|
 
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| REVIEW ARTICLE |
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| Year : 2014 | Volume
: 1
| Issue : 1 | Page : 7-16 |
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Cutaneous lymphomas: An update
Ashok Singh, Sudheer Arava, MK Singh
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| Date of Web Publication | 24-Jun-2014 |
Correspondence Address:
Sudheer Arava
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None  | Check |
Cutaneous lymphomas are heterogeneous and distinct entities which have been in controversy since the time of conception. WHO EORTC defined them as distinct pathological entity compared to the nodal counterpart. They are defined as lymphomas having primary cutaneous presentation without any systemic involvement. As such the diagnosis of cutaneous lymphomas is a diagnosis of exclusion. These lymphomas are distinct from the nodal lymphomas in their presentation, behaviour and prognosis. These lymphomas have been divided into B cell and T cell type based on the presence of predominance of atypical lymphocytes of B or T lineage. The most common cutaneous lymphomas are T cell immunophenotype, and Mycosis fungoides constitutes the majority of cutaneous lymphomas. Cutaneous lymphomas needs to be differentiated from pseudolymphomas which are benign proliferation of lymphoid cells mimicking lymphomas and mostly have a benign course Keywords: Cutaneous B cell lymphomas, cutaneous T cell lymphomas, Mycosis fungoides, pseudolymphomas
How to cite this article:
Singh A, Arava S, Singh M K. Cutaneous lymphomas: An update. Indian J Dermatopathol Diagn Dermatol 2014;1:7-16 |
| Introduction | |  |
Cutaneous lymphomas are defined as lymphomas which present primarily in the skin without any extracutaneous extension. [1]
These tumors are classified as per WHO- EORTC classification for cutaneous lymphomas into following categories.
| Cutaneous T cell lymphomas | | |
These are the most common form of cutaneous lymphomas constituting 70-78%. [2]
| Mycosis fungoides | | |
Mycosis fungoides is a slow-growing lymphoma with a natural history spanning from years to decades. Characteristically the disease starts as a patch, insidiously progresses to plaque and culminates terminally into tumor/nodular stage. In terminal stages, extra cutaneous dissemination occur. [3]
Clinical features
Typically seen in sixth to seventh decade with no sex predilection. [1],[2]
Histopathology
In early stages, band like infiltrate comprising of reactive and malignant lymphocytes is seen in the superficial dermis and may be overlooked as a reactive process. Focal epidermal infiltration by atypical lymphoid cell with cerebriform nucleus (epidermotropism) and small aggregates (Pautrier ' s micro abscess) [Figure 1]a and b may be seen in the absence of epidermal/follicular spongiotic reaction. With progression infiltration into the dermis becomes diffuse. [3],[4] Malignant cells express CD2, CD3, CD4, CD5 CD45 RO and are negative for CD8. [5],[6],[7] | Figure 1: Mycosis fungoides: (a) Showing infi ltration of the epidermis by atypical lymphocytes with pautrier's micro-abscess (b) Atypical cells are immunopositive for CD 4
Click here to view |
Genetic features
T-cell receptor rearrangements are seen. Chromosomal abnormalities do occur but are non-specific. [8]
Overall survival depends upon the stage, extent and systemic dissemination at the time of presentation. [8]
Treatment
Early stages of the disease are treated with phototherapy (PUVA -psoralen ultraviolet A), topical agents and radiotherapy. [9],[10]
| Variants of mycosis fungoides | | |
Folliculotropic MF
Characterized by infiltration of hair/adnexal structures by malignant cells. Preferentially located in the head and neck region. Mucinous degeneration of the hair and adnexal glands is also seen. Commonly associated with alopecia. [2],[11],[12]
Pagetoid reticulosis
Solitary variant (Woringer Kollop disease) is considered as representative of Pagetoid Reticulosis. Systemic form (Ketron Goodman disease) is considered as a type of aggressive form of CD 8+ T cell lymphoma. [2],[13]
Histopathology
There is an exclusive intraepidermal infiltrate of atypical T cells. Dermis is not involved. These cells are immunopositive for CD3 and either CD4 or CD 8. [14]
Therapy
Radiotherapy or surgery is the treatment of choice for localized disease. [2],[15]
Granulomatous slack skin
It is characterized clinically by thick loose folds of skin in intertriginous areas. [2]
Histopathology
Dense dermal infiltration by chronic inflammatory infiltrate admixed with atypical T cells. Numerous granulomas including giant cells are seen. The disease has an indolent but progressive course. Treatment is generally with radiotherapy and surgery. [2],[15],[16]
Sezary syndrome
Aggressive form of cutaneous T cell lymphoma characterized by erythroderma, generalized lymphadenopathy and circulating Sezary cells. [2],[3] Previous history of MF excludes the diagnosis of Sezary syndrome. The International Society for Cutaneous Lymphomas (ISCL), has laid down following criteria for the diagnosis of Sezary syndrome.
