Dermatology

Subcutaneous panniculitic T cell lymphoma (subcutaneous ’panniculitis-like’ T-cell lymphoma, previously termed cytophagic histiocytic panniculitis)

Subcutaneous panniculitic T cell lymphoma (subcutaneous ’panniculitis-like’ T-cell lymphoma, previously termed cytophagic histiocytic panniculitis) ICD-9 202.70

Are You Confident of the Diagnosis?

What you should be alert for in the history

Subcutaneous panniculitic T cell lymphoma (SPTCL) is currently defined as a distinct neoplasm characterized by neoplastic T-cells expressing alpha/beta T cell receptors and a cytotoxic phenotype which involves the subcutaneous fat exclusively. This current definition specifically excludes several different entities previously reported as SPTCL (such as gamma/delta T-cell lymphomas, Epstein-Barr virus (EBV) and associated extranodal NK/T-cell lymphoma).

SPTCL has considerable clinical and histologic overlap with lupus panniculitis (lupus profundus) and lupus panniculitis patients may have increased risk of developing SPTCL over time.

SPTCL should be considered in patients with chronic, recurrent subcutaneous plaques or nodules primarily on the extremities, but also on the trunk. Most patients are well, but some may have fever, chills, fatigue, or unintentional weight loss. Patients may have a history of cutaneous lupus, particularly lupus profundus.

Characteristic findings on physical examination

On physical exam, SPTCL patients have ill-defined subcutaneous plaques or nodules predominantly on the extremities and trunk, less likely on the face. They usually have overlying erythema, hyperpigmentation or subtle scaling, but can also simulate lipomas, without any surface change. Lesions are usually nontender (although occasionally they can be erythema nodosum-like) and not ulcerated.

Spontaneous resolution with post inflammatory hyperpigmentation and marked skin atrophy (lipoatrophy) may occur. While there is clinical overlap with lupus profundus, SPTCL lesions will often extend to the distal extremities more so than lupus profundus (which favors proximal extremities, breasts, buttocks). Lymphadenopathy is uncommon, although SPTCL patients with hemophagocytic syndrome may have hepatosplenomegaly.

Expected results of diagnostic studies

A generous incisional biopsy (or large 8mm punch biopsy) is strongly recommended and will show a lobular panniculitis with dense infiltrate of variably sized atypical lymphocytes with epidermal sparing. A histiocytic infiltrate, areas of karyorrhexis and necrosis, and ’rimming’ of adipocytes by lymphocytes are other common (albeit not 100% specific) features. Erythrophagocytosis when seen is a helpful clue (though not 100% specific either).

Given the overlap with lupus profundus, an interface dermatitis and/or mucin deposition may be seen in certain patients. Immunohistochemistry must be done to distinguish from other panniculitides. SPTCL malignant T-cells have an alpha/beta TCR phenotype (BetaF1+, CD3+) and are cytotoxic CD8+ T-cells (CD4-, CD8+, TIA-1+, granzyme B+, perforin+, MIB-1/Ki-67+, CD56-, CD30-, EBV in situ hybridization negative).

Molecular T-cell receptor gene rearrangement studies show a monoclonal population in most cases. Repeat biopsies are frequently necessary as a brisk reactive inflammatory component or extensive tissue necrosis can obscure the neoplastic infiltrate early in the course of disease.

Adjunctive tests include CBC with differential, lactate dehydrogenase (elevation reflects degree of skin activity) and comprehensive metabolic panel. Hemophagocytic syndrome (HPS) (anemia, thrombocytopenia, markedly elevated LDH, transaminitis, hyperbilirubinemia) occurs in a minority of SPTCL patients and portends a poor prognosis.

Either a CT scan with and without IV contrast (chest/abdomen/pelvis) or whole body PET CT scan should be ordered for systemic staging, although PET CT has greater sensitivity for highlighting affected skin areas than CT. Lymph node involvement is uncommon. If HPS is suspected, confirmation by liver or bone marrow biopsy is needed. Lupus serologies (ANA, dsDNA, etc) should be ordered in patients who have a history of or clinicohistologic features of lupus.

Diagnosis confirmation

Differential diagnosis includes:

  • Gamma/delta T-cell lymphoma with panniculitic involvement (lesions typically eventually ulcerate, the infiltrate frequently involves dermis and/or epidermis as well as panniculus, betaF1 immunohistochemical stain is negative, overall much poorer prognosis than SPTCL).

  • Lupus panniculitis (may coexist with SPTCL, histologically often demonstrating much overlap; lupus panniculitis may show more plasma cells, B-cell aggregates, is less likely to have Ki-67/MIB-1 + T-cells, and is less likely to have monoclonal TCR gene rearrangement).

  • NK/T-cell lymphoma (will have dermal and/or epidermal involvement, CD56+, EBV ISH+, TCR gene rearrangement should be negative for a monoclonal population).

  • Mycosis fungoides (clinical history, CD4+ immunophenotype).

  • CD30+ anaplastic large cell lymphoma (usually dermal involvement, CD4+ and CD30+).

