Paediatric mycosis fungoides - characteristics, management and outcomes with particular focus on the folliculotropic variant.

BACKGROUND: The literature on paediatric mycosis fungoides (MF) and especially its folliculotropic variant (FMF) is sparse. OBJECTIVES: To describe the clinical manifestations, treatments, outcomes and long-term course of paediatric MF, including FMF. METHODS: A retrospective analysis was conducted of all consecutive MF patients diagnosed at ≤18 years attending two medical centres in 1995-2015. RESULTS: The cohort included 71 patients, all but two of whom had early-stage disease: hypopigmented (55%), folliculotropic (42%) and classical MF (39%), alone or in combination. The head and neck area were involved in 43% of patients with early-stage FMF compared to 12% of the non-FMF group (P = 0.004). There was no difference in the involvement of other body areas between the groups. Pruritus, although mild, was more often recorded among patients with early-stage FMF compared to non-FMF (58% vs. 29%, respectively, P = 0.02). Complete response (CR) was achieved in 60 of the 69 patients with early-stage MF (87%) after an average of 1.8 treatment modalities. NBUVB was the most administered treatment to non-FMF patients with CR rates of 63% vs. 29% of FMF patients (P = 0.04). Systemic/bath PUVA and UVA+NBUVB were the most administered treatments to FMF patients with CR rates of 60% vs. 81% for non-FMF patients (P = 0.17). During a mean follow-up of 9.2 years (range 1-24), stage progression was observed in four (6%) of the patients with early-stage disease, two of whom (all FMF) to advanced stage. CONCLUSIONS: Paediatric MF presents as an early-stage disease with over-representation of hypopigmented and FMF variants. NBUVB and UVA-based therapies yield good response rates in non-FMF and FMF patients, respectively. Disease course is indolent, and even on relatively long follow-up, it has a very low progression rate from early to advanced-stage disease, occurring in patients with FMF. We propose a treatment algorithm for paediatric MF.

Unilesional mycosis fungoides is associated with increased expression of microRNA-17~92 and T helper 1 skewing.

BACKGROUND: The molecular basis of unilesional mycosis fungoides (MF), characterized by a solitary lesion that is clinicopathologically indistinguishable from multifocal patch or plaque MF (early MF), is unknown. OBJECTIVES: To investigate the microRNA profile in unilesional MF distinguishing it from early MF. METHODS: Biopsy samples of unilesional MF and early MF were evaluated with the Affymetrix microRNA array, with further comparison with inflammatory dermatosis, using quantitative polymerase chain reaction. NanoString technology was applied to analyse the gene expression of T helper (Th)1 immune markers, and immunohistochemistry was used to evaluate CXCR3 and GATA-binding protein 3 (GATA3) markers for Th1 and Th2 cells, respectively. RESULTS: Unilesional MF had a significantly higher level of expression of all members of the microRNA miR-17~92 cluster than early MF. Specifically, unilesional MF had a higher miR-17 level than early MF and inflammatory dermatoses. There was downregulation of the expression of phosphatase and tensin homolog (PTEN) and CREB1, known targets of miR-17~92 members; higher gene expression of interleukin-2 and interferon-γ; and a statistically lower average percentage of GATA3+ dermal cells (6·7% vs. 42·3%), were detected in unilesional MF compared with early MF. High immunoreactivity of CXCR3 was noted in both unilesional and early MF. CONCLUSIONS: Unilesional MF exhibits a microRNA profile distinct from that of conventional early MF, with a higher level of miR-17~92 members along with Th1 skewing. These findings suggest a robust reactive T-cell immune response in unilesional MF and might account for the localized nature of this disease.

Paediatric primary cutaneous marginal zone B-cell lymphoma: does it differ from its adult counterpart?

BACKGROUND: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) has rarely been reported in patients younger than 20 years. OBJECTIVES: To report our experience with PCMZL in the paediatric/adolescent age group. METHODS: Medical records of patients diagnosed with PCMZL before age 20 years and managed at two cutaneous lymphoma clinics in the U.S.A. and Israel from 1992 to 2015 were reviewed. RESULTS: The study group included 11 patients (six girls; median age 16 years, range 6-19·5); 10 had generalized/multifocal (T3) and one had regional/localized (T2) disease. Lesions were located on the limbs in all patients and the trunk in six; two had facial lesions. Staging in all but one was based on whole-body computed tomography or positron emission tomography. Initial management in most patients included nonradiation modalities: one patient with localized disease received intralesional steroids; six patients with multifocal disease received the following: topical/intralesional steroids (n = 3); excision (n = 2); 'watch and wait' (n = 1). No extracutaneous progression was noted during a median follow-up of 5·5 years (mean 7·5, range 0·5-14). At present, five patients are in complete remission. CONCLUSIONS: Based on our data (largest series in the literature with the longest follow-up), the clinicopathological presentation and course of PCMZL in the paediatric/adolescent age group are similar to those in adults. Given the indolent course and the long life expectancy of these young patients, the cumulative risk of imaging studies and the age-related potential toxicity of treatment, especially radiation, should be taken into consideration.

