B-Cell Lymphomas of the Skin

Introduction

Although B-cell lymphomas represent the majority of non-Hodgkin lymphomas (NHLs) arising within lymph nodes , they represent a minority of the NHLs whose primary site is the skin . In the classification of cutaneous lymphomas published by the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Project Group ( Table 119.1 ), B-cell lymphomas represented 22.5% of all cutaneous lymphomas . The WHO-EORTC classification has been integrated with only minor changes into the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published in 2008 and updated in 2016 (see Table 119.1 ) .

Primary cutaneous lymphomas are defined as malignant lymphomas confined to the skin at presentation after complete staging procedures . In general, most patients with primary cutaneous B-cell lymphoma (pCBCL) are diagnosed by dermatologists, as extracutaneous symptoms and signs are observed only very rarely at the onset of the disease. Consequently, dermatologists should be conversant with the clinicopathologic features of this group of diseases, in order to be able to establish the diagnosis in its early stages. Additionally, as aggressive treatment modalities are needed only in selected cases, these patients should be managed primarily by dermatologists with special expertise in cutaneous lymphomas.

History

In the past, cutaneous B-cell lymphomas were thought to be invariably secondary, that is, due to dissemination of extracutaneous (usually nodal) B-cell lymphomas to the skin. In the 1980s, it was recognized that B-cell lymphomas whose primary site is the skin, i.e. pCBCLs, represent a distinct group of extranodal lymphomas . The widespread use of immunohistochemical and molecular genetic techniques that can establish clonality, in particular the detection of rearrangements of immunoglobulin genes by PCR (utilizing routine biopsy samples), has shown that some of the cases previously classified as cutaneous B-cell pseudolymphomas harbor a monoclonal population of lymphocytes, thus representing low-grade malignant B-cell lymphomas of the skin .

Epidemiology

For the past several decades, the incidence of pCBCL had been rising, but now appears to have stabilized . pCBCLs may occur more frequently in specific regions of the world. For example, analysis of data from four academic centers in the US showed that they represented only 4.5% of all the cases of primary cutaneous lymphoma registered in those centers . In contrast, pCBCL represented 22.5% of all the cases of primary cutaneous lymphoma in the Dutch and Austrian registries for cutaneous lymphomas .

Regional variations have also been observed with regard to the incidence of specific types of pCBCL. In the two largest series published to date, the relative frequencies of follicle center lymphoma and marginal zone lymphoma varied considerably. Follicle center lymphoma represented 71% of all pCBCLs in the Netherlands, but only 41% in Graz; conversely, marginal zone lymphoma represented 42% of all cases of pCBCL in Graz, but only 10% in the Netherlands. On the other hand, the relative frequency of the third most common type of pCBCL, the diffuse large B-cell lymphoma, leg type, was similar in the two series (~15%), indicating that, in these two series, differences in the relative frequencies were confined to B-cell lymphomas characterized by an indolent behavior. This suggests that these variations may be due, at least in part, to a different classification of patients in different centers.

In addition to differences in diagnostic and classification standards, true regional variations in the incidence of special types of pCBCL may be due to the presence of different etiologic factors. For example, the association between pCBCL and infection with specific Borrelia species in endemic areas has been known for many years (see below and Ch. 74 ). This association may explain, in part, regional differences in the incidence of pCBCLs, but the relatively low percentage of such cases (even in countries with endemic Borrelia infections) suggests that other etiologies are also involved in regional variations.

pCBCL affects adults of both sexes. With the exception of precursor B lymphoblastic lymphoma/leukemia (which only rarely represents an example of true pCBCL), CBCLs are uncommon in children and adolescents.

Etiology and Pathogenesis

The pathogenesis of pCBCL is unknown. In contrast to the many nodal B-cell lymphomas that have been linked to specific genetic alterations (e.g. nodal follicular lymphomas and interchromosomal 14;18 translocations), there are relatively limited data on the specific genetic features of pCBCLs, especially for low-grade subtypes (for details see below).

Some similarities to the clinicopathologic features observed in B-cell lymphomas arising in the gastric mucosa (so-called mucosa-associated lymphoid tissue [MALT] lymphomas) led to the hypothesis that pCBCLs are caused by longstanding antigenic stimulation, possibly due to chronic infection with specific microorganisms. In fact, it has been long established that MALT lymphomas originating in the stomach are linked to chronic antigenic stimulation due to infection with Helicobacter pylori. As previously mentioned, Borrelia spp. are thought to play an etiologic role in a minority of cases of pCBCL, particularly in Europe. In patients from a region in Austria with endemic Borrelia infections, specific DNA sequences of Borrelia were detected in 18% of all cases of pCBCL ; similar findings have been reported from Scotland .

At present, no other microorganism has been convincingly linked to the development of pCBCL. However, it should be noted that pCBCLs have been described in immunosuppressed patients, including those with AIDS and solid organ transplant recipients, and reversible pCBCLs have been observed in patients undergoing therapy with methotrexate (in particular those with rheumatoid arthritis), thus suggesting that immune dysregulation may play a role in the development of this disease .