- Absolute sezary cell count of 1000 cells/mm 3
- Demonstration of immunophenotypical abnormality
- CD4/CD8 ratio of > 10
- Loss of T-cell antigen (CD2, CD3, CD5, CD4)
- Demonstration of T-cell clone in peripheral blood by molecular or cytogenetic methods. [17]
Histopathology shows a scant epidermotropic infiltrate comprising large atypical cells with markedly convoluted nuclei. Lymph node shows partial to complete effacement of architecture. Sezary cells are also seen in peripheral smear. Atypical cells are immunopositive for CD3/CD4 and immunonegative for CD8. [18]
Genetic features
T-cell rearrangements are known. Jun B has been found to be overexpressed. Prognosis is poor. [19]
Treatment with Interferon gamma, betaxerotene, and alemtuzumab has been reported with mixed results and requires further validation. [10],[20]
Differential diagnosis
Erythroderma due to atopic dermatitis, psoriasis, pityriasis rubra pilaris. [3]
Rarer variants of Mycosis fungoides include poikiloderma vasculare atrophicans, Psoriasisform MF, bullous/vesicular variant, hypopigmented MF, hyperpigmented MF, mycosis fungoides palmaris et plantaris, verrucous/Hyperkeratotic form, acanthosis nigricans -MF, pustular form and ichthyosiform MF.[3] Inspite of being distinct they are not considered as separate entities as they have clinical behaviour and prognosis similar to classical mycosis fungoides. [21]
| Adult T-cell leukemia/lymphoma | | |
These are aggressive lymphomas developing in persons infected with Human T cell leukemia/lymphoma (HTLV) virus. It is common in Japan, Caribbean islands and Central Africa where HTLV virus infection is prevalent. It has a long latency period before the manifestation of the disease. It is commonly seen in fifth to sixth decade with a male preponderance. Clinically, patient presents with generalized lymphadenopathy, peripheral blood involvement and skin lesions. Hypercalcemia is commonly seen. [22],[23],[24]
Histopathology
There is dense infiltrate by large atypical T lymphocytes with nuclear convolutions. Large cells with anaplastic features and prominent nucleoli are also seen. In early stages, differentiation from MF is difficult. Typical band like infiltrate of MF is not seen. Malignant cells are immunopositive for CD4/CD2/CD3/CD5. T-cell receptor rearrangements are seen. Acute and lymphomatous subtypes have decreased survival as compared to the chronic forms. [23],[24],[25],[26]
Therapy
Chemotherapy is the mainstay of treatment. [26]
| Primary Cutaneous CD 30 + lymphoproliferative disorders | | |
These are clinically less aggressive types where large atypical T-cells express CD30. This category includes (1) primary anaplastic large cell lymphoma (2) lymphomatoid papulosis and (3) borderline cases. Skin biopsies show a dense dermal infiltrate of large cells with marked anaplastic features and diffuse CD 30 positivity. [27]
| Primary cutaneous anaplastic large cell lymphoma (ALCL) | | |
It comprises large cells with immunoblastic morphology, marked nuclear pleomorphism and strong CD 30 expression by majority of tumor cells [Figure 2]a and b. Skin lesions in the form of nodules and papules are seen. Spontaneous regression of the disease is on record but recurrences are common. [27] | Figure 2: Cutaneous ALCL: (a) Dense dermal infiltrate of large atypical lymphocytes showing (b) strong immunopositivity for CD30
Click here to view |
Immunophenotype
CD 30, CD4+/Granzyme, Perforin and TIA-1 positive. Morphologically these cells are indistinguishable from cells of systemic ALCL with secondary skin infiltration, but are EMA and ALK-1 negative. [28],[29]
Genetic features
T-cell rearrangement is present but t (2:5) ALK translocation is not seen. Compared to its systemic counterpart, the prognosis is much better with survival rates of more than 90%. [27],[29]
Treatment
surgery and radiotherapy. [29]
| Lymphomatoid papulosis | | |
Cutaneous lymphoma with recurring papules and nodules in all stages of development. [27]
Clinical features
Seen in adults. It has a long natural history with fluctuating signs and symptoms as per the stage of disease. Many of these cases are succeeded by another lymphoma. [27]
Histopathology
There are three histologic subtypes with overlap of features
- Type A: Few clusters of CD 30+ cells in an inflammatory background.
