Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type: A Narrative Review
A B S T R A C T
Primary cutaneous lymphomas are rare manifestations of extranodal lymphomas. Comprising the majority of cutaneous lymphoma cases with neoplastic B-cell origins, three main subtypes exist. In general, grossly and microscopically these subtypes are similar. However, these are three distinct variants with diverse clinicopathologic, cytogenetic, molecular, and prognostic features. Primary cutaneous diffuse large B-cell lymphoma, leg type is an exceedingly rare and aggressive variant of primary cutaneous B-cell lymphomas. Thus, increased clinical awareness is needed to differentiate between the three subtypes because earlier identification not only leads to the appropriate treatment, but also improved survival. Here, characteristic features of the three predominant variants of primary cutaneous B-cell lymphomas are presented while remaining focused on the most aggressive subtype- primary cutaneous diffuse large B-cell lymphoma, leg type.
Keywords
Primary cutaneous lymphoma, primary cutaneous b-cell lymphoma, primary cutaneous diffuse large b-cell lymphoma, leg type, primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma
Introduction
Primary cutaneous lymphomas represent a rare manifestation of extranodal lymphomas. T-cell malignancies are the predominant etiologic agent for most cutaneous lymphomas [1]. Primary cutaneous B-cell lymphoma (PCBCL) accounts for approximately 25% of all primary cutaneous lymphoma cases [1, 2]. Comprising the majority of cutaneous lymphoma cases with neoplastic B-cell origins, three main subtypes have been described (Table 1). Grossly and microscopically these subtypes are primarily similar. Non-epidermotropic, or epidermis-sparing, infiltrates of monotonous centroblasts and immunoblasts admixed with local cells is characteristic (Table 2) [3, 4]. Although morphological similar, these variants have distinct clinicopathologic, cytogenetic, molecular, and prognostic features.
Discussion
I Epidemiology, Clinical, and Prognosis
PCDLBCL-LT is exceedingly rare, accounting for less than 5% of all cutaneous lymphomas [5]. Compared to the typically indolent PCFCL and PCMZL, the clinical course of PCDLBCL-LT is characteristically aggressive, and preferentially affects elderly females [6]. As its name implies, PCDLBCL-LT almost exclusively involves the legs. However, it has been reported to initially present at other dermatologic sites [3, 7]. PCFCL is the most common subtype of PCBCL and predominantly develops on the scalp and trunk of middle-aged males (Table 3). Increased clinical awareness of PCBCLs and its variants is needed as the distinction between them has important treatment implications. A small majority of PCFCLs develop on the legs [1, 3]. Interestingly, leg involvement of any PCBCL subtype correlates with a worse prognosis.
Poor prognostic factors for PCBCLs have been identified, such as multiple skin lesions, extracutaneous disease, elevated serum lactate dehydrogenase, BCL2 expression, and presence of a mutated MYD88 gene [8-10]. If PCDLBCL-LT is confirmed by excisional skin biopsy and treatment is started, refractory disease, recurrence, and extracutaneous dissemination is common [11]. Thus, compared to the more indolent neoplastic cutaneous B-cell entities, PCDLBCL-LT has a worse prognosis with only about 50% of patients achieving 5-year survival after completing first-line therapy [1]. Although no risk factors have been identified, several genetic mutations have been recently studied for their possible key roles in neoplastic cutaneous B-cell disorders. Borrelia burgdorferi’s role in PCMZL remains controversial and debated [12].
Table 1: Three main subtypes of primary cutaneous B-cell lymphoma according to World Health Organization classification [1].
Distinctive variants |
Primary cutaneous diffuse large B cell lymphoma, leg type, PCDLBCL-LT |
Primary cutaneous follicle center lymphoma, PCFCL |
Primary cutaneous marginal zone lymphoma, PCMZL |
Table 2: Summary of the common histologic findings for the main subtypes of primary cutaneous B-cell lymphoma.
|
PCDLBCL-LT |
PCFCL |
PCMZL |
Histology |
Diffuse non-epidermotropic infiltrates; commonly sheets of monotonous large rounded cells; many mitotic figures are common |
Nodular or diffuse non-epidermotropic infiltrates consisting of monotonous follicular cells |
Nodular or diffuse non-epidermotropic infiltrates |
Cyto-pathology |
Centroblasts and immunoblasts; small B-cells and reactive T-cells are rare |
Centrocytes with centroblasts and immunoblasts; admixed with follicular dentritic cells and numerous reactive T-cells; follicular architecture often ill-defined |
Lymphocytes, marginal zone B-cells, centrocyte-like cells, plasma cells, centroblasts, immunoblasts, and lymphoplasmacytic cells; reactive T-cells and germinal centers |
PCDLBCL-LT: primary cutaneous diffuse large B cell lymphoma- leg type; PCFCL: primary cutaneous follicle center lymphoma; PCMZL: primary cutaneous marginal zone lymphoma [3, 4].
