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Cutaneous B-Cell Lymphoproliferative Disorders
Report of the 2011 Society for Hematopathology/European Association for Haematopathology Workshop

Steven H. Swerdlow MD, Leticia Quintanilla-Martinez MD, Rein Willemze MDPhD, Marsha C. Kinney MD
DOI: http://dx.doi.org/10.1309/AJCPNLC9NC9WTQYY 515-535 First published online: 1 April 2013


The diagnosis and classification of the cutaneous B-cell lymphomas can be quite a challenge, with a definitive diagnosis sometimes being elusive, even when an extensive workup has been performed. Distinction of benign from neoplastic disorders can be difficult, with some hyperplasias mimicking lymphomas and vice versa. There are only a limited number of skin-specific B-cell lymphomas, including primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous marginal zone lymphomas have distinctive features but are classified with the other mucosa-associated lymphoid tissue lymphomas. It is important, however, to also remember that many other B-cell lymphomas/ plasma cell neoplasms can primarily, or more often secondarily, involve the skin. Some may mimic one of the skin-specific lymphomas but have very different clinical implications. Iatrogenic and senescent immunodeficiency-associated lymphoproliferative disorders that are often Epstein-Barr virus (EBV) positive can also primarily involve the skin, including cases also known as EBV-positive mucocutaneous ulcer.

Key Words
  • Skin
  • B-cell lymphoma
  • MALT lymphoma
  • Primary cutaneous follicle center lymphoma
  • Diffuse large B-cell lymphoma, leg type

Upon completion of this activity you will be able to:

  • list the criteria for the major primary cutaneous B-cell lymphomas.

  • predict the most likely diagnosis for a cutaneous B-cell lymphoma based on morphology and phenotype.

  • describe the findings in cutaneous immunodeficiency-associated lymphoproliferative disorders including Epstein-Barr virus–positive mucocutaneous ulcer.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.

The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Questions appear on p 553. Exam is located at www.ascp.org/ajcpcme.

Diagnosing a cutaneous B-cell lymphoma is a 3-step process, often with major challenges at all stages. In most cases, a biopsy demonstrates a variably dense nonepidermotropic, superficial, and deep lymphoplasmacytic infiltrate. The first step then is to determine if the infiltrate is benign or malignant; the second is to decide if it is a B-cell, T-/natural killer (NK)–cell, or other type of neoplasm; and the final step is to classify the B-cell lymphoma. The first step can be particularly problematic, because some benign infiltrates can be very extensive, resemble a lymphoma morphologically in many ways (as discussed by Sarantopoulos et al1 in this issue of the Journal), and even have monoclonal immunoglobulin gene rearrangements.2,3 Conversely, some lymphomas closely resemble a reactive proliferation with only a few neoplastic cells and a prominent reactive B-cell component that can include follicles and polyclonal plasma cells. The second step in distinguishing the lineage of the neoplasm is often straightforward based on the morphologic appearance and phenotypic studies, but in some cases, this can also be a major problem. As with the better-known T-cell–rich large B-cell lymphomas, many cutaneous marginal zone lymphomas (MZLs) also have numerous T cells and conversely, some cutaneous T-cell lymphomas, specifically primary cutaneous CD4+ small-medium T-cell lymphoma (which, in most cases, may not be a lymphoma at all, as discussed by Quintanilla-Martinez et al4 in this issue of the Journal), may have a very prominent B-cell population and even light chain–restricted plasma cells.5 Finally, classification may sometimes be obvious, but problematic in other cases for various reasons. A gold standard for distinguishing some of the indolent lymphomas from each other and even from some of the aggressive cutaneous B-cell lymphomas is lacking. One must remember some uncommon variants of aggressive B-cell lymphomas may present in the skin. In the absence of staging and other clinical data, one must always consider the possibility of secondary cutaneous involvement by a systemic B-cell lymphoma and be descriptive in the diagnosis (ie, do not use “primary cutaneous” in the diagnostic line). In cases with a diffuse population of large centrocytes, some would make a diagnosis of “if staging negative, consistent with primary cutaneous follicle center lymphoma” (PCFCL). Whereas, in the past, as briefly reviewed herein, competing classifications were a major issue, we can now use the 2008 World Health Organization (WHO) classification. This workshop report includes a brief description of how we currently classify the cutaneous B-cell lymphomas, reviews the basic features of the major primary B-cell lymphomas that involve the skin, and examines some of the problems and pitfalls highlighted by both primary and secondary B-cell/plasmacytic neoplasms submitted to the workshop.

