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Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorders Primary cutaneous CD30-positve T-cell lymphoproliferative disorders are divided into two major subtypes: (1) primary cutaneous anaplastic large cell lymphoma, and (2) lymphomatoid papulosis.
PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a pleomorphic T-cell lymphoma in which >75% of the tumor cells express CD30. This entity should be distinguished from transformation of mycosis fungoides to CD30+ large cell lymphoma, and secondary cutaneous involvement in systemic ALCL. Most patients show solitary skin lesions presenting as nodules or papules which may be ulcerated. Multifocal skin lesions are observed in about 20% of cases, and extranodal involvement may occur in about 10% of cases. Spontaneous regression has been observed. C-ALCL usually occurs in elderly patients with a median age of about 60 years. The male to female ratio is about 1.5–2:1. The prognosis for localized lesions is very good with a 5-year survival rate of over 90%, compared with 50% for generalized cutaneous ALCL. The conventional treatment for localized lesions is excision with or without radiation. Combination chemotherapy is recommended for disseminated skin disease.
Morphology (Figure 49.1) l
There is dense dermal infiltration with clusters or sheets of anaplastic large cells, surrounded by lymphocytes. Numerous Reed–Sternberg-like cells and/or multinucleated giant cells may be present. l Epidermal involvement is rare and may be associated with ulceration. Atlas of Hematopathology. DOI: http://dx.doi.org/10.1016/B978-0-12-385183-3.00049-8 © 2013 Elsevier Inc. All rights reserved.
l l
49
Extension into subcutaneous tissue may be present. A rare “pyogenic” variant has been described with numerous neutrophils.
Immunophenotype Immunophenotypic features include (Figure 49.2): l
Common expression of CD4 T-helper cell phenotype, and positivity for CD30; l Variable loss of pan-T-cell antigens; l Common expression of cytotoxic granule associated proteins TIA1, granzyme B, and perforin; l Absent ALK, EMA, and CD15.
Molecular and Cytogenetic Studies Most cases (>90%) show TCR gene rearrangement.
LYMPHOMATOID PAPULOSIS Lymphomatoid papulosis (LyP) is a chronic papular or nodular skin lesion consisting of large anaplastic lymphoid cells embedded in an inflammatory background, and often a central necrosis. The disease is recurrent and shows spontaneous regression with the disappearance of the individual lesions in 3–12 weeks. The male to female ratio is about 2.5:1. Most patients under age 19 are males and most over age 19 are females and have a high incidence of thyroiditis. Approximately 20% of patients may develop or show coexisting T-cell cutaneous lymphoma or Hodgkin lymphoma. LyP has an excellent prognosis.
Morphology (Figure 49.3) l
In early stages, there is perivascular and patchy dermal infiltration of large atypical lymphoid cells mixed with variable numbers of inflammatory cells. The atypical cells may be multinucleated or resemble Reed–Sternberg cells. l In advanced stages, there are sheets or large clusters of monotonous large atypical cells admixed with a small number of inflammatory cells.
562
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders FIGURE 49.1 Primary cutaneous anaplastic large cell lymphoma. Skin ulceration with extensive infiltration of dermis and subcutaneous tissue by pleomorphic large cells (A to F from low to high power).
A
B
C
D
E
F
There are three morphologic types: l
Type A: Clusters of CD30 positive large cells are found in a background of inflammatory cells. l Type B: Small atypical lymphoid cells with convoluted nuclei infiltrate upper dermis and epidermis (dermatotropic), resembling mycosis fungoides. This type is uncommon. l Type C: Sheets or large clusters of large atypical CD30-positive cells with scattered inflammatory cells.
Immunophenotype Immunophenotypic features include: l
Type A and type C lesions: Large atypical cells have phenotypic features similar to those seen in C-ALCL (see above); l Type B: CD4 T-cell phenotype but lack of CD30;
Molecular and Cytogenetic Studies l
TCR gene rearrangement has been reported in about 60% of cases.
l
The profile of the clonal rearrangement by PCR can be used to distinguish primary LP lesions from metastases of other T-cell lymphomas.
