Section 1 -

Mycosis Fungoides and Precursor Lesions Joan Guitart

The diagnosis of mycosis fungoides is often challenging for the clinician and the pathologists. Numerous dermatoses can present with relatively dense infiltrate composed of reactive intermediate to large lymphocytes that can closely resemble a cell T-cell lymphoma. Other dermatoses characterized by chronic epidermotropic reactive T-cells may resemble mycosis fungoides. Inflammatory conditions involving certain sites like intertriginous areas and non-glabrous skin are also more likely to present with dense lymphoid infiltrates. Interestingly many of these CTCL mimics tend to present with a relatively low CD8/CD4 ratio as compared to conventional CTCL Furthermore, reactive infiltrates with a predominance of large T cells often express CD30. For the pathologist, knowledge of the clinical scenario is of utmost importance to recognize these CTCL stimulants. Conditions that can resemble T-cell lymphoma (large cell type) include: VZV reaction, molluscum contagiosum, nodular scabies, and some case of "pagetoid reticulosis" Some conditions that can mimic plaque or patch stage of mycosis fungoides include: chronic actinic dermatitis/actinic reticuloid, HIV photodermatitis/CD8+ pseudo MF, drug hypersensitivity reaction (psycotropic drugs, antiepileptics, ACE-inhibitors, etc), lichenoid keratosis, lupus erythematosus, contact dermatitis and erythema annulare centrifigum. Cutaneous Lymphoid Dyscrasias (CLD) There are also a number of clinical entities that do not fulfill clinical and histopathological criteria for mycosis fungoides, but must be recognized as potential precursor olesions. In the last few years, we have also witnessed numerous studies reporting T-cell clonality (TCC) in a myriad of cutaneous conditions traditionally classified as benign dermatoses. This confusing trend has elicited some debate about the relevance of TCC in cutaneous infiltrates and the lack of specificity of TCC in the diagnosis of CTCL. However the detection of TCC in certain inflammatory dermatoses is probably a real event that should not be blamed to over sensitivity of the PCR based tests. There are a number of well-defined skin conditions characterized by persistent cutaneous lymphoid infiltrates composed of a clonal population of T-cells with minimal cytologic atypia. Furthermore all of these conditions can transform into bona fide CTCL and hence should be considered precursor lesions. The defining criteria for CLD are: Chronic dermatitis recalcitrant to steroids Unknown triggering event Small/intermediate lymphocytes without significant nuclear atypia Persistent T cell clone (monoclonal or oligoclonal) Potential for malignant transformation The CLD encompasses various conditions with distinct clinical and pathological characteristics. The following entities have been included in this group: Hypopigmented interface variant Pigmented purpuric variant Atypical lobular panniculitis Syringolymphoid hyperplasia with alopecia Idiopathic follicular mucinosis Folliculotropic T-cell lymphocytosis Pityriasis lichenoides chronica Parapsoriasis en plaque Idiopathic erythroderma (Pre-Sézary) The recognition of these entities is consistent with our present understanding of carcinogenesis as a multistep process with gradual accumulation of gene defects leading to T cell proliferation, antiapoptosis and gradual immune-suppresion. Even though the actual steps of lymphomagenis in CTCL are not understood and may well vary from case to case, there is mounting evidence that a preceding state characterized by chronic and relentless T cell activation of T cells with a limited T cell receptor repertoire can be often recognize in the early stages of CTCL. Mycosis Fungoides: Cutaneous T-cell Lymphoma Mycosis fungoides is the prototype of CTCL. There are approximately 0.3 new cases per 100,000 people diagnosed yearly with an estimated US prevalence of 18,000 to 20,000 cases. The majority of patients are 40 to 70 years of age with slight male and black predominance. MF is characterized by: Low grade lymphomas Cutaneous homing features (CLA+) T helper cells (CD4) Mature & primed T-cells (CD45R0+) TH2 cytokine profile Recent studies have further characterized the CTCL cell of origin. We had previously