Classification of Cutaneous B-Cell Lymphomas

As recently as 2005, cutaneous lymphomas were being classified in 2 major ways. The European Organisation for Research and Treatment of Cancer (EORTC) classification of cutaneous lymphomas, published in 1997, emphasized the need for a classification specifically for primary cutaneous lymphomas.6 The WHO classification of tumors of hematopoietic and lymphoid tissues published in 2001 covered all lymphomas and did include some skin-specific categories/ variants such as “cutaneous follicle center lymphoma.”7 Following discussions held at the editorial consensus conference for the WHO skin tumor bluebook in September 2003 in Lyon, France, and others in Zurich, Switzerland, in January 2004 (hosted by Günter Burg, MD), to resolve remaining issues related specifically to the B-cell lymphomas, a WHO-EORTC consensus classification was agreed upon. This classification was then published in 20058 and included in the 2006 WHO classification of skin tumors monograph.9 Most of that classification has now been incorporated in the 2008 WHO classification of hematopoietic and lymphoid tissue tumors, with some minor differences and some updates Table 1.10 The major differences between the WHO-EORTC consensus classification and the 2008 WHO classification were that cutaneous marginal zone B-cell lymphoma (.mucosa-associated lymphoid tissue [MALT]–type) is included in a category with other MALT lymphomas, the word “B-cell” is dropped, and the cutaneous “diffuse large B-cell, other” category is not specifically recognized (these cases would now be included in one of the other diffuse large B-cell lymphoma [DLBCL] categories). In addition to listing the recognized primary cutaneous lymphomas, the WHO-EORTC classification also included some extracutaneous lymphomas that “frequently” involve the skin as a secondary site. The workshop submissions included a high proportion of primary and mostly secondary cutaneous lymphomas that are not among the very limited number of classic primary cutaneous B-cell lymphomas specifically listed in the WHO classification. Remember also, that currently the definition of a primary cutaneous lymphoma requires no extracutaneous disease to be present at diagnosis.

View this table:

Extranodal MZL of Mucosa-Associated Lymphoid Tissue (MALT Lymphoma) (WHO-EORTC: Primary Cutaneous Marginal Zone B-Cell Lymphoma [MALT-Type])

Primary cutaneous marginal zone lymphomas (PCMZLs) make up about 7% of all cutaneous lymphomas.8,11 They are very indolent with cutaneous recurrences but rare extracutaneous dissemination and with a 99% to 100% 5-year disease-specific survival.8,1216 Patients with multiple nonlocalized lesions, however, are reportedly unlikely to have persistent complete remissions.17 In part, because of their extremely indolent even if persistent behavior, ongoing discussions are focused on whether at least a major subset of PCMZLs should be considered something other than an overt lymphoma. They have many features that might suggest a clonally restricted response to some form of chronic antigenic stimulation. The observation that both PCMZL and cutaneous lymphoid hyperplasia may develop from chronic stimulation by intradermally applied antigens, such as tattoo pigments, tick bites, antigen injections, etc, suggest that they represent a continuous spectrum of cutaneous B-cell proliferation.18

These lymphomas usually present as 1 or more papules, nodules, or plaques and are found more often on the extremities or trunk rather than in the head and neck region. Rarely, they may even involve the skin with minimal, if any, clinical findings and can also wax and wane.19,20 Among patients who have MZL first presenting in the skin, bone marrow involvement is reported in only 2% of cases (these cases then would no longer be considered a primary cutaneous lymphoma).21

PCMZLs have all the histopathologic features of other MALT lymphomas except that lymphoepithelial lesions are very rare and plasmacytic differentiation is very common, sometimes with few if any lymphocytes and often with the plasma cells at the periphery of the lymphoid nodules or at the subepidermal border.1215,22,23 They may closely resemble hyperplastic lesions, because a majority will have reactive follicles, a similar proportion are “top-heavy” compared with “bottom-heavy” lesions, and about 25% of cases contain eosinophils. Cases formerly known as “immunocytoma” as well as nonmyelomatous “plasmacytomas” of skin are now included in this diagnostic category.

Typically, the B cells are CD5 and CD10 negative, and distorted follicular dendritic cell meshworks are often present. About 75% of cases are monoclonal (light chain class restricted) using paraffin section immunostains, with monotypic plasma cells in most.12,14,15 It may be helpful to look for Dutcher bodies, which, although not specific, tend to be associated with neoplastic proliferations and may also help direct one to a neoplastic plasmacytic population when admixed with polytypic plasma cells. Several clouds surround this potential silver lining, however. First, it has been suggested that there may be cases of λ light chain– restricted cutaneous “atypical marginal zone hyperplasia” in “young” patients who lack molecular evidence of true monoclonality, analogous to the atypical marginal zone hyperplasia described in the appendix and tonsils of children.24 This should probably be considered controversial because molecular polymerase chain reaction (PCR) studies can be falsely negative and many accepted cutaneous MZLs only require very local therapies. Older reports describe cutaneous lesions with hyperplastic follicles and monotypic plasma cells,25 which, as discussed at a Society for Hematopathology slide workshop in 1997 and still accepted after this workshop, are felt to best be diagnosed as MZLs. As noted before, however, whether we should resurrect this concept is a matter of current discussion. It appears that only a few B cells are neoplastic in many cutaneous MZLs.26 The second major cloud is the reported rare cases of cutaneous lymphomas that include both a peripheral T-cell lymphoma and a monoclonal plasma cell or possibly monoclonal B-cell population.5,27 The workshop included 1 previously reported case in which a patient with an initial skin lesion considered to be a cutaneous MALT lymphoma was eventually found to have an angioimmunoblastic T-cell lymphoma.28 Perhaps a less problematic cloud (in most circumstances at least) is the observation that individual patients can have both κ- and λ-positive cutaneous MALT lymphomas.19,20 Whether these populations with different light chains are clonally related is uncertain.

