitotic figures are frequently observed. T-cells are rare. PCDLBCL, leg type is usually characterized by a high proliferation rate (>70%) and BCL-6, CD5, CD10, CD30, CD138, and cyclin D1 negativity.
Figure 1. Primary cutaneous DLBCL, leg type. There is a foci and sheets infiltration of lymphoid cells throughout the dermis. A Grenz zone can be seen separated from the epidermis. (HE staining).
Figure 2. The lymphoid cells are medium to large in size, with oval nuclei and distinct nucleoli. ( HE staining)
Figure 3. The cells are positive for CD20. (immunostaining)
Figure 4. Ki67 immunostaining shows a high proliferation rate. (immunostaining).
Treatment PCDLBCL, leg type is often managed as a systemic lymphoma depending on its staging and location, number of skin lesions, and general status of the patient. Immunochemotherapy with R-CHOP with or without involved-field radiotherapy as the first-line therapy for single, localized, or generalized lesions is recommended. The use of local radiotherapy or rituximab as a single agent can be considered in particular cases. In relapsed cases, the use of protocols for relapsed systemic DLBCLs is recommended (Swerdlow, et al ,2008. Selva, et al, 2017. Wilcox, 2016). Targeting of tumor cells and myeloid-derived suppressor cells using anti-PD-1/ anti -PD-L1 or anti-CD33 antibodies might be a worthwhile new approach to treat PCDLBCL, leg type.( Mitteldorf, et al. 2017)
Prognosis The prognosis of PCDLBCL, LT is poor and characterized by frequent relapses and extracutaneous spreading. The 5-year survival rate is 40%-55%. A location on the leg and multiple skin lesions are negative prognostic factors. Factors that have been reported to be linked to a worse prognosis are the high expression of MUM1 and FOX-P1, and deletion of the CDKN2A locus on chromosome 9p21 (Swerdlow, et al , 2008. Selva, et al, 2017).


Note Cytogenetic studies have revealed a frequent inactivation of CDKN2B (p15(INK4b)) and CDKN2A (p16(INK4a)) as a result of promoter hypermethylation (respectively, 11% and 44% of all PCDLBCLs) and chromosomal imbalances in up to 85% of PCDLBCL, leg type (mainly gains of chromosome 2q, 3, 7p, 12q, 18q and losses of 6q, 13,14,17p, 19). Translocations of MYC, BCL6, and IGH genes have been demonstrated by fluorescence in situ hybridization in PCDLBCL, leg type. PCLBCL leg type exhibits a unique mutational landscape, combining highly recurrent hotspot mutations in genes involved in NF-kb and B-cell signaling pathways, which provides a rationale for using selective inhibitors of the B-cell receptor (Swerdlow, et al ,2008. Selva, et al, 2017. Mareschal, et al.2017).

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.


Identification of Somatic Mutations in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type by Massive Parallel Sequencing
Mareschal S, Pham-Ledard A, Viailly PJ, Dubois S, Bertrand P, Maingonnat C, Fontanilles M, Bohers E, Ruminy P, Tournier I, Courville P, Lenormand B, Duval AB, Andrieu E, Verneuil L, Vergier B, Tilly H, Joly P, Frebourg T, Beylot-Barry M, Merlio JP, Jardin F
J Invest Dermatol 2017 Sep;137(9):1984-1994
PMID 28479318
Tumor Microenvironment and Checkpoint Molecules in Primary Cutaneous Diffuse Large B-Cell Lymphoma-New Therapeutic Targets
Mitteldorf C, Berisha A, Pfaltz MC, Broekaert SMC, Schön MP, Kerl K, Kempf W
Am J Surg Pathol 2017 Jul;41(7):998-1004
PMID 28504999
Molecular analysis of immunoglobulin variable genes supports a germinal center experienced normal counterpart in primary cutaneous diffuse large B-cell lymphoma, leg-type
Pham-Ledard A, Prochazkova-Carlotti M, Deveza M, Laforet MP, Beylot-Barry M, Vergier B, Parrens M, Feuillard J, Merlio JP, Gachard N
J Dermatol Sci 2017 Nov;88(2):238-246
PMID 28838616
A Literature Revision in Primary Cutaneous B-cell Lymphoma
Selva R, Violetti SA, Delfino C, Grandi V, Cicchelli S, Tomasini C, Fierro MT, Berti E, Pimpinelli N, Quaglino P
Indian J Dermatol 2017 Mar-Apr;62(2):146-157
PMID 28400634
Primary cutaneous B-cell lymphomas: part I
Suárez AL, Pulitzer M, Horwitz S, Moskowitz A, Querfeld C, Myskowski PL
Clinical features, diagnosis, and classification J Am Acad Dermatol
PMID 23957984
Cutaneous B-cell lymphomas: 2016 update on diagnosis, risk-stratification, and management
Wilcox RA
Am J Hematol 2016 Oct;91(10):1052-5
PMID 27650702
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.
Swerdlow SH, Webber SA, Chadburn A, et al.
Lyon : IARC press; 2008: 343-349. ISBN:978-92-832-2431-0


This paper should be referenced as such :
Ding-Bao Chen
Primary cutaneous DLBCL, leg type
Atlas Genet Cytogenet Oncol Haematol. 2018;22(11):439-442.
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