- Type B: Small cells with convoluted nuclei infiltrating into the epidermis, type B cells are CD3/CD4+, do not express CD30.
- Type C: Diffuse infiltration by large atypical CD 30+ cells. [2],[27]
Genetic features
T-cell rearrangements are present but translocation t (2:5) is not seen. In spite of being similar to ALCL they have excellent prognosis. [30]
Treatment
No definite treatment.
| Subcutaneous panniculitis like T-cell lymphoma (SPTCL) | | |
It is an uncommon entity with propensity for subcutaneous tissue infiltration and epidermal sparing. Tumor cells are small to medium with CD 8 + and α/β positive staining. Cases of subcutaneous panniculitis like lymphoma with γ/δ subtype are included in cutaneous γ/δ lymphomas and not considered in SPTLs. [2],[15],[31]
Clinical features
Common in young adults with female preponderance. It presents as nodules and plaques. The disease may linger for decades before getting fully developed. Many cases are complicated by concurrent hemophagocytic syndrome and are associated with poor prognosis. [31],[32]
Histopathology
There is septal and lobular infiltration by atypical lymphocytes i. These cells are small to medium sized. Large cell may also be seen. Rimming of adipocytes by tumor cells is noted with necrosis and karyorhexis. Tumor cells show cytotoxic T-cell phenotype with expression of CD8 + CD3+/CD4- and α/β+ [Figure 3]a and b. CD30 is not expressed and rare case shows positivity for CD56. Clonal rearrangement of T-cell receptor beta and gamma genes is seen in all cases without association with EBV. Overall 5-year survival is 80-82%. With development of hemophagocytic syndrome the 5-year survival rates fall to 41%. [31],[33] | Figure 3: Subcutaneous panniculitis like T-cell lymphoma: (a) Predominant subcutaneous involvement by atypical lymphocytes (b) Cells are immunopositive for CD8
Click here to view |
Therapy
Steroids can be used in localized disease with effectiveness. Systemic chemotherapy (CHOP regimen) has been used in advanced stages with mixed results. [31],[34]
| Extranodal NK/T cell lymphoma, nasal type | | |
It is a CD 8+ T-cell lymphoma with EBV association, comprises small to large pleomorphic cells with a propensity of nasal cavity/and nasopharyngeal involvement. Skin involvement is very commonly seen. [2] There is extensive destruction of involved soft tissue with prominent necrosis and angiodestruction. Patients present at advanced stage and have aggressive clinical course. [3],[35],[36],[37],[38]
Histopathology
Dense infiltrate of small to large cells. Necrosis and apoptosis are nonspecific but constant findings. Cells express CD2+, CD56+ and cytotoxic proteins. EBV detection is helpful in arriving at the diagnosis in cases which are negative on immunohistochemistry. Patients with cutaneous involvement have better prognosis as compared to those with systemic involvement. [15],[39],[40],[41],[42]
Treatment
Systemic chemotherapy is the preferred modality of treatment.
| Primary Cutaneous peripheral T-cell lymphoma, unspecified | | |
This encompasses all those lymphomas which are not included in any of the defined entities.