  • Atypical lobular panniculitis (no features of lupus panniculitis, no overt T-cell morphologic atypia or pleomorphism, less karhyorrhexis/necrosis, and can have a monoclonal T-cell receptor gene rearrangement).

Who is at Risk for Developing this Disease?

SPTCL affects primarily adults with equal sex distribution, though patients overlapping with lupus panniculitis have female predominance. SPTCL can rarely present in children.

SPTCL is a very rare subtype of cutaneous T-cell lymphoma, categorized as a ’cytotoxic CTCL’ and is much less common than MF or primary cutaneous CD30+ lymphoproliferative disorders and precise incidence rates are unknown (estimated less than 1% of all CTCLSs).

What is the Cause of the Disease?

Etiology

Pathophysiology

Etiology is unknown. No specific causative or genetic defects have been identified to date.

Systemic Implications and Complications

Overall the prognosis for SPTCL is excellent (82% 5 year survival for all patients). However patients with HPS have a worse survival rate (41% 5 year survival vs. 91% 5 year survival for patients without HPS). HPS will present with fatigue, malaise, low grade fevers, anemia, thrombocytopenia, elevated LDH, transaminitis, hyperbilirubinemia and an enlarged liver/spleen.

Patients with SPTCL can have associated autoimmune diseases (19% in a recent series) including lupus erythematosus, rheumatoid arthritis, Type I diabetes, Sjögren’s syndrome, immune thrombocytopenic purpura, and Raynaud’s.

Treatment Options

Treatment options are summarized in the Table I.

Table I.

Treatment Options for Subcutaneous Panniculitic T Cell Lymphoma
Skin-directed Systemic/Medical Surgical
Localized Intralesional steroids Oral prednisone
Electron beam radiation therapy Hydroxychloroquine
Methotrexate
Denileukin diftitox Excision (unilesional)
Cyclosporine
Chlorambucil
Multiagent chemotherapy
Generalized Total skin electron beam radiation therapy Same as above but also: Stem cell transplant (auto or allogeneic) N/A

Optimal Therapeutic Approach for this Disease

Optimal treatment of SPTCL remains an area of debate, given past confusion due to difficulty classifying panniculitis cases properly (ie alpha/beta vs. gamma/delta cases which have very different course and prognosis).

SPTCL has a chronic but overall indolent course unless HPS is present. Given the depth of the neoplastic infiltrate, topical and skin directed treatments are generally less effective than systemic agents. In addition, regardless of therapy, skin lesions tend to resolve leaving permanent skin atrophy due to nature of inflammatory infiltrate.

For unilesional or localized disease, intralesional kenalog 5mg/ml to start (this can be increased to 10mg/ml but there is a need to monitor for atrophy), local radiation therapy, or surgical excison could be tried first.

Most patients will have multiple lesions which require systemic therapy. First line treatment is oral corticosteroids (1mg/kg) slowly tapered over 1-2 months, but chronic steroids are frequently necessary for the majority of patients.

Steroid sparing agents include methotrexate (10-35mg weekly), cyclosporine (3-5mg/kg daily), denileukin diftitox, and retinoids (acitretin 10-50mg daily, isotretinoin 1 mg/kg daily, bexarotene 150-300mg/m2).

Patients with refractory lesions can be treated with systemic chemotherapy. Patients with lupus panniculitis overlap features can be tried on oral hydroxychloroquine. Given the cytotoxic phenotype of SPTCL, interferons should be avoided. Lesions on the distal legs will take longer to resolve than proximal lesions.

Patients with HPS will need hematology/oncology consultation and a more aggressive treatment approach if there is no response to initial oral steroids.

Patients should be counseled that permanent lipoatrophy is common after active lesions resolve.

Patient Management

Patients who have localized mild disease can be followed every 2-3 months but patients on systemic treatment for generalized disease should be seen monthly. Patients who respond to an initial 1-2 month course of oral prednisone can be tapered off therapy and observed. If clinical relapse occurs quickly, repeat oral prednisone combined with a steroid sparing agent such as methotrexate, cyclosporine, or denileukin diftitox should be started.

Patients with severe disease should start a steroid sparing agent before oral steroids are tapered and maintained until clear for 3-6 months before tapering. SPTCL is a disease with a course of waxing and waning lesions.

Patients with lesions refractory or rapidly progressive should have repeat incisional biopsies to confirm that the diagnosis is SPTCL (and not a more aggressive gamma delta CTCL or NK/T-cell process).

The clinical course of SPTCL is chronic and indolent, with periods of disease activity and periods of quiescence. Patients who develop new systemic symptoms should be evaluated for HPS.

Unusual Clinical Scenarios to Consider in Patient Management

A subset of patients with panniculitic lesions will have biopsies that are an overlap between lupus panniculitis and SPTCL that are diagnostically challenging.

Patients with ’atypical lobular panniculitis’ (lobular panniculitis with some but not all features of SPTCL, namely minimal cytologic atypia or pleomorphism) may evolve over time to SPTCL and need monitoring and repeat biopsies over time.

Tissue T-cell clonality should be interpreted within the context of the entire clinical, histologic, and immunophenotypic picture (and not automatically be equated with neoplasia).

