Cutaneous T-Cell and NK-Cell Lymphomas The WHO-EORTC Classification and the Increasing Recognition of Specialized Tumor Types

Transcription

1 AJCP / SHP/EAHP WORKSHOP Cutaneous T-Cell and NK-Cell Lymphomas The WHO-EORTC Classification and the Increasing Recognition of Specialized Tumor Types Marsha C. Kinney, MD, 1 and Dan Jones, MD, PhD 2 Key Words: Skin lymphoma; CD30; Mycosis fungoides; Dermatitis; Natural killer cell Abstract Cases drawn from Session 5 of the 2005 Society for Hematopathology/European Association for Haematopathology Workshop on progress in T-cell and natural killer (NK)-cell malignancies are used as a framework to review the current classification of T-cell and NK-cell malignancies in skin. In comparison with the typical pattern and course of mycosis fungoides (MF), selected variants of MF that can be difficult to diagnose are discussed. Cutaneous CD30+ lymphoproliferative disorders are also presented in detail. Particular focus is placed on the recognition of rare but clinically more aggressive cytotoxic lymphomas in the skin. Overall, diagnostic pitfalls and new information regarding disease pathogenesis brought up by the Workshop cases are provided. In addition, a general approach to the diagnosis of cutaneous T-cell lymphomas is discussed. Skin is the second most common site of extranodal lymphoma after the gastrointestinal tract. Cutaneous lymphomas can be primary in the skin or secondary to systemic disease an important distinction because many primary cutaneous lymphomas are indolent. 1 In contrast with other anatomic sites where B-cell tumors predominate, T-cell lymphomas (TCLs) represent approximately 75% to 80% of cutaneous lymphomas. 1,2 Cutaneous lymphoid infiltrates are particularly challenging, with diagnosis relying heavily on clinical correlation and multiparametric studies. Many pathologists and hematopathologists have some apprehension in evaluating cutaneous lymphoid infiltrates owing to small samples, variability in the histologic features over time, and overlap with a broad group of reactive processes. Similar growth patterns, including epidermotropism, subcutaneous infiltration, and vascular invasion, can be seen in several types of lymphoma. TCLs also tend to have numerous admixed reactive cells. The lack of specificity of morphologic features and immunophenotype underscore the need for a uniform, multiparametric approach in working up cutaneous lymphomas. Clinical features are essential for establishing the diagnosis and predicting prognosis and are often not readily available. As in other organ systems, the diagnosis begins with a low-magnification, growth pattern approach. Lesions are characterized by their pattern of infiltration (superficial band-like, diffuse or periadnexal, angiocentric or angioinvasive/angiodestructive) and the extent of infiltration of the epidermis or subcutaneous tissue (panniculitic). Most lymphocytes in the skin have some degree of nuclear irregularity, but attention should be given to the number of cerebriform lymphocytes and their size and how hyperchromatic the nuclear chromatin is. The number of large lymphocytes and their degree of nuclear 670 Am J Clin Pathol 2007;127: Downloaded 670 from

2 AJCP / SHP/EAHP WORKSHOP irregularity should also be evaluated. Most lymphoid infiltrates, benign and neoplastic, have a mixture of cell sizes and some admixed other inflammatory cells (histiocytes, plasma cells, eosinophils, or neutrophils). What Are the Most Useful Marker Studies in the Diagnosis of Cutaneous Lymphoma? In distinguishing the type of cutaneous lymphoid infiltrate, the density and localization of B cells detected by CD20 and T-cell subsets detected by CD4 and CD8 are the most useful initially. Most neoplastic T-cell infiltrates have few B cells present, so if there are large collections of B cells in a predominantly T-cell infiltrate, a reactive process is favored. A T-cell infiltrate would also be suggestive of neoplasia if the CD4/CD8 ratio was greater than 10:1 or, conversely, if the number of CD8+ cells was markedly greater than the number of CD4+ T cells. Antibodies to CD68 are useful to determine the number of histiocytes present and further confirm the T- cell subset distribution because histiocytes express CD4 to some degree. Loss of expression of pan-t antigens is a useful feature that can often be found in neoplastic infiltrates, and, thus, a panel of such markers including CD2, CD3, CD5, CD7, and CD45RO can be used. In mixed infiltrates with a large cell component, CD30 immunostaining should be performed to evaluate for lymphomatoid papulosis (LyP) or cutaneous anaplastic large cell lymphoma (C-ALCL). What Is the Current Classification of Cutaneous Lymphoma? With publication of the World Health Organization European Organization for Research and Treatment of Cancer (WHO/EORTC) classification in mid and the WHO Classification of Skin Tumors in 2006, 3 significant advances have been made in the clinical and diagnostic approach to skin-based clonal lymphoid proliferations. 4 There has been clarification of entities presented in the earlier WHO classification of lymphoid tumors 5 and several new provisional entities. Based on Dutch and Austrian cutaneous lymphoma registries, cutaneous TCLs have also been classified according to their clinical behavior into indolent and aggressive categories (disease specific 5-year survival of 75%-100% vs 16%-24%, respectively). Table 1 lists the cutaneous T-cell neoplasms grouped according to clinical behavior. Mycosis Fungoides Recognized by Alibert in France in the early 1800s, mycosis fungoides (MF) and its variants represent almost 50% Table 1 Primary Cutaneous T-Cell Lymphomas Classified According to the World Health Organization European Organization for Research and Treatment of Cancer Classification Indolent clinical behavior Mycosis fungoides Folliculotropic mycosis fungoides Pagetoid reticulosis Granulomatous slack skin Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional entity) Aggressive clinical behavior Sézary syndrome Primary cutaneous natural killer/t-cell lymphoma, nasal type Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (provisional entity) Primary cutaneous γδ T-cell lymphoma (provisional entity) Primary cutaneous peripheral T-cell lymphoma, unspecified of cutaneous lymphomas. 6 MF was included in the earliest lymphoma classification systems based on recognition of the characteristic cerebriform nuclear features of the lymphocytes. Patients have patches, plaques, and eventually tumors that typically occur on sun-protected skin. Diagnostic criteria include a band-like superficial dermal infiltrate of lymphocytes with enlarged, hyperchromatic, cerebriform nuclei and epidermotropism; a subset of cases (4%-38%) have Pautrier microabscesses. 