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.
Abstract: * Subcutaneous panniculitis-like T-cell lymphoma is a primary T-cell lymphoma that preferentially involves the subcutaneous tissue. Although subcutaneous panniculitis-like T-cell lymphoma has been recognized as a distinctive entity in the category of peripheral T-cell lymphoma in theWorld Health Organization classification, its diagnostic criteria has been redefined by the recent World Health Organization-European Organization for Research and Treatment of Cancer classification for primary cutaneous lymphomas. Subcutaneous panniculitis-like T-cell lymphoma is now restricted to primary cutaneous T-cell lymphoma expressing [alpha][beta] T-cell receptor phenotype. These lymphomas are usually CD[3.sup.+], CD[4.sup.-], CD[8.sup.+], and CD[56.sup.-], and usually have an indolent clinical course. The clinicopathologic features, differential diagnosis, immunophenotypic characteristics, and molecular features of subcutaneous panniculitis-like T-cell lymphoma are presented in light of the recent World Health Organization--European Organization for Research and Treatment of Cancer classification.

(Arch Pathol Lab Med. 2009;133:303-308)
Article Type: Disease/Disorder overview
Subject: T cells (Research)
T cells (Physiological aspects)
Lymphomas (Diagnosis)
Lymphomas (Care and treatment)
Lymphomas (Prognosis)
Panniculitis (Diagnosis)
Panniculitis (Care and treatment)
Panniculitis (Prognosis)
Authors: Parveen, Zahida
Thompson, Karen
Pub Date: 02/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2009 Source Volume: 133 Source Issue: 2
Topic: Event Code: 310 Science & research; 350 Product standards, safety, & recalls
Organization: Organization: World Health Organization
Accession Number: 230151967
Full Text: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a distinctive skin lymphoma that is characterized by infiltration of the subcutaneous tissue by neoplastic cytotoxic T cells mimicking panniculitis. It was first described by Gonzalez et al (1) in 1991, when they presented 8 cases of T-cell lymphoma localized primarily to the subcutaneous adipose tissue without evident lymph node involvement. It was recognized as a provisional entity and was included in the Revised European-American classification of lymphoid neoplasms in 1994 and later by the European Organization for Research and Treatment of Cancer (EORTC) in 1997. (2,3) Subcutaneous panniculitis-like T-cell lymphoma was then defined as a distinct entity by the World Health Organization (WHO) classification in 2001. (4) It was observed that SPTCL's clinical course was very different depending on the T-cell receptor (TCR) phenotype and immunophenotypic characteristics of the tumor cells. Lymphomas that were TCR[alpha][beta] phenotype were usually CD[4.sup.-], CD[8.sup.-], CD[56.sup.-] and had an indolent course. On the contrary, lymphomas that were TCR[gamma][delta] phenotype were usually CD[4.sup.-], CD[8.sup.-], CD[56.sup.+], had a worse prognosis, and were often fatal due to an accompanying hemophagocytic syndrome. (5) Clinical, histologic, and immunophenotypical features of TCR[alpha][beta] SPTCL and TCR[gamma][delta] SPTCL are summarized in Table 1. Based on these observations, in the recent World Health Organization-European Organization for Research and Treatment of Cancer (WHOEORTC) classification of primary cutaneous lymphomas, the category of SPTCL is now restricted to cases that express TCR[alpha][beta] phenotype, whereas cases with TCR[gamma][delta] phenotype are now placed in a new provisional category of cutaneous [gamma][delta] T-cell lymphoma (6) (Table 2).

