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Lupus profundus (panniculitis): potential mimic of subcutaneous panniculitis-like T-cell lymphoma.

REPORT OF A CASE

A25-year-old woman presented with tender, deep-seated nodules on the arms and flanks. Punch biopsy revealed a lobular panniculitis with extension into expanded interlobular septa (Figure 1, A through G). The infiltrate was predominantly lymphocytic, with scattered histiocytes and plasma cells. Mild atypia was appreciated in the lymphoid cells, characterized by nuclear enlargement. The atypical lymphoid cells focally encircled adipocytes. The infiltrate was peri-eccrine in areas and present in a background of increased dermal mucin. Nuclear debris was scattered among the infiltrate; however, there was no evidence of active leukocytoclastic vasculitis. Hyaline and myxoid changes were also noted, and in areas hyaline sclerosis extended from fat lobules into interlobular septa. Occasional lymphoid follicles were distributed paraseptally, with cytophagic histiocytes scattered throughout the infiltrate. The epidermis was unremarkable.

Immunohistochemical stains demonstrated that lymphoid aggregates were CD20 positive, but that the majority of the infiltrate and many of the cells ringing adipocytes were CD3-positive T cells (Figure 1, H and I). A few small clusters of large, activated CD30positive lymphoid cells were also present. CD68 highlighted infiltration by numerous histiocytes. Additionally, molecular assay for T-cell receptor [gamma]-chain gene rearrangement demonstrated no evidence of a clonal T-cell population. A diagnosis of lupus profundus (LP) or lupus panniculitis was made based on these findings.

COMMENT

The first observations of subcutaneous nodules in lupus erythematosus (LE) were made by Kaposi in 1883. Now known as LP, it is an uncommon variant of LE that develops in 1% to 3% of patients with cutaneous LE. (1,2) It may arise in patients with discoid LE or systemic LE, or as an isolated phenomenon. The diagnosis of LP may be particularly challenging in cases where involvement of the subcutis is the only manifestation of disease.

Lupus profundus is more common in women than men and most often presents as multiple subcutaneous nodules or plaques involving the upper arms, shoulders, buttocks, or face. Such areas are uncommonly involved in other panniculitides. The surface of lesions may show classic features of discoid LE or appear completely normal. Ulceration may also be present. Regressing lesions often appear as depressed scars. Lipoatrophy in the shoulder region is so characteristic as to allow retrospective diagnosis of LP. Typically patients with LP have a mild clinical form of lupus erythematosus. (3) Some cases of LP have been associated with an antecedent trauma to the site, such as previous injections. Additionally, exacerbation of LP lesions has been reported following excision. (4)

Panniculitis is broadly grouped into septal and lobular patterns depending on the primary location of the inflammatory infiltrate. However, determining septal versus lobular panniculitis may not be straightforward in many cases, particularly in the setting of limited biopsy material. A generous excisional wedge biopsy is necessary for adequate sampling and analysis of the subcutis. Punch biopsies should generally be discouraged, as they may be superficial and misleading. Correlation of histopathologic findings with clinical history and laboratory studies is essential to arrive at a definitive diagnosis. Additional studies, such as special stains for microorganisms, immunohistochemistry, and gene rearrangement studies to detect monoclonal T-cell and B-cell processes, are often required to rule out infection and lymphoma.

[FIGURE 1 OMITTED]

Histopathology

In greater than 50% of cases, histopathologic clues to the diagnosis in the form of typical changes of chronic discoid LE are present, including epidermal atrophy; interface changes; a thickened basement membrane; superficial and deep, perivascular and periadnexal lymphocytic inflammation; and increased dermal mucin. In the remainder of cases, findings consist of a predominantly lobular lymphocytic panniculitis in the absence of typical epidermal and dermal changes of lupus. (3) Lymphoid follicles with germinal center formation, which are rarely seen in other forms of panniculitis, are present in approximately 50% of cases and considered highly characteristic of LP (Figure 1, G and H). (5,6) Lymphoid follicles tend to extend interstitially between collagen bundles and into septa of the subcutis and often have many plasma cells at their peripheries. The lymphocytic infiltrate may show nuclear fragmentation, another clue to the diagnosis of LP, which is rarely seen in other forms of lobular panniculitis (Figure 1, C). Finally, hyaline sclerosis of lobules with focal extension into intralobular septa is another characteristic feature and a useful clue to the diagnosis of LP when present (Figure 1, B).