7 To date, approximately 15 variant forms of MF have been described, 8,9 and several are addressed in this review. Early patch lesions of MF are the most problematic lesions, and their diagnosis relies heavily on clinicopathologic correlation and multiple biopsies. The differential diagnosis includes interface or spongiotic dermatitis. Characteristic features of MF include significant epidermotropism with little spongiosis and vacuolar change, more atypical nuclear cytologic features in the epidermal lymphocytes compared with those in the dermis, and lining up of epidermal lymphocytes surrounded by halos along the basal layer. 10,11 In a study of 427 patients with early stage MF, common features included a band-like or patchy lichenoid infiltrate with coarse collagen bands in the superficial dermis. 7 Epidermotropism was present in the majority of cases and varied from single lymphocytes (22%), lymphocytes lining up along the basal layer (23%), Pautrier microabscesses (19%), haloed lymphocytes (40%), and disproportionate exocytosis (17%) to pagetoid epidermotropism (3%). The presence of atypical lymphocytes with extremely convoluted, cerebriform, large (7-9 µm) nuclei in the epidermis or clustered in the dermis is one of the most specific 12 but least sensitive parameters, seen in only 9% of cases. 7 Biopsies of MF can also show features of reactive dermatoses such as necrotic keratinocytes (23%), increased melanophages (8%), and extravasated erythrocytes (4%). These shared features may represent secondary changes due Downloaded from Am J Clin Pathol 2007;127:

3 Kinney and Jones / CUTANEOUS T-CELL AND NK-CELL LYMPHOMA to tumor-associated excoriation, superinfection, and skin breakdown and suggest the evolution of clonal MF from preexisting dermatitis in some cases. MF is overwhelmingly a tumor of CD4+ T cells with only a small percentage of cases that have the same clinical course and histologic appearance expressing CD8. 13 In common with a subset of normal skin homing T cells, MF typically shows absence of CD7 14 ; loss of pan T-cell markers, including CD2, CD3, and CD5, is usually a feature of disease progression and is rare in early-stage lesions. Low-grade MF typically has only small numbers of CD30+ tumor cells. Molecular studies may be helpful in diagnosis but should be used with caution. Although T-cell receptor (TCR) gene rearrangement studies by polymerase chain reaction will reveal a clonal rearrangement in 80% to 90% of MF cases, clonal and particularly oligoclonal T cell populations are also detected in many types of dermatoses. 15,16 An extremely helpful technique is to compare the TCR pattern at 2 different involved skin sites, with identical gene rearrangements indicative of systemic MF. 17 Among other T-cell neoplasms, CD4 expression and epidermotropism are also features of adult T-cell leukemia/lymphoma (ATLL), in which papular or tumoral skin lesions are present in 50% to 60% of cases. 2,18,19 Epidermotropism is present in most cases, and Pautrier microabscesses can be seen. 20 Classic diagnostic features such as hypercalcemia may not be present in ATLL cases, particularly when the disease is limited to the skin. Differentiating ATLL from MF relies on the marked nuclei irregularity of most ATLL cells and the typically uniform expression of CD25. Although ATLL is a rare disease in the United States, a history of residence in a human T-lymphotropic virus-1 endemic area (eg, the Caribbean or Asian-Pacific basin) should prompt study of viral serologic status. What Are the Uncommon Presentations and Variants of MF? MF may manifest with unusual clinical or pathologic features, making its recognition difficult. These variants include unusual anatomic sites of involvement, a solitary lesion, initial manifestation after transformation to large cell lymphoma, or association with masking clinical conditions such as ichthyosis. Folliculotropic MF Folliculotropic (also known as pilotropic or follicular) MF is a relatively commonly encountered variant characterized by cerebriform lymphocytes around and infiltrating hair follicle epithelium with a relative lack of infiltration of the surface epithelium Image 1. 21,22 This produces a clinical appearance of follicular prominence resembling acne, sometimes Image 1 (Case 92) Folliculotropic mycosis fungoides (MF). Skin biopsy specimen from a 57-year-old man with red nodules and plaques on the scalp, back, and chest. The growth pattern around and infiltrating the hair follicle epithelium and the lack of surface epidermotropism is characteristic of this variant MF (H&E). Contributed by R. Armand. with associated alopecia. The head and neck region is most commonly involved, and owing to the deeper nature of the infiltrate, folliculotropic MF may not respond as well to topical or UV therapy. Marked mucin accumulation in the follicle and dermis (follicular mucinosis) is often present, and follicular destruction can be present. The accompanying inflammatory changes can present diagnostic challenges as seen in a Workshop case of folliculotropic MF that showed obscuring acute inflammation due to secondary bacterial infection. It remains controversial whether folliculotropic MF with or without mucinosis has an adverse prognosis compared with conventional MF. 21 The unusual clinical appearance of folliculotropic MF with scaling rash and alopecia may raise the differential diagnosis with ichthyosis. Acquired ichthyosis can be seen in many clinical circumstances, including endocrine and autoimmune disorders, infection, nutritional disorders, medications affecting cholesterol metabolism, and renal disease, and, most important, as a paraneoplastic syndrome in association with solid tumors or, more frequently, lymphoproliferative disorders. Several cases of ALCL with acquired ichthyosis have also been reported. 23 An ichthyosiform pattern has been described in approximately 4% of MF cases, often accompanying patch-plaque or folliculotropic disease. 24 The relationship of MF with ichthyosis is further raised by a Workshop case in which MF subsequently developed in a patient with congenital ichthyosis. 672 Am J Clin Pathol 2007;127: Downloaded 672 from

