Section 6 -

Inflammatory Lesions Simulating Cutaneous Lymphoma Lyn M. Duncan

Clinical pathological correlation and awareness of some inflammatory infiltrates that may display particularly atypical features can be helpful in the approach to histological diagnosis of lymphoma simulants. The most common form of cutaneous lymphoma is the cutaneous T-cell lymphoma mycosis fungoides. It is often a challenge to distinguish benign inflammatory infiltrates from early mycosis fungoides histologically. Drug hypersensitivity reactions and lichen sclerosus are included in this differential diagnosis. Other forms of cutaneous T cell lymphoma are unusual and have more characteristic histological and clinical features. A few diagnostic dilemmas may arise including the distinction of lupus profundus from subcutaneous panniculitis-like lymphoma. Hypersensitivity reactions may also mimic pleomorphic small T cell lymphoma and CD30+ lymphoproliferative disorders. Cutaneous B-cell lymphomas often have a clinical presentation that does not allow for distinction from lymphoma. For these cases the histological consideration of a reactive lymphoid infiltrate is common. Processes that mimic cutaneous B –cell lymphomas include reactions to pharmaceutical agents, reactions to injected antigens such as from arthropod bite or tattoo, and reactions to infectious agents including borrelia burgdorferi. Simulants of Cutaneous T-cell Lymphoma Mycosis Fungoides: Drug hypersensitivity Lichen sclerosus Subcutaneous Panniculitis-like lymphoma: Lupus profundus CD30+ lymphoproliferative disorder: Arthropod bite reaction Simulants of Cutaneous B-cell Lymphoma: Drug hypersensitivity Bite reaction Tattoo reaction Infection Gene rearrangement studies Molecular detection of clonal rearrangement of TCR or Ig genes should be treated not as pathognomonic for lymphoma but as another factor in the overall evaluation of a case. Using very sensitive techniques clonal rearrangements may be detected in lesions from patients that do not progress to lymphoma (Nihal et al 2003). Lichen sclerosus, lichen planus, pityriasis lichenoides and hypersensitivity reactions to pharmaceutical agents and contacts allergens are some of the inflammatory dermatoses reported to display occasional clonal rearrangement of the gamma T-cell receptor (Brady et al. 1999; Magro et al 2002). Nevertheless, in general, the T-cell gamma gene rearrangements detected by multiplex PCR provide a good correlation with histological features of CTCL (Ponti et al. 2005). Cutaneous T-cell Lymphoma (CTCL) Mycosis Fungoides (MF) Benign processes that may resemble mycosis fungoides histologically include hypersensitivity reactions to pharmaceutical agents, and inflammatory dermatoses such as lichen sclerosus. Drug induced simulants of MF Anticonvulsant therapy is a known cause of MF-like cutaneous eruptions. The most common inciting agents are carbamazepine, phenytoin, phenobarbital and valproic acid. Antidepressant therapy has also been reported to be associated with an MF-like cutaneous eruption. These drug reactions may simulate MF clinically and histologically and may take over a month to resolve after the discontinuation of therapy. The duration between start of therapy and the development of skin lesions ranges from a few weeks to a year (Choi et al 2003). Most eruptions have a macular papular appearance and are generalized. Patients may also exhibit fever, leukocytosis, lymphadenopathy and elevated liver function values. Histological features shared by MF and MF-like drug eruptions include a lichenoid lymphoid infiltrate, epidermotropism of atypical lymphocytes and Pautrier microabcesses. Features that are more commonly observed in drug-associated MF than MF include epidermal dyskeratosis, spongiosis, papillary dermal erythrocyte extravasation, pigment laden macrophages, a polymorphous inflammatory infiltrate including eosinophils and / or neutrophils, and larger lymphocytes in the epidermis than the dermis. Molecular studies have found clonal rearrangement of TCR in up to 10% of patients with anticonvulsant associated MF-like eruptions. Lichen sclerosus as an MF simulant Lichen sclerosus most commonly presents in the genital skin and may affect patients of any age. Lichen