The incidence of SPTCL is less than 1% of the nonHodgkin lymphomas. (4) Since these data were collected prior to the new WHO-EORTC classification and include SPTCL with both TCR[alpha][beta] and TCR[gamma][delta] phenotypes, the true incidence of SPTCL is less than previously thought. Subcutaneous panniculitis-like T-cell lymphoma is most common in young adults with a median age of 36 years (range, 9-79 years), with 19% of patients being 20 years or younger. (7) There is a female predominance of this lymphoma, with a male to female ratio of 0.5. (7)

CLINICAL PRESENTATION

Patients present with multiple subcutaneous nodules or deeply seated plaques, most commonly on the extremities and trunk. Other sites of involvement include face, neck, and back. (8) The nodules are usually painless, but in rare cases can be painful. Ulceration of nodules in SPTCL is rare, and only 6% of the cases may show ulceration at some stage of the clinical course. (7) In the initial phases of illness, the subcutaneous nodules may regress spontaneously without treatment. New nodules appear at different sites. Hence, it is common to see subcutaneous nodules at various stages of "healing" and areas of lipoatrophy after regression of the nodules. Prodromal symptoms include fever, chills, weight loss, and myalgias. (7) More than 50% of patients have cytopenias; however, in most instances laboratory abnormalities are not severe. A minority of patients may have lymphadenopathy or hepatosplenomegaly. Clinically, however, these patients do not usually have any evidence of lymphoma outside the subcutis. Metastatic disease or visceral involvement is uncommon in SPTCL. Only cases with TCR[gamma][delta] phenotype tend to have metastasis to various organs, including lungs, liver, kidneys, and the central nervous system. (7,9,10)

Most cases described in the literature before the recent WHO-EORTC classification of cutaneous T-cell lymphomas recognized 2 distinct clinical courses. Hemophagocytic syndrome (HPS) was observed in more aggressive cases showing TCR[gamma][delta] phenotype and was fatal in most cases, whereas TCR[alpha][beta] phenotype had long clinical remissions and a favorable outcome. Hemophagocytic syndrome is present in both TCR[alpha][beta] SPTCL (17%) and TCR[gamma][delta] phenotype (45%) cases, but the disease is more aggressive in the TCR[gamma][delta] phenotype. (7)

HISTOPATHOLOGIC, IMMUNOPHENOTYPIC, AND MOLECULAR FEATURES

The diagnosis of SPTCL is based on the combination of clinical presentation, pathologic examination of skin/subcutaneous tissue, immunohistochemical staining pattern, and molecular analysis. The diagnosis can be difficult, and repeated biopsies may be required once there is clinical suspicion of lymphoma.

Histologically, dense lymphoid infiltrate of small- to medium- to large-sized lymphocytes is present preferentially in the subcutaneous tissue, predominantly in lobular pattern (Figure 1, a). Septal pattern is uncommon and represents secondary spillage of neoplastic lymphocytes from the lobules (Figure 1, b). In most cases, dermal invasion is minimal, and it is rare to see neoplastic cells in superficial dermis or epidermis (Figure 2). (11) Neoplastic cells may be found in deeper dermis and surrounding the sweat glands and hair follicles (Figure 3). (7) The lymphocytes show slight atypical features, including hyperchromatic, angulated nuclei and indistinct cell borders (Figure 4). (12) Admixed benign histiocytes, plasma cells, and neutrophils are present, which may give a false appearance of a benign panniculitis (Figure 5). Some cases have features of vague granuloma formation, which may lead to a misdiagnosis of granulomatous panniculitis (Figure 6). Scattered mitoses are common to see, as are apoptotic cells, karyorrhectic debris, and focal areas of fat necrosis (Figure 7). (12) Rimming of individual fat cells by neoplastic cells is a useful diagnostic clue. (13,14) However, this finding should be interpreted with caution, as rimming of the fat spaces may also be seen in other primary and secondary cutaneous lymphomas, as well as in lobular panniculitis. (15) In SPTCL, the cells that rim the fat spaces are CD[8.sup.-], and immunohistochemistry is very useful in identifying these cells (Figure 8, a and b). (13) Occasional vasculitis has been reported, but angiocentricity or angiodestruction is not a feature of SPTCL.

[FIGURES 1-8 OMITTED]

Immunophenotypically, the neoplastic cells are cytotoxic T cells that are CD[3.sup.+], CD[4.sup.-], CD[8.sup.-], and CD[56.sup.-]. (7,8) Scattered sparse, benign CD[20.sup.+] cells can be identified in the background (Figure 8, c). (12) The tumor cells express cytotoxic granular proteins, such as TIA-1, perforin, and granzyme A. All cases are [beta]F1 positive and TCR[delta]-1 negative. (7) Epstein-Barr virus is not detected and does not appear to play a role in the pathogenesis of this lymphoma.