identified a number of molecules that play a role in skin-homing such as CLA or LFA-1, now a new chemokine receptor CCR4 has been demonstrated by flow cytometry in several patients with Sézary syndrome [1]. The ligand for CCR4 in the skin antigen presenting cells is TARC. Carol Berger and the group from Yale recently suggested that CTCL may be a malignancy of T regulatory cells [2]. T regulatory cells, a small subset of peripheral lymphocytes, down regulate activated T cells in response to autoantigens, infectious agents and other antigens in order to maintain homeostasis of the immune system . The profound depletion of the T cell repertoire and the immunesuppressive complications observed in advanced CTCL patients support this new proposal. MF cells in vitro require signaling or a microenvironment which is uniquely provided by antigen presenting cells. In vivo by microscopy skin examination, one also observes the close proximity of MF cells to Langerhans cells and dermal dendrocytes. These interactions with antigen presenting cells are consistent with primed and mature T cell phenotype and may explain the histological parallels of MF with inflammatory skin conditions. However, details about the antigenic stimuli driving this interaction are not known. A group from France has proposed that antigens related to Epstein Barr virus may be driving this abnormal interaction. They identified EBV at the molecular and protein level in a few Langerhans cells from mycosis fungoides lesions [3]. Other members of the herpesviridae family like human herpesvirus 8 have also been reported in patients with MF and parapsoriasis. A superantigen effect associated to staphylococcus aureus has been proposed, based on the increased usage of V beta families associated with staphylococcus in MF cells as well as non-clonal T cells in MF lesions [4]. But knowing that EBV is a common and highly prevalent virus and that staphylococcus is commonly detected in the skin of MF patients, we have to question these infectious agents as an epiphenomenon linked to the immunesuppressive nature of this disease. The challenge in the diagnosis of CTCL is in the heterogeneity of clinical pathological presentation as well as the slow evolution of the disease. The classic histopathological features include: Upper dermal band-like lymphocytic infiltrate with variable adnexal involvement. Variable epidermal changes (from atrophy to marked acanthosis), often with some parakeratosis. Halo perinuclear effect with minimal spongiosis inmost cases. Epidermotropism with atypical T cells in epidermal compartment in a basal or suprabasal configuration, arranged in duplets/triplets and less commonly Pautrier microabscesses. Dermal fibroplasia reticulated (wiry type) or lamellar strands parallel to the DE junction. Nuclear atypia (small cerebriform cells--intermediate--large cells) more relevant if atypical cells are confined to the intraepidermal compartment. Some eosinophils and plasma cells can be seen, especially in advanced MF Massone et al recently published a thorough description of histological findings in early patch MF lesions [5]. Patients with the leukemic variant of MF, Sézary syndrome often lack the characteristic histopathological features just mentioned and present with a rather non-specific dermal lymphoid infiltrate. All patterns of inflammatory dermatoses have been reported in the histomorphology of MF. Some of these mycosis fungoides histological variants include: Follicular MF (+/-Follicular mucinosis). Syringotropic MF, Granulomatous MF (+\- elastolysis), Pustular MF, Ulcerative MF, Bullous MF, Hemorrhagic MF, Hypopigmented MF, Hyperpigmented MF, D'emblee MF, Eczematoid MF, Lichenoid MF, Ichthyosiform MF, papular MF, etc. Early on, the infiltrate in mycosis fungoides is rich in tumor-infiltrating lymphocytes (mostly CD-8 positive cells with clonotypic MHC-restricted cytotoxicity), Langerhans cells, dermal dendrocytes, and NK cells. With disease progression, the reactive T-cell and NK cell population is depleted with a concomitant increase of the malignant cells. Early on, the clonal T-cells tend to be localized in the intra-epidermal compartment. With tumor progression, epidermotropism is less prominent, and there is a gradual switch of the cytokine