Cutaneous T-Cell Lymphoma and Cutaneous B-Cell Lymphoma

Introduction and Classification

Non-Hodgkin T- and B-cell lymphomas can arise either primarily or secondarily in skin. Primary cutaneous lymphomas have no extracutaneous disease at diagnosis. They comprise a heterogeneous group of cutaneous T-cell lymphomas (CTCLs), cutaneous B-cell lymphomas (CBCLs), natural killer (NK) T-cell, and precursor hematopoietic neoplasms with distinct variability in clinical presentation, histopathology, immunophenotyping, gene rearrangements or mutations, and prognosis. The diversity of clinical and pathologic manifestations among cutaneous lymphomas has created controversies related to diagnosis and classification. New variants and consensus guidelines were published by World Health Organization and European Organization for Research and Treatment of Cancer (WHO/EORTC) in 2005. These guidelines were incorporated into the revised fourth WHO classification of tumors of hematopoietic and lymphoid tissues in 2008 using the existing framework for nodal lymphomas. However, differences remain, particularly to the subclassification of cutaneous B-cell lymphomas (CBCLs). Reclassification and consensus treatment guidelines for the CBCLs were published by the European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma in 2008.

The WHO/EORTC classifies cutaneous lymphomas as indolent, intermediate, or aggressive. The most common CTCLs are mycosis fungoides (MF), which starts as indolent skin lesions but may transform to large cells, and Sézary syndrome (SS), which is characterized by erythroderma, leukemia, pruritus, and poor overall survival (OS) ( Table 104.1 ). Together MF/SS patients make up 53% of all cutaneous lymphomas. The term CTCL is often used synonymously with MF/SS , but this is incorrect, overlooking other CTCLs. Human T-cell lymphotrophic virus type I (HTLV-I)–associated adult T-cell lymphoma/leukemia (ATLL) can have lesions clinically identical to MF/SS and is found in Japan and the Carribean.

Primary cutaneous CD30+ lymphoproliferative disorders comprise 10% to 20% of CTCLs. The benign end of the spectrum is self-regressing lymphomatoid papulosis (LyP), which overlaps with primary cutaneous anaplastic large cell lymphoma (pc-ALCL), which is characterized by nonregressing tumors. LyP includes self-regressing small papules that may ulcerate and leave scars. Pc-ALCL differs from type C LyP by larger lesions (>2 cm) and failure to regress. LyP histology may recapitulate other CTCLs, including HD (type A), MF (type B), ALCL (type C), and CD8+ (type D) as well as case reports of other uncommon variants. A new classification based on histology has recently been proposed by Kempf and coworkers. Although MF is not considered part of the CD30+ lymphoproliferative spectrum, MF may express CD30 and is distinguished from pc-ALCL by the coexistence of patch or plaque lesions. We found that the T-cell gene rearrangements were identical in lesions of LyP and MF patch or plaques, suggesting that the distribution of T cells in lesions is responsible for their clinical appearance and helps to explain the high incidence of second malignancies.

Cutaneous CD4+ small- to medium-sized pleomorphic T-cell lymphoma, formerly considered as a peripheral T-cell lymphoma, is now recognized as small- to medium-sized pleomorphic CD4+ T-cell lymphoproliferative disorder similar to T-cell pseudolymphoma. It presents as a solitary indolent papule or plaque with dermal lymphoid infiltrate composed of small to pleomorphic lymphocytes with mild atypia. Subcutaneous panniculitis–like T-cell lymphoma can share features of lupus panniculitis and is indolent and distinguished from the aggressive Epstein-Barr virus (EBV)–associated subcutaneous CTCL. Unclassifiable primary cutaneous peripheral T-cell lymphomas are grouped as a not otherwise specified lymphoma (PTCL-NOS). Provisional entities that can be aggressive or not include cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and cutaneous γ/δ T-cell lymphoma. Extranodal natural killer (NK)/T-cell lymphomas, nasal type, and non-nasal type, are aggressive EBV-associated cytotoxic lymphomas. The skin is the second most commonly involved area after the upper aerodigestive tract, and the prognosis is poor. NK T-cell lymphomas can also present in skin without EBV or nasal-mucosal involvement and rapidly progress. Blastic plasmacytoid dendritic cell neoplasms arise from plasmacytoid dendritic cells and may rapidly become leukemic. This rare and aggressive immature hematopoietic neoplasm was previously called blastic NK cell lymphoma and CD4+/CD56+ hematodermic neoplasm .