The presence of a B-cell–rich proliferation with the B cells not restricted to follicular structures also supports the diagnosis of a cutaneous MZL; however, as discussed herein and illustrated in the workshop, many cases have numerous T cells with relatively few neoplastic B cells present outside the often scattered follicles.26,29 Nuclear BCL10 expression has been reported in 46% of cases, reportedly associated with locally aggressive tumors.30 This antibody is not easy to use and has not achieved widespread use.

Genotypic studies are often used to document clonality in such cases. Even if the findings are not considered diagnostic, they can be very useful especially with the newer primers. Although lower yields were reported in the past, using BIOMED-2 PCR protocols,3133 a clonal B-cell population can be detected in 80% of cutaneous MZLs and only 4% of benign infiltrates or, as shown in another study, 83% of cutaneous MZLs but with 22% of benign infiltrates.34 One must remember also that which cases are considered lymphomas remains subjective—a more conservative hematopathologist will have a higher proportion of monoclonal cases (as well as more monoclonal cases among their hyperplastic lesions). Whether there are clonal true cutaneous lymphoid hyperplasias is controversial.3,35 One conclusion was that some of the clonal cases were “not really a hyperplasia at all but rather a clonal lymphoproliferative disorder that may progress occasionally to overt cutaneous lymphoma.”3 The conclusion at the workshop was that the clonal immunoglobulin heavy locus (IGH@) rearrangement by itself was insufficient to consider a case to be a lymphoma, but it could be important to help support such a diagnosis. It is also obvious that negative PCR findings do not exclude a cutaneous MALT lymphoma. Clonal T-cell receptor rearrangements can also be found in 35% of MALT lymphomas using BIOMED-2 primers, including cutaneous MALT lymphomas, without implying the presence of a coexistent T-cell lymphoma.26,36 Nevertheless, it is important to be cognizant of the possibility of a T-cell lymphoma, such as an angioimmunoblastic T-cell lymphoma or a primary cutaneous CD4+ small/medium T-cell lymphoma, that has features mimicking a cutaneous MZL. Some have reported the presence of the t(11;18) or other IGH@ translocations in cutaneous lymphomas, but others have not found them to be present.23,30,3739

Recent studies have demonstrated 2 types of cutaneous MZLs.26,40 The most frequent and most distinctive subtype has “class-switched” immunoglobulin (IgG>>>IgA or IgE) and is associated with a Th2 inflammatory background, both features unlike the majority of other MALT lymphomas (except that thyroid MALT lymphomas are also often IgG+).26,40,41 These cases typically have numerous T cells and B-cell follicles that, unless infiltrated, are non-neoplastic, and overall often have only a small proportion of neoplastic cells. It may be impossible to document a light chain–restricted B-cell population in some of these cases even when flow cytometric studies are performed, as was illustrated at the workshop (case 307) (and with some other MALT lymphomas often because of numerous admixed polytypic B cells and the lack of a distinctive phenotype in terms of CD5 and CD10). This pathologically distinctive type of MZL appears to include many of the truly primary cutaneous MZLs Image 1. The much less frequent IgM+ cases are most likely to demonstrate a predominance of B cells rather than T cells, a diffuse proliferation of B cells (vs the B cells mostly seen in nodules and scattered), CXCR3 (a receptor for IFN-γ–induced chemokines) expression (a feature shared with many other MALT lymphomas but not present in the IgG+ cases), and extracutaneous disease (hence, possibly not really primary cutaneous MALT lymphomas) Image 2.26 The IgM+ cases also may include the subset of cases associated with Borrelia burgdorferi.40 Although the relationship of some cutaneous B-cell lymphomas and specifically MALT lymphomas to B burgdorferi infection is well recognized, studies from the United States and Japan, and at least 1 from Europe, have not reported this association.23,30,39

Image 1

Classic primary cutaneous marginal zone lymphoma (MZL). A 43-year-old man with an 8-mm bluish-red nodule on the right shoulder. A, A superficial and deep, perivascular and periadnexal, dermal lymphoplasmacytic infiltrate is present with scattered follicles sometimes with CD10–, BCL6+ germinal centers and IgM+, IgD+ (not shown) mantle zones and a more polymorphous-appearing interfollicular proliferation that includes (B) plasma cells at the periphery. Immunohistochemical stains demonstrated (C) CD20+ B cells concentrated in the follicles and (D) numerous CD3+ T cells, clearly predominating in the interfollicular regions. E, The plasma cells express monotypic κ light chain (dual κ [black]/ λ [red] staining) and IgG (not shown). F, The patient developed multiple macular and papular lesions on the back and was subsequently treated with rituximab. (Case 4, courtesy of Steven H. Swerdlow, MD, and Larisa Geskin, MD.)

Image 2

Secondary skin involvement by an ocular marginal zone lymphoma. A, A 70-year-old woman with bilateral edematous infiltrative lesions of the eyelids. B, A superficial and deep vaguely nodular infiltrate is present with (C) marked predominance of CD20+ B cells and (D) numerous cells with cytoplasmic IgM including staining of numerous Dutcher bodies. (Case 80, courtesy of Antoine de Mascarel, MD, PhD, and Béatrice Vergier, MD, PhD.)