4 AJCP / SHP/EAHP WORKSHOP Given the absence of epidermotropism, transformation of folliculotropic MF to large cell lymphoma may be an especially difficult diagnosis. Important clues to the correct diagnosis are the distinctly perifollicular pattern in the upper portion of the dermis with infiltration of the hair follicle by small to medium-sized, irregular, cerebriform lymphocytes and, most important, a CD4+ T-cell immunophenotype. A case of folliculotropic MF with large cell transformation has been described in a patient with a clinical picture of dissecting cellulitis of the scalp. 25 Unilesional (Localized) MF and Pagetoid Reticulosis Although MF is nearly always multifocal, solitary lesions of MF often occurring on the trunk (particularly the breast in females) have been reported Although these lesions exhibit epidermotropism, there is often mild lymphocyte atypia and minimal papillary dermal fibrosis. Recurrences at the site of biopsy have been reported in approximately 10%, but typical MF does not develop in most patients. 26 A clonal T-cell population is detected in 50% of the specimens; however, as mentioned earlier, clonal T-cell populations have also been described in reactive conditions. 16 In a series of such localized cases, 50% of the patients were taking one or more medications, raising the possibility of a drug-related reactive lesion. 26 Clusters of CD20+ B cells were described in 75% of the biopsy specimens, a relatively infrequent finding in typical MF. Pagetoid reticulosis (Woringer-Kolopp disease) 30 is a much more well-established pattern of unilesional MF characterized by a slow growing, hyperkeratotic, or crusted patch or plaque, typically on the distal extremity There is marked epidermotropism (particularly in the basal layer) with significantly fewer lymphocytes in the dermis. Many reported cases of pagetoid reticulosis have had a CD8+ immunophenotype, which is unusual for MF. 13,33 Most patients with localized pagetoid reticulosis have an extremely benign course, only occasionally terminating in systemic MF. Mucocutaneous MF MF can involve the oral cavity and rarely other mucosal sites, as illustrated in one Workshop case in which the manifestation was a tongue lesion and cutaneous disease later developed. Oral involvement typically develops after cutaneous lesions and is usually manifested by ulcerated plaques or tumors of the gingiva, palate, or tongue. However, rare cases of MF primarily manifest in the mouth The differential diagnosis includes mucosal γδ TCL that is distinguished by its CD4 /CD8 or CD4 /CD8+ immunophenotype and frequent expression of CD56. Granulomatous Slack Skin Disease Granulomatous slack skin (GSS) is an extremely rare, indolent, but progressive variant of MF characterized by the development of large pendulous skin folds in flexural regions, particularly the axilla and groin. Since the first reported case in 1973, approximately 50 cases have been described. 37 GSS has a male predominance and initially manifests in the third or fourth decade; rare cases in children have been described. 38 Early lesions range from indurated plaques to erythematous scaling patches. 39 Biopsy specimens reveal a dermal lymphohistiocytic infiltrate of small to medium-sized lymphocytes associated with uniformly distributed noncaseating giant cells that have numerous (20-30) nuclei Image 2. Characteristically, lymphocyte atypia is mild and there is minimal epidermotropism. Giant cells show emperipolesis of small lymphocytes or contain phagocytized elastic fibers. A Verhoeff van Gieson stain reveals destruction and loss of elastic fibers in the dermis. Involvement of large vessels by the giant cells may be seen. At later stages, the infiltrate becomes dense and extends through the dermis and subcutis. The entity of GSS should be distinguished from granulomatous MF. The latter term is used for tumors with the histologic pattern of typical MF in which histiocytic or granulomatous inflammation is prominent but without the preferential flexural skin involvement or the degree of giant cell formation and marked loss of elastin fibers. 40 Similar to classic MF, nearly all GSS cases have a CD3+/CD4+/CD8 immunophenotype, with rare expression of CD30 41 and clonal TCR gene rearrangement. Trisomy 8 has been reported in 2 cases. 42,43 In a case presented at the Workshop, cytogenetic analysis revealed a t(3;9)(q12;p24) rearrangement, which is the first reported balanced translocation associated with this tumor. The clinical course of GSS is generally more indolent than MF; however, it is interesting that in approximately 20% to 50% of patients with GSS, Hodgkin lymphoma or other peripheral TCLs develop, a rate much higher than that seen in patients with typical MF. 37,39,44 What Are the Features of Large Cell Transformation of MF? Clinical progression and extracutaneous dissemination of MF is often associated with a shift to a large tumor cell. The incidence of such large cell transformation of MF, as defined by the presence of 25% or more large lymphocytes or as nodules of large cells, is highly variable (8%-55%) The median interval from initial MF diagnosis to transformation is 1.0 to 6.5 years, and this broad range is largely explained by variable lengths of follow-up and extent of clinical correlation. Transformation can be the initial manifestation in 18% to 41% of MF patients, as seen in 1 Workshop case. Transformation of MF is usually detected first at cutaneous sites but often heralds extracutaneous dissemination and may be seen initially in lymph node biopsy specimens in up to 35% of patients Downloaded from Am J Clin Pathol 2007;127:

5 Kinney and Jones / CUTANEOUS T-CELL AND NK-CELL LYMPHOMA A B Image 2 (Case 63) Granulomatous slack skin. Skin biopsy specimen from a 46-year-old man with thickened skin in the subscapular and axillary area. A, A dense, diffuse dermal lymphohistiocytic infiltrate is present with little infiltration of the epidermis (H&E). B, The evenly distributed large histiocytes with numerous nuclei and lymphocyte emperipolesis are characteristic (H&E). Contributed by I. Ikonomou. The clinical course of transformed MF is aggressive with a survival range of 22 to 37 months. The presence of extracutaneous transformation is particularly adverse, with a 5-year actuarial survival of approximately 10%.45,46 Several features of transformed MF lead to confusion with ALCL. As MF transforms, the epidermotropic property of tumor cells is often reduced or lost, most likely as a result of shifts in the pattern of receptor expression for chemotactic chemokines.48 Some degree of CD30 expression is present in 50% of transformed MF cases, with strong, uniform expression present in approximately 20% Transformation of MF is also associated with variable expression of cytolytic granule proteins such as TIA-1 and granzyme B,49 although only rarely with the uniform pattern common in CD8+ tumors, natural killer (NK)-cell