Immunofluorescence studies typically demonstrate linear deposition of immunoglobulin M (IgM) and C3 along the dermoepidermal junction, even in the absence of interface changes. (3) However, deposits in the subcutis are more inconsistent and technically difficult to demonstrate. Importantly, when a biopsy of a clinically typical lesion of LP shows equivocal histopathology, a positive lupus band test along the dermoepidermal junction supports a diagnosis of LP. (4,5) Antinuclear antibodies are present in approximately 50% of patients with the disease.

In a subset of reported cases of LP lymphocytes with pleomorphic nuclei involving subcutaneous lobules with a cytotoxic immunophenotype (positivity for CD3, CD8, and TCR[beta]F1), high proliferation index and monoclonal T-cell receptor [gamma] gene rearrangement have been observed, suggesting overlapping features with subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Thus, a screening Tcell lymphoma immunohistochemical panel (CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD56, TCR[beta]F1) is appropriate in cases of LP with atypical features.

Differential Diagnosis

Lupus profundus may demonstrate significant histologic overlap with several disease entities, both benign and malignant. Early lesions of LP may be confused with septal patterns of panniculitis, such as erythema nodosum. The greatest difficulty may be distinguishing connective tissue panniculitis, particularly morphea profunda (MP), from LP. However, the most important entities in the differential diagnosis of LP are SPTCL and lesions with overlapping features between LP and SPTCL, or so-called atypical lymphocytic lobular panniculitis.

Lupus profundus and MP may have identical clinical presentations consisting of deep-seated indurated plaques and nodules. Shared histopathologic features include lymphoplasmacytic inflammation, thickened septa, lymphocytic vasculitis, mucinous change, and the presence of occasional eosinophils. When present, associated findings typical of LE, such as epidermal changes (atrophy, vacuolar interface changes, basement membrane thickening), prominent dermal mucin, and hyaline septal and lobular sclerosis, are invaluable clues to the diagnosis of LP. Lupus profundus also tends to lack the prominent sclerosis of the dermis and subcutis compared with MP (Figure 2, A and B). In some cases, however, distinguishing between LP and MP cannot be accomplished by histology. In this circumstance careful correlation of all histopathologic, clinical, and laboratory information is required to make the correct diagnosis.

Subcutaneous panniculitis-like T-cell lymphoma is a lymphoma derived from mature cytotoxic T cells that involves only subcutaneous fibroadipose tissue, resembling panniculitis. Subcutaneous panniculitis-like T-cell lymphoma is rare, representing less than 1% of all non-Hodgkin lymphomas. A subset of SPTCL was previously reported as cytophagic histiocytic panniculitis, fatal panniculitis, and malignant histiocytosis. (7) The current World Health Organization criteria restrict the diagnosis of SPTCL to cases expressing the [alpha][beta] T-cell receptor. (8) Cases expressing the [gamma][delta] T-cell receptor are now classified as primary cutaneous [gamma][delta] T-cell lymphoma, a distinct entity that frequently involves the epidermis, dermis, and subcutis.

Subcutaneous panniculitis-like T-cell lymphoma is slightly more common in females and occurs in a broad age range, with a median age of presentation of 35 years. There is an association with autoimmune disorders, with approximately 20% of patients having an associated autoimmune disease, most commonly systemic LE. Lesions may show overlapping features with LP and early lesions may closely mimic lobular lymphocytic panniculitis, but whether benign lobular lymphocytic panniculitis precedes SPTCL in patients without systemic LE is unclear. Patients with SPTCL usually present with multiple subcutaneous nodules or plaques, typically on the extremities and/or trunk. The lesions may become necrotic, but rarely ulcerate. Systemic symptoms, such as fever, fatigue, or weight loss, may arise in up to 50% of patients. The 5-year disease-specific survival is 80%, with dissemination being uncommon. However, hemophagocytic syndrome may occur in 15% to 20% of patients and is the cause of death in a majority of cases. (7-9)

[FIGURE 2 OMITTED]

Histopathology demonstrates infiltration of subcutaneous fat lobules by neoplastic cells in a lacelike pattern reminiscent of lobular lymphocytic panniculitis (Figure 3, A). The lipotrophic infiltrate is composed of small to intermediate-sized lymphoid cells admixed with histiocytes, and is frequently associated with areas of fat necrosis. Subcutaneous panniculitis-like T-cell lymphoma generally demonstrates sparing of the dermis and epidermis. The degree of lymphoid atypia is variable among cases; however, neoplastic cells are commonly pleomorphic with hyperchromatic, irregular nuclei surrounded by a rim of palestaining cytoplasm. A helpful diagnostic feature is rimming of atypical cells around individual fat adipocytes, although it must be said that this feature has been reported in cases of LP (Figure 3, B). (10) While histiocytes are present in both LP and SPTCL, other inflammatory cells, particularly plasma cells (which are commonly seen in LP), are absent. The neoplastic cells of SPTCL may also show angiocentricity and vascular invasion. Karyorrhexis is frequently prominent. (11-13)