Subcutaneous Panniculitis-Like T-Cell Lymphoma Subcutaneous panniculitis-like T-cell lymphoma is a rare lymphoma which involves subcutaneous fat without dermal or epidermal infiltration, leading to erythematous or violaceous nodules, plaques, or both. The clinical manifestation of subcutaneous panniculitis-like T-cell lymphoma is variable, ranging from indolent course to a rapidly fatal hemophagocytic process. The systemic hemophagocytosis is characterized by fever,
CUTANEOUS γδ T-CELL LYMPHOMA
563
FIGURE 49.2 Primary cutaneous anaplastic large cell lymphoma, immunophenotype. The neoplastic cells express CD2 (A), CD3 (B), CD4 (C), CD5 (D), and CD30 (F) by immunohistochemical stains. They are negative for CD7 (F).
A
B
C
D
E
F
hepatosplenomegaly, lung infiltration, liver dysfunction, coagulation abnormalities, and pancytopenia. This hemophagocytic syndrome may develop before or during the manifestation of T-cell lymphoma. Local radiation therapy and/or systemic chemotherapy are used. The 5-year survival rate has been reported as 80% in a recent study.
l
MORPHOLOGY (FIGURES 49.4 AND 49.5)
The tumor cells in most patients show clonal TCR gene rearrangement.
The subcutaneous infiltrate consists of a mixture of small, medium to large atypical cells with areas of necrosis. The neoplastic T-cells have a tendency to rim around adipocytes. l The infiltrate often contains reactive histiocytes which may show hemophagocytosis.
Mature cytotoxic T-cell phenotype with expression of CD3, CD8, and TCR-αβ; l Expression of cytotoxic markers TIA1, granzyme B, and perforin; l Negativity for CD56.
MOLECULAR AND CYTOGENETIC STUDIES
l
IMMUNOPHENOTYPE Immunophenotypic features include:
Cutaneous γδ T-Cell Lymphoma Cutaneous γδ T-cell lymphoma was previously considered a subtype of subcutaneous panniculitis-like T-cell lymphoma, accounting for 25% of cases. Morphologic features
564
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
A A
B B FIGURE 49.3 Lymphomatoid papulosis. Skin biopsy demonstrates a polymorphous infiltrate with atypical large lymphocytes and Reed– Sternberg-like cells (arrows) (A, low power; B, high power).
are similar to those of subcutaneous panniculitis-like, except that dermal and epidermal involvement may be present. Cutaneous γδ T-cell lymphoma is a more aggressive disease than subcutaneous panniculitis-like T-cell lymphoma. The disease has a poor prognosis with a median survival of less than 2 years. The neoplastic cells are of TCR-γδ type, positive for CD2, CD3, and CD56, with strong expression of cytotoxic markers. They are mostly negative for both CD4 and CD8, though some cases may be positive for CD8. The tumor cells are also negative for CD5 with variable loss of CD7. Southern blot analysis using the TCR-β probe is negative in these cases, but PCR analysis for TCR-γ will usually be informative. However, negativity for TCR-β clonality alone cannot always be used to infer γδ origin.
C FIGURE 49.4 Subcutaneous panniculitis-like t-cell lymphoma. Skin biopsy (A, low power; B, high power). The infiltrating lymphocytes are CD3+ (C).
Differential Diagnosis
565
FIGURE 49.5 Subcutaneous panniculitis-like t-cell lymphoma. Subcutaneous fatty tissue shows infiltrate (A, low power; B, high power).
A
B
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma
Epstein–Barr Virus-Associated Hydroa Vacciniforme-Like Cutaneous Lymphoma of Childhood
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is characterized by localized or disseminated eruptive skin lesions (papules, nodules, tumors) with epidermal infiltration of CD8+ cytotoxic T-cells and an aggressive clinical course. Tumor cells vary from small to large, show pleomorphic or blastic nuclei, and express CD3, CD8, βF1, plus cytotoxic proteins. The neoplastic cells are negative for CD4, with variable loss of CD2, CD5, and CD7. There is evidence of clonal TCR gene rearrangement.
