Case 6 -

Subcutaneous Panniculitis-like T-cell Lymphoma (SCPTCL) Marsha C. Kinney and Steven H. Swerdlow

Clinical History 71 year old male with nodules on arms and abdomen Diagnosis: Subcutaneous Panniculitis-like T-cell Lymphoma (SCPTCL). Case 6 - Figure 1 - Subcutaneous panniculitis-like T-cell lymphoma, skin/soft tissue. Tumor cells infiltrate subcutaneous tissue in a lobular pattern. Areas of fat necrosis are present. Case 6 - Figure 2 - Subcutaneous panniculitis-like T-cell lymphoma, skin/soft tissue. Tumor cells rim the fat cells and partially invade a small vessel. Most tumor cells are medium to large and have hyperchromatic, irregular nuclei. Focal areas of fat necrosis are present (Upper right). Case 6 - Figure 3 - Subcutaneous panniculitis-like T-cell lymphoma, skin/soft tissue. Macrophages are prominent in areas of necrosis and some show erythrophagocytosis. Immunophenotype: CD8+, b F-1+,CD45RO+,CD43+,TIA-1+, CD56-, CD30- Subcutaneous panniculitis-like T-cell lymphoma, an uncommon T-cell lymphoma localized to the subcutaneous tissue, was initially described by Gonzalez et al., 1994. [68] SCPTCL is included in the WHO classification after being listed as a provisional entity in the REAL classification. It is a pleomorphic T-cell infiltrate, primarily in the subcutaneous fat that can mimic reactive panniculitis. As over half of the patients have a rapidly fatal course, often due to complications of a hemophagocytic syndrome (HPS), it is very important to recognize. Discussion of Case 6: Clinical and pathologic features of SCPTCL Hemophagocytic syndrome in T-cell malignancies Reactive and neoplastic lymphoproliferations causing panniculitis Clinical features of SCPTCL: [45, 68, 69, 70, 71, 72, 73] Median age 43 years (broad range <1-84 years) Male: female 1:1.6 Fever and constitutional symptoms are common Multiple, or less often solitary, erythematous to violaceous, deep-seated 0.5-12 cm nodules or plaques Legs>arms>trunk>face Ulceration is uncommon Extracutaneous involvement is uncommon (even at autopsy); rarely regional lymph nodes are positive; [46, 69] an exceptional case with terminal leukemic transformation has been reported [70] Hemophagocytosis in ~40%-50% [41, 72, 74] Clinical course of SCPTCL: Course is variable with aggressive disease from the onset or a prolonged indolent period with regression and recurrence of lesions, ultimately becoming aggressive Aggressive course correlates with B symptoms, presence of hemophagocytic syndrome, more pronounced cytologic dysplasia, and gd phenotype Median survival is approximately 2 years; overall survival <1 mo-11 years Death due to complications of HPS (cytopenias, coagulation abnormalities) Histologic features of SCPTCL: Lobular pattern of infiltration of the subcutis; some interlobular septae may be involved The deep reticular dermis is involved in some cases; the papillary dermis and epidermis are spared; more dermal involvement seen with gd phenotype Pleomorphic lymphocytes vary in size from small, medium to large Nuclei are dysplastic, folded and vary from hyperchromatic to dispersed chromatin with more prominent nucleoli Lymphocytes rim fat spaces and impart a "lacelike" appearance; focally the lymphocytes may have a more sheet-like growth pattern. Lymphocytes infiltrate small venules but angiodestructive lesions are not present Necrosis of fat and/or connective tissue septae is seen in all cases, but it may be focal Benign histiocytes are present in variable numbers and often exhibit erythrophagocytosis or phagocytosis of nuclear elements (cytophagocytosis); Non-caseating granulomas are present in a small number of cases and may mimic granulomatous panniculitis [45, 68, 73] Erythrophagocytosis, by benign histiocytes, can be seen in the marrow, liver and spleen, but tumor is not present Immunophenotypic features of SCPTCL: Most cases express the ab T-cell receptor protein but approximately 25% have a gd phenotype [40, 41, 44, 45, 75, 76, 77, 77a] gd SCPTCL arise from the V d2 subset of gd T-cells corresponding to the subset of gd T-cells normally found in the skin and have a cytotoxic phenotype (TIA-1+) Most SCPTCL are CD56-; however SCPTCL with a gd T-cell phenotype is more likely to be CD56+ and have