Background

This is a rare variant of a skin lymphoma. The majority of skin lymphomas are derived from T-cells. T cells have receptors on their surfaces which allow it to interact with other cells and proteins. The T-cell receptor (TCR) is either gamma-delta or alpha-beta heterodimer. About 95% of all T-cells will express the alpha-beta TCR. The remainder express the gamma-delta TCR. In the normal development of T-cells, the gamma-delta TCR occurs first. T-cells expressing this receptor have cytotoxic capabilities recruiting lymphokines. Most of these gamma-delta T-cells lack CD4 and CD8 surface markers, the most common T-cell surface markers, which designate T-helper and T-suppressor cells. Rare cells are CD8 positive.

Overall, these tumors are very rare but important to correctly diagnose. The cytotoxic capabilities of non-neoplastic gamma-delta T-cells is recapitulated in cutaneous T-cell lymphomas derived from these cells lines. Patients have an aggressive and stormy course and are often resistant to multiagent chemotherapy and radiation. There are multiple lesions of plaques and nodules on the extremities. This is in contrast to the usual cases of mycosis fungoides. Patients may also develop the hemophagocytic syndrome, resulting in hepatosplenomegaly and infiltration of multiple organs by histiocytes engulfing red blood cells. Thus, it is important to distinguish this variant of a cutaneous T-cell lymphoma from mycosis fungoides. The pathologist is responsible for analyzing the T-cell receptor type as well as examining special stains that will aid in the diagnosis.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

 

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	Rare
AGE RANGE-MEDIAN	13-82 years
SEX (M:F)	2:1

 

PATHOGENESIS	CHARACTERIZATION
Overlap with subcutaneous T-cell lymphoma	Subcutaneous nodules are present in both diseases and both share the gamma-delta TCR phenotype
TCR delta variable region 2 gene
Chromosomal anomalies	Negative to date
Epstein-Barr virus	Negative to date

 

HISTOLOGICAL TYPES	CHARACTERIZATION
SKIN	Dense dermal and subcutaneous infiltration by atypical lymphocytes lacking a cerebriform nucleus Epidermotropism similar to mycosis fungoides
Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Massone C, Chott A, Metze D, Kerl K, Citarella L, Vale E, Kerl H, Cerroni L. Department of Dermatology, University of Graz, Austria.	Am J Surg Pathol. 2004 Jun;28(6):719-35. Abstract quote   A new group of subcutaneous, natural killer (NK), NK/T-cell, and other cytotoxic T-cell lymphomas of the skin has been recently described, and some have been included as distinct clinicopathologic entities in the classification of hematologic malignancies recently proposed by the World Health Organization. In the European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas, they would be classified either as CD30- large T-cell lymphoma, small/medium pleomorphic T-cell lymphoma, or subcutaneous T-cell lymphoma. Precise clinicopathologic and prognostic features of all of them have not yet been well characterized. We studied retrospectively 81 biopsies from 50 patients with subcutaneous, blastic natural killer (NK), NK/T-cell, or other non-mycosis fungoides cytotoxic T-cell lymphomas of the skin. Clinical, morphologic, phenotypical, and genetic features and data on Epstein-Barr virus association allowed us to classify our cases according to the following 7 categories: a) subcutaneous "panniculitis-like" T-cell lymphoma (SPTCL): 10 cases (estimated 5-year survival: 80%); b) blastic NK-cell lymphoma: 12 cases (estimated 5-year survival: 0%); c) nasal-type extranodal NK/T-cell lymphoma: 5 patients (estimated 5-year survival: 0%); d) epidermotropic CD8+ T-cell lymphoma: 5 cases (estimated 5-year survival: 0%); e) cutaneous gamma/delta T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); f) cutaneous alpha/beta pleomorphic T-cell lymphoma: 8 cases (estimated 5-year survival: 0%); and g) cutaneous medium/large pleomorphic T-cell lymphoma, not otherwise specified: 2 cases. Our study shows that these cutaneous lymphomas can be classified according to precise diagnostic categories. With the exception of SPTCL, analysis of follow-up data from our patients showed that these groups of lymphomas are characterized by an aggressive course, regardless of the diagnostic category.
HEMATODERMIC NEOPLASMS CD4+ CD56+
CD4(+)CD56(+) hematodermic neoplasms bear a plasmacytoid dendritic cell phenotype. Urosevic M, Conrad C, Kamarashev J, Asagoe K, Cozzio A, Burg G, Dummer R. Department of Dermatology, University Hospital Zurich, Zurich 8091, Switzerland.	Hum Pathol. 2005 Sep;36(9):1020-4. Abstract quote   CD4(+)CD56(+) hematodermic neoplasms (HNs) with initial presentation in the skin are characterized by highly aggressive behavior and poor prognosis. Recent studies indicate that malignant cells, which are devoid of common T-, B-, NK-, and myeloid lineage markers, may be of plasmacytoid dendritic cell (pDC) origin. We undertook a study to assess the expression of several pDC-associated molecules on a series of 5 CD4(+)CD56(+) HN cases. CD123 was expressed in all 5 cases, with some heterogeneity in individual cases. All but one case revealed fine membranous BDCA-2 staining of the dermal infiltrate. pDC-like phenotype of the malignant infiltrating cells was confirmed by costaining of BDCA-2(+) cells with CD123 and CD4. MxA protein, representing the surrogate marker for lesional type I interferon activity, was expressed in 4 of 5 evaluated cases. Our findings further substantiate the putative pDC origin of CD4(+)CD56(+) HNs.

