Mycosis Fungoides and Granulomatous Slack Skin: A Single Entity With Distinct Clinical Phenotypes.

ABSTRACT: Granulomatous cutaneous T-cell lymphoma includes mycosis fungoides with significant granulomatous inflammation (GMF) and granulomatous slack skin (GSS), listed in the WHO classification as a subtype of mycosis fungoides (MFs). 1 These overlapping entities have shared clinical and histopathologic features which can present a diagnostic challenge. The dominance of the granulomatous infiltrate and the often sparse lymphocytic infiltrate frequently with minimal cytological atypia are features that distract from the correct diagnosis, even when raised by the clinician. We describe the clinical and histopathologic characteristics of 3 cases of granulomatous cutaneous T-cell lymphoma, illustrate the close clinical and pathologic relationship between GMF and GSS and emphasize the diagnostic difficulties that the granulomatous infiltrate can present. Furthermore, we demonstrate, for the first time, considerable elastolysis in a significant proportion of classical (Alibert-Bazin) MF lesions and therefore postulate that the differences observed between GMF and GSS are one of degree and secondary to their anatomic location rather than reflecting meaningful separate entities.

Follicular T-Helper Cells in Marginal Zone Lymphoma: Evidence of an Organoid Immune Response.

INTRODUCTION: Primary cutaneous marginal zone B-cell lymphoma (MZL) follows an indolent clinical course. Histopathologically, there is a polymorphous infiltrate that includes small lymphocyte-like and centrocyte-like B cells and plasma cells usually with a substantial T-cell fraction. Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, in which the signature cells have a follicular T-helper (TFH) phenotype and are admixed with numerous B cells. Thus, both present histologies of combined B-cell and T-cell infiltrates and represent differential diagnoses. The presence of TFH in MZL has yet to be elucidated. METHODS: Forty-one biopsies from 40 cases of MZL and 7 cases of lymphoid hyperplasia cutis (LCH) were stained with antibodies to follicular T-helper cells, including Bcl-6, PD-1, ICOS, and CD10, as part of their diagnostic workup, were reviewed, and the stained slides were evaluated semiquantitively. Five reactive lymph nodes were also evaluated as controls. RESULTS: All cases of MZL and LCH contained TFH, albeit usually in low proportions. There were repeated differences in levels of expression between TFH markers, with PD1 and Bcl-6 being the most prevalent. The pattern of involvement in MZL and LCH closely mirrored that observed in the reactive lymph nodes. CONCLUSION: MZL includes TFH cells, similar to reactive lymph nodes, and a complexity of cell types. This provides evidence of an organoid immune response challenging its simple categorization as a malignancy.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder or Primary Cutaneous Marginal Zone B-Cell Lymphoma? Two Distinct Entities With Overlapping Histopathological Features.

ABSTRACT: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder and primary cutaneous marginal zone B-cell lymphoma are 2 distinct entities with several overlapping features which can result in diagnostic uncertainty. Clinically, they both follow an indolent course and present with solitary or multiple papules or nodules. Histologically, they are characterized by polymorphous dermal infiltrates rich in mixed populations of B cells and T cells, often in similar proportions. The histological hallmark of primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder is the presence of follicular T-helper cells within the infiltrate and has historically been used as a marker for differentiating between the 2 conditions. However, there is now mounting evidence that follicular T-helper cells are also seen in primary cutaneous marginal zone B-cell lymphoma and nodal marginal zone lymphoma. The 2 cases presented herein caused diagnostic uncertainty because they displayed appreciable features of both conditions. We discuss the potential mechanisms behind these overlapping histopathological features and hypothesize a model that explores the idea of a collective organoid response to an antigenic stimulus.

Prominent Blasts in Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder. A Reconsideration of Diagnostic Criteria.

ABSTRACT: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD), recently downgraded from a T-cell lymphoma, is a poorly characterized histopathological entity. Presenting as a solitary lesion that often grows rapidly, it may raise suspicion for a cutaneous B-cell lymphoma. However, classically, the dermal lymphoid proliferation is predominantly CD4+ with a follicular T-helper profile and a smaller B-cell fraction. Diagnostic uncertainty may arise when B cells are present in large numbers, a B-cell clone is present, or large cell populations are seen. To meet the diagnostic criterion of PCSM-LPD, large cells should not constitute more than 30% of the infiltrate. The 2 cases presented in this article caused diagnostic uncertainty owing to the observation of high numbers of large cells and in one case the presence of a B-cell clone, on the background of otherwise typical clinicopathological features of PCSM-LPD. We review the literature specifically regarding the prevalence of large cell populations and their immunophenotypic characteristics and in light of this discuss whether a current diagnostic criterion should be reconsidered.

Management of skin cancer in recipients of solid organ transplants.

Recent improvements in post-transplant care have led to an increased life expectancy for recipients of organ transplants. These patients require lifelong immunosuppression, which is associated with an increased incidence of malignant disease. Skin cancers are the most common malignancies seen in recipients of organ transplants and are associated with significant morbidity and mortality. This review describes factors pertaining to the development and prognosis of skin cancers in recipients of organ transplants, as well as outlining prevention and management strategies in this cohort.

