—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 3 - Mycosis Fungoides

Marshall E. Kadin
Roger Williams Medical Center
Providence, RI





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Clinical History:
The patient is a 64 year old Caucasian woman with a 4 year history of pruritic/burning skin lesions on breasts and trunk. Repeated skin biopsies revealed chronic dermatitis. Treatment consisted of medium-strength topical steroids as well as anti-histamines for pruritus. Physical exam revealed atrophic red-brown scaly patches with telangiectasia. There was minimal enlargement of axillary and inguinal lymph nodes. Clinical stage IIA (T2, N1, M0, B0). Biopsy of an abdominal lesion was performed.


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Pathology:
The biopsy reveals at low power an atrophic epidermis with a band-like lymphocytic infiltrate at the dermal-epidermal junction. Dermal vessels are dilated. The epidermis shows parakeratosis. At higher magnification, there is lymphocyte "tagging" of the basal layer of the epidermis with individual atypical lymphocytes surrounded by clear spaces (halos). The atypical lymphocytes have a CD4+, CD7-, CLA+, CCR4+ phenotype. Epidermotropism of atypical lymphocytes with convoluted nuclei is seen with formation of Pautrier microabscesses which consist of aggregates of atypical lymphocytes and Langerhans cells within the epidermis. There is evidence of cytopathic changes in individual keratinocytes including apoptosis, formation of Civatte bodies in the epidermis and colloid bodies in the dermis.

Diagnosis:
The presence of atypical lymphocytes with cerebriform nuclei and formation of Pautrier microabscesses establish the diagnosis of mycosis fungoides. The band-like infiltrate at the DE-junction and accompanying cytopathic changes in the epidermis are consistent with a lichenoid tissue reaction (LTR). Lichenoid changes in 12 patients with mycosis fungoides were well described by Guitart and colleagues (JAAD 1997). These patients represented 5.3% of the total population with mycosis fungoides seen at Northwestern University from 1985-95. Patients with LTR complained of intense pruritus or burning sensation, or both, more severe than in other patients with mycosis fungoides. Their mean age at presentation was 65 years; there were 8 women and 4 men; 8 were Caucasian, 2 Hispanic, and 2 African-American. Three patients were taking drugs frequently associated with an LTR. Lymphocyte atypia was noted in all patients with. Pautrier microabscesses were found in 10 of 12 cases. Reticular (wiry) fibrosis was noted in all cases. Eosinophils were observed in 8 of 12 and plasma cells in 6 of 12 cases. An accelerated course was noted in one-half of patients leading the authors to hypothesize that MF with LTR may be associated with a poor prognosis, but this must be tested in clinical trials.

Differential diagnosis:
The differential diagnosis in this case includes pityriasis lichenoides, lichenoid actinic keratosis and squamous neoplasms, lichenoid drug reaction, lichen planus, and lichen aureus. Clinical presentation, absence of extravasated erythrocytes, and predominance of CD4+ over CD8+ lymphocytes appears to exclude pityriasis lichenoides, although children with clinical features of pityriasis lichenoides who have histopathologic findings of mycosis fungoides have been reported (Ko, Br J Dermatol 2000). Lack of keratinocyte atypia, loss of cellular polarity, and solar keratosis exclude squamous neoplasm and lichenoid keratosis. Clinical history, predominance of CD4+ cells, presence of cerebriform lymphocytes, and absence of eosinophils are against lichenoid drug reaction, although anti-histamines are among the drugs associated with clonal T cell dyscrasia (Magro, Hum Pathol 2003). Lichen planus is unlikely because of the absence of shiny flat-topped violaceous papules, oral lesions (Wickham's striae) or irregular acanthosis ("sawtoothing"), and lack of cerebriform lymphocytes. Lichen aureus has extravasated erythrocytes and hemosiderin laden macrophages not seen in this biopsy. It tends to present with asymmetric lesions on extremities and affect younger male patients. Although T-cell monoclonality could be demonstrated in one-half of 23 lichen aureus patients in one study, no progression to mycosis fungoides was found (Fink-Puches, 2008). The epidermis is usually spared in CD30+ CTCL.

Discussion:
Epidermotropism of malignant T lymphocytes is associated with IFN inducible protein 10 (IP-10) which is chemotactic for CD4+ lymphocytes. IP-10 is confined to basal layer keratinocytes of normal skin but is markedly increased and extended to the superbasal keratinocytes of CTCL patients (Sarris, Blood 1995, 86:651). IFN g secreted by Th1 malignant cells in mycosis fungoides induces ICAM-1 expression on keratinocytes and binds to LFA-1 on malignant T-cells ( Shioahara, Int J Dermatol 1988; Griffiths, J Am Acad Dermatol 1989). In Sezary syndrome, ICAM-1 expression by keratinocytes is markedly diminished, favoring extra-cutaneous dissemination of the malignant T-cell clone (Nickoloff, JAMA 1989).