Hydroa-like cutaneous T-cell lymphoma (hydroa-like CTCL) is a rare EBV-associated T-cell lymphoma of childhood presenting as cutaneous rash characterized by edema, blisters, ulcers, crusts, and scars, resembling hydroa vacciniforme. It is seen mainly on the face and sometimes on the extremities. The lesion consists of T-cell infiltration of the skin and subcutis with variable exocytosis and angiocentricity (Figure 49.7). There is often ulceration of the overlying epidermis. The neoplastic cells are small to medium size, often with no significant atypia or increased mitosis. They are either cytotoxic T-cells or NK-cells and express EBVEBER. Cases with cytotoxic T-cell phenotype show TCR gene rearrangement.
Primary Cutaneous CD4+ Small/ Medium T-Cell Lymphoma This cutaneous lymphoma consists of a pleomorphic small to medium sized lymphocytes, often appearing as a solitary lesion on the face, neck, or upper trunk (Figure 49.6). Unlike MF, there is absence of patches. There is a dense nodular infiltration of the dermis with a tendency to extend into the subcutis. Epiderrmotropism may be focally present. The neoplastic cells express CD3 and CD4, with variable loss of pan-T-cell markers. They are negative for CD8, CD30, plus cytotoxic proteins. The TCR genes are clonally rearranged.
Differential Diagnosis The main distinguishing morphologic, immunophenotypic, and molecular/cytogenetic features of different types of primary cutaneous T-cell lymphomas are summarized in Table 49.1. The differential diagnosis of primary cutaneous T-cell lymphomas also includes a garden variety of benign reactive skin disorders and secondary cutaneous lymphomas.
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Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
A
B
C
D
E
F
FIGURE 49.6 Primary cutaneous CD4+ t-cell lymphoma. Skin biopsy section demonstrating a patchy dermal lymphoid infiltration consisting of small to medium sized lymphocytes (A, low power; B, intermediate power; C, high power). The lymphocytes are positive for CD3 (D), and CD4 (E), and negative for CD8 (F).
Differential Diagnosis
567
Table 49.1
Differential Diagnosis of Primary Cutaneous T-Cell Lymphomas Immuno phenotype
Morphology
Mycosis fungoides
Patches, plaques, CD3+, CD4+, TCR tumors, βF1+, rearranged epidermotropism, CD7−, Pautrier CD8− microabscesses, cells with cerebriform nuclei Often solitary tumor CD3+, CD4+, TCR with ulceration, CD30+, rearranged pleomorphic CD8−, infiltrate of EMA−, large atypical ALK− cells, including multinucleated forms
C-ALCL1
A
SPTCL2
Subcutaneous CD3+, CD8+, nodules, βF1+, tumor cells rim CD8− individual fat cells, prominent apoptosis γδ T-cell Subcutaneous, CD3+, lymphoma dermal, CD56+, epidermal, TCR-γ-1+, tumor cells rim CD4−, individual fat CD8− cells, prominent apoptosis CD8+ aggressive Pagetoid CD3+, CD8+, epidermotropic epidermotropism, βF1+, adenexal CD4−, destruction CD5−, CD56− CD4+ small/ Solitary or CD3+, CD4+, medium T-cell localized lesions, βF1+, lymphoma monotonous CD8− dermal infiltrates of small to medium sized lymphocytes
B
1
Molecular/ Cytogenetics
Type
TCR rearranged
TCR-γ rearranged
TCR rearranged
TCR rearranged
C-ALCL, cutaneous anaplastic large cell lymphoma. SPTCL, subcutaneous panniculitic T-cell lymphoma. Adapted from Jaffe ES, Harris NL, Vardiman JW, et al. Hematopathology. Saunders/Elsevier, Philadelphia, 2010.⊡ 2
C FIGURE 49.7 Hydroa vacciniforme-like t-cell lymphoma. Small to medium sized lymphoid cells infiltrate the dermis (A). Infiltrate extends into subcutaneous tissue (B). Nearly all lymphoid cells are EBV-EBER+ (C). From Jaffe ES, Harris NL, Vardiman JW, et al. Hematopathology. Saunders/Elsevier, Philadelphia, 2010, by permission.