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma (provisional entity)
Rare variant with proliferation of CD 8+ atypical lymphocytes showing epidermotropism. [2],[15],[29]
Clinical features
Disease of adults with median age of 53 years. Presents with patches, papules, nodules, and necrotic/ulcerated lesions which may be localized or disseminated. [43]
Histopathology
Patch stage lesions show epidermotropic infiltrates of small to medium sized cells. Tumor cells show marked pleomorphism with lichenoid pattern of infiltrate. Late tumoral lesions show dense infiltrate by medium to large atypical T lymphocytes. Follicular and vascular invasion is also noted. [2],[5]
Immunophenotype
CD3+/CD8+ positive, while negative for CD4, CD5, and CD7. Not associated with EBV. [5],[43]
Genetic features
TCR-γ rearrangements are present. Association with HTLV virus has been reported. Highly aggressive clinical course with poor survival rates. Recurrences are known to occur. [5],[43],[44]
Therapy
Systemic chemotherapy is the preferred modality of treatment. [5],[44]
| Cutaneous gamma/delta T cell lymphoma (provisional entity) | | |
Composed of clonal proliferation of atypical T cells with CD8+, gamma/delta + phenotype. These are high-grade lymphomas with very poor prognosis. [45]
Clinical features
Seen in adults in fifth decade. The lesions are usually disseminated at presentation. [31],[46]
Histopathology
Diffuse infiltration by medium to large atypical, pleomorphic cells with extensive necrosis and vascular involvement. Infiltration may be predominantly epidermal, dermal, or subcutaneous. [15]
Immunophenotype
CD 3+, CD2+, CD56+, CD4, and CD8 are both absent. [45]
Genetic features
TCR -γ clonal rearrangements are seen. EBV association is not known. [15],[46]
Prognosis
Median overall survival ranges from 11 to 15 months. [46]
Primary cutaneous CD4 + small/medium-sized pleomorphic T-cell lymphoma (provisional entity)
It is characterized by dense dermal infiltration with subcutaneous extension of small to medium-sized CD4+ cells, and presents as a localized skin lesion over face and trunk. Adnexal and vascular infiltration is noted. Patches and plaques should raise the suspicion of MF and should be excluded. Average age at presentation is fifth decade. [2],[15]
Immunophenotype
CD 3+ and CD 4+, CD2, CD7, CD 8 expression is not seen.
Prognosis
Indolent behavior with 5-year survival of 60-80%. [15],[47]
| Precursor hematologic neoplasm | | |
0CD4+/CD56+ hematodermic neoplasm (blastic NK cell lymphoma)
High-grade lymphoma with aggressive clinical course and poor outcome. It isbelieved to arise from natural killer cell. [48],[49],[50]
Clinical features
Disease of older individual with localized to diffuse cutaneous lesions and/or systemic involvement in the form of nodal, visceral and bone marrow involvement. Relentless progression culminating in death. [49]
Histopathology
Lesions show diffuse infiltrate of small to medium-sized monomorphic cells with atypical nuclear features and high mitotic activity with epidermal sparing. No adnexal or vascular invasion is noted. [48],[51],[52]
Immunophenotype
CD4+, CD56+, CD45+, CD45 RA +, CD123. [50]
Genetic features
Germline configuration of T-cell receptor gene is seen. No EBV association is seen. [2],[15],[51]
Prognosis
Dismal survival inspite of aggressive treatment regimens with median survival of14 months. [52]
| Cutaneous B-cell lymphomas | | |
Primary cutaneous B-cell neoplasms have been classified as per the morphology, immunophenotypic, genetic, and clinical behavior into the following entities:
Primary Cutaneous Marginal zone B-cell lymphoma
It is an indolent lymphoma with cutaneous manifestations composed of small to medium-sized cells with cleaved nucleus. Large cells and plasmacytoid cells are also seen. According to WHO 2008, this entity belongs to the broad category of Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. [2],[15]
Clinical features
Common in fourth to fifth decade with male preponderance. Patients present with single to multiple lesions comprising papules, nodules or plaques over the trunk and extremities. [53],[54],[55],[56]
Histopathology
Dense infiltrate of small cleaved cells in the dermis and extension into the subcutaneous tissue. Epidermis is relatively spared. Plasma cells, plasmacytoid cells, and reactive chronic inflammatory infiltrate are also noted. Role of infectious agent is questionable with Borrelia species being identified in some studies.