lymphomas, and ALCL. In a T-cell lesion with CD30 expression, transformed MF is best confirmed by obtaining a clinical history of preexisting patchplaque disease or determining whether an admixed population of smaller CD4+ cerebriform lymphocytes is present.45 What Are the Helpful Features in Classifying Primary Cutaneous CD30+ Lymphoproliferative Disorders? Transformed MF shares CD30 expression with a group of other cutaneous lymphoproliferative disorders, namely primary C-ALCL and LyP, which represent approximately 30% of primary cutaneous lymphoid neoplasms.50 The presence of borderline lesions between LyP and C-ALCL and the fact that 674 Am J Clin Pathol 2007;127: Downloaded 674 from 5% to 20% of cases with LyP progress to or have concurrent or antecedent ALCL, MF, or Hodgkin lymphoma51-53 indicates that there is a continuous spectrum of CD30+ lymphoproliferative disorders.2,54 Therefore, the prediction of the disease course of any individual lesion remains problematic. Distinguishing Clinical Features of C-ALCL and LyP Following the initial description of ALCL by Stein et al55 in 1985, Kadin et al56 established that ALCL could arise in the skin as part of systemic disease or as a primary disease. Numerous studies have documented that such C-ALCL has an indolent course, with a disease-related 5-year survival greater than 90%, compared with a 5-year cumulative survival of 29% to 44% in adults with secondary cutaneous lesions as part of systemic ALCL.51,57-59 LyP and C-ALCL have distinct but sometimes overlapping clinical features. Clinical features supporting the diagnosis of C-ALCL over LyP are size greater than 2 cm and duration of any single lesion for more than 3 months without regression. C-ALCL arises in older patients (median age, years) but rarely arises in children (<2% of CALCL).51,60,61 In pediatric patients, CD30+ skin lesions are much more likely to be secondary to anaplastic lymphoma kinase (ALK)+ systemic ALCL. C-ALCL lesions are typically solitary or clustered or, less frequently, multiple nodules or tumors that are often ulcerated and occur, in decreasing order, on the extremities, head and neck, and trunk. Most lesions progressively enlarge, although partial or complete regression can be seen in 23% to 44% of cases.51,58,62

6 AJCP / SHP/EAHP WORKSHOP In contrast, the always regressing LyP lesions present initially in young to middle-aged adults (median age, 45 years) and less often in children. 63 LyP lesions proceed through a 6- to 8-week cycle of papular to papulonecrotic lesions that are usually smaller than 1 cm. The lesions heal with a scar. In the classic syndrome, the course of LyP is chronic with numerous recurrences of lesions over several months to years. A more limited clinical form of LyP is also noted that may be more closely related to exaggerated allergic or insect-bite reactions. Distinguishing Pathologic Features of Systemic ALCL, C-ALCL, and LyP In most cases, LyP and C-ALCL can also be distinguished by the density and distribution of the large CD30+ tumor cells. In C-ALCL, tumor cells are typically present in large clusters and sheets and extend into the subcutaneous tissue. Tumor cells may surround, infiltrate, and expand blood vessel walls, but overt vascular destruction is usually not present 64,65 Tumor cytomorphologic features are predominantly anaplastic with indented folded nuclei (hallmark) or embryoid nuclei, but approximately 20% of C-ALCL cases show irregular hyperchromatic or immunoblastic nuclear features. Neutrophil-rich ALCL (also known as pyogenic or LyP-like) is more difficult to diagnose owing to the relatively sparse tumor cells and requires clinical correlation with the size and number of lesions and whether there is history of regression Pseudoepitheliomatous hyperplasia can lead to confusion with squamous cell carcinoma. 69 The patterns of skin infiltration in LyP are highly variable and correlate with the age of the lesions and the degree of chronicity in a given patient. Three histologic variants types A, B, and C have been described based on cytologic features and the number of large cells. 70,71 Type A LyP has a wedgeshaped perivascular pattern of infiltration with small numbers of large cells, often Reed-Sternberg like, in a background of small lymphocytes with variable numbers of eosinophils and neutrophils. Type B resembles MF with a band-like infiltrate of cerebriform lymphocytes and fewer CD30+ large cells. Type C contains numerous large CD30+ cells and is difficult to distinguish histologically from ALCL except by clinical history and depth of tumor invasion. LyP has minimal if any involvement of subcutaneous tissue. Immunostaining can be helpful for excluding cutaneous involvement by systemic ALCL. ALK expression is highly associated with systemic disease and is only rarely present in C-ALCL Loss of pan T-cell antigens is common in C- ALCL and LyP (eg, CD3 loss in 70% of C-ALCL cases) but is not as frequent as in systemic ALK+ ALCL. 75 Similarly, ZAP-70, a TCR-associated kinase, is lost in 43% to 71% of C- ALCL cases and in up to 90% of systemic ALCL cases. 75,76 But most markers will not distinguish between types of CD30+ tumors. Approximately 50% to 75% of C-ALCL and LyP cases express one or more cytotoxic granule proteins (eg, TIA-1 or granzyme B), and approximately 20% to 30% express epithelial membrane antigen; therefore, the presence of epithelial membrane antigen cannot be taken as evidence of systemic disease. 62,77,78 Clusterin is also expressed in most cases of systemic and primary C-ALCL and in 14% of LyP cases in a small number tested. 80 CD56 expression has been reported in 0% to 50% of LyP and 12% to 75% of C- ALCL cases (usually <20%) and does not seem to be associated with the worse prognosis seen in patients with CD56+ systemic ALCL. 77,82,83 There are no immunophenotypic features yet identified that clearly distinguish C-ALCL from LyP. Both lesions are CD4+ T-cell proliferations in more than 90% of cases with only rare CD8+ cases reported. 84 Expression of bcl-2 is infrequent in LyP but may correlate with lack of regression. Variable expression of cutaneous lymphocyte antigen, as detected by antibody HECA-452, has been reported in 44% of C-ALCLs, 85 but the percentage of cutaneous lymphocyte antigen positive atypical cells may be higher in LyP (82% of the cells) than in C-ALCL (13%). 86 Fascin is expressed in 24% of LyP cases, 64% of ALCL cases, and 60% of LyP cases that progress to systemic lymphoma. 