B-cell tumors comprise only 20% to 25% of all cutaneous lymphomas. The WHO/EORTC classification includes three main types of primary CBCL: mucosa-associated lymphoid tissue (MALT), follicle center cell lymphoma, and diffuse large B-cell lymphoma (DLBCL), leg type. There exist DLBCL, other, that may have evolved from a follicular center cell lymphoma representing transformed disease. Other morphologic variants of DLBCL and intravascular large B-cell lymphoma, defined by intravascular accumulation of malignant B lymphocytes, are usually recognized as systemic lymphoma involving the skin secondarily.

Epidemiology

Cutaneous lymphomas represent about 3.9% of all non-Hodgkin lymphomas (NHLs). Frequency and survival data used in the WHO/EORTC classification are based on Dutch and Austrian registries. Cutaneous lymphoma incidence patterns were studied using data from 3884 patients from 16 Surveillance Epidemiology and End Results (SEER) program registries in the United States from 1980 through 2005. CTCLs accounted for 71% and CBCLs for 29% of all lymphomas. MF accounted for 38% of all CTCLs followed by cutaneous PTCL (20%) and CD30+ lymphoproliferative disorders (10%). The age-adjusted annual incidence of CTCLs in the United States with most cases classified as MF has increased from 2.8 per million (1973–1977) to 9.6 per million (1998–2002), according to data from Criscione and Weinstock, and from 5.0 per million to 12.7 per million, according to Bradford and associates. MF is the most common type of CTCL, with a predominance of male to female patients of approximately 2 : 1 and a predominance of African American patients of 1.6 : 1. The median age at presentation is between 50 and 70 years with only a small number of cases occurring in children and young adults. CBCL incidence rates are highest in non-Hispanic whites with a male predominance and an exponential increase with age. The most common primary CBCL subtypes are cutaneous DLBCL, follicle center cell lymphoma, and marginal zone lymphoma, comprising 40%, 30%, and 25% of all cases of CBCL, respectively.

Etiology

Despite rising incidence rates of CTCL, its exact cause is still mostly unknown and may reflect the disease heterogeneity. Persistent antigen stimulation could be provided by various sources coupled to loss of apoptosis, and unchecked T-cell activation should result in accumulation of skin-homing helper/memory T cells. Although a single common antigen is not expected, microbiological, environmental, occupational, and lifestyle factors have been proposed. Geographical hotspots of MF have recently been reported as well. Unlike ATLL, which can clinically resemble MF, most patients with CTCL are serologically negative for HTLV-I. Other investigators have found serologic evidence for EPV and cytomegalovirus (CMV), but these findings have not been substantiated. Immunosuppression, immunosuppressive therapy, or both might be another risk factor for CTCL documented in patients after treatment with tumor necrosis factor-α (TNF-α) antagonists, organ transplant, Hodgkin disease, and human immunodeficiency virus (HIV)-infection.

Cutaneous T-Cell Lymphoma

Mycosis Fungoides and Sézary Syndrome

Mycosis fungoides is the prototype of CTCL and the best studied. Classic MF appears in middle age and has an indolent course; even without treatment, MF has slow progression over years or even decades. There have been several large cohort studies of OS in patients with MF/SS.

The median OS time of a US cohort of MF/SS patients was 24 years and only in advanced patients were males more common than females. MF commonly presents with chronic dermatitis in sun-protected areas of the lower abdomen and waist, upper thighs, buttocks, inner upper arms, and breasts in women. MF may start as subtle erythematous pink, white, or tan patches present on less than 10% of the body surface area (BSA; T1) to more extensive patches or plaques on more than 10% BSA (T2) ( Fig. 104.1 ). About 30% of patients have skin tumors (T3) or erythroderma (T4) at initial presentation. Pruritus or burning may be associated. In the majority of patients, MF stays limited to the skin, but 10% to 20% of patients progress to higher stages or extracutaneous disease, which has an estimated 5-year survival rate of 25% to 40%. A recent study suggests that patients who were cared for in a setting with more patients had better survival.