Immunophenotype
Tumor cells express CD20, CD79a, and Bcl-2 and are immunonegative for Bcl-6, CD5 and CD10, CYCLIN D1. [2],[15],[56],[57]
Genetic features
Translocation t (14:18), t (1:18), and t (3:14) has been reported in minority of cases. Immunoglobulin heavy chain IgH gene rearrangements seen in majority of cases. [56],[58],[59]
Prognosis
Recurrences and relapses are common but overall survival is extremely good (>99%). [56],[60]
The closest differential diagnosis is primary cutaneous follicular center cell lymphoma.
Treatment
Localized and systemic chemotherapy, radiotherapy and surgery are the current modalities of treatment. [61]
Primary cutaneous follicle center lymphoma
Cutaneous lymphoma comprising atypical B- cells [Figure 4]a and b showing features of germinal center centrocytes infiltrating in a nodular, nodular to diffuse and diffuse pattern in the dermis with extension to subcutaneous tissue. [15] | Figure 4: Cutaneous follicle center cell lymphoma: (a) Predominant infiltration dermis with formation of lymphoid nodules (b) Strong immunopositivity for CD 10
Click here to view |
Clinical features
Seen in adults in the fifth to sixth decade with a male preponderance. Lesions are most commonly seen over head and neck followed by trunk and upper extremities. [15],[62],[63]
Histopathology
Three patterns of infiltration 1) Diffuse 2) Nodular and diffuse and 3) Nodular. In initial stages ill-defined follicles are seen composed of malignant B cells. In later stages follicular distinction is lost with marked adnexal structure destruction. [15],[63]
Immunophenotype
Cells express B-cell markers CD20, CD79a and surface immunoglobulin (sIg) and are negative for CD5 and CD43. Bcl-6 is consistently expressed (>90%) of cells. Bcl-2 expression is not seen. [62],[64]
Genetic features
Clonal rearrangement of immunoglobulin genes is present. Translocation t (14:18) seen in nodal follicular lymphomas is conspicuous by its absence in cutaneous follicular lymphomas. [15],[65] Rare transformation to Large B-cell lymphoma is reported. [66]
Prognosis
Prognosis is independent of growth pattern and morphological type and overall prognosis is very good with disease-free 5-year survival of 87% and 95%. [62]
Treatment
Localized lesions are treated with radiotherapy. Other modalitiesare systemic chemotherapy and surgical interventions. [67]
Primary cutaneous diffuse large B-cell lymphoma (DLBCL)
B cell cutaneous lymphoma composed of large cells with nuclear atypia and prominent nucleoli. [15]
Two types
- Primary cutaneous DLBCL, leg type (DLBCL-LT)
- Primary cutaneous DLBCL, other
Primary cutaneous DLBCL leg type
Primary cutaneous DLBCL leg type is characterized by diffuse infiltration of large cells with immunoblastic morphology. Median age of presentation is 7 th -8 th decade with female preponderance. [68],[69]
Typical presentation is with a mass over the legs increasing in size in a short span of time. Presentation at sites other than legs doesn't exclude the diagnosis of PCLBCL-LT. Patients may present with systemic involvement at the time of presentation. Lesions may disappear completely on treatment but recurrences are common. [62],[70]
Histopathology
Monomorphic diffuse infiltration of the dermis and subcutis by large cells with prominent nucleoli (centroblastic to immunoblastic). High mitotic activity is seen. Epidermis is essentially unremarkable. No follicle formation is noted nor is CD21-positive cells indicative of follicles. [70]
Immunophenotype
B-cell markers CD20 and CD 79a are positive. Bcl2 and Bcl6 are expressed in majority of cases. [41],[70],[71],[72]
Genetic features
Translocation t (14:18) is not seen as compared to its nodal counterpart. [70]
Prognostic features
Despite being an aggressive lymphoma it has a good prognosis and 5-year survival rates varying from 52%, 55%, and 62% in different studies have been reported. Adverse prognostic factors include multiple skin lesions, old age, round cell morphology, and expression of Bcl2, MUM-1 and FOXP1. [73],[74]
Treatment
Systemic chemotherapy is the preferred choice. (Anthracycline based). [68],[70]
Primary cutaneous DLBCL, other
Comprises large B-cell lymphoma cases not included in the PCLBCL-LT group but having similar presentation. Encompasses large B-cell lymphomas with primary cutaneous presentation like plasmablastic/anaplastic variants of DLBCL and T-cell/histiocyte rich large B-cell lymphomas. [74]
Intravascular Large B-cell lymphoma
Rare subtype with peculiar growth of atypical B cells within the small caliber blood vessels mostly in the capillaries. It is a disease of adults seen in sixth-seventh decade. It is an aggressive lymphoma with poor prognosis. [15],[75]
Patients generally present at late stage with systemic involvement and hepatosplenomegaly. Lymph node involvement is typically not seen. [76]
There are two major clinical subtypes
- Western type: Presents with cutaneous and neurological complications
- Asian type: Presents with multiorgan failure, hepatosplenomegaly, and hemophagocytic syndrome. [77]
Immunophenotype
CD5, CD20, CD79, CD10, Bcl-6, MUM1, and Bcl-2 expression is noted. Neoplastic cell have defective Beta 1 integrin and CD11a which results in ineffective diapedesis and accumulation in the vascular surface. [76],[77],[78]
Genetic features
No characteristic genetic abnormalities are seen. [79] Prognosis: Western type is associated with better prognosis as compared to the Asian type. Overall survival is extremely poor (median 3-year survival of 27%). [77],[78]
Therapy
Anthracycline-based chemotherapy is the current treatment of choice with partial response. [76]
Pseudolymphoma (Cutaneous lymphoid hyperplasia)
Is a benign proliferation of mature lymphocytes in the dermis. There is often subcutaneous involvement with relative epidermal sparing. It is composed of an admixture of B and T cells [Table 1] and [Table 2] forming vague nodules or infiltrating diffusely, giving a false impression of lymphomatous process. The term cutaneous pseudo lymphoma is now replaced by cutaneous lymphoid hyperplasia (CLH). [80],[81] | Table 2: Differential diagnosis of B cell cutaneous lymphoid hyperplasia
Click here to view |
Clinical features
Seen generally in adults. Median age of presentation is fifth to sixth decade. Patients present with slow growing patches, plaques and nodules. Lesions are most commonly seen over the trunk and head and neck region. [82]
Histopathology
On the basis of infiltration pattern, three types are identified. Diffuse, nodular and band like. Apart from lymphocytic infiltrate, plasma cells and macrophages are also seen within the infiltrate. Germinal centers are identified except in diffuse type. [80] [Figure 5]a and b. | Figure 5: Cutaneous Lymphoid B cell hyperplasia: (a) Dermal lymphoid follicle with prominent germinal center. (b) Epidermis is free with clear grenz zone
Click here to view |
Etiological agents for development of pseudolymphoma are diverse and include drug reactions, arthropod infestation, tattoo reaction, vaccination, and perniosis. Immunophenotype depends on the predominant population of infiltrating cells. Cells are polyclonal as compared to clonal proliferation in cutaneous B-cell lymphomas. [83],[84]
Genetic features
No specific genetic abnormalities are seen. No clonal rearrangements of heavy chain genes are seen. [84]
Therapy
Surgical excision is the preferred modality with complete cure. Intralesional steroids have also been effective. [84]
Prognosis
Excellent with no recurrences in adequately treated cases. [84]
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]
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