568
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
Additional Resources Akilov OE, Pillai RK, Grandinetti LM, et al: Clonal T-cell receptor β-chain gene rearrangements in differential diagnosis of lymphomatoid papulosis from skin metastasis of nodal anaplastic large-cell lymphoma, Arch Dermatol 147:943–947, 2011.
Kadin ME: Pathobiology of CD30+ cutaneous T-cell lymphomas, J Cutan Pathol 33(Suppl 1):10–17, 2006.
Barrionuevo C, Anderson VM, Zevallos-Giampietri E, et al: Hydroalike cutaneous T-cell lymphoma: a clinicopathologic and molecular genetic study of 16 pediatric cases from Peru, Appl Immunohistochem Mol Morphol 10:7–14, 2002.
Morimura S, Sugaya M, Tamaki Z, et al: Lymphomatoid papulosis showing γδ T-cell phenotype, Acta Derm Venereol 91:712–713, 2011.
Belloni-Fortina A, Montesco MC, Piaserico S, et al: Primary cutaneous CD30+ anaplastic large cell lymphoma in a heart transplant patient: case report and literature review, Acta Derm Venereol 89:74–77, 2009. Beltraminelli H, Leinweber B, Kerl H, et al: Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases, Am J Dermatopathol 31:317–322, 2009. Cetinözman F, Jansen PM, Willemze R: Expression of Programmed Death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types of cutaneous T-cell lymphoma, Am J Surg Pathol 36:109–116, 2012. Diamantidis MD, Myrou AD: Perils and pitfalls regarding differential diagnosis and treatment of primary cutaneous anaplastic large-cell lymphoma, ScientificWorldJournal 11:1048–1055, 2011. Garcia-Herrera A, Song JY, Chuang SS, et al: Nonhepatosplenic γδ T-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation, Am J Surg Pathol 35:1214–1225, 2011. Go RS, Wester SM: Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature, Cancer 101:1404–1413, 2004. Gormley RH, Hess SD, Anand D, et al: Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma, J Am Acad Dermatol 62:300–307, 2010. Guitart J, Querfeld C: Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue, Semin Diagn Pathol 26:131–140, 2009.
Kagaya M, Kondo S, Kamada A, et al: Localized lymphomatoid papulosis, Dermatology 204:72–74, 2002.
Ohmatsu H, Sugaya M, Fujita H, et al: Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma in a human T-cell leukaemia virus type-1 carrier, Acta Derm Venereol 90:324–325, 2010. Parveen Z, Thompson K: Subcutaneous panniculitis-like T-cell lymphoma: redefinition of diagnostic criteria in the recent World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas, Arch Pathol Lab Med 133:303–308, 2009. Plaza JA, Ortega P, Lynott J, et al: CD8-positive primary cutaneous anaplastic large T-cell lymphoma (PCALCL): case report and review of this unusual variant of PCALC, Am J Dermatopathol 32:489–491, 2010. Querfeld C, Khan I, Mahon B, et al: Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options, Oncology (Williston Park) 24:574–587, 2010. Rosen ST, Querfeld C: Primary cutaneous T-cell lymphomas, Hematology Am Soc Hematol Educ Program:323–330, 513, 2006. Shunmugam M, Chan E, O'Brart D, et al: Cutaneous γδ T-cell lymphoma with bilateral ocular and adnexal involvement, Arch Ophthalmol 129:1379–1381, 2011. Sim JH, Kim YC: CD8+ lymphomatoid papulosis, Ann Dermatol 23:104–107, 2011. Tripodo C, Iannitto E, Florena AM, et al: Gamma-delta T-cell lymphomas, Nat Rev Clin Oncol 6:707–717, 2009. Wang Y, Li T, Tu P, et al: Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma clinically simulating pyoderma gangrenosum, Clin Exp Dermatol 34:e261–e262, 2009. Xu Z, Lian S: Epstein-Barr virus-associated hydroa vacciniforme-like cutaneous lymphoma in seven Chinese children, Pediatr Dermatol 27:463–469, 2010.