Differential Diagnostic Difficulties

In addition to the problematic distinction from cutaneous lymphoid hyperplasia (which led to only descriptive panel diagnoses for some of the cases submitted to the workshop), other cases raised various neoplastic differential diagnoses. Particularly with the IgM+ and B-cell–rich cases one must always worry about the possibility of systemic disease and the differential diagnosis of secondary involvement by a MALT lymphoma originating elsewhere or a lymphoplasmacytic lymphoma Image 3. Cases with numerous small B cells not appearing very “monocytoid” and without plasmacytic features may be confused with cutaneous involvement by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Image 4. CLL/SLL has been reported to involve the skin in 2% of cases.42 These cases can be identified as at any other site, based on morphology (even including proliferation centers) and immunophenotype. Cases rich in plasma cells will raise the possibility of a plasma cell neoplasm. One must be careful not to confuse cutaneous involvement by plasma cell myeloma with an indolent MALT lymphoma with a marked predominance of plasma cells Image 5. One must also consider IgG4-related sclerosing disease43 (which may also be related to “cutaneous plasmacytosis”44) in the differential diagnosis.

Image 3

Secondary skin involvement by lymphoplasmacytic lymphoma (LPL), in a 49-year-old man with a 6-year history of IgM-κ LPL. A, Superficial and deep, dense, perivascular, and periadnexal dermal lymphocytic infiltrate (B) composed of numerous small lymphocytes, plasmacytoid lymphocytes, and plasma cells, some with Dutcher bodies (insert). (C) The lymphocytes strongly express CD79a (CD20 was weaker, not shown) and (D) IgM. The plasma cells and Dutcher bodies expressed κ light chain (not shown). (Case 234, courtesy of James R. Cook, MD, PhD.)

Image 5

Secondary skin involvement by plasma cell myeloma (PCM) in a 68-year-old man with PCM who experienced a relapse at 9 months with 13 large skin lesions. A, Sheets of dysplastic plasma cells were present and expressed (B) CD56 and (C) κ light chain. They were also IgA, CD138, and cyclin D1 positive (not shown). (D) Fluorescence in situ hybridization studies using dual color dual fusion probes (IgH, green; CCND1, red) showed multiple red and green signals without fusion signals, suggestive of hyperdiploidy, but did not demonstrate definitive evidence of translocation. (Case 98, courtesy of Viera Nelson, MD, Mariela Vasquez, MD, and Guoxian Sun, MD.)

Cases with increased numbers of transformed cells may raise the differential diagnosis of one of the large B-cell lymphomas and, as seen with some cases in the workshop, those with more prominent follicular structures may suggest a PCFCL or systemic follicular lymphoma. The differential diagnosis with T-cell lymphomas was discussed briefly earlier (those lymphomas are discussed in more detail by Quintanilla-Martinez et al4 in this issue of the Journal).

Primary Cutaneous Follicle Center Lymphoma

PCFCL makes up about 9% to 11% of cutaneous lymphomas8,11 and usually presents with solitary or grouped plaques or tumors, mostly on the head and neck or trunk regions (rare on legs).45 Involvement may take the form of erythematous papules and plaques, which are sometimes associated with nodules as well (“Crosti lymphoma”); some patients have small papules more than 10 to 15 cm away from the main lesion.46 Other patients may only have “multiple, miliary, or agminated [grouped] papules.”47 The prognosis is excellent, without evidence that the category should be further subdivided in any way (5-year survival >95%).8,16 It has been reported that PCFCLs arising on the leg are more aggressive than those arising elsewhere.48 In spite of their well-advertised indolent nature, some cases at the workshop showed PCFCL and either progression to a DLBCL or a coexistent DLBCL, so that must be kept in mind (clonal identity between the 2 components in the workshop cases was not documented and in 1 case the 2 components were probably distinct). The case with the associated DLBCL had MYC translocation that was not found on the biopsy specimen with PCFCL, which might be a sign of progression Image 6. Most cases are treated with radiation therapy including cutaneous relapses. Consensus therapeutic recommendations from the EORTC and International Society for Cutaneous Lymphomas (ISCL) were published in 2008.49

Image 6

Diffuse large B-cell lymphoma (DLBCL) with coexistent primary cutaneous follicle center lymphoma (PCFCL) in a 45-year-old man with skin lesions on the chest and back, thought to be cysts. One year later a biopsy performed on a third enlarging lesion on the right scapula showed (A) DLBCL containing immunoblasts and fewer centroblasts. The tumor cells were CD10+, BCL2 negative, and fluorescence in situ hybridization (FISH) demonstrated an MYC rearrangement but no evidence of IgH, BCL2, or BCL6 rearrangements (not shown). The original nodules, with biopsies performed at the same time, demonstrated a PCFCL with (B) a dense, follicular, and diffuse lymphocytic infiltrate (C) composed of centroblasts and centrocytes. The neoplastic cells were CD10+, BCL2 negative and FISH did not demonstrate an MYC rearrangement. IgH gene rearrangement studies, using BIOMED2 primers, of the DLBCL and the PCFCL showed different sized polymerase chain reaction clonal IgH products, suggesting that they were most likely clonally distinct, but the possibility of clonal diversion related to somatic hypermutation cannot be excluded. Positron emission tomography–computed tomography and bone marrow biopsy were negative. The patient was treated with rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone or prednisolone (R-CHOP) and irradiation and has no evidence of recurrence at 8 months’ follow-up. (Case 182, courtesy of Joe A. Chorny, MD, and Teresa Launder, MD.)