DIFFERENTIAL DIAGNOSIS

Subcutaneous panniculitis-like T-cell lymphoma can be misdiagnosed as benign panniculitis, leading to a wrong or delayed diagnosis. Most commonly, this is due to both the clinical presentation as well as histologic picture. Since in the initial phase of the disease the subcutaneous lesions resolve spontaneously and generally respond well to steroid therapy, this may mimic the clinical presentation of benign panniculitis. Histologically, the presence of a mixed inflammatory infiltrate of lymphohistiocytic cells, plasma cells, and neutrophils may give the impression of a benign process. In addition, the lymphoid infiltrate in most cases is without overt atypia. (9) In benign panniculitis, in contrast to SPTCL, aggregates of CD[20.sup.+] B cells are present, mixed with CD[3.sup.+] cells that are both CD[4.sup.+] and CD[8.sup.-] in equal proportions and with a slight predominance of CD[4.sup.+] cells; cells that are TIA-[1.sup.+] are only occasionally seen. (12) Cases showing vacuolar interface change and abundant interstitial mucin deposition may mimic lupus erythematosus panniculitis. (8,9,16) Histologically, unlike SPTCL, lupus erythematosus panniculitis does not show rimming of individual fat cells with CD[8.sup.-] T cells and, immunophenotypically, lupus erythematosus panniculitis shows a predominance of CD[4.sup.+] cell collection with germinal center formation. (17) The presence of germinal centers is usually seen in reactive processes. It is not known whether lupus erythematosus panniculitis progresses to SPTCL, but it is thought that in some cases benign panniculitis may progress to SPTCL, and it has been proposed to call these cases atypical lymphocytic lobular panniculitis. (18)

Another important differential diagnosis includes primary cutaneous CD[56.sup.+] natural killer-like T-cell lymphoma, which may show clonal TCR gene rearrangement and may express T-cell associated and cytotoxic antigens. However, CD[56.sup.+] natural killer-like T-cell lymphoma shows angiocentricity and angiodestruction, a predominantly dermal infiltrate, and Epstein-Barr virus positivity. (19) Other cutaneous lymphomas should be in the differential diagnosis. In most cutaneous lymphomas also involving the subcutaneous tissue, lymphoid infiltrate is usually in the form of dense sheets, and rimming of individual fat spaces by CD[8.sup.-] T cells is usually not seen. (12)

TREATMENT AND PROGNOSIS

In the past, before SPTCL was restricted to the category of TCR[alpha][beta] phenotype only, patients were treated with doxorubicin-based chemotherapy, radiotherapy, and/or bone marrow transplantation. However, since it has been observed that TCR[alpha][beta] SPTCL behaves in an indolent fashion, recent studies suggest that these patients can have long-term remission with high-dose systemic corticosteroids. Most patients with aggressive disease who fail with initial immunosuppressive therapy are treated with anthracyclinebased and anthracenedione-based chemotherapy with combined cyclophosphamide, doxorubicin, vincristine, and prednisone. In localized disease without hemophagocytic syndrome, radiation can produce longterm remissions. In addition, radiation therapy can be used for palliative purposes. High-dose chemotherapy and stem cell transplantation has been shown to be very effective, with a high complete remission rate. (7) Therefore, high-dose chemotherapy and stem cell transplantation is usually considered in primary refractory or recurrent cases.

SUMMARY

Subcutaneous panniculitis-like T-cell lymphoma is a rare cytotoxic T-cell lymphoma that can be misdiagnosed as a benign panniculitis due to histologic similarities between the 2 entities. Subcutaneous panniculitis-like T-cell lymphoma is a clonal lymphoproliferative disorder characterized by infiltration of subcutaneous tissue by CD[3.sup.+], CD[4.sup.-], CD[8.sup.-], and CD[56.sup.-] cells. It is important to recognize the clinical, pathologic, and molecular features of SPTCL and limit cases in this entity to subcutaneous lymphomas expressing TCR[alpha][beta] phenotype based on the recent WHO-EORTC classification. Long-term follow-up of these patients is important to monitor the course of disease.

