Case 3 -
Marshall E. Kadin
Roger Williams Medical Center
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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.
Case 3 - Slide 1
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.
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.
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.
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)
lichenoid tissue reaction, interface dermatitis,
chemokines, mycosis fungoides, cutaneous T-cell lymphoma, lichen planus.
- Guitart J, Peduto M, Caro WA, Roenigk HH. Lichenoid changes in mycosis fungoides. J Am Acad Dermatol 1997, 36:417-22.
- Ko JW, Seong JY, Suh KS, Kim ST. Pityriasis lichenoides-like mycosis fungoides in children. Br J Dermatol 2000, 142:347-52.
- 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.
- 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.
- 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.
- Shirohara T, Moriya N, Nagashima M. The lichenoid tissue reaction. A new concept of pathogenesis. International Journal of Dermatology, 1988, 27:365-374.
- 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.
- 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.
- Crowson AN, Magro CM, Mihm MC, Jr. Interface dermatitis. Arch Pathol Lab Med 2008, 132:652-666.
- Dutz JP. T-cell-mediated injury to keratinocytes: insights from animal models of the lichenoid tissue reaction. J Invest Dermatol 2009, 129:309-14.
- 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.
- 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.
- Meller S, Gilliet M, Homey B. Chemokines in the pathogenesis of lichenoid tissue reactions. J Invest Dermatol 2009, 129:315-19.
- 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.
- 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.