PCFCL is defined as a lymphoma composed of neoplastic follicular center cells, specifically centrocytes with variable numbers of centroblasts. In some cases, the large centrocytes appear spindled. PCFCLs can have a follicular, follicular and diffuse, or diffuse growth pattern. Cases that appear diffuse may sometimes demonstrate some foci of CD21+ follicular dendritic cells but in other cases they are totally absent Image 7.46 The growth pattern is not considered to be of any clinical significance and it should be recognized that even “early” lesions may be totally diffuse.46 The only difference the cytologic composition would make is if there were pure sheets of centroblasts without any centrocytes growing diffusely, in which case it would be diagnosed as 1 of the types of DLBCL. In other words, these lymphomas are not graded, in contrast to follicular lymphomas occurring at any other site. The cases that are totally diffuse often do have many large centrocytes and, partly because of this and because a moderate number of centroblasts can be present, a significant subset of these cases would fulfill the criteria for a DLBCL at other sites. Many cases have a relatively high proportion of Ki-67+ cells, with 1 report showing that 9 of 24 cases of “early” diffuse PCFCL had 60% to 90% Ki-67+ cells.46 It remains critical to exclude other primary or secondary cutaneous lymphomas. One interesting difference between primary and secondary cutaneous follicular lymphomas is that the former are significantly more likely to have a “floral” growth pattern (32% vs 5%).50 Caution is advised, however, because cutaneous lymphoid hyperplasia with progressive transformation of germinal centers has been described, which can mimic PCFCL with floral growth patterns.51 These cases may demonstrate at least portions of germinal centers at the periphery of the large nodules that include many small B cells.

Image 7

Primary cutaneous follicle center lymphoma (PCFCL) with a diffuse growth pattern in a 62-year-old woman with a 5-mm pearly scalp papule of 3 months’ duration. A, A large mass of lymphocytes extends diffusely from the upper reticular dermis to the subcutaneous tissue. B, The lymphocytes are predominantly large centrocytes with some centroblasts. Some of the cells appear spindled. C, They express BCL6 and lack CD10 (not shown). D, Immunostaining for CD21 revealed very focal small remnants of follicular dendritic cell meshworks. (Case 35, courtesy of Brian Olsen, MD.)

PCFCL is composed of monoclonal B cells but may lack surface immunoglobulin. BIOMED-2 primers are reported to demonstrate B-cell clonality in 91% to 100% of cases, with 4% to 22% “clonal” reactive proliferations.33,34 Whether those reporting a high proportion of “clonal” reactive proliferations simply have a higher threshold for diagnosing a lymphoma or whether their studies reflect different patient populations or technical factors is uncertain. Different lesions in the same patient may, however, be clonally distinct.52 As noted before, and as seen in at least 1 submitted PCFCL, some B-cell lymphomas may demonstrate TCR gene rearrangements. One should also be aware of T-cell “pseudoclonality” when only a few T cells are present in a sample. CD10 expression is variable and less often found in diffuse lesions but BCL6 should be present. IRF4/ MUM-1 is not expressed and, unlike DLBCL, leg type, cytoplasmic IgM and IgD are usually negative (some cases presenting on the leg are IgM+ in 1 of 2 studies).53,54 Although perhaps still controversial, BCL2 protein expression ranging from weak to strong is reported in 0% up to 86% of primary cutaneous follicular lymphoma, with its presence more common in cases with fewer centroblasts.50IGH@/BCL2 translocations are reported in 10% to 41% of primary cutaneous follicular lymphomas, with its presence also more common in cases with fewer centroblasts.50 One must remember that PCFCL is a broader category than follicular lymphoma so that these studies do not reflect the proportions one would find using the 2008 WHO criteria for PCFCL. A study of “early” diffuse PCFCL reported BCL2 protein expression in 29% of cases (majority of cells positive in 17%) and a BCL2 translocation in 8%.46 In general, however, BCL2 expression and BCL2 translocations are more common in nodal-type follicular lymphoma. Their presence in a primary cutaneous follicular lymphoma is not, however, thought to be of clinical significance. Nevertheless, when present, they should raise the possibility of secondary involvement. Other genotypic abnormalities are also reported, including c-REL amplification (63%) as seen in germinal center type DLBCL, deletion of 14q32.33 (68%, which may account at least in part for the surface immunoglobulin–negative cases) and aberrant somatic hypermutation of certain proto-oncogenes.55,56 9p21 abnormalities that are a feature of leg-type DLBCL are not reportedly present.57,58 However, as illustrated by 1 workshop case, they may have a very complex phenotype (Case 316: 89, XXXX, −4,−6,−8,−10,+12,t(14;18) (q32;q21)x2[cp3]/46, XX[18]).