What is the Evidence?

Willemze, R, Jansen, PM, Cerroni, L, Berti, E, Santucci, M, Assaf, C. "Subcutaneous panniculitis-like T cell lymphoma: definition, classification and prognostic factors. An EORTC Cutaneous Lymphoma Group study of 83 cases". Blood. vol. 111. 2008. pp. 838-45.

(63 cases of alpha/beta SPTCL were reviewed and compared to 20 gamma delta panniculitic lymphoma cases. Alpha/beta SPTCL was associated with an 82% 5 year overall survival, with 17% of cases having HPS. Therapies were reviewed and given the overall favorable course of alpha/beta SPTCL, the authors recommended systemic steroids over cytotoxic chemotherapy as first line treatment.)

Pincus, LB, LeBoit, PE, McCalmont, TH, Ricci, R, Buzio, C, Fox, LP. "Subcutaneous panniculitis-like T-cell lymphoma with overlapping clinicopathologic features of lupus erythematosus: coexistence of 2 entities?". Am J Dermatopathol. vol. 31. 2009. pp. 520-6.

(This study describes five patients with SPTCL and some clinical, serologic, or histological features of lupus erythematosus.)

Magro, CM, Crowson, AN, Byrd, JC, Soleymani, AD, Shendrik, I. "Atypical lymphocytic lobular panniculitis". J Cutan Pathol. vol. 31. 2004. pp. 300-306.

(The authors describe 12 patients with a chronic waxing and waning lobular panniculitis that did not fulfill the criteria of either lupus profundus or SPTCL. Eight had a CD4 immunophenotype, four were CD8+, and the majority demonstrated clonal T-cell receptor gene rearrangements. These ’atypical lymphocytic lobular panniculitis’ patients were felt to represent a cutaneous T-cell dyscrasia, analagous to other chronic cutaneous T-cell disorders such as parapsoriasis, pityriasis lichenoides, atypical pigmented purpura, and should therefore be monitored for progression to SPTCL.)

Hoque, SR, Child, FJ, Whittaker, SJ, Ferreira, S, Orchard, G, Jenner, K. "Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathological, immunophenotypic, and molecular analysis of six patients". Br J Dermatol. vol. 148. 2003. pp. 516-25.

(This small series also demonstrates the difference in immunophenotype and clinical course between alpha/beta SPTCL (three patients) and gamma/delta panniculitic T-cell lymphoma (three patients).)

Hathaway, T, Subtil, A, Kuo, P, Foss, F. "Efficacy of denileukin diftitox in subcutaneous panniculitis-like T-cell lymphoma". Clin Lymph Myeloma. vol. 7. 2007. pp. 541-5.

(Two patients with alpha/beta SPTCL were treated with corticosteroids and denileukin diftitox with a complete clinical response.)

Willemze, R, Jaffe, ES, Burg, G, Cerroni, L, Berti, E, Swerdlow, SH. "WHO-EORTC classification of cutaneous lymphomas". Blood. vol. 105. 2005. pp. 3768-85.

(In this landmark paper, primary cutaneous lymphomas are reclassified based on both clinical and histopathologic characteristics. SPTCL is restricted to cases that have alpha beta phenotype and is described as having indolent behavior (82% disease specific 5 year survival) and represents 1% of all primary cutaneous lymphomas in their series of 1905 patients. Gamma delta CTCLs are described as a separate entity.)

Massone, C, Chott, A, Metze, D, Kerl, K, Citarella, L, Vale, E. "Subcutaneous, blastic natural killer (NK), NK/T cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients". Am J Surg Pathol. vol. 28. 2004. pp. 719-35.

(This paper was one of the first to demonstrate that extensive immunophenotyping is necessary to precisely classify subtypes of cytotoxic CTCL. Alpha/beta SPTCL cases emerge having a less aggressive course (estimated 5 year survival 80%) among cytotoxic skin lymphomas.)

Kong, YY, Dai, B, Kang, JC, Zhou, XY, Lu, HF, Shen, L. "Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathologic, immunophenotypic and molecular study of 22 Asian cases according to WHO-EORTC classification". Am J Surg Pathol. vol. 32. 2008. pp. 1495-502.

(This series of 22 Chinese patients with SPTCL demonstrate that angioinvasion on histology can be a poor prognostic factor.)

Cerron, L, Gatter, K, Kerl, H. Subcutaneous ’panniculitis-like’ T-cell lymphoma. Skin Lymphoma: The Illustrated Guide. Wiley-Blackwell. 2009. pp. 87-96.

(An up to date and comprehensive review of prior history and current definition of SPTCL.)

Magro, CM, Crowson, AN. "Subcutaneous panniculitis-like T-cell lymphoma". In The Cutaneous Lymphoid Proliferations: a comprehensive textbook of lymphocytic infiltrates of the skin. Wiley-Liss. 2007. pp. 371-80.

(Another review of SPTCL with more extensive discussion of atypical lymphocytic lobular panniculitis and the presence of T-cell clonality in not only SPTCL, but also some cases of ALLP and lupus profundus.)
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