87 Loss of transforming growth factor β inhibition by mutation of the receptor for transforming growth factor β and decreased CD30 ligand expression in LyP supports progression of LyP to ALCL. 88 Molecular studies may be more useful in differentiating LyP and C-ALCL. As expected, given the higher density of tumor cells, clonal TCR gene rearrangements are more frequently detected in ALCL than in LyP This may also be because some CD30+ large cells in LyP, particularly in the sporadic LyP disease group, could represent infiltrating reactive (polyclonal) T cells. 93 Progression of LyP to C-ALCL The EORTC classification published in 1997 and the WHO classification in 2001 emphasized the problem of borderline C-ALCL LyP cases with discordant clinical and histologic features. The current WHO classification has formally recognized LyP, type C, as a part of the spectrum of LyP and dropped the term C-ALCL of the LyP type. A borderline lesion now refers to cases that manifest clinically with features of one entity but have histologic features of another and, despite careful clinicopathologic correlation, cannot be given a definitive diagnosis. The lack of specific markers to define these lesions remains frustrating for pathologists and clinicians trying to assign a precise diagnosis and therapy and predict prognosis. One of the Workshop cases illustrated the close relationship of ALCL and LyP and the difficulty in diagnosing borderline lesions and predicting their course. A 10-year-old girl had a solitary, enlarging, 2-cm lesion on the nose of 2 weeks duration that was unresponsive to antibiotic therapy Image 3, Downloaded from Am J Clin Pathol 2007;127:

7 Kinney and Jones / CUTANEOUS T-CELL AND NK-CELL LYMPHOMA followed by development of numerous disseminated papules compatible with LyP. A transient response to steroid treatment followed by a durable remission of 16 years was obtained after treatment with oral methotrexate. Although manifestation as a solitary large lesion, invasion of the subcutis, and numerous large cells suggested C-ALCL, the subsequent development of multiple small lesions that responded to methotrexate and absence of lesions during long-term follow-up was most compatible with LyP. This case illustrates the spectrum of CD30+ lymphoproliferative disorders with borderline cases defying subcategorization and the importance of clinical correlation and close follow-up in defining these CD30+ lymphoproliferative disorders. CD30+ C-ALCL in the Posttransplantation Setting Primary C-ALCL can occur as a posttransplantation lymphoproliferative disorder, predominantly after renal transplantation Like other T-cell posttransplantation lymphoproliferative disorders, C-ALCL arises late, a median of 5 years (range, 10 months to 16 years) after transplantation. Fewer than 25% are Epstein-Barr virus (EBV)-associated, and there is little response to decreased immunosuppression. Similar to other C-ALCLs, the tumors are ALK, and EBV is expressed in about 20% to 30% of cases. CD56 is expressed in approximately 50% of cases. Most patients have a relapse or die of disease within 12 to 18 months. What Are the Uncommon and Often Aggressive Variants of Lymphoproliferative Disorders Involving Skin? Given the highly aggressive clinical behavior of most of the cutaneous NK-cell and T-cell tumor types that are not MF or C-ALCL, it is vitally important to recognize and subclassify them. Clues to the diagnosis of these rare tumors include their involvement of subcutaneous tissue, zonal necrosis, or, particularly, an absence of CD4 and CD8 expression or a CD8+ cytotoxic immunophenotype. A secondary marker panel including TCRβ (BetaF1), CD56, EBV-encoded RNA in situ hybridization, and cytotoxic granule antigens (eg, TIA- 1 or granzyme B) is useful for distinguishing these tumors. Extranodal NK/TCL, Nasal Type NK cells are an immune cell type that frequently exhibits homing to extranodal sites. After the nasal cavity or nasopharynx, the skin is the second most common site of involvement by nasal-type NK/TCL. 99 Skin lesions may be primary, but 25% to 50% have involvement of the nasal cavity or other sites such as the gastrointestinal tract, lung, or testis. Patients have a median age of 52 to 66 years but a broad range (19-76 years) Image 3 (Case 84) Lymphomatoid papulosis with a dominant tumor nodule. Skin biopsy specimen from a 10-yearold girl with a 2-cm lesion on the nose. Epidermal ulceration and pseudoepitheliomatous hyperplasia are present overlying this infiltrate (H&E) with numerous large atypical lymphocytes (inset, H&E) that expressed CD30 (not shown). Although these features supported the diagnosis of cutaneous anaplastic large cell lymphoma, within a few weeks, multiple small lesions of lymphomatoid papulosis developed. Treatment with low-dose methotrexate resulted in disease remission, and 16 years of follow-up showed no evidence of disease. This case illustrates the need for clinical correlation and follow-up and the diagnostic value of the term CD30+ lymphoproliferative disorder. Contributed by M. Kadin. and are more frequently from Asia, Central America, and South America. The clinical course is aggressive, particularly when there is extracutaneous involvement, with a median survival of less than 15 months. 100 Lesions are typically multiple tumor nodules or plaques on the trunk or extremities. Tumor cells vary from small to medium and large, with most cases having medium to large cells. The characteristic histologic features are angioinvasion and angiodestruction with large, zonal areas of necrosis. Although the pattern of infiltration is often perivascular and periappendageal imparting a columnlike appearance, extension of the infiltrate into the subcutaneous tissue is common and may predominate, mimicking subcutaneous panniculitis-like TCL (SPTCL) Image ,102 Most nasal-type NK/TCLs are thought to be of true NKcell origin, as evidenced by expression of CD2, CD7, cytoplasmic CD3, and CD56; absence of surface CD3 and CD5 expression; and no evidence of clonal TCR gene rearrangements. However, a subset of tumors in some series have evidence of T-cell lineage. 103 A common feature of all cases is the 676 Am J Clin Pathol 2007;127: Downloaded 676 from