Differential Diagnostic Difficulties

As with the cutaneous MZL, the first major problem with these cases is being certain that they are neoplastic. Follicular hyperplasia that can mimic a PCFCL (or even a DLBCL) is well recognized, for example, with B burgdorferi infection or tick bites.59 As mentioned before, in several cases in the workshop even the panel could not decide with certainty whether a lymphoma represented a PCFCL or MZL (sometimes with possible follicular colonization). Although cells with CD10 and/or strong BCL6 positivity outside the follicles would favor a PCFCL, it may be difficult to assess what actually is still within the follicles; even in PCFCL, the cells outside the follicles may be negative. In addition, moderate BCL6 staining, which may be spurious, is seen sometimes in non–germinal center type B cells, including marginal zone cells. In both benign situations and MZLs, the follicles present may appear as if some germinal center type areas are at the periphery of the follicles abutting the interfollicular areas, rather than in the more central portions, or simply eccentrically placed as in usual hyperplastic follicles. This unusual appearance should not be taken as absolute evidence of a PCFCL. Another issue, clearly illustrated in the workshop cases, is the distinction of PCFCL from secondary cutaneous involvement by nodal-type follicular lymphoma. Staging data are critical in making this distinction, and in their absence, only a differential diagnosis can be provided.

Primary Cutaneous DLBCL, Leg Type

Primary cutaneous DLBCL, leg type, is the only other type of skin-specific B-cell lymphoma recognized by the 2008 WHO classification. It is a rapidly growing lymphoma that occurs most frequently in elderly women and is defined as an aggressive B-cell lymphoma that usually, but not always, presents on the (lower) leg; it is composed of a generally monotonous proliferation of immunoblasts or, perhaps less often, centroblast-like transformed cells with few admixed reactive cells Image 8.6063 Most primary cutaneous lymphomas composed of large B cells that are not PCFCLs are of the leg type, but the literature is not consistent. In contrast to PCFCLs, the leg-type DLBCLs are more likely to disseminate to extracutaneous sites (50%), predominantly regional lymph nodes.48,61 An association with testicular DLBCL, another non–germinal center type DLBCL, has been reported.64 Primary cutaneous DLBCLs, leg type, are aggressive and have a 5-year survival rate of 55%.8 Current EORTC/ISCL recommendations are that DLBCL, leg type, should be treated with rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone or prednisolone (R-CHOP) with or without radiation therapy; however, the efficacy of this approach is not well documented.49 Whether radiation therapy alone is sufficient for single small lesions is “a matter of debate.”49 The presence of multiple lesions is an adverse prognostic indicator in some but not clearly in all studies.48,61,65

Image 8

Primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type, occurring predominantly as a subcutaneous mass at a non-leg site in an 89-year-old woman with history of DLBCL involving the dermis/subcutaneous tissue of the left shoulder 2 years earlier, presented with a slow growing 6-cm subcutaneous mass (A) localized on positron emission tomography– computed tomography scan to the right lower abdominal wall. B, A diffuse monotonous proliferation of large lymphocytes with a centroblast-like or rarely immunoblastic appearance is present. The tumor cells strongly express (C) BCL2 and (D) IRF4/ MUM1. They only focally express BCL6 and lack CD10 (not shown). This immunophenotype was the same as the earlier DLBCL; fluorescence in situ hybridization demonstrated a complex karyotype (not shown) with multiple MYC signals (also present in the earlier DLBCL). The patient was treated with rituximab, cyclophosphamide, hydroxydaunorubicin, Oncovin (vincristine), and prednisone or prednisolone (R-CHOP) and is in complete remission at 15 months’ follow-up. (Case 253, courtesy of Daniel Boyer, MD, PhD, and Judith Ferry, MD.)

Immunophenotypic studies are helpful in distinguishing these cases from other large B-cell lymphomas, including PCFCL. They have strong BCL2 expression (vs little in diffuse follicle cell lymphomas), express BCL6 but not CD10 in most cases, and are IRF4/MUM-1+ and FOXP1+ (vs usually absent in PCFCL).53,54.66 As with many lymphomas, exceptions to the classic immunophenotype are well documented. Also unlike most PCFCLs, they express cytoplasmic IgM ± IgD.53,54 One of 2 studies reports that PCFCL occurring on the leg is IgM+.

B-cell clonality is reportedly demonstrable in 100% of cases using BIOMED-2 primers, with the same clone sometimes found in lymph nodes, bone marrow, and/or blood (suggesting that the cases at least in this small study may not have truly met the criteria for a primary cutaneous lymphoma or have subtle dissemination).34 Based on the phenotypic profile, it is not surprising to learn that the leg-type DLBCLs have an activated B-cell gene expression profile.67 One cytogenetic FISH study demonstrated MYC8 or BCL67 translocations in 11 of 14 large B-cell lymphomas of the leg.68 Some conflicting cytogenetic findings have been reported which are difficult to reconcile.69 Leg-type DLBCLs sometimes show high-level amplification of the BCL2 gene and demonstrate deletion and/or methylation of the CDKN2A region on chromosome 9p21.3.5558 In one study, all 7 patients showing the latter abnormalities died of their disease.55 A subsequent larger study found a similar but less striking trend and noted that “Caution is warranted before these results are incorporated into clinical decision making.”70IGH@/BCL2 translocations are not present.