Jaffe ES, Harris NL, Vardiman JW, et al: Hematopathology, Philadelphia, 2010, Saunders/Elsevier.
Yamane N, Kato N, Nishimura M, et al: Primary cutaneous CD30+ anaplastic large-cell lymphoma with generalized skin involvement and involvement of one peripheral lymph node, successfully treated with low-dose oral etoposide, Clin Exp Dermatol 34:e56–e59, 2009.
Jang MS, Baek JW, Kang DY, et al: Subcutaneous panniculitis-like T-cell lymphoma: successful treatment with systemic steroid alone, J Dermatol 39:96–99, 2012.
Yip L, Darling S, Orchard D: Lymphomatoid papulosis in children: experience of five cases and the treatment efficacy of methotrexate, Australas J Dermatol 52:279–283, 2011.
Primary Cutaneous CD30-Positive T-Cell Lymphoproliferative Disorders Primary cutaneous CD30-positve T-cell lymphoproliferative disorders are divided into two major subtypes: (1) primary cutaneous anaplastic large cell lymphoma, and (2) lymphomatoid papulosis.
PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a pleomorphic T-cell lymphoma in which >75% of the tumor cells express CD30. This entity should be distinguished from transformation of mycosis fungoides to CD30+ large cell lymphoma, and secondary cutaneous involvement in systemic ALCL. Most patients show solitary skin lesions presenting as nodules or papules which may be ulcerated. Multifocal skin lesions are observed in about 20% of cases, and extranodal involvement may occur in about 10% of cases. Spontaneous regression has been observed. C-ALCL usually occurs in elderly patients with a median age of about 60 years. The male to female ratio is about 1.5–2:1. The prognosis for localized lesions is very good with a 5-year survival rate of over 90%, compared with 50% for generalized cutaneous ALCL. The conventional treatment for localized lesions is excision with or without radiation. Combination chemotherapy is recommended for disseminated skin disease.
Morphology (Figure 49.1) l
There is dense dermal infiltration with clusters or sheets of anaplastic large cells, surrounded by lymphocytes. Numerous Reed–Sternberg-like cells and/or multinucleated giant cells may be present. l Epidermal involvement is rare and may be associated with ulceration. Atlas of Hematopathology. DOI: http://dx.doi.org/10.1016/B978-0-12-385183-3.00049-8 © 2013 Elsevier Inc. All rights reserved.
l l
49
Extension into subcutaneous tissue may be present. A rare “pyogenic” variant has been described with numerous neutrophils.
Immunophenotype Immunophenotypic features include (Figure 49.2): l
Common expression of CD4 T-helper cell phenotype, and positivity for CD30; l Variable loss of pan-T-cell antigens; l Common expression of cytotoxic granule associated proteins TIA1, granzyme B, and perforin; l Absent ALK, EMA, and CD15.
Molecular and Cytogenetic Studies Most cases (>90%) show TCR gene rearrangement.
LYMPHOMATOID PAPULOSIS Lymphomatoid papulosis (LyP) is a chronic papular or nodular skin lesion consisting of large anaplastic lymphoid cells embedded in an inflammatory background, and often a central necrosis. The disease is recurrent and shows spontaneous regression with the disappearance of the individual lesions in 3–12 weeks. The male to female ratio is about 2.5:1. Most patients under age 19 are males and most over age 19 are females and have a high incidence of thyroiditis. Approximately 20% of patients may develop or show coexisting T-cell cutaneous lymphoma or Hodgkin lymphoma. LyP has an excellent prognosis.
Morphology (Figure 49.3) l
In early stages, there is perivascular and patchy dermal infiltration of large atypical lymphoid cells mixed with variable numbers of inflammatory cells. The atypical cells may be multinucleated or resemble Reed–Sternberg cells. l In advanced stages, there are sheets or large clusters of monotonous large atypical cells admixed with a small number of inflammatory cells.