Mycosis fungoides has numerous clinical and histologic variants. Juvenile MF is a CD8+ hypopigmented variant appearing in children often with very low vitamin D levels and responds to ultraviolet (UV) B phototherapy. Besides the conventional type of MF, three distinct variants have been recognized in the 2005 WHO/EORTC classification and multiple others described. Folliculotropic MF can present as a patch of alopecia mucinous or with numerous skin lesions, including erythematous follicular papules, plaques, and nodules; alopecia areata; and comedones, acneiform, and cystic lesions, often associated intractable pruritus. Folliculotropic MF frequently presents on scalp, face, or neck in contrast to conventional MF, which favors sun shielded areas. The histology shows perifollicular T cells with or without mucin deposition. Folliculotropic MF is more aggressive, and patients may not respond to topical therapy and may require systemic therapy, especially electron-beam radiation, to achieve clinically meaningful responses. The 10-year progression-free survival (PFS) rate is 45% compared with 91% in patients with conventional MF. A variant is syringotropic MF characterized by T-cell infiltrates in the sweat glands. Pagetoid reticulosis or Woringer-Kolopp disease presents in middle-aged men as a solitary psoriasiform plaque or tumor located on the foot or lower leg. In contrast to classic MF, the epidermotropic atypical lymphocytes have a CD8+ phenotype. Granulomatous slack skin syndrome is extremely rare and evolves over time from deep red patches and plaques to pendulous areas ( Fig. 104.2 ). Poikilodermatous patches in the groin or axilla first appear with subsequent dermal elastosis forming lax skin. The histology shows a diffuse dermal infiltrate of giant cells and atypical lymphocytes with destruction of elastic fibers and a rearranged T-cell receptor gene.

Sézary syndrome is the most severe leukemic, erythrodermic variant of CTCL-MF by the International Society for Cutaneous Lymphomas (ISCL) ( Table 104.2 ). A total of 3% to 5% of all newly reported cases of CTCL are SS, and 10.3% are erythrodermic. Erythrodermic MF SS can either develop de novo or may progress from preexisting MF. Erythrodermic patients may also have coexisting patches, plaques, or tumors. The criteria for the diagnosis of SS requires blood involvement with more than 1000 circulating, atypical, malignant T lymphocytes with cerebriform nuclei (Sézary cells), erythroderma defined as 80% of the body surface, and lymphadenopathy, which can be dermatopathic or effacement. Patients who do not fit this criteria are called erythrodermic MF or leukemic MF (or CTCL). Severe, disabling pruritus, ectropion, lymphoma-associated alopecia, palmoplantar keratoderma with fissures, and dystrophic nails are other common associated features ( Fig. 104.3 ). Concomitant infection with dermatophytes is found in 60% of SS patients with keratoderma. Patients with SS are immunocompromised because of defective T-cell function and predisposed to opportunistic skin infection. In addition, the erythroderma is worsened by chronic colonization with Staphylococcus aureus in 60% .

Table 104.2

Proposed Classification for Erythrodermic Cutaneous T-Cell Lymphoma (CTCL) and Relative Hematologic Criteria Devised by the International Society for Cutaneous Lymphoma

From Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas . J Am Acad Dermatol . 2002;46:95–106.

Erythrodermic CTCL	Preexisting MF	Blood Findings	TNMB Classification
Sézary syndrome	Rarely	Leukemic	T4, N0–N3, M0–M1, B2 a
Erythrodermic MF	Always	Absent or minimal	T4, N0–N3, M0–M1, B0–B1 a
Erythrodermic CTCL, NOS	Absent	Absent or minimal	T4, N0–N3, M0–1, B0–1B a

MF, Mycosis fungoides; NOS, not otherwise specified; TNMB, tumor, node, metastasis, blood.

a B0, <5% circulating Sézary cells; B1, Sézary cell count of <1000 cells/m ³ or <20% atypical T cells on peripheral smear; B2, Sézary cell count of >1000 cells/m ³ or >20% atypical T cells on peripheral smear.