 

LABORATORY TESTING

CHARACTERIZATION

A Novel Four-Color PCR Assay to Assess T-Cell Receptor Gamma Gene Rearrangements in Lymphoproliferative Lesions Francisco Vega, MD, PhD, L. Jeffrey Medeiros, MD, Dan Jones, MD, PhD, Lynne V. Abruzzo, MD, PhD, Raymond Lai, MD, PhD, John Manning, MD, Valerie Dunmire, MS, and Rajyalakshmi Luthra, PhD

Am J Clin Pathol 2001;116:17-24 Abstract quote We describe a novel 4-color polymerase chain reaction (PCR) assay combined with GeneScan analysis to assess for T-cell receptor gamma chain gene (TCRgamma) rearrangements and evaluate its usefulness in 86 lymphoproliferative lesions. In this assay, each variable region (Vgamma) family primer is 5' end-labeled with a different fluorescent dye, allowing determination of the Vgamma family involved in each TCRgamma rearrangement. PCR products were analyzed by capillary electrophoresis. We detected clonal TCRgamma rearrangements in 60 (98%) of 61 T-cell lymphomas, 2 (15%) of 13 B-cell lymphomas, and 3 (25%) of 12 reactive lesions. These results compared favorably with conventional PCR methods using denaturing gradient gel electrophoresis, which revealed clonal TCRgamma rearrangements in 37 (90%) of 41 T-cell lymphomas, 1 (25%) of 4 B-cell lymphomas, and 2 (25%) of 8 reactive lesions. This 4-color PCR assay is at least equivalent to conventional PCR methods and is convenient, allows accurate size determination of TCRgamma rearrangements, and identifies the specific Vgamma family involved, providing more specific information about TCRgamma rearrangement.

 

SPECIAL STAINS/ IMMUNOPEROXIDASE	CHARACTERIZATION
Gamma-delta T-cell receptor	Lack CD4 and CD8 usually
Cytotoxic profile	TIA-1 Granzyme B Perforin

 