562
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders FIGURE 49.1 Primary cutaneous anaplastic large cell lymphoma. Skin ulceration with extensive infiltration of dermis and subcutaneous tissue by pleomorphic large cells (A to F from low to high power).
A
B
C
D
E
F
There are three morphologic types: l
Type A: Clusters of CD30 positive large cells are found in a background of inflammatory cells. l Type B: Small atypical lymphoid cells with convoluted nuclei infiltrate upper dermis and epidermis (dermatotropic), resembling mycosis fungoides. This type is uncommon. l Type C: Sheets or large clusters of large atypical CD30-positive cells with scattered inflammatory cells.
Immunophenotype Immunophenotypic features include: l
Type A and type C lesions: Large atypical cells have phenotypic features similar to those seen in C-ALCL (see above); l Type B: CD4 T-cell phenotype but lack of CD30;
Molecular and Cytogenetic Studies l
TCR gene rearrangement has been reported in about 60% of cases.
l
The profile of the clonal rearrangement by PCR can be used to distinguish primary LP lesions from metastases of other T-cell lymphomas.
Subcutaneous Panniculitis-Like T-Cell Lymphoma Subcutaneous panniculitis-like T-cell lymphoma is a rare lymphoma which involves subcutaneous fat without dermal or epidermal infiltration, leading to erythematous or violaceous nodules, plaques, or both. The clinical manifestation of subcutaneous panniculitis-like T-cell lymphoma is variable, ranging from indolent course to a rapidly fatal hemophagocytic process. The systemic hemophagocytosis is characterized by fever,
CUTANEOUS γδ T-CELL LYMPHOMA
563
FIGURE 49.2 Primary cutaneous anaplastic large cell lymphoma, immunophenotype. The neoplastic cells express CD2 (A), CD3 (B), CD4 (C), CD5 (D), and CD30 (F) by immunohistochemical stains. They are negative for CD7 (F).
A
B
C
D
E
F
hepatosplenomegaly, lung infiltration, liver dysfunction, coagulation abnormalities, and pancytopenia. This hemophagocytic syndrome may develop before or during the manifestation of T-cell lymphoma. Local radiation therapy and/or systemic chemotherapy are used. The 5-year survival rate has been reported as 80% in a recent study.
l
MORPHOLOGY (FIGURES 49.4 AND 49.5)
The tumor cells in most patients show clonal TCR gene rearrangement.
The subcutaneous infiltrate consists of a mixture of small, medium to large atypical cells with areas of necrosis. The neoplastic T-cells have a tendency to rim around adipocytes. l The infiltrate often contains reactive histiocytes which may show hemophagocytosis.
Mature cytotoxic T-cell phenotype with expression of CD3, CD8, and TCR-αβ; l Expression of cytotoxic markers TIA1, granzyme B, and perforin; l Negativity for CD56.
MOLECULAR AND CYTOGENETIC STUDIES
l
IMMUNOPHENOTYPE Immunophenotypic features include:
Cutaneous γδ T-Cell Lymphoma Cutaneous γδ T-cell lymphoma was previously considered a subtype of subcutaneous panniculitis-like T-cell lymphoma, accounting for 25% of cases. Morphologic features
564
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
A A
B B FIGURE 49.3 Lymphomatoid papulosis. Skin biopsy demonstrates a polymorphous infiltrate with atypical large lymphocytes and Reed– Sternberg-like cells (arrows) (A, low power; B, high power).
are similar to those of subcutaneous panniculitis-like, except that dermal and epidermal involvement may be present. Cutaneous γδ T-cell lymphoma is a more aggressive disease than subcutaneous panniculitis-like T-cell lymphoma. The disease has a poor prognosis with a median survival of less than 2 years. The neoplastic cells are of TCR-γδ type, positive for CD2, CD3, and CD56, with strong expression of cytotoxic markers. They are mostly negative for both CD4 and CD8, though some cases may be positive for CD8. The tumor cells are also negative for CD5 with variable loss of CD7. Southern blot analysis using the TCR-β probe is negative in these cases, but PCR analysis for TCR-γ will usually be informative. However, negativity for TCR-β clonality alone cannot always be used to infer γδ origin.
