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Cutaneous T-cell lymphomas in the revised 4th edition of World Health Organization classification of tumors of hematopoietic and lymphoid tissues (2017)* * Work conducted at the Faculdade de Medicina, Centro Universitário Católico Unisalesiano Auxilium, Araçatuba (SP), Brazil.

Abstract:

Recently, the World Health Organization published the revised 4th edition of its classification of tumors of hematopoietic and lymphoid tissues. The present paper is a concise comparative review of the main primary cutaneous T-cell hematopoietic tumors, with emphasis on their immunohistochemical profiles.

Keywords:
Dermatology; Immunohistochemistry; Lymphoma, T-Cell, cutaneous; Pathology

INTRODUCTION

The World Health Organization's recently published revised 4th edition of the classification of tumors of the hematopoietic and lymphoid tissues reflects the advances in the molecular and pathological understanding of these lesions, establishing new criteria for primary cutaneous lymphomas. 11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,22 Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-90.

Cutaneous T-cell lymphomas are represented mainly by mycosis fungoides (MF) and CD30+ T-cell lymphoproliferative disorders.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017.,44 Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol. 2015;68:1003-10. Thus, the present paper offers a brief explanation of those entities, establishing a comparative immunohistochemical panel using the Portuguese language nomenclature.55 Zerbini MCN, Soares FA, Morais JC, Vassallo J, Velloso EDRP Chaufaille MLLF, et al. Classificação dos tumores hematopoéticos e linfoides de acordo com a OMS: padronização da nomenclatura em língua portuguesa. 4th ed. J Bras Patol Med Lab. 2011;47:643-8.

MYCOSIS FUNGOIDES

Regarding the immunohistochemical profile, we discuss whether there is loss of CD7 expression in MF, or whether MF is a neoplasm of CD7-negative helper T lymphocytes.33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017. Another point is CD8 positivity of neoplastic cells, which is more common in the pediatric population.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017. In addition, the presence of CD30-positive cells in plaque stage does not seem to have a prognostic significance, unlike cases with transformation to large cell lymphoma when their positivity is associated with better survival.33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017.

PRIMARY CUTANEOUS CD30+ T-CELL LYMPHOPROLIFERATIVE DISORDERS

This category is the second most frequent group of cutaneous T-cell lymphomas, corresponding to approximately 30% of the cases.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,44 Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol. 2015;68:1003-10.,66 Sanches Jr JA, Moricz CZM, Neto CF. Lymphoproliferative processes of the skin. Part 2 - Cutaneous T-cell and NK-cell lymphomas. An Bras Dermatol. 2006;81:7-25.

Lymphomatoid papulosis (LyP)

In addition to the previously described variants A, B and C, other forms have been introduced. Type D is characterized by epidermotropic CD8+ and CD30+ T-cell lymphocytes, differentiated from type B by the immunohistochemical profile. Type E is defined as small- to medium-sized pleomorphic T cell neoplasia with CD8+ and CD30+ immunophenotype and angiocentric and angiodestructive infiltration.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,77 Cerroni L. Skin Lymphoma: The Illustrated Guide. 4th ed. Oxford: Wiley-Blackwell; 2014. Positivity for CD5677 Cerroni L. Skin Lymphoma: The Illustrated Guide. 4th ed. Oxford: Wiley-Blackwell; 2014. is rarely observed. LyP with 6p25.3 rearrangement corresponds to less than 5% of the cases that are characterized by rearrangement involving DUSP22-IRF4 in the 6p25.3 locus, which presents a histopathological picture resembling that of MF in transformation to large cell lymphoma (Table 1).11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.

Table 1
Classification of lymphomatoid papulosis according to the revised 4th edition of WHO’s classification of hematopoietic tumors11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.