Making a histopathological diagnosis of MF or SS may be difficult, especially if steroids have been applied recently. In early lesions and erythroderma, inflammatory T cells often predominate, resembling benign dermatoses. Patients may have multiple biopsies before the definite diagnosis. The dermatopathologist may not appreciate that perivascular distribution, not epidermotropism, is a diagnostic feature.

An algorithm for diagnosis of early MF was proposed by the ISCL and the Cutaneous Lymphoma Task Force of the EORTC that takes the clinical and histopathological findings into account ( Table 104.3 ). In addition, the staging and classification of MF/SS was published by Olsen and coworkers. Early MF has a sparse papillary dermal band–like infiltrate with epidermotropism of atypical lymphocytes with a CD4+ T-helper (Th2)/memory phenotype. The atypical lymphocytes have hyperchromatic, hyperconvoluted nuclei and are epidermotropic with infrequent Pautrier microabscesses ( Fig. 104.4 ) Pagetoid reticulosis and hypopigmented juvenile MF lymphocytes have a cytotoxic/suppressor T-cell CD8+ phenotype. SS biopsies show perivascular infiltrates and loss of epidermotropism, and flow cytometry shows an aberrant T-cell clone that lacks CD26 or CD7. Tumor stage MF (T3) presents with or without large cell transformation and must be differentiated from non-MF subtypes of CTCL such as PTCL NOS, γδ-CTCL, ALCL, or NK T-cell lymphoma. In conventional MF, tumor lesions usually develop in the setting of patch or plaque disease, but de novo tumors (d'emblée MF) can arise on the face (folliculotropic) or express CD30 like pc-ALCL. It should be noted that MF cannot be diagnosed from a lymph node (LN) biopsy and will be incorrectly diagnosed as PTCL-NOS if cutaneous lesions are not appreciated and biopsied.

Table 104.3

Key Diagnostic Criteria for Mycosis Fungoides/Sézary Syndrome

From Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC). Blood . 2007;110:1713–1722.

Criteria	Major (2 Points)	Minor (1 Point)
CLINICAL
Persistent and/or progressive patches or plaques plus:	Any 2	Any 1
Sun-protected areas
Size or shape variation
Poikiloderma
HISTOPATHOLOGICAL
Superficial lymphoid infiltrate plus:
Epidermotropism without spongiosis	Both	Either
Lymphoid atypia
Molecular
Clonal TCR rearrangement		Present
Immunophenotypic
CD2, CD3, CD5 <50% of T cells		Any 1
CD7 <10% T cells
Epidermal discordance from CD2, CD3, CD5, or CD7 phenotype of dermal T cells

TCR, T-cell receptor.

Immunophenotyping by immunohistochemistry or flow cytometry plays an important role in evaluating the type of CTCL and making a correct diagnosis. There is no unique marker for the malignant lymphocyte, but an increased CD4-to-CD8 ratio with an aberrant loss of T-cell lineage markers such as CD5, CD7, or CD26 is a common finding. Clonal gene rearrangements of the T-cell receptor β or γ chains are detected in many cases and support the diagnosis. Standard polymerase chain reaction (PCR) methods and high-input genomic sequencing are becoming standards of care. However, clonality may be detected in benign skin disorders. Furthermore, data on microsatellite DNA studies suggest that tumor cells may arise from multiple subclones and show a multiple-lineage progression.

