Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma

INTRODUCTION — The peripheral T cell lymphomas (PTCL) are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas in adults. (See "Classification of hematopoietic neoplasms".)

Among these, in decreasing frequency of occurrence, are:

●Peripheral T cell lymphoma, not otherwise specified

●Anaplastic large cell lymphoma, primary systemic type

●Angioimmunoblastic T cell lymphoma

●Extranodal NK/T cell lymphoma, nasal type

●Subcutaneous panniculitis-like T cell lymphoma

●Enteropathy associated T cell lymphoma

●Hepatosplenic T cell lymphoma

Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a PTCL derived from a mature cytotoxic T cell that often mimics panniculitis [1]. Patients present with subcutaneous nodules or plaques that on pathologic evaluation consist of cellular infiltrates in the subcutaneous fat, generally with sparing of the overlying epidermis. (See "Panniculitis: Recognition and diagnosis".)

Since its original description, the definition of SPTCL has undergone revisions. The diagnosis of SPTCL is now restricted to primary cutaneous T cell lymphomas expressing alpha/beta T cell receptors (TCR) [2]. SPTCL appears to have a much better prognosis than histologically similar tumors expressing gamma/delta TCRs, which are now classified as cutaneous gamma/delta T cell lymphomas.

The clinical presentation, pathologic features, and diagnosis of SPTCL will be reviewed here. The diagnosis of other subtypes of PTCL and the treatment of the PTCLs are discussed separately. (See "Initial treatment of peripheral T cell lymphoma" and "Treatment of relapsed or refractory peripheral T cell lymphoma".)

EPIDEMIOLOGY — SPTCL is an uncommon peripheral T cell lymphoma accounting for less than 1 percent of all non-Hodgkin lymphoma subtypes. The exact incidence and variation in incidence with geography have not been well characterized.

Patients present at a median age of 36 years (range 9 to 79 years) with approximately 20 percent of patients presenting under the age of 20 [3]. There appears to be a female predominance with a male:female ratio of 0.5. Up to 20 percent of patients have at presentation an associated autoimmune disease such as systemic lupus erythematosus, juvenile idiopathic arthritis, Sjögren's disease, or type 1 diabetes mellitus.

CLINICAL PRESENTATION — Patients with SPTCL typically present with one or more usually painless subcutaneous nodules or poorly circumscribed indurated plaques involving the legs (71 percent), arms (62 percent), trunk (56 percent), and/or face (25 percent) [3,4]. Nodule diameter can vary from 0.5 cm to more than 20 cm. Necrosis may be present, but ulceration is uncommon (6 percent). Single lesions are rare and approximately 80 percent of patients have multiple nodules and/or plaques.

The lesions may have been previously misdiagnosed as panniculitis or other cutaneous diseases, resulting in one series in a median time from lesion development to diagnosis of seven months (range one month to 10 years) [3]. It is not uncommon for these nodules to initially demonstrate a waxing and waning course and the development of new nodules at different sites [5]. Given this course, nodules may be seen in various stages of growth and healing, resulting in the presence of lipoatrophy in previously involved areas that have since regressed.

It is extremely unusual for patients with SPTCL to have evidence of lymphoma outside of the subcutaneous tissue. Systemic B symptoms (fevers, night sweats, and weight loss) and bone marrow abnormalities are reported in approximately 60 and 20 to 30 percent, respectively [3]. Bone marrow involvement by lymphoma is highly unusual; the most common bone marrow abnormality is hemophagocytosis.

In a series of 83 patients with SPTCL, 17 percent had secondary hemophagocytic lymphohistiocytosis (HLH) [3]. HLH is an often fatal complication that may present with high fevers, maculopapular rash, failure to thrive, central nervous system symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, coagulopathy, abnormal liver function tests, and extremely high serum levels of ferritin and soluble IL-2 receptor. Both HLH and SPTCL are linked to germline mutations that disrupt expression of TIM3, an immune checkpoint molecule [6,7]. (See 'Genetic features' below and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Approximately 45 percent of patients with SPTCL have laboratory abnormalities, the most common of which are anemia, leukopenia, thrombocytopenia, and/or elevated liver function tests. Radiologic abnormalities on computed tomography (eg, lymphadenopathy, hepatomegaly, pleural effusions) are seen in less than 10 percent of patients.