Accepted for publication July 7, 2008.

References

(1.) Gonzalez CL, Medeiros LJ, Braziel RM, et al. T-cell lymphoma involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg Pathol. 1991;15:17-27.

(2.) Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361-1392.

(3.) Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer. Blood. 1997; 90:354-371.

(4.) Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. World Health Organization Classification of Tumours.

(5.) Takeshita M, Okamura S, Oshiro Y, et al. Clinicopathologic differences between 22 cases of CD56-negative and CD56-positive subcutaneous panniculitislike lymphoma in Japan. Hum Pathol. 2004;35:231-239.

(6.) Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768-3785.

(7.) Willemze R, Jansen PM, Cerroni L, et al. Subcutaneous panniculitis-like T-cell lymphoma: definition, classification, and prognostic factors: an EORTC Cutaneous Lymphoma Group Study of 83 cases. Blood. 2008;111:838-845.

(8.) Cassis TB, Fearneyhough PK, Callen JP. Subcutaneous panniculitis-like T-cell lymphoma with vacuolar interface dermatitis resembling lupus erythematosus panniculitis. J Am Acad Dermatol. 2004;50:465-469.

(9.) Ma L, Bandarchi B, Glusac EJ. Fatal subcutaneous panniculitis-like T-cell lymphoma with interface change and dermal mucin, a dead ringer for lupus erythematosus. J Cutan Pathol. 2005;32:360-365.

(10.) Guizzardi M, Hendrickx IA, Mancini LL, Monti M. Cytotoxic gamma/delta subcutaneous panniculitis-like T-cell lymphoma: report of a case with pulmonary involvement unresponsive to therapy. J Eur Acad Dermatol Venereol. 2003;17: 219-222.

(11.) Wang CY, Su WP, Kurtin PJ. Subcutaneous panniculitic T-cell lymphoma. Int J Dermatol. 1996;35:1-8.

(12.) Kumar S, Krenacs L, Medeiros J, et al. Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T lymphocytes. Hum Pathol. 1998;29:397403.

(13.) Salhany KE, Macon WR, Choi JK, et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol. 1998;22:881-893.

(14.) Yamazaki K. An ultrastructural study of cutaneous panniculitis-like T-cell lymphoma: cytoplasmic granules and active cellular and cell-to-matrix interaction mimic cytotoxic T-cells. Ultrastruct Pathol. 2002;26:185-190.

(15.) Lozzi GP, Massone C, Citarella L, Kerl H, Cerroni L. Rimming of adipocytes by neoplastic lymphocytes: a histopathologic feature not restricted to subcutaneous T-cell lymphoma. Am J Dermatopathol. 2006;28:9-12.

(16.) Gonzalez EG, Selvi E, Lorenzini S, et al. Subcutaneous panniculitis-like T-cell lymphoma misdiagnosed as lupus erythematosus panniculitis. Clin Rheumatol. 2007;26:244-246.

(17.) Magro CM, Crowson AN, Kovatich AJ, Burns F. Lupus profundus, indeterminate lymphocytic lobular panniculitis and subcutaneous T-cell lymphoma: a spectrum of subcuticular T-cell lymphoid dyscrasia. J Cutan Pathol. 2001;28:235247.

(18.) Magro CM, Crowson AN, Byrd JC, Soleymani AD, Shendrik I. Atypical lymphocytic lobular panniculitis. J Cutan Pathol. 2004;31:300-306.

(19.) Yamashita Y, Tsuzuki T, Nakayama A, Fujino M, Mori N. A case of natural killer/T cell lymphoma of the subcutis resembling subcutaneous panniculitis-like T cell lymphoma. Pathol Int. 1999;49:241.