Staging and Prognosis

Accurate staging of patients with MF/SS is essential both for its prognostic value and for treatment decisions. The widely used and recommended staging system for CTCL relies on the TNMB (tumor, node, metastasis, blood) classification adopted by Bunn and Lamberg in 1979, which was revised by the ISCL and EORTC ( Table 104.4 ). It considers the extent of skin involvement (T), presence of LN (N) and visceral disease (M), and detection of Sézary cells in the peripheral blood (B). Patients with patch or plaque disease are classified as either stage IA (T1, N0, M0, B0) with less than 10% of BSA involved or stage IB (T2, N0, M0, B0) with more than 10% BSA involved. By rule of thumb, the palm and digit of one patient hand represent 1% of BSA. Stage IIA disease (T1–2, N1, M0, B0) includes patients with skin findings of stage IA/IB disease with architectural preservation of any clinically abnormal LNs. Currently, two histopathological grading systems, the Dutch and the National Cancer Institute/Veterans Administration (NCI-VA) classification system for LN evaluation, are used. Whereas the Dutch system is based on the presence of large cerebriform nuclei (>7.5 µm) and the degree of architectural effacement, the NCI-VA system uses the relative numbers of such cells in the paracortex of LNs and nodal architecture to determine the extent of disease. Nodal involvement is characterized by partial (N2) or complete (N3) architectural effacement. Stage IIB (T3, N0–2, M0, B0) is associated with the development of skin tumors with or without associated LN involvement. The ISCL/EORTC has recommended definitions based on the degree of blood involvement for subsets of erythrodermic patients. B1 rating is defined as a Sézary cell count of more than 250 cells (B0) and less than 1000 cells/m ³ or less than 20% Sézary cells on peripheral smear. B2 rating is more than 1000 cells/m ³ or greater than 20% Sézary cells on peripheral smear. Patients with erythroderma without significant LN involvement are stratified into stage IIIA (T4, N0–2, M0, B0) and stage IIIB (T4, N0–2, M0, B1) based on the presence of low blood tumor burden (B0 or B1) that allows for tracking of its prognostic significance in erythrodermic CTCL. High blood tumor burden B2 (>1000) SS and B3 (>10,000) SS cells are independent prognostic variables as shown; the B2 rating is now considered to be comparable to nodal involvement (N3). Stage IVA is therefore any skin stage with either blood (B2) or nodal disease (N3). Stage IVB is defined by any stage with visceral involvement (M1). The ISCL/EORTC considers splenomegaly even without biopsy confirmation as visceral disease. Suspected liver or bone marrow disease should be confirmed by biopsy. Bone marrow biopsies are not commonly done and are not part of the staging system; however, many consider their weight similar to blood involvement (IVA1).

Table 104.4

TNMB Classification and Staging for Patients With Mycosis Fungoides/Sézary Syndrome

T (SKIN)
T1	Limited patch or plaque (<10% of BSA)
T2	Generalized patch or plaque (>10% of BSA) T2a = patch only
T3	One or more tumors (>1 cm)
T4	Generalized erythroderma (>80% of BSA)
N (NODES)
N0	No clinically abnormal peripheral lymph nodes
N1	Clinically abnormal peripheral lymph nodes Dutch grade 1, NCI grade LN0–LN2
N1a	Clone negative
N1b	Clone positive
N2	Clinically abnormal peripheral lymph nodes Dutch grade 2, NCI grade LN3
N2a	Clone negative
N2b	Clone positive
N3	Clinically abnormal peripheral lymph nodes Dutch grade 3, NCI grade LN4, clone positive or negative
Nx	Clinically abnormal peripheral lymph nodes No histologic confirmation
M (VISCERA)
M0	No visceral organ involvement
M1	Visceral organ involvement (pathology confirmation required)
B (BLOOD)
B0	Atypical circulating cells not present (<5%)
B0a	Clone negative
B0b	Clone positive
B1	Atypical circulating cells present (>5%)
B1a	Clone negative
B1b	Clone positive
B2	≤≥1000/µL Sézary cells, clone positive
Stage	T	N	M	B
IA	1	0	0	0, 1
IB	2	0	0	0, 1
IIA	1, 2	1, 2	0	0, 1
IIB	3	0–2	0	0, 1
IIIA	4	0–2	0	0
IIIB	4	0–2	0	1
IVA 1	1–4	0–2	0	2
IVA 2	1–4	3	0	0–2
IVB	1–4	0–3	1	0–2

BSA, Body surface area; TNMB, tumor, node, metastasis, blood.