8 AJCP / SHP/EAHP WORKSHOP A B C D Image 4 (Case 136) Nasal-type natural killer/t-cell lymphoma in a 27-year-old Caribbean woman with fever, nasal congestion, hoarseness, and skin nodules on the upper arms, back, and chest. A, At low magnification, the tumor shows focal involvement of the dermis with predominant infiltration of subcutaneous tissue (H&E). B, Tumor cells diffusely extend into the subcutaneous tissue and large areas of zonal necrosis are present (H&E ); tumor cells are pleomorphic and medium to large (inset, H&E). C, Tumor cells strongly express CD56. D, Epstein-Barr virus is present in numerous cells (Epstein-Barr virus encoded RNA in situ hybridization). Contributed by L. Tsao. expression of cytotoxic granule proteins (TIA-1, granzyme B, or perforin) and EBV in greater than 75% of cutaneous nasaltype NK/TCLs, particularly in patients from the Far East or Central or South America (Image 4).83, Lack of any one typical marker, such as CD56, should not preclude diagnosis of nasal-type NK/TCL if typical histologic and other immunophenotypic features are present. One confusing feature can be the expression of CD30, which is usually expressed in a subset of NK/TCL tumor cells, likely as a feature of histologic progression.105 Although ALCL can also express CD56 and exhibit angioinvasion,64,65 tumor cells are uniformly positive for CD30 and rarely positive for EBV.106,107 However, there is 1 report from India in which 20% of ALCL cases were EBV+, raising the possibility of geographic variation for EBV in ALCL.108 One of the controversial issues at the present is the relationship between disseminated nasal/nasal-type NK/TCL with a bone marrow/leukemic phase109,110 and aggressive NK-cell leukemia that can rarely secondarily involve the skin These 2 tumors have a similar phenotype, and differentiation requires correlation with clinical features and staging studies with bone marrow examination. Nasal-type NK/TCL only rarely involves the bone marrow and blood. Aggressive NKcell leukemia has blood involvement with patchy infiltration of Am J Clin Pathol 2007;127: Downloaded from

9 Kinney and Jones / CUTANEOUS T-CELL AND NK-CELL LYMPHOMA the bone marrow. According to a recent study from Japan, the higher incidence of skin involvement in nasal-type NK/TCL and much less frequent involvement of the skin in aggressive NK-cell leukemia suggest that these 2 diseases are different. 114 In addition, nasal-type NK/TCL only infrequently involves lymph nodes, whereas lymphadenopathy is common in aggressive NK-cell leukemia. Clinically, aggressive NK-cell leukemia typically occurs in young patients and nasal/nasaltype NK/TCL is a disease of middle-age to older adults. Another EBV+ tumor, hydroa vacciniforme like cutaneous TCL, is a rare cytotoxic T-cell or NK-cell lymphoma affecting children in Latin America and Asia that manifests with vesiculopapular lesions on sun-exposed skin. 2,99, Fever, wasting, hepatosplenomegaly, lymphadenopathy, and hypersensitivity to insect bites are seen clinically. The tumors are predominantly CD8+ T cells with variable CD56 expression. The prognosis is poor, with a 2-year survival of 36%. A final area of classification that remains problematic is the reported cases of EBV+ cutaneous TCL that do not match precisely nasal-type NK/TCL. Two such unclassifiable EBV+ cases submitted to the Workshop were clonal T-cell proliferations with involvement of the skin or soft tissue. Dissemination to bone marrow and other extranodal sites and death occurred rapidly in one patient and after 29 months in the other. The rapidly fatal tumor had zonal necrosis and may represent a nasaltype NK/TCL with dissemination or an aggressive variant of T- cell large granular lymphocyte leukemia. 118 Subcutaneous Panniculitis-like TCL During the last decade, a distinctive, rare, cytotoxic T-cell tumor involving the subcutis termed subcutaneous panniculitis-like TCL has been recognized. 119,120 The clinical course of SPTCL is variable. In the case series used for the WHO- EORTC classification, SPTCL with an αβ TCR had a favorable disease-specific 5-year survival of 82% (following reclassification of γδ cases; see the next section). 2 Many patients had a protracted course with recurrent lesions but without extracutaneous disease. However, SPTCL can be aggressive, particularly if associated with systemic hemophagocytic syndrome (HPS). The features of low-grade SPTCL are similar to lesions described previously as cytophagic histiocytic panniculitis, suggesting that some cases of SPTCL represent clonal progression of cytophagic histiocytic panniculitis. 121 The SPTCL name derives from the pattern of subcutaneous infiltration, which is usually lobular and lace-like with rimming of the fat cells by neoplastic lymphocytes Image 5. Areas of sheet-like growth are present in some cases. The lymphocytes vary from small to large and often infiltrate, but do not destroy, small blood vessels. Fat necrosis and individual cell apoptosis are common. Histiocytes are frequently present and contain phagocytized cellular debris and RBCs. When the cytophagocytosis is pronounced, the term beanbag cell has been applied to the histiocytes. Tumor cells in SPTCL are most often CD8+ cytotoxic lymphocytes expressing one or more cytotoxic granule proteins including TIA-1, granzyme B, and perforin and the αβ TCR. The tumor cells are often only focally positive for CD56 and negative for granzyme M, bcl-2 and EBV Rimming of the fat spaces is not specific for SPTCL and can be seen in other lymphomas and leukemia 125 and in reactive panniculitis. 126 The cytologically atypical lymphocytes and relative lack of plasma cells and reactive follicles distinguish SPTCL from lupus profundus. Other forms of lobular panniculitis are distinguished by a lack of cytologic atypia, their polyclonal nature, a septal pattern of infiltration (erythema nodosum), and characteristic features such as Miescher radial nodules in erythema nodosum and tuberculoid granulomas and foreign body giant cells in erythema induratum/nodular vasculitis. It is also important to correlate the finding of erythrophagocytosis noted in the subcutis with clinical evidence of systemic HPS. Highly aggressive HPS manifests with fever, splenomegaly, cytopenias and hypofibrinogenemia, and/or hypertriglyceridemia and is related to dysregulated cytokine production by activated T cells and histiocytes. Not all lymphomas demonstrating histologic evidence of erythrophagocytosis demonstrate the clinical findings of systemic HPS. Cutaneous γδ TCL Before the WHO-EORTC classification, cutaneous T-cell tumors expressing γδ TCR 2, were included in SPTCL. Based on their highly distinctive clinical behavior and particular histologic features, these tumors are now classified as a provisional entity within the primary cutaneous peripheral TCL, unspecified category. 133 Patients with cutaneous γδ TCL are typically middle-aged, and there is an approximately equal incidence in men and women. Cases usually manifest with large multifocal plaques, deep dermal/subcutaneous nodules, or tumors on the extremities; extracutaneous dissemination is rare until late in the disease course. Cutaneous γδ TCL with subcutaneous involvement has a high frequency of associated HPS, particularly in cases with extensive subcutaneous infiltration. 134,135 Peripheral blood involvement is described but has not been carefully evaluated in most cases of cutaneous γδ TCL. 136 Most patients lack bone marrow, lymph node, or liver involvement. In contrast with SPTCL, γδ TCL tumor cells almost always infiltrate the dermis and the subcutaneous tissue Image 6 and can also extend into the epidermis. 137 The growth pattern in the subcutaneous tissue may be lace-like, as in SPTCL, or mass-forming. The cells are usually mediumsized with coarsely clumped hyperchromatic nuclei and typically distinct but small nucleoli. Hemophagocytic and cytophagic histiocytes can be numerous, and some patients have systemic HPS. 678 Am J Clin Pathol 2007;127: Downloaded 678 from