a more aggressive clinical course [77a] ~ 25% - 40% are CD30+ Pathogenesis of SCPTCL: The pathogenesis is unknown. No cytogenetic abnormalities have been reported. Most cases are EBV negative [45, 46] , except some from Japan [78] Hemophagocytic Syndromes A hemophagocytic syndrome can be a grave complication of infection (particularly viral), malignancy, and immune dysregulation. It is a prominent feature in SCPTCL and also occurs in hepatosplenic lymphoma, nasal/nasal type NK/T-cell lymphoma, and anaplastic large cell lymphoma: Classification of hemophagocytic syndromes: [79, 80] Primary hemophagocytic lymphohistiocytosis   Familial and sporadic; commonly elicited by viral infections Secondary hemophagocytic syndromes:   Infection-associated (particularly in immunocompromised hosts)   Malignancy associated: Lymphoma Anaplastic large cell lymphoma Subcutaneous panniculitis like T-cell lymphoma Nasal/nasal type NK/T-cell lymphoma Hepatosplenic lymphoma Aggressive NK-cell leukemia Angioimmunoblastic T-cell lymphoma B-cell lymphoma Hodgkin's disease Acute lymphoblastic and myeloid leukemia Chronic lymphocytic and hairy cell leukemia Multiple myeloma Thymoma Germ cell tumor Carcinoma: ovarian, gastric   Other: Immune defects (rheumatoid arthritis; SLE) Hyperalimentation Chediak-Higashi Langerhans cell histiocytosis Definition/pathogenesis of a hemophagocytic syndrome (HPS): A clinicopathologic diagnosis Clinically, patients have fever, splenomegaly, cytopenias, hypofibrinogenemia, and/or hypertriglyceridemia Characterized pathologically by the accumulation of cytologically benign macrophages with phagocytosis of erythrocytes, platelets, and leukocytes throughout the reticuloendothelial system Note: The presence of a few macrophages with ingested RBCs, as is often seen in marrow aspirates, does not establish a diagnosis of a HPS Cytokines such as IFN - g, macrophage inflammatory protein-1 (MIP-1 a), and IL-10 produced by activated T-cells are important in its pathogenesis [81]   MIP-1 alpha can promote macrophage chemotaxis and IFN- g causes macrophage activation via Mig (monokine induced by IFN).   MIP-1 alpha gene contains NF-kappa B regulatory elements and EBV-LMP serves as a potent activator of NF-kappa B. Hence, the probable mechanism whereby EBV is often associated with HPS The differential diagnosis of SCPTCL (See Table 8): Includes reactive causes of panniculitis and neoplastic lymphoproliferations Careful examination of the lymphocytes for dysplasia is the first step Reactive causes include lupus profundus, erythema nodosum, erythema induratum, and a controversial entity-- cytophagic histiocytic panniculitis [82, 83] In general, neoplastic disorders other than SCPTCL show more dermal involvement and have a sheet-like pattern of infiltration Neoplastic T- cell or NK-cell proliferations involving the subcutaneous tissue include anaplastic large cell lymphoma, nasal/nasal type NK/T-cell tumors, and other less well characterized NK-cell tumors General features of "reactive" panniculitis: Cannot be distinguished based on gross morphology and distribution of lesions; most occur on the extremities with less frequent involvement of the trunk or head and neck. Histologic features overlap and change with evolution of the lesions; initially a predominance of acute inflammatory cells and later lymphocytes and histiocytes or granulomatous infiltrates. Focal or more extensive necrosis is often present and is usually associated with acute inflammatory cells Reactive lymphoproliferations in the differential diagnosis of SCPTCL: [84, 85, 86] Lupus profundus Erythema nodosum ­ Erythema induratum Note: Weber-Christian disease (relapsing febrile nodular nonsuppurative panniculitis) was characterized by recurrent fever and tender subcutaneous nodules. A variable histologic spectrum with a neutrophilic or histiocytic infiltrate, lobular panniculitis ultimately with fibroblastic proliferation, and fibrosis. Current opinion is that Weber-Christian disease is not a specific entity but includes cases of other types of panniculitis. [84] It is differentiated from SCPTCL and cytophagic histiocytic panniculitis in that cytophagocytosis is not prominent and there are more foamy macrophages [86] Note: Rosai-Dorfman disease may occur in the skin and involves the dermis and less frequently subcutaneous tissue. It is characterized by a dense cellular infiltrate composed of lymphocytes, relatively large numbers of plasma cells, epithelioid histiocytes and variable neutrophils. The histiocytes are S-100+ and show some lymphocytophagocytosis but not phagocytosis of red cells or karyorrhectic debris. Lupus erythematosis profundus: Seen in 2%-5% of patients with systemic lupus erythematosis or with localized cutaneous disease; also occurs in patients with no evidence of lupus Nodules and plaques, proximal arms and legs, buttocks Septal pattern with some infiltration of the periphery of the fat lobule Lymphocytes and plasma cells; lymphoid aggregates with germinal centers Hyaline ghost-like fat necrosis; septal fibrosis May see changes of discoid lupus erythematosis in the overlying dermis Lymphocytes may infiltrate small vessels Erythema nodosum: Tender, erythematous nodules most common on the shins Septal pattern with some infiltration of the periphery of the fat lobule Lymphocytes, histiocytes, and later foreign body giant cells Miescher's radial nodules composed of clusters of macrophages around small blood vessels or slit-like spaces may be seen Inflammation of septal veins and hemorrhage (may be focal) Hypersensitivity reaction to microorganisms or drugs; also associated with systemic inflammatory disorders (inflammatory bowel disease, sarcoidosis, Behçet's syndrome) Erythema induratum/nodular vasculitis: Chronic, recurrent tender erythematous nodules or plaques on the lower extremities (primarily calf) of women>men Lobular panniculitis with fat necrosis Lymphocytes, histiocytes, and Langerhans and foreign body giant cells; tuberculoid granulomas may be present Fat necrosis with intense inflammation Lymphohistiocytic vasculitis involving venules, veins, arterioles and small septal arteries; can have vessel wall necrosis Hypersensitivity reaction to a TB infection at a non-cutaneous site; if no known history of TB, should be called nodular vasculitis Cytophagic histiocytic panniculitis (CHP): [74, 82] Initially described by Winkelmann and Bowie in 1980 [87] Median age 44 years (range 5-81 years); M:F=1.25:1 Multiple inflammatory subcutaneous nodules and plaques; may be ulcerated Pancytopenia, liver failure and DIC seen in all the original patients Fever, hepatosplenomegaly, mucosal ulcers, serosal effusion Variable clinical course from 6 mos-10 years with a terminal hemorrhagic diathesis; may respond to cyclosporine and prednisone [74] Non-fatal forms of CHP have been described and are distinguished by lack of systemic symptoms [88, 89] Histology of CHP: Lobular and septal panniculitis Dermis frequently involved Predominantly small, regular lymphocytes; few mitoses Fat necrosis occasionally present Erythrophagocytosis and cytophagocytosis always present Pathogenesis of CHP and its relationship to SCPTCL: CHP represents a reactive proliferation of cytophagic histiocytes as a result of an abnormal or exaggerated T cell response. It is thought that T-cells, either in response to an infectious agent, immune dysregulation (eg, rheumatologic or congenital disease), or after malignant transformation produce cytokines (particularly interferon- g, macrophage inflammatory protein 1 a) in an uncontrolled fashion resulting in histiocyte proliferation and cytophagocytosis. [85, 90, 91, 92] Supporting this concept, CHP has been reported following interferon therapy. [93] The relationship of CHP to SCPTCL is not clear. Prior to the recognition of SCPTCL, cases of SCPTCL were included in the rubric of CHP. Also, SCPTCL with a protracted CHP-like phase has been described. [71, 94] These findings have led some to suggest they represent a continuum and that CHP may represent a "smoldering" lymphoid neoplasm rather than an inflammatory disease. [88, 90] Others believe they are different. [74] Although a hemophagocytic syndrome has often been reported in viral infection (VAHS, viral associated hemophagocytic syndrome) or other infections (IAHS), it is difficult to find references to cytophagic panniculitis in viral infections. [86] Also, EBV has not been identified in CHP. The main