Differential Diagnostic Considerations and Other Types of Aggressive Type B-Cell Lymphomas Involving the Skin

As reviewed before, one of the major considerations to exclude before diagnosing a primary cutaneous DLBCL, leg type, is a PCFCL that is diffuse and has many large B cells. A second major consideration would be secondary skin involvement by a systemic DLBCL. Some may have spindle cell features (although many of these cases are now thought to represent PCFCL).63 Clinical data are required because it is unclear that DLBCL, leg type, has any easily documented unique features. Other considerations include other specific types of large B-cell lymphomas, a subject much too large to review here. The workshop included an example of a posttransplant lymphoproliferative disorder of B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and DLBCL type that was an MYC with BCL6 “double hit” lymphoma (which arose 17 years after transplantation); several CD30+ extracavitary primary effusion lymphomas that are human herpesvirus 8+ but usually not restricted to the skin; and 2 intravascular large B-cell lymphomas (IVL), including one that presented and recurred in angiomas Image 9.71 Primary cutaneous IVLs may be more frequent in women and may be more indolent than IVL in general.72 One case submitted to the workshop was treated with bimonthly rituximab, and the patient was alive with no evidence of disease at 5 years (Case 312). It is important to exclude a cutaneous intravascular T-cell lymphoma and skin involvement by systemic intravascular anaplastic large cell lymphoma.73,74 One must also exclude intralymphatic histiocytosis (an obscure subject brought to the attention of those at the workshop).75,76 Other specific types/subtypes of large B-cell lymphomas that may present in the skin also include cutaneous T-cell/histiocyte–rich large B-cell lymphoma which is believed to be more indolent than nodal cases77 and cutaneous plasmablastic lymphoma.78 Mantle cell lymphoma can present in the skin, as seen in 1 case submitted to the workshop, with most of these cases being blastoid.79 Finally, B lymphoblastic lymphoma/leukemia must be considered even with localized cutaneous lesions Image 10. These cases are well documented, and when properly treated can do well.80 One should remember to perform a terminal deoxynucleotidyl transferase stain whenever the possibility of a B lymphoblastic lymphoma/leukemia is in the differential diagnosis. These cases can resemble a DLBCL and can occur in adults as well as children. They need to be distinguished from myeloid neoplasms that can also express some lymphoid-associated antigens.81

Image 9

Intravascular large B-cell lymphoma (IVLBCL) arising and recurring in migratory cherry hemangiomas in a 76-year-old woman with a 4-mm cherry-red papule on her neck. A, Numerous small, dilated, dermal vessels are present. B, Some contain large transformed lymphocytes which express (C) CD45RB (LCA) and (D) CD79a. They also express CD20, BCL6, BCL2, IRF4/ MUM1 and focal, dim CD10, but lacked CD5, CD30, and Epstein-Barr virus–encoded small nuclear RNA (not shown). Results of staging studies were negative, and the patient declined therapy. At 2.5 years, a crop of 2- to 3-mm red papules arose on the flank and showed IVLBCL. Over the next few years, similar cutaneous lesions recurred. Some shrunk and others progressed with no evidence of systemic disease. Six years after initial presentation, the patient became unconscious; central nervous system lesions and diffuse lymphadenopathy were found, and the patient died 2 days later. (Case 41, courtesy of Harleen K. Sidhu, MBBCh, Daniel P. Bellina, MD, and Jagmohan S. Sidhu, MD.)

Image 10

Cutaneous B lymphoblastic lymphoma in a 78-year-old woman with a 1-year history of a slowly enlarging nodule on her left leg. A, A diffuse, monotonous, dermal infiltrate of medium to large lymphocytes with finely dispersed chromatin and variably prominent nucleoli is present. B, The lymphocytes lack CD20, but (C) strongly express CD19, PAX5 (not shown) (D) terminal deoxynucleotidyl transferase, and to a lesser extent CD79a (not shown). Although IRF4/MUM1 was strongly expressed, CD138 was negative, as were CD34 and CD99 (not shown). Results of staging studies were negative, and the patient was treated with multiagent chemotherapy. She experienced a relapse with several cutaneous nodules followed by an orbital mass. (Case 180, courtesy of Nicolas Ortonne, MD, PhD.)