Subcutaneous panniculitis-like T-cell lymphoma has a mature [alpha][beta] cytotoxic T-cell phenotype, and is usually [CD3.sup.+], [CD8.sup.+], [CD4.sup.-], with expression of cytotoxic markers such as TIA1, perforin, and granzyme B (Figure 3, C and D). The neoplastic cells express TCRbF1 and are CD56 negative, separating it from cutaneous [gamma][delta] T-cell lymphoma. Distinguishing SPTCL from cutaneous [delta][gamma] T-cell lymphoma is important, as the latter has a much poorer prognosis. Subcutaneous panniculitis-like T-cell lymphoma is EpsteinBarr virus-negative, in contradistinction to extranodal natural killer/T-cell lymphoma. (7) While cytotoxic [CD8.sup.+] T cells maybe observed in LP, theygenerallydo not constitute the majority population as in SPTCL.

[FIGURE 3 OMITTED]

Cases with overlapping features between LP and SPTCL have been described. (10,14,15) Magro and colleagues (10,14) have suggested that such lesions represent a form of cutaneous lymphoid dyscrasia with a pattern of lobular lymphocytic panniculitis. Such lesions have been designated as atypical lymphocytic lobular panniculitis by some authors. This concept assumes that some cases of subcutaneous lymphoma are preceded by a clonal lymphoid-rich infiltrate, which otherwise does not fulfill criteria for lymphoma. This construct is somewhat controversial and not widely accepted at this time. Regardless, there is clinical utility in identifying the subset of patients who have features of both LP and SPTCL, as these patients mayprogress to lymphoma and therefore require close clinical surveillance in spite of subthreshold findings for a definitive diagnosis of subcutaneous lymphoma. Atypical lymphocytic lobular panniculitis appears to be a chronic condition, which spontaneously resolves in most cases. Concern for overt lymphoma should be raised in cases that fail to respond to systemic steroids or steroid-sparing agents, or in the setting of disease progression. (16)

Prognosis and Treatment

Lupus profundus is a chronic relapsing condition in which painful lesions may heal with significant lipoatrophy and scarring. Treatment options include intralesional and systemic steroids, antimalarials, mycophenolate mofetil, dapsone, cyclosporine, and thalidomide. Most cases of LP have a good prognosis. Given the overlap among LP, atypical lymphocytic lobular panniculitis, and SPTCL, some authors believe that these disorders represent a spectrum of subcuticular T-cell lymphoid dyscrasia. However, at present time the relationship among these entities is not completely clear. As LP overlaps with SPTCL, further investigation is warranted if LP remains refractory to treatment or systemic symptoms arise.

SUMMARY

Lupus profundus is a rare presentation of LE and often presents as multiple subcutaneous nodules or plaques involving characteristic sites such as the upper arms, shoulders, buttocks, or face. Morphea profunda demonstrates more dermal and subcutaneous sclerosis than LP and lacks other typical histopathologic features of cutaneous lupus, although some cases of MP cannot be distinguished from LP by histology. The most important distinction is between LP and SPTCL. Cases of atypical lymphocytic lobular panniculitis with overlapping features between LP and SPTCL require long-term follow-up, as future subcutaneous lymphoma cannot be ruled out.

Caption: Figure 1. Lupus profundus. A, Punch biopsy shows lobular lymphocytic panniculitis with extension into expanded intralobular septa. B, Hyaline sclerosis extended from lobules into septa. C, Clusters of phagocytes containing nuclear debris were identified in sclerotic areas. D, The infiltrate was predominantly lymphocytic with scattered histiocytes and plasma cells. E, Mildly atypical lymphoid cells focally surrounded adipocytes. F, The infiltrate was peri-eccrine in areas and present in a background of increased dermal mucin. Paraseptal lymphoid aggregates were present (G), which were CD20 positive (H). I, The majority of cells ringing adipocytes were CD3-positive T cells (hematoxylin and eosin, original magnifications320 [A], 3200 [B, D, F, and G], and3400 [C and E]; CD20, original magnification3200 [H]; CD3, original magnification3200 [I]).