Zahida Parveen, MD; Karen Thompson, MD

From the Maui Memorial Medical Center, Clinical Laboratories of Hawaii, Wailuku (Dr Parveen); and the Department of Pathology, Kapiolani Medical Center for Women and Children, Honolulu, Hawaii (Dr Thompson).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Zahida Parveen, MD, Maui Memorial Medical Center, The Clinical Laboratories of Hawaii, 221 Mahalani St, Wailuku, HI 96793 (e-mail: zahipar@yahoo.com).
Table 1. Comparison of Clinicopathologic Features of [alpha][beta]
T-Cell Receptor (TCR) and TCR[gamma][delta] Subcutaneous
Panniculitis-like T-Cell Lymphoma (SPTCL) *

                    TCR[alpha][beta]SPTCL

Age at              Younger (median age, 36 y)
  presentation
Clinical            Subcutaneous nodules, B-symptoms +/-, cytopenias
  presentation      +/-, commonly associated with other autoimmune
                    disorders
Lesions             Self-healing subcutaneous plaques and nodules
                    without ulceration
Histology           Predominant infiltration of subcutaneous tissue
                    by medium to large lymphocytes with mild
                    pleomorphism, minimal tumor invasion in
                    superficial dermis, mild to moderate apoptosis,
                    patchy necrosis
Immunophenotype     [CD3.sup.+], [CD4.sup.-], [CD8.sup.+], most
                    [CD.sup.56-], cytotoxic [proteins.sup.+],
                    [[beta]F1.sup.+], [TCR[delta]-1.sup.-],
                    [CD.sup.30-]
Clinical course     Prolonged course with recurrent panniculitis,
                    HPS uncommon (17%), metastasis rare
Treatment           Long-term control with high-dose systemic
                    corticosteroids, recurrent or resistant cases
                    treated with CHOP or CHOP-like chemotherapy
Prognosis           Excellent without HPS
Five-year overall
  survival          82%

                    TCR[gamma][delta] SPTCL

Age at              Older (median age, 59 y)
  presentation
Clinical            Same presentation as TCR[alpha][beta] SPTCL;
  presentation      however, the B-symptoms and laboratory
                    abnormalities are more common and severe
Lesions             Disseminated plaques, ulceronecrotic nodules
Histology           Infiltration of subcutaneous tissue with
                    medium to large blastlike lymphocytes with
                    significant pleomorphism, involves entire
                    dermis, angioinvasion common, extensive
                    apoptosis, massive necrosis
Immunophenotype     [CD3.sup.+], [CD4.sup.-], [CD8.sup.-], most
                    [CD56.sup.+], cytotoxic [proteins.sup.+],
                    [[beta]F1.sup.-], [TCR[delta]-1.sup.+],
                    many [CD30.sup.+]
Clinical course     Rapid clinical deterioration, HPS common
                    (45%), metastasis common (lungs, liver,
                    kidneys, CNS, and oral mucosa)
Treatment           Multiagent chemotherapy; however, most have
                    poor response to therapy, including
                    allogenic stem cell transplantation
Prognosis           Poor with or without HPS
Five-year overall
  survival          11%

* Data derived in part from Willemze et al. (7) HPS indicates
hemophagocytic syndrome; CNS, central nervous system; and
CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Table 2. World Health Organization-European
Organization for Research and Treatment of Cancer
Classification of Cutaneous T-Cell and Natural Killer
(NK) Cell Lymphomas *

Mycosis fungoides

Mycosis fungoides variants and subtypes
  Folliculotropic mycosis fungoides
  Pagetoid reticulosis
  Granulomatous slack skin

Sezary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous [CD30.sup.+] lymphoproliferative disorders
  Primary cutaneous anaplastic large cell lymphoma
  Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type

Primary cutaneous peripheral T-cell lymphoma, unspecified
  Primary cutaneous aggressive epidermotropic [CD8.sup.+] T-cell
    lymphoma (provisional)
  Cutaneous [gamma][delta] T-cell lymphoma (provisional)
  Primary cutaneous [CD4.sup.+] small/medium-sized pleomorphic
    T-cell lymphoma (provisional)

* Reprinted with permission. This research was originally published
in Willemze et al. WHO-EORTC classification for cutaneous lymphomas.
Blood. 2005;105:3768-3785.6 [c] The American Society of Hematology.
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