10 AJCP / SHP/EAHP WORKSHOP A C Cutaneous γδ TCLs express CD2, CD3, and frequently CD56 but are usually negative for CD4, CD8, and CD5; a subset are CD5+. The neoplastic cells strongly express functional cytotoxic granule proteins, including TIA-1, granzyme B, and perforin, in contrast with hepatosplenic γδ lymphomas that typically express only TIA-1. TCR γδ expression, as detected by δ TCR specific reagents, is characteristic of the entity. Because there is no suitable paraffin-reactive pan-tcrγ or pan-tcrδ antibody, lack of expression of the αβ TCR in the appropriate setting can be used as presumptive evidence of γδ origin.138 Most cutaneous γδ TCLs are negative for EBV,128 as were 4 cases submitted to the Workshop, but the classification of EBV+ γδ lesions involving skin remains problematic. The γδ TCLs arising at mucocutaneous sites (particularly nasal) and rarely nodal γδ TCL and hepatosplenic lymphomas are EBV Hepatosplenic γδ TCL clearly represents a different entity, but it remains unclear whether mucosal γδ lymphomas B Image 5 (Case 109) Subcutaneous panniculitis-like T-cell lymphoma with hemophagocytic syndrome in a 26-year-old woman with multiple cutaneous nodules predominantly on the trunk. A, This subcutaneous biopsy specimen from the left axilla shows a lace-like lobular pattern of invasion of subcutaneous fat by small to medium-sized irregular lymphocytes (H&E). The tumor cells express the αβ T-cell receptor protein (not shown) and are CD8+ (B) and TIA-1+ (C). Bone marrow examination revealed minimal involvement by tumor and marked hemophagocytosis (not shown). Contributed by M. Kremer. should also be separated from the cutaneous subtype.131 The distinction between primary and secondary cutaneous involvement by γδ TCL may not be clinically relevant because both have a poor response to current chemotherapy regimens and an aggressive course with a median survival of 10 to 15 months. In 1 series, there was a trend toward decreased survival for cases with subcutaneous fat involvement (median survival, 13 months) vs disease limited to the dermis and epidermis (median survival, 29 months).129 What Are the Provisional or Evolving Cutaneous Lymphoproliferative Entities? In addition to cutaneous γδ TCL, several other provisional categories are included in the newest WHO classification.133 One of them, primary cutaneous aggressive epidermotropic Am J Clin Pathol 2007;127: Downloaded from

11 Kinney and Jones / CUTANEOUS T-CELL AND NK-CELL LYMPHOMA CD8+ cytotoxic TCL, is extremely rare, representing fewer than 1% of cutaneous lymphomas. It manifests with rapidly developing multifocal, disseminated plaques or nodules that are usually ulcerated. 132,143,144 Like pagetoid reticulosis, the tumor shows extensive epidermal infiltration, and there is variable spongiosis and occasional blister formation. Dermal involvement is variable. Invasion of adnexal structures is often present. Spread to extranodal sites (lung, testis, central nervous system, and oral mucosa) is seen, but lymph nodes are usually spared. The tumor expresses CD8, TCRαβ, and cytotoxic granule proteins. The median survival in 1 series was 32 months. 133 A possible differential diagnosis is with hypopigmented MF, which is usually a CD8+ tumor occurring frequently in dark-skinned children and young adults that has a very indolent course and lacks ulcerative lesions. 145 Another provisional entity, primary cutaneous smallmedium CD4+ TCL (formerly small-medium pleomorphic TCL) is likely more common but currently has an imprecise definition that may overlap with MF and its variants. 133 These tumors usually occur in adults with multiple tumors or nodules, usually on the face, neck, or upper part of the trunk, in contrast with the slowly evolving patches and plaques on sunprotected skin as seen in MF. Most of these neoplasms express CD4 and lack cytotoxic features. The estimated 5-year survival of 60% to 80% is favorable, particularly if solitary or localized lesions are present. Despite the progress in defining the limits of these tumor types, certain lymphomas involving skin remain difficult to classify because they comprise presently unrecognized biologic groups or incomplete clinicopathologic data are available. What Reactive Conditions Mimic Cutaneous TCL? It is well known that drug reactions and other benign conditions (excessive lymphoid responses in response to other antigenic stimuli such as insect bites, viruses, bacteria, and light) can mimic lymphoma (ie, lymphomatoid reaction pattern) Drug reactions are often associated with ingestion of more than 1 drug, including drugs with immune regulatory effects, or occur in patients with an underlying abnormal immune system (autoimmune disease, immunodeficiency, or lymphoma). 149 Furthermore, immunophenotypic hallmarks of cutaneous lymphoma, such as predominance of CD4+ T cells with loss of CD7 expression, and clonal TCR rearrangements can be seen in reactive conditions, adding to the complexity of diagnosing these lymphoma-like reactions. 150 Because CD30 is regulated as an activation antigen, CD30+ large T cells are commonly present in cutaneous inflammatory lesions associated with drugs, arthropod assault, viral infection, and lymphocyte recovery after chemotherapy and stem cell transplantation. 