Primary cutaneous anaplastic large cell lymphoma

This diagnosis always requires the exclusion of any evidence or history of MF, which may present a CD30+ or CD30- tumor evolution. Clinically, C-ALCL is a localized, ulcerated lesion appearing in elderly people, on the face, trunk or gluteus, with a 5-year survival rate above 90%.88 Brown RA, Fernandez-Pol S, Kim J. Primary cutaneous anaplastic large cell lymphoma. J Cutan Pathol. 2017;44:570-7. The vast majority of C-ALCL cases are negative for anaplastic lymphoma kinase 1 (ALK) epithelial membrane antigen.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,44 Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol. 2015;68:1003-10. ALK protein positivity may occur more frequently in children and may correspond to a higher probability of progression to the systemic form.88 Brown RA, Fernandez-Pol S, Kim J. Primary cutaneous anaplastic large cell lymphoma. J Cutan Pathol. 2017;44:570-7. There may be spontaneous regression in 20 to 42% of the cases, with relapse occurring in half of them.77 Cerroni L. Skin Lymphoma: The Illustrated Guide. 4th ed. Oxford: Wiley-Blackwell; 2014.,88 Brown RA, Fernandez-Pol S, Kim J. Primary cutaneous anaplastic large cell lymphoma. J Cutan Pathol. 2017;44:570-7.

SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA

A rare CD8+ cytotoxic αβ T-cell lymphoma, with involvement restricted to subcutaneous tissue,33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017. is associated with autoimmune diseases in 20% of the cases. It has a good prognosis, with neoplastic cells surrounding individual adipocytes. Positive gamma-delta cases should be excluded from this category.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017.,44 Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol. 2015;68:1003-10.,66 Sanches Jr JA, Moricz CZM, Neto CF. Lymphoproliferative processes of the skin. Part 2 - Cutaneous T-cell and NK-cell lymphomas. An Bras Dermatol. 2006;81:7-25. The absence of plasma cells and clusters of CD123-positive plasmacytoid dendritic cells aid in the differentiation of lupus panniculitis.77 Cerroni L. Skin Lymphoma: The Illustrated Guide. 4th ed. Oxford: Wiley-Blackwell; 2014.

PRIMARY CUTANEOUS GAMMA DELTA T-CELL LYMPHOMA

It is defined as a clonal proliferation of mature and activated gamma-delta T cells expressing cytotoxic markers. Clinically, it is characterized by infiltrated plaques on legs, trunk and arms, usually in elderly people.99 Guitart J, Weisenburger DD, Subtil A, Kim E, Wood G, Duvic M, et al. Cutaneous ?d T cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol. 2012;36:1656-65. In 60% of cases, erosion or necrosis occurs. Histologically, the disease is variable and can affect the epidermis, dermis and subcutaneous tissues by medium to large cell infiltrates with frequent angioinvasion and necrosis. LyP and MF cases can express gamma-delta receptors; however, these cases should continue to be diagnosed as LyP and MF. It has a poor prognosis.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,44 Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol. 2015;68:1003-10.,66 Sanches Jr JA, Moricz CZM, Neto CF. Lymphoproliferative processes of the skin. Part 2 - Cutaneous T-cell and NK-cell lymphomas. An Bras Dermatol. 2006;81:7-25. and subcutaneous involvement is an indicator of worse prognosis.1.91 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017. The estimated 5-year survival is 19.9%​​.99 Guitart J, Weisenburger DD, Subtil A, Kim E, Wood G, Duvic M, et al. Cutaneous ?d T cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol. 2012;36:1656-65.

PRIMARY CUTANEOUS CD8+ AGGRESSIVE EPIDERMOTROPIC CYTOTOXIC T-CELL LYMPHOMA

Provisional entity characterized by epidermotropic CD8+ T-cell lymphoma that demonstrates aggressive clinical behavior. The cells vary in size from small to large. Epidermotropism can be intense or even localized. Ulceration, necrosis, adnexal destruction and blister formation are common. When there is CD30 expression, the histopathological and immunohistochemical profile is indistinguishable from LyP type D; differentiation is based on the clinical history.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017. It presents an estimated 5-year survival of 0%,33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017. which is not related to cell morphology (small versus large cells) nor to the presence of localized or diffuse disease.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.