C FIGURE 49.4 Subcutaneous panniculitis-like t-cell lymphoma. Skin biopsy (A, low power; B, high power). The infiltrating lymphocytes are CD3+ (C).
Differential Diagnosis
565
FIGURE 49.5 Subcutaneous panniculitis-like t-cell lymphoma. Subcutaneous fatty tissue shows infiltrate (A, low power; B, high power).
A
B
Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma
Epstein–Barr Virus-Associated Hydroa Vacciniforme-Like Cutaneous Lymphoma of Childhood
Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma is characterized by localized or disseminated eruptive skin lesions (papules, nodules, tumors) with epidermal infiltration of CD8+ cytotoxic T-cells and an aggressive clinical course. Tumor cells vary from small to large, show pleomorphic or blastic nuclei, and express CD3, CD8, βF1, plus cytotoxic proteins. The neoplastic cells are negative for CD4, with variable loss of CD2, CD5, and CD7. There is evidence of clonal TCR gene rearrangement.
Hydroa-like cutaneous T-cell lymphoma (hydroa-like CTCL) is a rare EBV-associated T-cell lymphoma of childhood presenting as cutaneous rash characterized by edema, blisters, ulcers, crusts, and scars, resembling hydroa vacciniforme. It is seen mainly on the face and sometimes on the extremities. The lesion consists of T-cell infiltration of the skin and subcutis with variable exocytosis and angiocentricity (Figure 49.7). There is often ulceration of the overlying epidermis. The neoplastic cells are small to medium size, often with no significant atypia or increased mitosis. They are either cytotoxic T-cells or NK-cells and express EBVEBER. Cases with cytotoxic T-cell phenotype show TCR gene rearrangement.
Primary Cutaneous CD4+ Small/ Medium T-Cell Lymphoma This cutaneous lymphoma consists of a pleomorphic small to medium sized lymphocytes, often appearing as a solitary lesion on the face, neck, or upper trunk (Figure 49.6). Unlike MF, there is absence of patches. There is a dense nodular infiltration of the dermis with a tendency to extend into the subcutis. Epiderrmotropism may be focally present. The neoplastic cells express CD3 and CD4, with variable loss of pan-T-cell markers. They are negative for CD8, CD30, plus cytotoxic proteins. The TCR genes are clonally rearranged.
Differential Diagnosis The main distinguishing morphologic, immunophenotypic, and molecular/cytogenetic features of different types of primary cutaneous T-cell lymphomas are summarized in Table 49.1. The differential diagnosis of primary cutaneous T-cell lymphomas also includes a garden variety of benign reactive skin disorders and secondary cutaneous lymphomas.
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Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
A
B
C
D
E
F
FIGURE 49.6 Primary cutaneous CD4+ t-cell lymphoma. Skin biopsy section demonstrating a patchy dermal lymphoid infiltration consisting of small to medium sized lymphocytes (A, low power; B, intermediate power; C, high power). The lymphocytes are positive for CD3 (D), and CD4 (E), and negative for CD8 (F).