Chromosomal anomalies in primary cutaneous follicle center cell lymphoma do not portend a poor prognosis.

BACKGROUND: The t(14;18)(q32;q21) chromosomal translocation is found in the majority of nodal follicular lymphomas but only rarely in primary cutaneous follicle center cell lymphomas (PCFCL). Recent studies have postulated that the translocation is more prevalent in PCFCL than previously described and that it might be a molecular prognostic marker. OBJECTIVES: The purpose of our study was to analyze cases of PCFCL for the presence of a t(14;18) translocation using fluorescence in situ hybridization to detect balanced translocations involving either the BCL2 or MALT1 loci and to correlate the results with growth pattern, immunophenotype, and clinical outcome. METHOD: In all, 57 patients with PCFCL were extracted from our cutaneous lymphoma database. Retrospective analysis of clinical parameters including lesion type, location, diagnostic stage, lactate dehydrogenase, initial treatment, relapse rate, and survival was performed. RESULTS: In all, 57 patients with PCFCL were included in this study. We detected 1 BCL2 chromosomal amplification, 4 translocations of BCL2, and 1 IGH/MALT1 translocation. LIMITATIONS: This was a case series retrospective study. CONCLUSIONS: PCFCL has an excellent 5-year overall survival (100% disease-specific survival). Chromosomal abnormalities of either BCL2 or MALT1 were detected in 10% of cases but do not correlate with a specific immune pathology or clinical outcome.

Expanding the spectrum of frontal fibrosing alopecia: a unifying concept.

BACKGROUND: In frontal fibrosing alopecia (FFA), scalp alopecia dominates the clinical picture. However, eyebrow loss and hair loss in other body sites may also occur; this has been documented clinically, but rarely histopathologically. We describe the clinicopathological findings of 13 cases of FFA, with histopathologic data from the scalp, eyebrow, and body hair. METHODS: Thirteen patients with a diagnosis of FFA, seen between 2006 and 2008, were included. Scalp biopsies were performed in all patients for histology and direct immunofluorescence (DIF). Biopsy specimens for histology were taken from the eyebrow in 6 patients and from the upper limb in 5 patients. RESULTS: All 13 patients were female, 11 of whom were postmenopausal. The median age at onset of alopecia was 57 years. Clinical examination revealed a band of frontal hairline recession in all patients. Eyebrow loss was present clinically in all patients, with loss of body hair in 10 of 13. Histopathologic examination of the scalp, eyebrow, and upper limb skin biopsy specimens showed similar features, including a marked reduction in the number of hair follicles and a perifollicular lymphoid cell infiltrate with perifollicular fibrosis. Direct immunofluorescence was negative in all cases. LIMITATIONS: Not all patients consented to biopsies of the eyebrows or upper limbs. CONCLUSION: Eyebrow and peripheral body hair loss is not uncommon in FFA-a finding that is likely underreported. We have demonstrated that alopecia of the upper limbs in FFA is indeed common and, histopathologically, shows features of lichen planopilaris and scarring, similar to findings in the scalp and eyebrows. Consequently, the process of lichen planopilaris with scarring alopecia is generalized rather than localized only to the frontal scalp and eyebrows.

Downregulation of Fas gene expression in Sézary syndrome is associated with promoter hypermethylation.

Sézary Syndrome (SS) is an aggressive leukemic variant of primary cutaneous T-cell lymphoma characterized by the presence of tumor or Sézary cells that generally display a mature memory T-cell immunophenotype. Sézary cells proliferate poorly and therefore their accumulation may be due to defective T-cell homeostasis involving resistance to apoptosis. In this study, we analyzed Fas expression in CD4+ lymphocytes at the mRNA and protein levels in a large cohort of SS patients as compared with healthy controls. Fas mRNA expression was dysregulated in 34/47 patients, with significant under- and overexpression of Fas mRNA detected in 21 and 13 patients respectively (P<0.01). Examination of cell-surface Fas expression showed correlation with the observed downregulation of mRNA in CD4+ T cells. Mutational analysis demonstrated that functional FAS gene mutations are rare. Moreover, 16 SS patients who showed significant under-expression of Fas mRNA also showed significant positional hypermethylation within the FAS CpG island, which was not present in healthy controls or SS patients determined to have normal or overexpression of Fas mRNA. These data demonstrate that dysregulation of Fas expression is a common feature of SS, and provide a rationale for targeted therapies to restore the extrinsic Fas-dependent apoptotic pathway in this malignancy.

Congenital anetoderma in a preterm infant.

Isolated, small lesions of anetoderma presenting at birth have been reported in twins born at 25 weeks of gestational age. We report the first case of widespread congenital anetoderma occurring in an infant born at 24 weeks of gestation weighing 640 g and discuss the potential factors in its etiology.

Genital herpes masquerading as a cutaneous T-cell lymphoma: a report of two cases.