differential of SCPTCL is with cytophagocytic histiocytic panniculitis (CHP). Unfortunately this is a controversial area with few concrete answers. If cytophagocytosis is present with some necrosis and lack of definite cytologic dysplasia in the lymphocytes, CHP is in the differential diagnosis. If systemic symptoms are present, a bone marrow should be performed to evaluate for eythrophagocytosis. If present this may have a bad prognosis despite lack of evidence of neoplasia. Some CHP has responded to cyclosporine and prednisone. Although not tested, staining for TIA-1 may be useful in that in SCPTCL most lymphocytes are positive and CHP may show fewer cells that are positive. Lymphomas in the differential diagnosis of SCPTCL (See Table 8): The large cell lymphomas in the differential of SCPTCL include anaplastic large cell lymphoma (see case 7) and nasal/nasal type NK/T-cell lymphoma (see case 8) and poorly defined NK cell lymphomas in the skin. ALCL tumor cells spread from the superficial dermis into the subcutaneous tissue in a sheet-like, rather than lobular, pattern that destroys the fat spaces. Virtually all tumor cells are strongly CD30+ and most cases are CD4+ as opposed to SCPTCL where less than 25% are CD30+ (generally with focal reactivity) and the CD8+ phenotype predominates. Nasal or nasal-type T/NK-cell lymphomas are distinguished by angiodestruction and/or zonal necrosis and more frequent CD56 expression and association with EBV; however, it should be noted that a significant number of angiocentric lymphomas in the skin, particularly those primary to the skin, do not express EBV or CD56. [95, 96] Table 8. Differential Diagnosis of Panniculitis with a Significant Lymphocytic/Histocytic Component Type Clinical Features Location Predominant Cell type(s) Fat Necrosis Phago-cytosis Other SCPTCL Subcutaneous nodules or plaques; legs>trunk>head and neck Lobular Pleomorphic, small, medium and large lymphocytes and histiocytes Present, may be focal Present Some infiltration of small vessels by lymphocytes CD8+>CD4+;EBV- Cytophagic histocytic panniculitis 2-20 cm nodules on legs, thighs, and upper extremities; fever, hepatosplenomegaly and pancytopenia present Lobular and septal; may extend to reticular dermis Histocytes; small uniform lymphocytes; neutrophils may be present May be present Present and usually prominent Reported in viral infection, immunosup-pression, familial hemophagocytic lymphohistio-cytosis Erythema nodosum Tender, erythematous nodules; shins most common Septal, may extend into the periphery of the lobule Early, lymphohistiocytic; later granulomatos panniculitis Absent Absent Venular infiltration with hemorrhage; hypersensitivity reaction to microorganisms or drugs Lupus erythema-tosis profundus Nodules and plaques, proximal arms and legs, buttocks Septal with infiltration of the periphery of the fat lobule Lymphocytes and plasma cells; lymphoid aggregates with germinal centers Hyaline ghost-like fat necrosis; septal fibrosis Absent May see changes of DLE in the overlying dermis; lymphocytes may infiltrate small vessels Erythema induratum (nodular vasculitis) Recurrent tender erythematous nodules on the lower extremities, particularly calves of women more often than men Lobular; can involve the septae Lymphocytes, histocytes and Langerhans and foreign body giant cells; tuberculoid granulomas may be present Present with intense inflammation; later foamy histiocytes and fibrosis Absent Vasculitis involving venules, veins, arterioles and small septal arterioles; can have vascular wall necrosis Anaplastic large cell lymphoma Single or multiple tumor masses Dermal and subcutaneous Large dysplastic transformed lymphocytes No May be rarely present Strong CD30 expression in all tumor cells, CD4+ Nasal or nasal-type NK/T- cell lymphoma Single or multiple purple nodules, often ulcerated Mid and lower dermis and subcutaneous with lobular pattern Dysplastic, pleomorphic lymphocytes, small to large Zonal necrosis, including fat Occasional erythro-phagocytosis or cytophago-cytosis Often involves extracutaneous sites including nasal, breast; EBV may be positive DLE = discoid lupus erythematosis References 40. 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