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
CD8 variant of mycosis fungoides	Nodular ulcerative lesions with marked epidermotropism Extensive involvement of the palms, soles, and oral mucosa
Subcutaneous panniculitis-like T-cell lymphoma	May represent a spectrum of skin and clinical involvement Less epidermal involvement
Hepatosplenic gamma-delta T-cell lymphoma	Expresses the Vdelta1 gene, corresponding to the normal T-cells expressing this in the spleen Two recurrent chromosomal anomalies, 7q and trisomy 8
Cutaneous CD30 lymphoma	CD30 positive
Cutaneous Natural Killer cell lymphomas	Usually men >50 years CD56+ and CD4+
Lupus profundus, indeterminate lymphocytic lobular panniculitis and subcutaneous T-cell lymphoma: a spectrum of subcuticular T-cell lymphoid dyscrasia. Magro CM, Crowson AN, Kovatich AJ, Burns F. Ohio State University Medical Center, Columbus, Ohio, USA.	J Cutan Pathol 2001 May;28(5):235-47 Abstract quote INTRODUCTION: The diagnosis and classification of lymphocytic lobular panniculitis (LLP) has historically proven to be a difficult challenge. We encountered 32 cases of primary LLP which could be categorized as: 1) lupus erythematosus profundus (LEP) (19 patients); 2) an indeterminate group termed indeterminate lymphocytic lobular panniculitis (ILLP) (6 patients); and 3) subcutaneous T-cell lymphoma (SCTCL) (7 patients). OBJECTIVE: We attempted to better define the subtypes of LLP by morphologic, phenotypic and genotypic features and to correlate those features to clinical presentation and outcome. METHOD: Skin biopsy material was studied by conventional light microscopy, through immunophenotyping performed on sections from paraffin-embedded, formalin-fixed tissue and in some cases on sections of tissue frozen after receipt in physiological (Michel's) medium, and by polymerase chain reaction single-stranded conformational polymorphism analysis to assess for clonality of T-lymphocytes. Clinical features were correlated to histologic, phenotypic, and genotypic analyses. RESULTS: Patients with LEP had a prior diagnosis of LE or overlying skin changes which light microscopically were characteristic of LE. Patients with ILLP had no concurrent or prior history of LE, no systemic symptoms or cytopenias, and a clinical course not suggestive of lymphoma. Cases of SCTCL showed hemophagocytic syndrome and/or lesional progression with demise attributable to the disease. Lesions in all groups showed proximal extremity predilection. Females predominated in the LEP group. The average age of onset was 38, 40 and 55 years in the LEP, ILLP and SCTCL groups, respectively. Cytopenia was seen in 4 LEP patients; 1 also developed fever. In LEP and ILLP, lesions resolved with hydroxychloroquine and/or steroid therapy, with recurrences following cessation of therapy. In the SCTCL group 4 developed hemophagocytic syndrome, 4 died within 2 years of diagnosis, and 3 went into remission following chemotherapy. The LEP and SCTCL groups manifested histological similarities: dense perieccrine and lobular lymphocytic infiltration, lymphoid atypia, histiocytes with ingested debris, eosinophilic necrosis of the fat lobule and thrombosis. The atypical lymphocytes although pleomorphic did not have a cerebriform morphology. The infiltrate in ILLP had a similar cytomorphology and distribution with variable angioinvasion which in all save one case was of lesser intensity and was not associated with significant fat necrosis or vasculitis. Germinal centers, dermal/subcuticular mucin deposition and an atrophying interface dermatitis with hyperkeratosis and follicular plugging were largely confined to the LEP group. Erythrophagocytosis, characteristic of SCTCL, usually indicated a supervening subcuticular lymphoid dyscrasia when encountered in ILLP and LEP. SCTCL showed a selective loss of CD5 expression with or without diminution in CD7 and monoclonal CD3 expression. Of 4 cases studied, 3 showed a CD8 dominant infiltrate while 2 others exhibited CD56 and CD30 positivity, respectively. All cases of SCTCL with amplifiable DNA showed T-cell clonality. Similar molecular and phenotypic features indicative of subcuticular lymphoid dyscrasia were encountered in cases of LEP and ILLP including a reduction in CD5, CD7, and/or monoclonal CD3 expression, a preponderance of CD8 lymphocytes within the subcutaneous fat and T-cell clonality. These cases showed lymphoid atypia with variable erythrophagocytosis. Cases of phenotypically abnormal and/or clonal LEP showed one or more of local destruction, lesional size progression, fever, and cytopenias, but lesions responded to hydroxychloroquine and/or prednisone therapy and death attributable to panniculitis could not be documented. Cases that were phenotypically normal and without clonality had none of the aforesaid atypical clinical features. CONCLUSION: Lymphoid atypia, erythrophagocytosis, loss of certain pan T-cell markers, a reduced CD4/8 ratio and TCR rearrangement define subcuticular T-cell lymphoid dyscrasia, including a subset of LEP and ILLP. The subcuticular lymphoid infiltrates represent a spectrum of histologic, immunophenotypic, and molecular abnormalities which range from those which are clearly benign to those which are clearly neoplastic, and also encompasses those cases which defy precise classification into the two aforesaid poles.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
Prognostic Factors	Aggressive course complicated by hemophagocytic syndrome
5 Year Survival	In a limited study, 12/16 died within 2 years and all 16 died within 5 years
Treatment	Multiagent chemotherapy with/without radiation therapy

Arch Dermatol 2000;136:1024-1032
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Mycosis Fungoides

PTCL (Peripheral T-cell Lymphoma)

Skin Lymphomas

Subcutaneous T-cell Lymphoma (Panniculitis-like T-cell Lymphoma)

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Last Updated September 28, 2005

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