Genital herpes simplex virus (HSV) infection is usually a straightforward clinical diagnosis, rarely requiring histological confirmation. We report two cases of immunosuppressed patients in which the clinical and pathological features were initially suspicious for cutaneous lymphoma with a T-cell clone detected in one case. A diagnosis of HSV infection was eventually made on the basis of histological features and confirmed with immunohistochemistry.

Three cases of lymphomatoid papulosis with a CD56+ immunophenotype.

We report 3 cases of lymphomatoid papulosis (LyP) with a CD56+, cytotoxic immunophenotype. All 3 patients presented with clinical histories typical of LyP, with one patient having associated mycosis fungoides. Histologically, two cases were type A LyP and one was type B. All 3 cases demonstrated a T-cell receptor clone in lesional skin without evidence of blood involvement. The atypical lymphocytes in each of the 3 cases expressed cytotoxic granules (T-cell intracellular antigen-1+ and granzyme B+) and were CD8+ and CD56+. Expression of CD56 is associated with a poor prognosis in subcutaneous panniculitis-like T-cell lymphoma and blastic natural killer cell lymphoma. However, the two cases of CD56+ LyP previously reported and the 3 cases in this series all appear to be pursuing an indolent course with no evidence of systemic disease.

Mycosis fungoides with a CD56+ immunophenotype.

We report 3 cases of mycosis fungoides (MF) with a CD56+ cytotoxic immunophenotype. Each patient presented with a different clinical phenotype: one exhibited limited poikilodermatous patches (skin stage T1); one, widespread hypopigmented lesions (skin stage T2); and one, poikiloderma with a single cutaneous tumor (skin stage T3). MF was confirmed both histologically and by the presence of a T-cell receptor clone in lesional skin in all cases. CD56 and T-cell intracellular antigen-1 were expressed by the malignant lymphocytes in all patients and two expressed CD8. No sample demonstrated loss of the pan T-cell markers CD2 or CD3. None of the 3 developed systemic disease and T-cell receptor gene analysis of peripheral blood was polyclonal in all cases. Only 3 cases of CD56+ MF have been reported previously, none of which exhibited tumor-stage disease. Currently, the disease in our patients appears to be behaving in a manner similar to that predicted for MF with a normal immunophenotype but the prognosis has to be guarded in view of the rarity of this subtype.

Fine mapping of chromosome 10q deletions in mycosis fungoides and sezary syndrome: identification of two discrete regions of deletion at 10q23.33-24.1 and 10q24.33-25.1.

Previous cytogenetic studies in mycosis fungoides (MF) and Sezary syndrome (SS) have identified a large and poorly defined area of chromosomal deletion on chromosome 10q. We report an extensive fine-mapping allelotyping study using 19 microsatellite markers in the region 10q22.3-10q26.13. Allelic loss was identified by loss of heterozygosity analysis in 26 of 60 (43%) cases: 15 of 45 (33%) with MF and 11 of 15 (73%) with SS. MF and SS samples showed similar patterns of allelic loss with the identification of two discrete regions of deletion which were mutually exclusive in all but two cases. Within the first region of deletion at 10q23.33-10q24.1, around microsatellite marker D10S185 (2.77 Mb), 23 genes were identified, including three (KIF11, HHEX, and HELLS) with functions that, if dysregulated, could be critical in MF and SS. The second region of deletion, 10q24.33-10q25.1, around microsatellite marker D10S530 (3.92 Mb), encodes 11 genes, the majority of which have poorly identified functions. This extensive allelotyping study provides the basis for future highly selective candidate gene analyses.

Outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study.

BACKGROUND: Mycosis fungoides (MF) is predominantly a disease of older patients, but occasionally occurs in children. The aims of the current study were to describe the clinical presentation, pathologic features, and disease progression (DP) in patients who developed MF before age 16 years. METHODS: A retrospective study was performed. Patients with juvenile-onset MF were identified from our databases. Clinical features were determined from the medical records and patient interviews. Histologic, immunohistochemical, and T-cell receptor (TCR) gene analysis was performed. RESULTS: Thirty-four patients were identified: 50% had Stage IA disease, 47% had Stage IB disease, and 3% had Stage IIA disease. The male-to-female ratio was 2:1. Clinical features included hypopigmented lesions (24%), poikiloderma (26%), pilotropic disease (9%), and disease associated with lymphomatoid papulosis (18%). Twenty-eight patients had diagnostic histology, and six patients were included on the basis of compatible histology and a TCR clone in lesional skin. A cytotoxic immunophenotype was observed in 38%, including 71% of patients with hypopigmented lesions. Overall disease-specific survival (DSS) rates at 5 and 10 years were 95% and 93%, respectively. DP rates were 5% at 5 years and 29% at 10 years. Subgroup analysis demonstrated improved DSS and reduced DP in patients with Stage IA disease, those with hypopigmented or poikilodermatous lesions, and those with associated lymphomatoid papulosis. CONCLUSIONS: The prognosis for juvenile-onset MF is similar to that of adult-onset disease. There was an overrepresentation of a cytotoxic phenotype, which was most marked in hypopigmented variants. Widespread cutaneous disease (Stage IB) indicated a less favorable outcome.