sclerosus characteristically shares with MF a lichenoid (band-like) lymphoid infiltrate. In cases that mimic MF the infiltrate extends into the lower epidermis and resembles in this way the epidermotropism of MF (Citarella et al. 2003). Lichen sclerosus may also display the course papillary dermal collagen bundles observed in MF. Genetic studies reveal clonal rearrangement of TCR in up to 10% of cases of MF-like lichen sclerosus. Features that may help distinguish lichen sclerosus from MF include the clinical picture: MF rarely only involves the genitalia. Histologically, the infiltrate in lichen sclerosus is mostly confined to the lower half of the epidermis, and the characteristic homogeneous dermal sclerosis of lichen sclerosus is often observed focally. Subcutaneous panniculitis-like lymphoma: Lupus profundus The panniculitis associated with lupus may present as an indurated plaque that histologically displays a dense lymphoid infiltrate diffusely occupying the deep reticular dermis and subcutaneous fat. The differential diagnosis in these cases may include subcutaneous panniculitis-like lymphoma (Magro et al. 2001). Lupus panniculitis usually presents in the lower extremities of women in 4th decade of life. Histological features shared by lupus panniculitis and subcutaneous lymphoma include a diffuse infiltrate of the fat lobules by medium-sized atypical lymphocytes, fat necrosis, and histiocytes containing cellular debris. Changes that support a diagnosis of lupus include the presence of lymphoid follicles, eosinophilic hyaline change of the necrotic fat lobules, hyaluronic acid deposits (connective tissue mucin), and overlying changes of the epidermis (atrophy, vacuolar interface dermatitis, follicular plugging). Features more characteristically observed in subcutaneous lymphoma include erythrophagocytosis, and rimming of the adipocyte spaces by atypical lymphocytes. Both lupus panniculitis and subcutaneous lymphoma may be characterized by a predominance of CD8+ CD5- T cells. In cases of subcutaneous lymphoma expressing CD56 or CD30 this immunophenotype supports the diagnosis of lymphoma. Genetic studies nearly always reveal clonal TCR rearrangement in subcutaneous lymphoma, a similar result may be observed in some cases of lupus panniculitis. CTCL, other: Drug reaction mimics of pleomorphic cutaneous T cell lymphoma Hypersensitivity reactions to pharmaceutical agents may also lead to eruptions that simulate non-epidermotropic pleomorphic CTCL (Cogrel et al 2001). Anticonvulsant medications are the most common association and may provoke a dense dermal infiltrate of atypical medium-sized lymphocytes. Histological features that support a reactive process include the presence of a polymorphous infiltrate including some B cells and CD30+ lymphocytes. Similar to other CTCL-like drug reactions, gene rearrangement studies may reveal clonal TCR rearrangement. CD30+ Lymphoproliferative disorder: Recent studies have revealed that CD30+ large cells are not an uncommon finding in inflammatory and infectious dermatoses (Kempf 2006; Cepeda et al. 2003; Su et al 2000). CD30+ cells may also be observed in drug hypersensitivity reactions and in the setting of lymphocyte recovery. In many of these cases clinical presentation and the presence of characteristic epidermal changes allow for accurate diagnosis. Arthropod bite reaction Nearly 75% of hypersensitivity reactions to arthropod bites or infestations reveal CD30+ cells (Cepeda et al. 2003; Gallardo et al. 2002). Reactions to injected antigens as with an arthropod bite may lead to a dense atypical lymphoid infiltrate extending into the deep reticular dermis. Particularly in persistent lesions, CD30+ large cells may be observed. In these cases the CD30+ cells usually occupy less than 5% of the infiltrate and are scattered as individual cells rather than arranged in clusters. In persistent bite reactions the epidermis often displays features of lichen simplex chronicus (hyperkeratosis, hypergranulosis and epidermal acanthosis). The presence of a polymorphous infiltrate with eosinophils also supports the diagnosis of a bite reaction. The presence of CD30+ large cells in a cutaneous infiltrate is not always an indication of a CD30+ lymphoproliferative