Cutaneous Immunodeficiency-Associated Lymphoproliferative Disorders Including Epstein-Barr Virus–Positive Age-Related Lymphoproliferative Disorders and “Mucocutaneous Ulcer”

Probably the most complicated issue for the panel to deal with was the cutaneous immunodeficiency-associated lymphoproliferative disorders. These cases were mostly Epstein-Barr virus (EBV)–positive, generally polymorphous lymphoplasmacytic proliferations with a significant large transformed/immunoblastic and often Reed-Sternberg–like component. Some resembled DLBCLs more closely and others had many Hodgkin-like features, with the distinction from classical Hodgkin lymphoma sometimes very difficult if not impossible. The diagnosis, however, of classical Hodgkin lymphoma in the skin, should be made only with extreme caution. The majority of these lesions were related either to methotrexate or “old age” (EBV+ DLBCL of the elderly). The biggest issue raised at the workshop related to whether they should be categorized based on the 2008 classification (iatrogenic-associated lymphoproliferative disorder or EBV+ DLBCL of the elderly) or if, independent of the cause for the immunodeficient state, a significant subset should be categorized as “EBV+ mucocutaneous ulcer.”8284 These clinically frightening lesions can involve the skin; are composed of a polymorphous infiltrate with large, atypical, transformed B cells with variable CD20 expression that often resemble Reed-Sternberg cells and variants; and are CD30 and EBV-encoded small nuclear RNA in situ hybridization positive Image 11. Almost half of the cases reported also were CD15+, which, together with the histopathology, will cause confusion with Hodgkin lymphoma. Some have clonal IGH rearrangements, some clonal TCR gene rearrangements, and others are polyclonal. One case report describes Reed-Sternberg–like cells that had both IGH and TCR rearrangements.83 Most of these cases have been associated with “age-related immunosenescence” but others are seen in patients, for example, who are receiving methotrexate. The disease appears to be indolent, with spontaneous remissions and response to reduction in iatrogenic immunosuppression. In fact, among those with age-related EBV+ lymphoproliferative disorders, the disease-related mortality for the mucocutaneous ulcer group overlapped those with reactive hyperplasia; 100% of both groups were still alive at the time of publication.84 Some received varied antineoplastic therapies. Whether this subset of cases does well because it is a localized proliferation was discussed. Although still controversial, the panel members at the workshop considered those cases associated with methotrexate as a type of methotrexate-associated lymphoproliferative disorder. It was also felt that the precise criteria for distinction from cases of EBV+, diffuse, large B-cell lymphoma of the elderly in the presence of numerous transformed cells needed to be refined. Whatever terminology is used, however, it is imperative that these cases be recognized for what they are so they are not overtreated. Use of distinctive terminology may aid in this endeavor. In addition, these cases should be distinguished from traumatic ulcerative granuloma with stromal eosinophilia which occurs in oral mucosa including the lower lip and also may have CD30+ cells and a monoclonal population of T cells (as discussed by Sarantopoulos et al in this issue of the Journal).1,85,86 EBV also may be present.85 Recently it was suggested that traumatic ulcerative granuloma with stromal eosinophilia may in fact be considered a CD30+ lymphoproliferative disorder.87

Image 11

Epstein-Barr virus (EBV)+ age-related lymphoproliferative disorder presenting as an ulcerated cutaneous mass (“mucocutaneous ulcer”) in a 79-year-old man with a rapidly growing ulcerating mass on the right cheek. A, A dense, diffuse, somewhat band-like, polymorphic lymphoid infiltrate is present below a sharply circumscribed, ulcerated epidermis. B, Many of the lymphocytes are large pleomorphic cells, and some have a Reed-Sternberg (RS)–like appearance. Many of the cells at the ulcer base are (C) CD30+, (D) Epstein-Barr virus–encoded small nuclear RNA+ (LMP1+, not shown), with (E) numerous, smaller, CD3+ T cells (predominantly CD4+, not shown) concentrated at the ulcer base. F, The large cells express CD20 and (G) some RS-like cells express CD15. Despite the aggressive clinical and histologic appearance, the lesion underwent spontaneous regression. (Case 246, courtesy Qing Yan Liu, MD, Stefan D. Dojcinov, MD, and Elaine S. Jaffe, MD.)


Important diagnostic pearls are summarized Table 2. Evaluation of nonepidermotropic lymphoplasmacytic cutaneous infiltrates in the absence of features suggesting a specific benign diagnosis often raises the question of one of the B-cell lymphomas. Evaluation of these cases requires a multiparameter approach including a good clinical history, histologic sections of a representative biopsy, immunophenotypic findings, and sometimes molecular and cytogenetic studies. Consider the possibility of either a benign diagnosis or one of the major primary cutaneous lymphomas—an MZL in which the neoplastic cells may make up only a minor component; a cutaneous follicle center lymphoma which may resemble a typical nodal follicular lymphoma or be totally diffuse, with many large cells and a significant centrocyte population; or a diffuse large B-cell lymphoma, leg type, that might not even be on the leg. Also remember the possibility of one of the B-cell lymphomas that typically occurs elsewhere but can present in the skin, the possibility of secondary cutaneous involvement by a nodal or other type of extranodal B-cell lymphoma, or even a T-cell lymphoma that might have monotypic plasma cells. In many cases, a definitive diagnosis will be possible; however, in a moderate number of cases even the experts can only provide a descriptive diagnosis. Particularly for the indolent lymphomas, an overly conservative diagnosis is preferable to a falsely positive one in which a benign process is diagnosed as a malignant lymphoma.

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We thank the workshop participants for their case submissions and for use of their images.


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