PATHOLOGIC FEATURES

Morphology — Skin biopsy demonstrates a subcutaneous infiltrate of atypical lymphocytes involving the fat lobules, but typically sparing the septa, overlying dermis, and epidermis (picture 1). The neoplastic cells often surround, or rim, the individual fat cells and may invade the deeper dermis, surrounding the sweat glands and/or hair follicles [1,5,8]. Fat necrosis and karyorrhexis are common. Vascular invasion is seen in some cases.

The neoplastic infiltrate may be comprised of small, medium, or large atypical cells. The cell size is usually relatively uniform within a given tumor [2]. The nuclei are irregular and hyperchromatic with a rim of pale cytoplasm. Reactive lymphocytes and macrophages with vacuoles, phagocytized nuclear debris and/or ingested lipid are numerous, the latter due to extravasation of lipid from necrotic adipocytes. Other inflammatory cells, such as plasma cells, neutrophils, and eosinophils, are generally absent. Non-necrotizing granulomas with multinucleated giant cells may be present.

Immunophenotype — SPTCLs typically have the following immunophenotypic features:

●They express CD3, CD8, and the alpha/beta T cell receptor (TCR), and are negative for CD4 and CD56.

●There is strong expression of the cytotoxic granule proteins granzyme B, T cell intracellular antigen (TIA)-1, and perforin (picture 1) [2].

●There is loss of expression of CD2, CD5, or CD7 in 10, 50, and 44 percent of cases, respectively [3].

●Staining is positive for TCR beta and negative for TCR gamma.

●Scattered, benign CD20 expressing cells may be identified in the background [5].

Genetic features — Clonal T cell receptor (TCR) rearrangements are present, but specific cytogenetic abnormalities have not been described and in situ hybridization for Epstein-Barr encoded RNA (EBER) is negative [2,3,8]. A study of 13 Asian patients used next-generation sequencing to identify somatic mutations in components of the PI3K/AKT and JAK/STAT signaling pathways and epigenetic regulators [6]. That study and a second study of 17 patients of mixed ethnic background identified frequent germline loss-of-function mutations in HAVCR2, a gene that encodes the immune checkpoint protein TIM3 [7] . HAVCR2 mutations were strongly correlated with the presence of hemophagocytic lymphohistiocytosis (HLH), suggesting that the absence of TIM3 on the tumor cell population may contribute to sustained activation of immune cells and the development of HLH.

DIAGNOSIS — The diagnosis of SPTCL is made with a deep skin biopsy that includes subcutaneous tissue (eg, excisional biopsy), and relies on the constellation of pathologic and immunophenotypic findings described above in the context of a characteristic clinical picture (table 1). Repeat biopsies may be required. Shave biopsies are not appropriate because they do not include subcutaneous tissue. (See "Skin biopsy techniques".)

The specific pathologic features of SPTCL are described above. The most important features pointing to the diagnosis are rimming of individual adipocytes by atypical lymphocytes with hyperchromatic nuclei, and demonstration of a cytotoxic T cell immunophenotype by immunohistochemistry, which usually shows expression of CD3, CD8, TCR beta, and cytotoxic granule proteins by the neoplastic cells. PCR-based tests for clonal TCR gene rearrangements may help to confirm the diagnosis. (See 'Pathologic features' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SPTCL includes benign and malignant lesions that demonstrate infiltration of the subcutaneous fat with lymphocytes (table 1).