disorder. Cutaneous B-cell Lymphoma (CBCL) Follicular lymphoma and marginal zone B-cell lymphoma The differential diagnosis of primary cutaneous low grade B cell lymphoma includes a range of non-neoplastic dermatoses. Hypersensitivity reactions to drugs, arthropod bites and tattoo can all lead to dense dermal infiltrates similar to those observed in B-cell lymphoma. Infection, particularly with treponemal organisms may lead to cutaneous lymphoid hyperplasia that resembles B-cell lymphoma (Grange et al 2002, McComb et al. 2003). Bite reaction Histological features that support the diagnosis of an arthropod bite reaction include the presence of the epidermal changes of lichen simplex chronicus and a polymorphous inflammatory infiltrate containing eosinophils and neutrophils (Baldassano et al. 1999). Infection Infection with Borrelia burgdorferi may lead to infiltrates that mimic follicular lymphoma or marginal zone B-cell lymphoma (Leinweber et al 2004; Grange et al 2002a). Histological features that support the diagnosis of B cell lymphoma include a reduced mantle zone, a paucity of tangible body macrophages, monomorphic lymphoid follicles, and irregularly shaped or fused lymphoid follicles. Follicles lacking a mantle zone are often observed in borrelia infection; these reactive follicles usually contain tangible body macrophages and a predominance of centroblasts with few immunoblasts and centrocytes (Leinweber et al 2004). In marginal zone lymphoma the follicles resemble typical reactive lymphoid follicles with mantle zones and tangible body macrophages. Immunohistochemical studies may reveal aggregates or clusters of CD10+ bcl6+ cells in the interfollicular dermis this finding supports the diagnosis of follicular lymphoma. Likewise the presence of bcl-2 expression by bcl-6+ follicle center cells allows for the diagnosis of follicular lymphoma. Follicular lymphoma also displays a reduced proliferation fractionwith MIB-1 antibody, in contrast to most cases of borrelia induced infiltrates and marginal zone lymphoma. T(14:18) translocation is not observed in CBCL or borrelia infection. Clonal rearrangement of IgH is detected in up to 10% of borrelia-associated atypical lymphoid infiltrates, and approximately 50% of tested cases of follicular lymphoma and marginal zone B-cell lymphoma. Large B-cell Lymphoma Rarely borrelia infection can lead to an infiltrate that mimics large B-cell lymphoma (Grange et al. 2002b). Several reports exist of patients diagnosed and treated for CBCL and subsequently found to have borrelia infection. In endemic areas some authors recommend a high index of suspicion and a trial of antibiotic therapy as a first-line approach. The organisms of B. burgdorferi endemic in Europe persist in the skin in contrast to those acquired in North America. In some cases the etiologic role of B. burgdorferi may be confirmed by serology, polymerase chain reaction analysis of B. burgdorferi DNA within the lesional skin, and response to antibiotic therapy. Characterizing the lymphoid follicles immunophenotypically can be helpful in the differential diagnosis of reactive lymphoid hyperplasia and cutaneous B-cell lymphoma (de Leval et al. 2001; Hoefnagel JJ et al. 2003). The neoplastic cells of primary cutaneous follicular lymphoma express bcl-6, CD10 (although sometimes weakly) and are generally without staining for bcl-2. In contrast the neoplastic cells of marginal zone B-cell lymphoma have a bcl-2+ bcl-6- CD10- immunophenotype. The lymphoid follicles in marginal zone lymphoma and reactive lymphoid hyperplasia express bcl-6 and CD10 without bcl-2 expression. Primary cutaneous B-cell lymphoma of the leg displays a bcl-2+ bcl-6+ CD10- immunophenotype, usually with more intense bcl-2 staining of the neoplastic cells than the admixed non-neoplastic lymphocytes. References Baldassano MF. Bailey EM. Ferry JA. Harris NL. Duncan LM. Cutaneous lymphoid hyperplasia and cutaneous marginal zone lymphoma: comparison of morphologic and immunophenotypic features. Am J Surg Pathol. 23(1):88-96, 1999 Brady SP. Magro CM. Diaz-Cano SJ. Wolfe HJ. Analysis of clonality of atypical cutaneous lymphoid infiltrates associated with drug therapy by PCR/DGGE. 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