Histologic classification of LN involvement also has prognostic value and for treatment decisions in patients diagnosed with MF/SS. LN rating correlates with disease progression and survival. Moreover, detection of a monoclonal T-cell population within the LNs is associated with an inferior survival and outcome regardless of the LN class. LN1 rating defines reactive changes, LN2 and LN3 nodes describe small or large clusters of atypical cells in paracortical T-cell regions, and LN4 nodes define frank effacement.

The most important prognostic factors for survival remain the T stage (skin tumor burden), extracutaneous manifestation, and patient age. The Stanford experience with MF/SS patients demonstrates the impact of stage on OS rate (see Fig. 104.4 ). Although the OS rates of all patients with MF are 68% at 5 years and 17% at 30 years, the specific survival of patients ranges widely depending on T classification and stage at initial presentation. Patients with SS have an estimated 5-year survival rate of 24%. In our study of erythrodermic CTCL, all patients had median survival time of 7 years, with a 5-year median survival for patients who were B2 and 2.5 years for B3. The Stanford study, consisting of 525 patients, showed an OS of 97% in patients with T1 (<10% body surface involvement) at 5 years compared with 40% and 41% in T3 and T4 disease, respectively.

In addition, several independent adverse prognostic factors have been identified, including large-cell transformation, follicular mucinosis, thickness of tumor infiltrate, and increased lactate dehydrogenase (LDH) and β ₂ -microglobulin levels. Patients with large rather than small circulating Sézary cells were also found to have a worse prognosis. A high Sézary cell count, loss of T-cell subset markers such as CD5 and CD7, and chromosomal abnormalities in T cells are also independently associated with a poor outcome. The existence of a blood clonal T-cell population, detected by PCR, was of poor predictive survival value, independent of the T stage and LN involvement. Recent multivariant analyses in survival outcomes and prognostic factors of MF and SS patients using the ISCL/EORTC revised staging proposal confirmed that the presence of a T-cell clone in blood (identical to the cutaneous T-cell clone) in the absence of morphologic evidence of blood involvement (B0b) was associated with a significantly worse OS rate and disease-specific survival (DSS) rate compared with patients with no peripheral blood T-cell clone (B0a). In contrast, the presence of a high number of cytotoxic CD8+ T lymphocytes in the cutaneous infiltrate, as well as the density of epidermal Langerhans cells greater than 90 cells/mm ² , is associated with a better prognosis.

Transformed Mycosis Fungoides and Sézary Syndrome

Large-cell transformation in skin or blood has always been associated with a poor outcome. A study on prognostic factors in 100 patients with large-cell transformed MF showed a median survival rate of 24 months (range, 1–235 months) with a 5-year DSS and OS rate of 38% and 33%, respectively. These results are similar to those from previous studies with median survival periods ranging from 12 to 36 months and 5-year OS rate from 11% to 32%. The most important prognostic factors included advanced stage at transformation, CD30 negativity, folliculotropic MF, and increased extent of skin lesions. There is no difference in outcome in patients with clinical stage IIB with or without large-cell transformation. In contrast, another recent study of 1502 patients with MF/SS, including 70 patients with transformed MF at the time of first diagnosis, suggested a better prognosis of patients with large cell transformation (LCT) compared with all previous studies; the median survival time was 8.3 years, and the 5-year OS and DSS rates were 63% and 65%, respectively. A retrospective study from our center found 187 or 9.8% of 1900 CTCL patients had LCT in skin or nodes. LCT was present in 73% at time of diagnosis, and their median OS time was 3.6 years compared with 8.8 year OS if their diagnosis was delayed or 4.8 years for all 187. Older age and elevated lactic dehydrogenase were also associated with worse OS and greater than 10% CD30+ on lymphocytes with improved survival. Although current guidelines recommend a more aggressive approach to patients with large-cell transformation, not all patients with large-cell transformation do badly, especially if their disease is limited and can be treated with local radiation.

Biological Properties

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