Primary cutaneous gamma/delta T cell lymphoma — In the original World Health Organization (WHO) classification system, SPTCL included both alpha/beta and gamma/delta subtypes of T cell lymphoma. However, subsequent studies have noted that patients with these two entities have different pathologic features and a significantly different prognosis. As a result, the current WHO classification system limits SPTCL to tumors expressing alpha/beta T cell receptors. Tumors expressing gamma/delta T cell receptors are now categorized as primary cutaneous gamma/delta T cell lymphoma (TCL) [2,9]. (See "Primary cutaneous T cell lymphomas, rare subtypes".)

Unlike SPTCL, cutaneous gamma/delta TCL commonly involves the dermis and epidermis and often causes epidermal ulceration; however, like SPTCL it can sometimes have panniculitis-like morphology [2]. The immunophenotype partially overlaps with that of SPTCL, as cutaneous gamma/delta TCL also expresses CD3 and cytotoxic molecules (TIA-1, granzyme B, and/or perforin) and lacks expression of CD4, but unlike SPTCL expresses CD56 and TCR delta.

Extranodal NK/T cell lymphoma — Extranodal NK/T cell lymphoma is a peripheral T cell lymphoma of either natural killer (NK) or T cell lineage that is associated with Epstein-Barr virus (EBV) infection and typically presents with a mid-facial mass. It sometimes involves the skin but is never restricted to the subcutaneous tissue. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

While both SPTCL and extranodal NK/T cell lymphoma express CD3 and cytotoxic molecules (TIA-1, granzyme B, and/or perforin) and lack expression of CD4, extranodal NK/T cell lymphoma differs from SPTCL in that it lacks expression of CD8, expresses CD56, and is uniformly associated with EBV. In addition, TCR genes are typically in a germline configuration in extranodal NK/T cell lymphoma (most of which are of natural killer cell origin) but are rearranged in SPTCL.

Primary cutaneous anaplastic large cell lymphoma — Primary cutaneous anaplastic large cell lymphoma (ALCL) is a peripheral T cell lymphoma characterized by the diffuse infiltration of the upper and deep dermis and the subcutaneous tissue by large lymphoid cells. Like SPTCL, primary cutaneous ALCL expresses CD3 and cytotoxic molecules (TIA-1, granzyme B, and/or perforin), but differs in virtually always expressing CD30 and often expressing CD4. T cell receptor genes are rearranged in both. (See "Primary cutaneous anaplastic large cell lymphoma".)

Lymphomatoid papulosis and secondary dermal spread of a systemic ALCL should also be considered in the differential diagnosis. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Mycosis fungoides — Mycosis fungoides (MF) is a cutaneous T cell lymphoma typically diagnosed using a point-based diagnostic algorithm (table 2). Similar to SPTCL, MF expresses CD3, does not express CD56 or demonstrate Epstein-Barr virus infection, and has clonally rearranged TCR genes. MF differs from SPTCL in that it is centered on the dermis and epidermis not the subcutaneous tissue, expresses CD4, and does not express CD8 or cytotoxic molecules (TIA-1, granzyme B, and/or perforin). (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides", section on 'Immunophenotyping'.)

Blastic plasmacytoid dendritic cell neoplasm — Blastic plasmacytoid dendritic cell neoplasm (BPDCN; previously called type 2 dendritic cell acute leukemia, acute plasmacytoid dendritic cell leukemia, or CD4+CD56+ hematodermic neoplasm) is a rare neoplasm that commonly presents with cutaneous nodules or tumors and shows evidence of plasmacytoid dendritic cell differentiation [10]. Unlike SPTCL, BPDCN frequently involves the marrow and peripheral blood.

Immunophenotype and molecular studies can distinguish these disorders because, unlike SPTCL, in BPDCN the TCR genes are germline and the tumor cells express CD4, CD56, CD123, and TCL1, and do not express CD3, CD8, or cytotoxic molecules (TIA-1, granzyme B, and/or perforin). (See "Blastic plasmacytoid dendritic cell neoplasm".)