Differential Diagnosis
567
Table 49.1
Differential Diagnosis of Primary Cutaneous T-Cell Lymphomas Immuno phenotype
Morphology
Mycosis fungoides
Patches, plaques, CD3+, CD4+, TCR tumors, βF1+, rearranged epidermotropism, CD7−, Pautrier CD8− microabscesses, cells with cerebriform nuclei Often solitary tumor CD3+, CD4+, TCR with ulceration, CD30+, rearranged pleomorphic CD8−, infiltrate of EMA−, large atypical ALK− cells, including multinucleated forms
C-ALCL1
A
SPTCL2
Subcutaneous CD3+, CD8+, nodules, βF1+, tumor cells rim CD8− individual fat cells, prominent apoptosis γδ T-cell Subcutaneous, CD3+, lymphoma dermal, CD56+, epidermal, TCR-γ-1+, tumor cells rim CD4−, individual fat CD8− cells, prominent apoptosis CD8+ aggressive Pagetoid CD3+, CD8+, epidermotropic epidermotropism, βF1+, adenexal CD4−, destruction CD5−, CD56− CD4+ small/ Solitary or CD3+, CD4+, medium T-cell localized lesions, βF1+, lymphoma monotonous CD8− dermal infiltrates of small to medium sized lymphocytes
B
1
Molecular/ Cytogenetics
Type
TCR rearranged
TCR-γ rearranged
TCR rearranged
TCR rearranged
C-ALCL, cutaneous anaplastic large cell lymphoma. SPTCL, subcutaneous panniculitic T-cell lymphoma. Adapted from Jaffe ES, Harris NL, Vardiman JW, et al. Hematopathology. Saunders/Elsevier, Philadelphia, 2010.⊡ 2
C FIGURE 49.7 Hydroa vacciniforme-like t-cell lymphoma. Small to medium sized lymphoid cells infiltrate the dermis (A). Infiltrate extends into subcutaneous tissue (B). Nearly all lymphoid cells are EBV-EBER+ (C). From Jaffe ES, Harris NL, Vardiman JW, et al. Hematopathology. Saunders/Elsevier, Philadelphia, 2010, by permission.
568
Other Primary Cutaneous T-Cell Lymphoproliferative Disorders
Additional Resources Akilov OE, Pillai RK, Grandinetti LM, et al: Clonal T-cell receptor β-chain gene rearrangements in differential diagnosis of lymphomatoid papulosis from skin metastasis of nodal anaplastic large-cell lymphoma, Arch Dermatol 147:943–947, 2011.
Kadin ME: Pathobiology of CD30+ cutaneous T-cell lymphomas, J Cutan Pathol 33(Suppl 1):10–17, 2006.
Barrionuevo C, Anderson VM, Zevallos-Giampietri E, et al: Hydroalike cutaneous T-cell lymphoma: a clinicopathologic and molecular genetic study of 16 pediatric cases from Peru, Appl Immunohistochem Mol Morphol 10:7–14, 2002.
Morimura S, Sugaya M, Tamaki Z, et al: Lymphomatoid papulosis showing γδ T-cell phenotype, Acta Derm Venereol 91:712–713, 2011.
Belloni-Fortina A, Montesco MC, Piaserico S, et al: Primary cutaneous CD30+ anaplastic large cell lymphoma in a heart transplant patient: case report and literature review, Acta Derm Venereol 89:74–77, 2009. Beltraminelli H, Leinweber B, Kerl H, et al: Primary cutaneous CD4+ small-/medium-sized pleomorphic T-cell lymphoma: a cutaneous nodular proliferation of pleomorphic T lymphocytes of undetermined significance? A study of 136 cases, Am J Dermatopathol 31:317–322, 2009. Cetinözman F, Jansen PM, Willemze R: Expression of Programmed Death-1 in primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma, cutaneous pseudo-T-cell lymphoma, and other types of cutaneous T-cell lymphoma, Am J Surg Pathol 36:109–116, 2012. Diamantidis MD, Myrou AD: Perils and pitfalls regarding differential diagnosis and treatment of primary cutaneous anaplastic large-cell lymphoma, ScientificWorldJournal 11:1048–1055, 2011. Garcia-Herrera A, Song JY, Chuang SS, et al: Nonhepatosplenic γδ T-cell lymphomas represent a spectrum of aggressive cytotoxic T-cell lymphomas with a mainly extranodal presentation, Am J Surg Pathol 35:1214–1225, 2011. Go RS, Wester SM: Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature, Cancer 101:1404–1413, 2004. Gormley RH, Hess SD, Anand D, et al: Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma, J Am Acad Dermatol 62:300–307, 2010. Guitart J, Querfeld C: Cutaneous CD30 lymphoproliferative disorders and similar conditions: a clinical and pathologic prospective on a complex issue, Semin Diagn Pathol 26:131–140, 2009.
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