microenvironment to a predominantly TH-2 pro-immune-suppressive cytokine profile. Consequently, the patients often develop anergy, hypergammaglobulinemia, hypereosinophilia, and loss of epidermotropism. This immune-suppressive state favors the growth of the T-cell clone by depleting the cell-mediated immune system. Immunohistochemical evaluation of epidermotropic infiltrates with CD4 and CD8 on paraffin embedded tissue can be very useful. MF-mimics tend to have a predominance of CD8 cells in the intraepidermal compartment. There are two exceptions of rare CTCL variants with intraepidermal CD8+ cells. "Epidermotropic aggressive CD8 CTCL" first reported by Berti, which is an aggressive and often lethal disease characterized by diffuse necrotic lesions with confluent necrotic keratinocytes and active cytotoxic features. The juxtaepidermal variant is a recently described variant seen in young patients often of African ancestry. The course is indolent responds relatively well to topical therapies. Epidermotropic infiltrates composed of large T-cells without tumor lesions are unusual in mycosis fungoides. Patch lesions of MF with large cells should not be equated with large cell transformation and hence is not necessarily associated with a poor prognosis. Pagetoid reticulosis is also characterized by epidermotropic large cells. This rare and obscure entity has a typical presentation with verrucous lesions in an acral distribution. The epidermotropic infiltrate is more often CD8+ than CD4+ and CD30 is commonly expressed. Many cases lack T-cell clonality. A pseudolymphomatous process has been suspected for many of these cases that present in young paitents with an entirely indolent course. Cutaneous T-cell Lymphoma, Large Cell Type Diffuse, dense (superficial and deep) and mostly non-epidermotropic mononuclear cell infiltrate. When a patient with a history of mycosis fungoides develops new tumor lesions the differential diagnosis includes: Tumor progression commonly associated with large cell transformation (CD30 + or -) CD30 Lymphomas/lymphomatoid papulosis which commonly coexist with MF Other tumors: Patients with MF are prone to develop other malignancies including B-cell lymphoma and Hodgkin's disease. Pseudotumors (nodules without tumor cells) like picker's nodule (neurodermatitis), as occasionally seen in follicular MF patients suffering from severe pruritus. Large cell transformation (LCT) of mycosis fungoides carries a poor prognosis with a 5-year survival of 11 to 19% [6, 7]. We must be careful not to confuse a primary cutaneous CD30 lymphoproliferative disorder with MF with LCT. This is particularly important since both conditions may coexist on the same patient and both entities can present with a similar dermal infiltrate with predominantly large T cells with variable CD30 expression References Sokolowska-Wojdylo M, Wenzel J, Gaffal E, Lenz J, Speuser P, Erdmann S, Abuzahra F, Bowman E, Roszkiewicz J, Bieber T, Tuting T. Circulating clonal CLA(+) and CD4(+) T cells in Sezary syndrome express the skin-homing chemokine receptors CCR4 and CCR10 as well as the lymph node-homing chemokine receptor CCR7. Br J Dermatol. 2005 Feb;152(2):258-64. Berger CL, Tigelaar R, Cohen J, Mariwalla K, Trinh J, Wang N, Edelson RL. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood. 2005 Feb 15;105(4):1640-7. Knol AC, Guilloux Y, Quereux G, Marques-Briand S, Pandolfino MC, Khammari A, Dreno B.CD8(+) T lymphocytes reactive against Epstein-Barr virus antigens in skin lesions of a patient with Sezary syndrome. J Am Acad Dermatol. 2005 Nov;53(5):897-900. Vonderheid EC, Bigler RD, Hou JS. On the possible relationship between staphylococcal superantigens and increased Vbeta5.1 usage in cutaneous T-cell lymphoma. Br J Dermatol. 2005 Apr;152(4):825-6 Massone C, Kodama K, Kerl H, Cerroni L. Histopathologic features of early (patch) lesions of mycosis fungoides: a morphologic study on 745 biopsy specimens from 427 patients. Am J Surg Pathol. 2005 Apr;29(4):550-60 Diamandidou E et al. Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis. Blood. 1998 Aug 15;92(4):1150-9. Cerroni L et al. Clinicopathologic and immunologic features associated with transformation of mycosis fungoides to large-cell lymphoma. Am J Surg Pathol. 1992 Jun;16(6):543-52