PRIMARY CUTANEOUS ACRAL CD8+ T-CELL LYMPHOMA

A rare clonal cutaneous infiltration of CD8-positive medium-sized cytotoxic T lymphocytes. It involves the acral skin, with ears being the most common site. It usually does not affect the epidermis, presents neither mitotic figures nor necrosis, and has a good prognosis.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017.

PRIMARY CUTANEOUS CD4+ SMALL/MEDIUM-SIZED T-CELL LYMPHOPROLIFERATIVE DISORDER

Previously called “primary cutaneous CD4+ small/medium T-cell lymphoma”, it was renamed “lymphoproliferative disorder” because it is a localized neoplasm with a certain resemblance to clonal proliferations secondary to medication use. Characterized by small- to medium-sized atypical CD4+ T cells, it usually appears as a single nodular lesion or plaque on the head and neck. This diagnosis requires that the hypothesis of MF be excluded, emphasizing that a small proportion of large and pleomorphic cells (<30%) can be identified. The prognosis is good, depending on whether it is a type of lymphoma, a precursor lesion, a totally benign lesion or a pseudolymphoma.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.,33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017.

HYDROA VACCINIFORME-LIKE LYMPHOPROLIFERATIVE DISORDER

Hydroa vacciniforme-like lymphoma has started to be considered a lymphoproliferative disorder due to its clinical presentation and its relation to active Epstein-Barr virus infection. It is a chronic lesion occurring in childhood and is associated with a risk of developing systemic lymphoma. It should be classified into two types: the classic self-limited type, characterized by vesicles in sun-exposed areas and a benign course; and the severe type, with extensive cutaneous involvement and systemic manifestations such as fever, hepatomegaly and lymphocytosis in peripheral blood.33 Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017. There is no morphological or clinical basis capable of predicting biological behavior.11 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.

CONCLUSION

In summary, based on the abovementioned book, we suggest a practical immunohistochemical approach according to Table 2. However, it is emphasized that many cases escape the typical immunophenotype and must be interpreted with other clinical and histopathological data.

Table 2
Differential diagnosis of cutaneous T cell neoplasms
  • *
    Work conducted at the Faculdade de Medicina, Centro Universitário Católico Unisalesiano Auxilium, Araçatuba (SP), Brazil.
  • Financial support: None.

REFERENCES

  • 1
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised. 4th ed. Volume 2. Lyon: IARC; 2017.
  • 2
    Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-90.
  • 3
    Jaffe ES, Arber DA, Campo E, Harris NL, Leticia Quintanilla-Fend L. Hematopathology 2nd ed. Philadelphia, PA: Elsevier; 2017.
  • 4
    Sidiropoulos KG, Martinez-Escala ME, Yelamos O, Guitart J, Sidiropoulos M. Primary cutaneous T-cell lymphomas: a review. J Clin Pathol. 2015;68:1003-10.
  • 5
    Zerbini MCN, Soares FA, Morais JC, Vassallo J, Velloso EDRP Chaufaille MLLF, et al. Classificação dos tumores hematopoéticos e linfoides de acordo com a OMS: padronização da nomenclatura em língua portuguesa. 4th ed. J Bras Patol Med Lab. 2011;47:643-8.
  • 6
    Sanches Jr JA, Moricz CZM, Neto CF. Lymphoproliferative processes of the skin. Part 2 - Cutaneous T-cell and NK-cell lymphomas. An Bras Dermatol. 2006;81:7-25.
  • 7
    Cerroni L. Skin Lymphoma: The Illustrated Guide. 4th ed. Oxford: Wiley-Blackwell; 2014.
  • 8
    Brown RA, Fernandez-Pol S, Kim J. Primary cutaneous anaplastic large cell lymphoma. J Cutan Pathol. 2017;44:570-7.
  • 9
    Guitart J, Weisenburger DD, Subtil A, Kim E, Wood G, Duvic M, et al. Cutaneous ?d T cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol. 2012;36:1656-65.

Publication Dates

  • Publication in this collection
    Nov/Dec 2018

History

  • Received
    07 Jan 2018
  • Accepted
    26 Mar 2018
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