Interface dermatitis can be classified according to the cell type that dominates the infiltrate and the intensity of the interface infiltration (Crowson, 2008). Lymphocyte Interface dermatitis (ID) is a term used interchangeably with LTR. Unifying concepts behind this injury reaction pattern are (1) epidermal cell damage with hydropic changes and keratinocyte death most pronounced at the basal-cell layer (2) Formation of Civatte bodies in the epidermis and colloid bodies in the dermis (3) prominent mononuclear cell infiltrate which obscures the DE junction (4) Cytotoxic lymphocytes with a Th1 profile, secreting IFN. The LTR/lymphocyte ID pattern is mediated by interaction between IFN-inducible chemokines CXCL9 and CXCL10 and their cognate chemokine receptor , CXCR3. Cytotoxic CXCR3+ lymphocytes invade the epidermis and induce keratinocyte apoptosis. CD123+ plasmacytoid dendritic cells which produce type I IFN are increased in skin lesions of lichen planus and lupus. IFNa inducible proteins (MxA, CXCL9 and CXCL10) are increased ( Meller, JID 2009).

The ID pattern in CTCL is well represented by CD8+ CTCL in which keratinocyte apoptosis appears to be mediated by cytotoxic CD8+ tumor cells (Agnarsson, JAAD, 1990; Berti, Am J Pathol 1999). Lichen planus is the prototypic autoimmune skin disorder with a LTR/lymphocyte ID pattern. The pathogenesis of the ID pattern in lichen planus is beautifully illustrated by Wenzel and Tueting (JID 2009). Using gene expression analysis, they showed that CXCL9, which is the ligand for CXCR3, is the best marker to distinguish lichen planus from other inflammatory skin disorders, such as atopic dermatitis and psoriasis. In fixed drug eruption, intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable population of memory T-cells, transiently acquire an NK-like phenotype, expressing cytotoxic granules. Influx into the epidermis of CD4+ T cells, including Foxp3+ Tregs, serves to minimize epidermal damage. IL-15 from lesional epidermal keratinocytes could maintain survival of intra-epidermal CD8+ T cells even in absence of antigenic stimulus over a prolonged period (>4 years) Mizukawa 2008).

Key words
lichenoid tissue reaction, interface dermatitis, chemokines, mycosis fungoides, cutaneous T-cell lymphoma, lichen planus.

References:
  1. Guitart J, Peduto M, Caro WA, Roenigk HH. Lichenoid changes in mycosis fungoides. J Am Acad Dermatol 1997, 36:417-22.

  2. Ko JW, Seong JY, Suh KS, Kim ST. Pityriasis lichenoides-like mycosis fungoides in children. Br J Dermatol 2000, 142:347-52.

  3. Magro CM, Crowson AN, Kovatic AJ, Burns F. Drug-induced reversible lymphoid dyscrasia: a clonal lymphomatoid dermatitis of memory and activated T cells. Hum Pathol 2003, 34:119-29.

  4. Fink-Puches R, Wolf P, Kerl H, Cerroni L. Lichen aureus: clinicopathologic features, natural history and relationship to mycosis fungoides. Arch Dermatol 2008, 144:1169-73.

  5. Sarris AH, Esgleyes-Ribot T, Crow M et al. Cytokine loops involving interferon-gamma and IP-0, a cytokine chemotactic for CD4+ lymphocytes: an explanation for epidermotropism of cutaneous T-cell lymphoma,? Blood, 1995, 86:651-58.

  6. Shirohara T, Moriya N, Nagashima M. The lichenoid tissue reaction. A new concept of pathogenesis. International Journal of Dermatology, 1988, 27:365-374.

  7. Griffiths CE, Voorhees JJ, Nickoloff BJ. Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant gamma interferon and tumor necrosis factor. J Am Acad Dermatol 1989, 20:617-29.

  8. Nickoloff BJ, Griffiths CE, Baadsgaard O, Voorhees JJ, Hanson CA, Cooper KD. Markedly diminished epidermal keratinocyte expression of intercellular adhesion molecule-1 (ICAM-1) in Sezary syndrome. JAMA 1989, 262:2217-21.

  9. Crowson AN, Magro CM, Mihm MC, Jr. Interface dermatitis. Arch Pathol Lab Med 2008, 132:652-666.

  10. Dutz JP. T-cell-mediated injury to keratinocytes: insights from animal models of the lichenoid tissue reaction. J Invest Dermatol 2009, 129:309-14.

  11. Agnarsson BA, Vonderheid EC, Kadin MD. Cutaneous T cell lymphoma with suppressor/cytotoxic (CD8) phenotype: identification of rapidly progressive and chronic subtypes. J Am Acad Dermatol 1990, 22:569-77.

  12. Berti E, Tomasini D, Vermeer MH et al, Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphoma. A distinct clinicopathologic entity with an aggressive clinical behavior. Am J Pathol 1999, 155:483-92.

  13. Meller S, Gilliet M, Homey B. Chemokines in the pathogenesis of lichenoid tissue reactions. J Invest Dermatol 2009, 129:315-19.

  14. Wenzel J, Tueting T. An IFN-associated cytotoxic cellular immune response against viral, self-, or tumor antigens is a common pathogenetic feature in "interface dermatitis". J Invest Dermatol 2009, 128:2392-2402.

  15. Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Clin Lab Invest 2008, 158:1230-38.