151,152 Image 6 (Case 80) γδ T-cell lymphoma of skin in a 22-year-old man with ulcerated nodules on the leg. The tumor is periadnexal in the dermis and infiltrates the subcutaneous tissue in a lace-like and lobular distribution (H&E). Involvement of the dermis is a tip-off to the γδ nature of the tumor, as is expression of CD56 (not shown). Contributed by B. Sawan. Reactive CD30+ T-cell infiltrates have been described with antiepileptic drugs, histamine receptor antagonists, antidepressants, phenothiazines, calcium channel blockers, angiotensin converting enzyme inhibitors, and antibiotics. Separation of reactive CD30+ conditions from LyP or C- ALCL is based on the scattered pattern of CD30+ cells and (usually) the absence of a clonal T-cell gene rearrangement in reactive lesions. A variety of other atypical dermal lymphoid infiltrates have been reported with use of the immunomodulatory drugs directed against cytokines, such as tumor necrosis factor α, and include thalidomide (Thalomid), infliximab (Remicade), etanercept (Enbrel), adalibumab (Humira), and lenalidomide (Revlimid). These popular therapeutic agents for the treatment of inflammatory conditions such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, and lymphoproliferative disorders can produce mildly pruritic rashes, macules, or indurated papules and plaques that have an annular appearance. 153 A middermal mixed interstitial granulomatous dermatitis is the most commonly described histologic pattern, with a predominance of CD4+ T cells. 154 Other patterns of reaction to these drugs include leukocytoclastic vasculitis, lichenoid drug eruptions, urticaria, perniosis (chilblains), and folliculitis TCLs have also been described. 159,160 Skin lesions generally resolve after discontinuation of the drug but may persist for several months. A case presented at the Workshop showed an atypical persistent CD8+ proliferation 680 Am J Clin Pathol 2007;127: Downloaded 680 from

12 AJCP / SHP/EAHP WORKSHOP that developed after treatment with efalizumab (anti-cd11a antibody) and then infliximab for psoriasis and Crohn disease, respectively. 161 It is likely that as new immunomodulatory agents are developed, novel patterns of atypical lymphoid infiltrates will need to be considered in the differential diagnosis before diagnosing lymphoma. It should also be remembered that abnormal cutaneous lymphoid infiltrates are seen in patients with autoimmune disease before treatment with these drugs. 162,163 Summary Considerable progress has been made in the classification of cutaneous TCLs in the last 20 years. However, frontiers remain with still unclassifiable lesions. In this review and summary of the Workshop findings, major points to remember include the following: Although MF and primary cutaneous CD30+ lymphoproliferative disorders (ie, C-ALCL and LyP) typically have an indolent, slowly progressive, or waxing and waning course, most of the remaining cutaneous TCLs have an aggressive course, making their recognition imperative. Although a CD8+ cytotoxic immunophenotype is often associated with aggressive histologic features and clinical course, the rare CD8+ cases of MF (including many pagetoid reticulosis and hypopigmented subtypes) and CD8+ C-ALCL and LyP have an indolent course similar to their more typical CD4+ counterparts. Preferential involvement of the subcutaneous tissue favors reactive panniculitis (autoimmune disease, erythema nodosum, erythema induratum, and interstitial granulomatous drug reactions) or SPTCL (αβ TCR+), but other lymphomas such as γδ TCL, nasal-type NK/TCL, and C-ALCL can, at least partially, have this pattern of infiltration. Systemic ALCL can also manifest rarely with skin lesions and extensive involvement of subcutaneous tissue. 164 EBV expression most often favors the diagnosis of a nasal-type NK/TCL; however, rare aggressive NK-cell leukemias, a subset of γδ TCLs, and some unclassifiable cutaneous TCLs are also EBV+, and this may reflect an alteration of the patient s immune system or progression of the tumor. A lymphoma with a CD30+/CD56+ immunophenotype may be difficult to classify. A subset of C-ALCL and LyP cases are CD56+ and are typically indolent, in contrast with systemic CD56+ ALCL cases that can be aggressive. CD30 expression can be present in nasaltype NK/TCL, but nasal-type NK/TCL is usually, but not always, EBV+. Despite careful workup, some lesions remain unclassifiable or have discordant clinical and pathologic features (particularly borderline C-ALCL/LyP type C). In such circumstances, a descriptive sign-out with a differential diagnosis and suggestions for clinical correlation and appropriate staging is recommended. From the Departments of 1 Pathology, Division of Hematopathology, The University of Texas Health Science Center, San Antonio; and 2 Hematopathology, The University of Texas, M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr Kinney: Division of Hematopathology, University of Texas Health Science Center, Mail Code 7750, 7703 Floyd Curl Dr, San Antonio, TX Acknowledgments: The following were contributors or cocontributors of cases to this session: B. Alobeid, H. Amin, R. Armand, M. Bayerl, C. Berthelot, G. Bhagat, C. Bueso-Ramos, M. Burtelow, F. Camacho, D. Cassarino, A. Castellano-Sanchez, R. Catchatourian, L.E. Clarke, R. Chiu, T. Davis, G. Deeb, J. Delabie, I. de Prada, M. Duvic, A. Ehsan, R.E. Felgar, D.B. Flack, H. Foster, T.I. George, M. Gonzales, J. Guitart, R. Gupta, N.L Harris, H. Holte, I. Ikonomou, D. Jones, M.E. Kadin, C. Keller, M.C. Kinney, S. Konoplev, P. Kovarik, F.H.C. Kreisel, M.A. Kremer, A.J.F. Lazar, C. Leith, J.M. Losi, W.L. Macaulay, M.R. Mariappan, L.J. Medeiros, Y. Natkunam, D. Newton, D.P. O Malley, A. Orazi, C.Y. Park, S.L. Perkins, S. Puttaswamy, J. Ramirez, E. Ranheim, P. Rapini, R.S. Robetorye, B. Sawan, E.J. Schlette, E. Schwartz, H. Shao, D. Tamkus, L. Tsao, E. Vakiani, D. Variakojis, and D. Viswanatha. References 1. Bouaziz JD, Bastuji-Garin S, Poszepczynska-Guigne E, et al. Relative frequency and survival of patients with primary cutaneous lymphomas: data from a single-centre study of 203 patients. Br J Dermatol. 2006;154: Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105: LeBoit PE, Burg G, Weedon D, et al, eds. Pathology and Genetics of Skin Tumours. Lyon, France: IARC Press; World Health Organization Classification of Tumours. 4. Slater DN. The new World Health Organization European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol. 2005;153: Jaffe ES, Harris NL, Stein H, et al, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; World Health Organization Classification of Tumours. 6. Burg G, Kempf W, Smoller B, et al. Mycosis fungoides. In: LeBoit P, Burg G, Weedon D, et al, eds. Pathology and Genetics of Skin Tumours. Lyon, France: IARC Press; 2006: World Health Organization Classification of Tumours. 7. Massone C, Kodama K, Kerl H, et al. Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol. 2005;29: Kodama K, Fink-Puches R, Massone C, et al. Papular mycosis fungoides: a new clinical variant of early mycosis fungoides. J Am Acad Dermatol. 2005;52: Downloaded from Am J Clin Pathol 2007;127: