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Dermatopathology
Primary cutaneous T-cell lymphomas: a review Konstantinos G Sidiropoulos,1 M Estela Martinez-Escala,2 Oriol Yelamos,2 Joan Guitart,2 Michael Sidiropoulos1,3,4 1
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada 2 Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA 3 Department of Pathology, Lakeridge Health, Oshawa, Ontario, Canada 4 Department of Pathology and Laboratory Medicine, University Health Network, Toronto, Ontario, Canada Correspondence to Dr Michael Sidiropoulos, Department of Pathology, Lakeridge Health, 1 Hospital Court, Oshawa, Ontario, Canada L1G 2B9; michael.sidiropoulos@utoronto. ca Received 2 November 2015 Accepted 5 November 2015
To cite: Sidiropoulos KG, Martinez-Escala ME, Yelamos O, et al. J Clin Pathol 2015;68:1003–1010.
ABSTRACT Primary cutaneous T-cell lymphomas (CTCLs) represent a number of extranodal lymphomas arising from a malignant population of lymphocytes in the skin, with the most common type being mycosis fungoides (MF) representing half of all primary CTCLs. Despite advances in immunohistochemistry and molecular methodology, significant diagnostic challenges remain due to phenotypic overlap of primary CTCLs with several inflammatory dermatoses, secondary lymphomas, among other conditions. Clinical features such as presentation and morphology, staging, histology, immunophenotype and molecular features must be considered in detail before a diagnosis is made in order to minimise falsepositive, false-negative and indeterminate diagnoses. Herein, we review primary CTCLs, including epidemiological data, a brief summary of clinical presentations, immunophenotype, molecular signatures and differential diagnoses.
INTRODUCTION There are two main forms of lymphoma including Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL), and among NHL, nodal and extranodal NHL are differentiated. The skin is the second most common site of involvement in extranodal NHL, after the gastrointestinal tract, with an overall incidence of approximately 1:100 000.1 Primary cutaneous lymphomas first arise on the skin without any systemic involvement, and these are important to differentiate from secondary cutaneous lymphoma due to prognostic and predictive implications. Primary cutaneous lymphomas can be confusing histopathologically since primary and secondary cutaneous lymphomas are very similar and at times identical. As such, complete staging investigations can be required in order to avoid any diagnostic problems.2 T-cell lymphomas are the most common group of lymphomas to be found in the skin, whereas B-cell lymphomas represent the majority of nodal lymphomas, accounting for 30% of the lymphomas first found on the skin.3 In this review, we will focus on primary cutaneous T-cell lymphomas (CTCLs). CTCLs are a heterogeneous group composed of a clonal population of skin-homing malignant T or natural killer (NK) cells.1 The WHO-EORTC classification of primary cutaneous lymphomas lists many entities of CTCLs; however the most common subtypes, comprising 95%, include mycosis fungoides (MF), which represents half of cases, followed by Sézary syndrome and CD30+ lymphoproliferative disorders (LPDs).2 4 5 Each entity has unique prognostic and predictive characteristics. CTCLs are generally considered incurable with the control of symptoms, cosmesis and extending survival as the main goals
of therapy.6 Allogeneic stem cell transplantation may provide survival benefits including a possible cure.6
MYCOSIS FUNGOIDES MF is the most common entity of all T-cell lymphomas, seen most frequently in adults/elderly, but it is also observed in adolescents and children.2 4 5 The male-to-female ratio is 2:1.1 4 MF arises from a clonal expansion of memory T-helper (CD45RO+, CD4+) lymphocytes.7 As such, MF is used as a prototype from which other CTCLs are separated as different entities. MF clinically varies in presentation, however, and usually presents as erythematous patches, plaques or tumours with a scaly wrinkled atrophic surface that initially arise on double-covered and sun-protected sites such as the breast, buttock, inner thighs, upper inner arms and hips. MF has an indolent clinical course with slow progression over years to decades, with patches progressing to more infiltrative plaques, eventually evolving into tumours and becoming more generalised.4 In advanced stages, extra-cutaneous dissemination may occur to blood, lymph nodes, liver, spleen and lungs.1 4 There are many different MF variants described in the literature, and three of them are accepted by the current WHO classification. These variants include follicular MF, pagetoid MF and granulomatous slack skin syndrome. Dyschromic presentations of MF, also known as hypopigmented MF, are frequently diagnosed in children, despite the fact that in most cases they do not correspond to a true MF. We have seen that these cases do not fit the whole histological criteria to call them MF, and they are better categorised as a T-cell dyscrasia, hypopigmented interface dermatitis subtype.8 With these clinical variants, MF may be misdiagnosed as inflammatory mimics such as psoriasis, atopic dermatitis or chronic actinic dermatitis.9 10 Histologically, there is a variation of presenting skin lesions that may be seen under the microscope depending on the stage of MF. As stated above, MF clinically tends to progress in a stepwise pattern, from patches to plaques to tumours. Generally, MF histopathologically is characterised by several features which will vary on the stage and the morphology that is biopsied.11 MF is characterised by epidermotropic infiltrates of small-to-medium-sized T lymphocytes with cerebriform nuclei.4 Most histological features are not entirely specific for MF, with the exception of Pautrier’s microabscesses, which are usually absent in early disease; however, they are found in 4%–37.5% of MF including the plaque stage4 5 11–13 (figure 1). Some of the histological features of MF such as linear
Sidiropoulos KG, et al. J Clin Pathol 2015;68:1003–1010. doi:10.1136/jclinpath-2015-203133
1003
Downloaded from http://jcp.bmj.com/ on November 4, 2017 - Published by group.bmj.com
Dermatopathology Figure 1 Histological features of mycosis fungoides. (A) Striking epidermotropism of atypical lymphocytes, associated with fibroplasias on the superficial dermis. (B) Close-up view of the atypical lymphocytes with clear halo around nucleus. (C) Tumour stage of mycosis fungoides with dense dermal infiltrate. (D) A Pautrier’s microabscess is noted in the epidermis.
arrangement of atypical epidermal lymphocytes and Pautrier’s microabscesses can also be lost after treatment such as phototherapy.14 In the patch stage (or early MF), there is an infiltrate of mild-to-moderate atypical lymphocytes that exhibit epidermotropism and/or adnexotropism (figure 1A). These early patch lesions show superficial band-like or lichenoid infiltrates along the dermal–epidermal junction (tagging), mainly consisting of lymphocytes and histiocytes.4 The lesions may also show atypical cells confined to the basal layer of the epidermis (basilar epidermotropism—defined as one to five basal lymphocytes per 20× field) with minimal associated spongiosis which are often small cells with cerebriform nuclei (as large as a basal keratinocyte nucleus, ∼7–9 μm), with a perinuclear clearing or halo (figure 1B). Haloed lymphocytes have been shown to be a good discriminator between MF and inflammatory mimics.12 In the tumour stage of MF, the infiltrate is more prominent in the reticular dermis, and around the vascular plexi (figure 1C). The dermal infiltrates become more diffuse and epidermotropism may be lost. The T cells may exhibit increased variability, increasing in cellular size and varying in shape. Histological transformation may occur with >25% large lymphoid cells in the dermal infiltrate and can eventually be detected in the peripheral blood, lymph nodes and viscera. These T cells show variable proportions from small-to-medium sized to large cerebriform cells, blast cells with prominent nuclei and intermediate forms.1 4 5 Recognising early (patch to plaque) infiltrates can be quite difficult but can be aided by flow cytometry, immunohistochemistry and T-cell receptor analysis.4 Flow cytometry for MF is usually CD26− or dim expression. Immunohistochemistry assists in diagnosis with an increased CD4:CD8 ratio and lower CD4 surface expression,15 and a CD8:CD3 ratio
Dermatopathology
Primary cutaneous T-cell lymphomas: a review Konstantinos G Sidiropoulos,1 M Estela Martinez-Escala,2 Oriol Yelamos,2 Joan Guitart,2 Michael Sidiropoulos1,3,4 1
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada 2 Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA 3 Department of Pathology, Lakeridge Health, Oshawa, Ontario, Canada 4 Department of Pathology and Laboratory Medicine, University Health Network, Toronto, Ontario, Canada Correspondence to Dr Michael Sidiropoulos, Department of Pathology, Lakeridge Health, 1 Hospital Court, Oshawa, Ontario, Canada L1G 2B9; michael.sidiropoulos@utoronto. ca Received 2 November 2015 Accepted 5 November 2015
To cite: Sidiropoulos KG, Martinez-Escala ME, Yelamos O, et al. J Clin Pathol 2015;68:1003–1010.
ABSTRACT Primary cutaneous T-cell lymphomas (CTCLs) represent a number of extranodal lymphomas arising from a malignant population of lymphocytes in the skin, with the most common type being mycosis fungoides (MF) representing half of all primary CTCLs. Despite advances in immunohistochemistry and molecular methodology, significant diagnostic challenges remain due to phenotypic overlap of primary CTCLs with several inflammatory dermatoses, secondary lymphomas, among other conditions. Clinical features such as presentation and morphology, staging, histology, immunophenotype and molecular features must be considered in detail before a diagnosis is made in order to minimise falsepositive, false-negative and indeterminate diagnoses. Herein, we review primary CTCLs, including epidemiological data, a brief summary of clinical presentations, immunophenotype, molecular signatures and differential diagnoses.
INTRODUCTION There are two main forms of lymphoma including Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL), and among NHL, nodal and extranodal NHL are differentiated. The skin is the second most common site of involvement in extranodal NHL, after the gastrointestinal tract, with an overall incidence of approximately 1:100 000.1 Primary cutaneous lymphomas first arise on the skin without any systemic involvement, and these are important to differentiate from secondary cutaneous lymphoma due to prognostic and predictive implications. Primary cutaneous lymphomas can be confusing histopathologically since primary and secondary cutaneous lymphomas are very similar and at times identical. As such, complete staging investigations can be required in order to avoid any diagnostic problems.2 T-cell lymphomas are the most common group of lymphomas to be found in the skin, whereas B-cell lymphomas represent the majority of nodal lymphomas, accounting for 30% of the lymphomas first found on the skin.3 In this review, we will focus on primary cutaneous T-cell lymphomas (CTCLs). CTCLs are a heterogeneous group composed of a clonal population of skin-homing malignant T or natural killer (NK) cells.1 The WHO-EORTC classification of primary cutaneous lymphomas lists many entities of CTCLs; however the most common subtypes, comprising 95%, include mycosis fungoides (MF), which represents half of cases, followed by Sézary syndrome and CD30+ lymphoproliferative disorders (LPDs).2 4 5 Each entity has unique prognostic and predictive characteristics. CTCLs are generally considered incurable with the control of symptoms, cosmesis and extending survival as the main goals
of therapy.6 Allogeneic stem cell transplantation may provide survival benefits including a possible cure.6
MYCOSIS FUNGOIDES MF is the most common entity of all T-cell lymphomas, seen most frequently in adults/elderly, but it is also observed in adolescents and children.2 4 5 The male-to-female ratio is 2:1.1 4 MF arises from a clonal expansion of memory T-helper (CD45RO+, CD4+) lymphocytes.7 As such, MF is used as a prototype from which other CTCLs are separated as different entities. MF clinically varies in presentation, however, and usually presents as erythematous patches, plaques or tumours with a scaly wrinkled atrophic surface that initially arise on double-covered and sun-protected sites such as the breast, buttock, inner thighs, upper inner arms and hips. MF has an indolent clinical course with slow progression over years to decades, with patches progressing to more infiltrative plaques, eventually evolving into tumours and becoming more generalised.4 In advanced stages, extra-cutaneous dissemination may occur to blood, lymph nodes, liver, spleen and lungs.1 4 There are many different MF variants described in the literature, and three of them are accepted by the current WHO classification. These variants include follicular MF, pagetoid MF and granulomatous slack skin syndrome. Dyschromic presentations of MF, also known as hypopigmented MF, are frequently diagnosed in children, despite the fact that in most cases they do not correspond to a true MF. We have seen that these cases do not fit the whole histological criteria to call them MF, and they are better categorised as a T-cell dyscrasia, hypopigmented interface dermatitis subtype.8 With these clinical variants, MF may be misdiagnosed as inflammatory mimics such as psoriasis, atopic dermatitis or chronic actinic dermatitis.9 10 Histologically, there is a variation of presenting skin lesions that may be seen under the microscope depending on the stage of MF. As stated above, MF clinically tends to progress in a stepwise pattern, from patches to plaques to tumours. Generally, MF histopathologically is characterised by several features which will vary on the stage and the morphology that is biopsied.11 MF is characterised by epidermotropic infiltrates of small-to-medium-sized T lymphocytes with cerebriform nuclei.4 Most histological features are not entirely specific for MF, with the exception of Pautrier’s microabscesses, which are usually absent in early disease; however, they are found in 4%–37.5% of MF including the plaque stage4 5 11–13 (figure 1). Some of the histological features of MF such as linear
Sidiropoulos KG, et al. J Clin Pathol 2015;68:1003–1010. doi:10.1136/jclinpath-2015-203133
1003
Downloaded from http://jcp.bmj.com/ on November 4, 2017 - Published by group.bmj.com
Dermatopathology Figure 1 Histological features of mycosis fungoides. (A) Striking epidermotropism of atypical lymphocytes, associated with fibroplasias on the superficial dermis. (B) Close-up view of the atypical lymphocytes with clear halo around nucleus. (C) Tumour stage of mycosis fungoides with dense dermal infiltrate. (D) A Pautrier’s microabscess is noted in the epidermis.
arrangement of atypical epidermal lymphocytes and Pautrier’s microabscesses can also be lost after treatment such as phototherapy.14 In the patch stage (or early MF), there is an infiltrate of mild-to-moderate atypical lymphocytes that exhibit epidermotropism and/or adnexotropism (figure 1A). These early patch lesions show superficial band-like or lichenoid infiltrates along the dermal–epidermal junction (tagging), mainly consisting of lymphocytes and histiocytes.4 The lesions may also show atypical cells confined to the basal layer of the epidermis (basilar epidermotropism—defined as one to five basal lymphocytes per 20× field) with minimal associated spongiosis which are often small cells with cerebriform nuclei (as large as a basal keratinocyte nucleus, ∼7–9 μm), with a perinuclear clearing or halo (figure 1B). Haloed lymphocytes have been shown to be a good discriminator between MF and inflammatory mimics.12 In the tumour stage of MF, the infiltrate is more prominent in the reticular dermis, and around the vascular plexi (figure 1C). The dermal infiltrates become more diffuse and epidermotropism may be lost. The T cells may exhibit increased variability, increasing in cellular size and varying in shape. Histological transformation may occur with >25% large lymphoid cells in the dermal infiltrate and can eventually be detected in the peripheral blood, lymph nodes and viscera. These T cells show variable proportions from small-to-medium sized to large cerebriform cells, blast cells with prominent nuclei and intermediate forms.1 4 5 Recognising early (patch to plaque) infiltrates can be quite difficult but can be aided by flow cytometry, immunohistochemistry and T-cell receptor analysis.4 Flow cytometry for MF is usually CD26− or dim expression. Immunohistochemistry assists in diagnosis with an increased CD4:CD8 ratio and lower CD4 surface expression,15 and a CD8:CD3 ratio