Clinical Features

In the WHO-EORTC 2005 and WHO 2008/2016 classification schemes, pCBCLs have been divided into four major types (see Table 119.1 ) . Follicle center lymphoma and marginal zone B-cell lymphoma are characterized by an indolent clinical behavior, whereas diffuse large B-cell lymphoma, leg type, and intravascular diffuse large B-cell lymphoma have an aggressive clinical behavior. It must be emphasized that, in addition to pCBCLs, the skin can be a site of secondary involvement for practically all types of extracutaneous (usually nodal) B-cell lymphomas and leukemias. Consequently, complete staging should be performed in all patients with a confirmed diagnosis of B-cell lymphoma involving the skin. This includes a complete blood examination, flow cytometry of peripheral blood, CT examination of the chest, abdomen and pelvis, and, if possible, positron emission tomography (PET). Internationally, bone marrow biopsy (with flow cytometry of the aspirate) is still recommended in follicle center lymphoma, diffuse large B-cell lymphoma, leg type, and intravascular diffuse large B-cell lymphoma, but seems to be of limited value in cutaneous marginal zone lymphoma . In fact, the need for extensive staging investigations in patients with a confirmed diagnosis of cutaneous marginal zone lymphoma is questionable. Likewise, extensive radiologic imaging seems to be superfluous in the follow-up of patients with indolent types of pCBCL confined to the skin . A recommended staging evaluation for patients with CBCL is summarized in Table 119.2 .

Primary Cutaneous Follicle Center Lymphoma

P rimary c utaneous f ollicle c enter l ymphoma (PCFCL) is defined as a neoplastic proliferation of germinal center cells confined to the skin. It represents a common subtype of pCBCL.

Clinically, patients present with solitary or grouped, pink- to plum-colored papules, plaques or tumors, which, especially on the trunk, can be surrounded by patches of erythema ( Figs 119.1 & 119.2 ) . The term Crosti's lymphoma has been used to denote those patients with a peripheral patch of erythema. Ulceration is uncommon. Occasionally patients present with miliary and/or agminated small papules that can have an acneiform appearance . Preferential locations are the scalp and forehead or the back. The skin lesions are usually asymptomatic, and, as a rule, B symptoms (i.e. fever, night sweats, weight loss) are rare. The serum level of lactate dehydrogenase (LDH), which is a powerful prognostic factor in systemic lymphomas, is within normal limits.

The prognosis is favorable . Recurrences are observed in up to 50% of patients, but dissemination to lymph nodes or internal organs is rare.

Primary Cutaneous Marginal Zone B-Cell Lymphoma (Extranodal Marginal Zone Lymphoma of the Mucosa-Associated Lymphoid Tissue - MALT Lymphoma)

P rimary c utaneous m arginal z one B-cell l ymphoma (PCMZL) has been recognized as a distinct variant of low-grade malignant pCBCL . In the WHO classification of 2008/2016 , it has been grouped with other extranodal marginal zone lymphomas of m ucosa- a ssociated l ymphoid t issue (i.e. MALT lymphomas). Of note, cases classified in the past as primary cutaneous immunocytoma or primary cutaneous plasmacytoma represent examples of PCMZL with prominent lymphoplasmacytic or plasmacytic differentiation, respectively, and the terms cutaneous immunocytoma and cutaneous plasmacytoma are not used in the WHO-EORTC and WHO 2008/2016 classification schemes .

Clinically, patients present with recurrent pink–violet to red–brown papules, plaques, and nodules that favor the extremities (upper > lower) or trunk ( Figs 119.3 & 119.4 ). Generalized lesions can be observed in a small number of patients. Ulceration rarely occurs and skin lesions are usually asymptomatic. As a rule, B symptoms (i.e. fever, night sweats, weight loss) are not present. The serum level of LDH is within normal limits. In some instances, resolution of lesions may be accompanied by secondary anetoderma due to loss of elastic fibers in the area of the tumor infiltrate.

The prognosis of PCMZL is excellent. In a study of 32 patients with PCMZL, none of them developed lymph node or internal involvement during a mean follow-up of more than 4 years .

Of note, PCMZL can arise in areas affected by acrodermatitis chronica atrophicans and it may be linked to infection by Borrelia spp. more frequently than are other types of pCBCL, particularly in Europe .

Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type

Primary cutaneous d iffuse l arge B - c ell l ymphoma, l eg t ype (DLBCLLT), represents a form of pCBCL that is characterized by a predominance of large round cells (centroblasts, immunoblasts) positive for Bcl-2, MUM-1 ( mu ltiple m yeloma oncogene 1 or interferon regulatory factor 4 [expressed by post germinal center B cells and plasma cells]), and FOX-P1 . It occurs almost exclusively in elderly patients, predominantly women.

Clinically, patients present with solitary or clustered, erythematous to red–brown nodules, located primarily on the distal aspect of one leg ( Fig. 119.5 ). In some patients, lesions may arise on both lower extremities contemporaneously or within a short interval of time. Ulceration may occur. Small erythematous papules can be seen adjacent to larger nodules. It must be emphasized that in ~20% of patients, tumors with similar morphologic and phenotypic features can arise in areas other than the lower extremities, but the designation DLBCLLT is still applied .

The prognosis of DLBCLLT is less favorable than that of other types of pCBCL, with an estimated disease-specific 5-year survival rate of 40–50% . Molecular data revealed that 9p21 deletions, possibly due to loss-of-function of CDKN2A (encodes p16 and p14 ^ARF ), are associated with a worse prognosis .

It must be stressed that some patients with nodal large B-cell lymphoma can present with secondary cutaneous lesions located exclusively on the legs, underlying the need for complete staging investigations before a diagnosis of DLBCLLT can be established. The addition of PET scans to CT studies is a useful way of discovering evidence of systemic disease.