Caption: Figure 2. Morphea profunda (MP). MP and lupus profundus (LP) share many histopathologic features. MP lacks typical changes of lupus (interface changes, epidermal atrophy, and mucin). Most helpful for diagnosis, MP demonstrates prominent sclerosis of the dermis (A) and subcutis (B), unlike LP (hematoxylin-eosin, original magnifications320 [A] and3200 [B]).

Caption: Figure 3. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL). A, SPTCL showing infiltration of subcutaneous fat lobules by neoplastic cells in a lacelike pattern like that of lobular lymphocytic panniculitis, a finding that may be seen in lupus profundus (LP). B, SPTCL demonstrating rimming of atypical cells around individual adipocytes, another overlapping feature with LP. The majority of atypical cells are CD8 positive (C) and express cytotoxic markers like TIA-1 (D) (hematoxylin-eosin, original magnifications320 [A] and3200 [B]; CD8, original magnification 3200 [C]; TIA-1, original magnification3200 [D]).

References

(1.) Diaz-Jouanen E, DeHoratius RJ, Alarcon-Segovia D, et al. Systemic lupus erythematosus presenting as panniculitis (lupus profundus). Ann Intern Med. 1975;82(3):376-379.

(2.) Tuffanelli DL. Lupus erythematosus panniculitis (profundus). Arch Dermatol. 1971;103(3):231-242.

(3.) Requena L, Sanchez YE. Panniculitis: part II: mostly lobular panniculitis. J Am Acad Dermatol. 2001;45(3):325-361.

(4.) Winkelmann RK. Panniculitis in connective tissue disease. Arch Dermatol. 1983;119(4):336-344.

(5.) Massone C, Kodama K, Salmhofer W, et al. Lupus erythematosus panniculitis (lupus profundus): clinical, histopathological, and molecular analysis of nine cases. J Cutan Pathol. 2005;32(6):396-404.

(6.) Sanchez NP, Peters MS, Winkelmann RK. The histopathology of lupus erythematosus panniculitis. J Am Acad Dermatol. 1981;5(6):673-680.

(7.) McDivitt Duncan L, Kumar S. Primary cutaneous T-cell lymphomas: rare subtypes. In: Jaffe ES, Harris NL, Vardiman JW, Campo E, Arber DA, eds. Hematopathology. 1st ed. Philadelphia, PA: Saunders Elsevier; 2011:617-628.

(8.) Jaffe ES, Gaulard P, Ralfkiaer E, et al. Subcutaneous panniculitis-like T-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC; 2008:294-295.

(9.) 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(2):838-845.

(10.) Magro CM, Crowson AN, Kovatich AJ, et al. Lupus profundus, indeterminate lymphocytic lobular panniculitis and subcutaneous T-cell lymphoma: a spectrum of subcuticular T-cell lymphoid dyscrasia. J Cutan Pathol. 2001;28(5): 235-247.

(11.) Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas: report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer. 2003; 97(3):610-627.

(12.) Weenig RH, Ng CS, Perniciaro C. Subcutaneous panniculitis-like T-cell lymphoma: an elusive case presenting as lipomembranous panniculitis and a review of 72 cases in the literature. Am J Dermatopathol. 2001; 23(3):206-215.

(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(7):881-893.

(14.) Magro CM, Schaefer JT, Morrison C, et al. Atypical lymphocytic lobular panniculitis: a clonal subcutaneous T-cell dyscrasia. J Cutan Pathol. 2008;35(10): 947-954.

(15.) Pincus LB, LeBoit PE, McCalmont TH, et al. Subcutaneous panniculitis-like T-cell lymphoma with overlapping clinicopathologic features of lupus erythematosus: coexistence of 2 entities? Am J Dermatopathol. 2009;31(6):520-526.

(16.) Guitart J. Subcutaneous lymphoma and related conditions. Dermatol Ther. 2010;23(4):350-355.

David P. Arps, MD; Rajiv M. Patel, MD

Accepted for publication May 16, 2013.

From the Departments of Pathology (Dr Arps) and Dermatology (Drs Arps and Patel), University of Michigan, Ann Arbor.

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

Presented at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; Homestead Resort; August 3-5, 2012; Glen Arbor, Michigan.

Reprints: Rajiv M. Patel, MD, Department of Pathology, University of Michigan Health System, Medical Science I, 1301 Catherine St., M-3261, Ann Arbor, MI 48109 (e-mail: rajivpat@med.umich.edu).
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Author:Arps, David P.; Patel, Rajiv M.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Case study
Geographic Code:1USA
Date:Sep 1, 2013
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