Panniculitis — The clinical findings of SPTCL may resemble other diseases that are characterized by inflammation involving the subcutaneous fat (panniculitis). In comparison with SPTCL, benign panniculitis does not display cytologic atypia and lacks clonal TCR gene rearrangements. (See "Panniculitis: Recognition and diagnosis".)

In particular, lupus profundus panniculitis typically presents as a firm nodular lesion in patients with systemic lupus erythematosus. Unlike SPTCL, these nodules are often painful and can appear in the mid-dermal, deep dermal, or subcutaneous layers. Histology demonstrates perivascular infiltrates of mononuclear cells plus panniculitis, manifested as hyaline fat necrosis with mononuclear cell infiltration and lymphocytic vasculitis (picture 2A-B). Unlike SPTCL, in lupus profundus panniculitis clonal TCR gene rearrangements are absent. (See "Panniculitis: Recognition and diagnosis", section on 'Inflammatory disorders'.)

TREATMENT — The treatment of SPTCL is discussed separately. (See "Treatment of relapsed or refractory peripheral T cell lymphoma".)

PROGNOSIS — Most patients with SPTCL have an indolent course with a five-year overall survival rate of approximately 80 percent [3]. Occasionally, SPTCL resolves spontaneously. Spread to lymph nodes and other organs is rare.

The main predictor of a poor prognosis is presentation with hemophagocytic lymphohistiocytosis (HLH), which in one series occurred in 17 percent of patients [3]. Five-year survival was significantly lower in the patients with HLH (46 versus 91 percent). Many of these patients have germline loss-of-function mutations in HAVCR2, a gene that encodes the immune checkpoint protein TIM3 [6,7]. (See 'Clinical presentation' above and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Prognostic models used for other types of non-Hodgkin lymphoma have limited applicability to patients with SPTCL. Most patients fall into the low risk category when assessed with either the International prognostic index (IPI) or the Prognostic index for T cell lymphomas (PIT) (table 3) [11,12]. However, these prognostic tools do not take into account the adverse prognostic effect of HLH. (See "Prognosis of diffuse large B cell lymphoma", section on 'International Prognostic Index'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

SUMMARY

●Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a peripheral T cell lymphoma derived from a mature cytotoxic T cell that accounts for less than 1 percent of non-Hodgkin lymphoma. Up to 20 percent of patients will have an associated autoimmune disease. (See 'Epidemiology' above.)

●Patients typically present with one or more usually painless subcutaneous nodules or poorly circumscribed indurated plaques involving the extremities or trunk. The skin lesions can demonstrate a waxing and waning course with spontaneous regression and the development of new lesions at different sites. Spread outside the subcutis is extremely unusual. (See 'Clinical presentation' above.)

●Less than 20 percent of cases are associated with the hemophagocytic syndrome, an often-fatal complication, which may present with high fevers, maculopapular rash, failure to thrive, central nervous system symptoms, hepatosplenomegaly, lymphadenopathy, cytopenias, coagulopathy, abnormal liver function tests, or an extremely high serum ferritin. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

●The diagnosis of SPTCL is made with a deep skin biopsy that includes the subcutis. Repeat biopsies may be required. SPTCL is characterized by a subcutaneous infiltrate of atypical lymphocytes that characteristically rim individual adipocytes and express CD3, CD8, the alpha/beta T cell receptor, and cytotoxic granule proteins (granzyme B, T cell intracellular antigen [TIA]-1, and perforin) (table 1 and picture 1). (See 'Pathologic features' above and 'Diagnosis' above.)

●The differential diagnosis of SPTCL includes benign and malignant lesions that demonstrate infiltration of the subcutaneous fat with lymphocytes. (See 'Differential diagnosis' above.)

●Most patients with SPTCL appear to have an indolent course with a five-year overall survival rate of approximately 80 percent. The main factor associated with a poor prognosis is the presence of hemophagocytic lymphohistiocytosis (HLH), which is linked to germline mutations in HAVCR2, the gene that encodes the immune checkpoint protein TIM3. (See 'Prognosis' above.)