Table 3: Summary of etiopathogenesis and characteristic clinical features of primary cutaneous B-cell lymphoma variants.
|
PCDLBCL-LT |
PCFCL |
PCMZL |
Epidemiology
|
- 20% of all primary B-cell lymphomas - seventh decade - female predominance [11] |
- 60% of all primary B-cell lymphomas - fifth decade - male predominance[3] |
- fifth and sixth decades - male predominance [12] |
Pathogenesis |
- no identifiable risk factors or hereditary tendencies [13] - MYC, BCL6, IGH, MALT1, CDKN2A/2B, PDL1/2, FOXP1, PAX5, PIM1, MYD88, CARD11, CD79B, and TNFAIP3/A20 mutations [10, 13] - Borrelia burgdorferi [6] |
||
Clinical |
- violaceous papules, plaques, or nodule(s) +/- ulceration - multifocal - 80% leg involvement - aggressive - high relapse rate, in general - 60% extracutaneous dissemination [1,3,11] |
- violaceous papules, plaques, or nodule(s) +/- ulceration - 75% solitary - head/scalp > trunk - 5% on the legs - indolent - 10% extracutaneous dissemination [1,3] |
- violaceous papules, plaques, or nodule(s) +/- ulceration - 50% solitary - trunk > arms - indolent - higher relapse rate if multiple skin lesions present - extracutaneous dissemination rare [1,3,12] |
First-line therapy [4] |
Polychemotherapy |
Radiotherapy, surgery |
Radiotherapy, surgery |
Additional therapies [4] |
- Radiotherapy, surgery - Monoclonal antibodies - Lenalidomide - Ibrutinib |
Polychemotherapy |
Polychemotherapy |
Prognosis |
5-year overall survival, 50-60% [1] |
5-year overall survival, 95% [1] |
5-year overall survival, 97% [8] |
PCDLBCL-LT: primary cutaneous diffuse large B cell lymphoma- leg type; PCFCL: primary cutaneous follicle center lymphoma; PCMZL: primary cutaneous marginal zone lymphoma; MYC: proto-oncogene; BCL6: B-cell lymphoma 6; IGH: Immunoglobulin heavy locus; MALT1: Mucosa-associated lymphoid tissue lymphoma translocation protein 1; CDKN2A/2B: cyclin-dependent kinase inhibitor 2A/2B, PDL1/2: programmed death‐1/2; FOXP1: Forkhead box P; PAX5: Paired Box 5; PIM1: proto-oncogene and serine/threonine kinase; MYD88: Myeloid differentiation primary response protein; CARD11: Caspase recruitment domain-containing protein 11; CD79B: Cluster of differentiation 79B; TNFAIP3/A20: Tumor necrosis factor, alpha-induced protein 3 or A20; Polychemotherapy, e.g. rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
II Immunohistochemistry
MUM1 and BCL2 expression can allow for the distinction between PCDLBCL-LT from the less-aggressive PCFCL subtype. However, approximately 10% of PCDLBCL-LT case specimens lack MUM1 or BCL2 immunoreactivity. As a result, careful clinicopathologic correlation is required for definitive diagnosis [19]. While the germinal center marker CD10 is usually negative, BCL6 is variably positive [20-22]. CD20, PAX5, and CD79a immunoreactivity can also be used to help confirm the diagnosis. [19-22].
Based on their germinal-center origins, PCFCL specimens consistently are positive for BCL6 markers by IHC but can be variably immunoreactive for CD10. MUM1 testing by IHC and genetic studies is negative [23]. PCFCLs typically lack BCL2, MUM1, FOX-P1, and IgM immunoreactivity [19]. However, PCFCLs with leg involvement have been reported anecdotally as positive for BCL2, MUM1, FOX-P1, and IgM markers [19]. Similar to the other main PCBCLs subtypes, PCMZL will be IHC-positive for B-cell markers such as CD20, CD79a, and PAX5. However, PCMZL is positive for BCL2, and negative for BCL6 or CD10 expression. This feature allows PCMZL to be distinguished from PCFCL (Table 4) [12].
Table 4: Immunophenotypes of primary cutaneous B-cell lymphoma variants.
PCBCL variants |
B-cell markers |
GC-markers |
PG/PC markers |
Other markers |
|||||||
CD20 |
CD79a |
PAX5 |
CD10 |
BCL6 |
MUM1 |
CD138 |
MYC |
BCL2 |
CD30 |
PD-1 |
|
PCDLBCL-LT |
+ |
+ |
+ |
- |
-/+ |
+ |
- |
+/- |
+ |
- |
+/- |
PCFCL |
+ |
+ |
+ |
-/+ |
+ |
- |
-/+ |
- |
-/+ |
- |
-/+ |
PCMZL |
+ |
+ |
+ |
- |
- |
- |
+/- |
+/- |
+ |
- |
-/+ |