Unilesional folliculotropic mycosis fungoides: a unique variant of cutaneous lymphoma.

BACKGROUND: Unilesional folliculotropic mycosis fungoides (UFMF) has been rarely reported. OBJECTIVE: The aim of this study was to describe our experience with UFMF. METHODS: Data were collected on all patients with clinicopathological UFMF who attended the Department of Dermatology of a tertiary university-affiliated medical centre in 1996-2013 and were followed prospectively. RESULTS: The sample included seven patients (five male, two female) of mean age 38 years at diagnosis; two were aged <18 years. The lesion presented as a solitary patch/plaque with follicular accentuation in five patients, an infiltrated plaque devoid of hair in one and with follicular nodules in one. Four patients had alopecia, and one, secondary anetoderma. The lesion was located on a limb in four patients, the trunk in two, and the face in one. In all cases, the atypical folliculotropic lymphocytes expressed mainly surface CD4(+). Monoclonality was detected in three of the six patients analysed. Treatment consisted of localized electron beam in five patients, all of whom had a complete response (CR), and excision in one patient. The remaining patient, a 9-year-old boy, was treated with topical psoralen and UVA with CR. The duration of follow-up was 0.5-10 years (mean 4). There were no recurrences in six patients and local recurrence in one. CONCLUSION: UFMF presents at a young age, usually with early disease clinical morphology. The treatment goal should be cure. Our experience indicates an excellent prognosis of early UFMF with no multifocal/internal spread.

NB-UVB (311-312 nm)-induced lentigines in patients with mycosis fungoides: a new adverse effect of phototherapy.

BACKGROUND: Lentigines are a common pigmentary disorder in adults and in patients treated by psoralen and ultraviolet A (PUVA) radiation. Their appearance following treatment with narrow-band ultraviolet B (NB-UVB) radiation has been reported in only two patients. OBJECTIVE: To describe the clinical and histological features of NB-UVB-induced lentigines their relation to dosimetry and the course of the eruption in patients with mycosis fungoides (MF). METHODS: The files of all patients with MF treated in our department in 2003-2010 were searched to identify those in whom lentigines appeared following monotherapy with NB-UVB radiation. RESULTS: Of the 73 patients with early stage MF identified, 10 met the study criteria. Lentigines were detected in skin previously involved by MF in seven patients, and in both involved and uninvolved skin in three patients. They appeared during therapy in three patients, after a mean of 56 exposures (range 50-61), and several months (mean 7.8) following completion of treatment in seven patients, after a mean of 69 exposures (range 32-157). Histopathological study of lesions from five patients revealed basal hyperpigmentation relative to adjacent normal-looking skin. Two lesions had a slight increased number of normal-looking melanocytes on immunohistochemical staining with melanoma cocktail. One lesion had elongated rete ridges. The lesions persisted throughout follow-up (mean 26.7 months) in 8 patients. CONCLUSIONS: Patients with MF treated with NB-UVB may acquire lentigines. As opposed to PUVA-induced lentigines which are a known common side-effect of long-term treatment, NB-UVB-induced lentigines are uncommon but appear earlier, even after a few months of treatment.

Idiopathic guttate hypomelanosis-like lesions in patients with mycosis fungoides: a new adverse effect of phototherapy.

BACKGROUND: Idiopathic guttate hypomelanosis (IGH) is a common pigmentary disorder, the aetiology and pathogenesis of which are largely unknown. The appearance of IGH-like lesions during phototherapy has been reported previously in only one patient. OBJECTIVE: To describe the clinical and histological features of phototherapy-induced IGH-like lesions, their relation to ultraviolet dosimetry and the course of this eruption in patients with mycosis fungoides (MF). METHODS: The files of all patients with MF who underwent phototherapy in our centre from 1992 to 2008 were searched to identify those in whom IGH-like lesions appeared during treatment. Results Among 87 patients with early-stage MF who underwent phototherapy, seven acquired IGH-like lesions during monotherapy with narrow-band ultraviolet B (NB-UVB; four patients) or psoralen and ultraviolet A (PUVA; three patients). All but one had a light complexion. The lesions appeared in areas exposed to ultraviolet light, and not exclusively on the skin previously involved by the disease. The mean number of exposures until appearance of the lesions was 92 for NB-UVB and 137 for PUVA. Biopsy study showed a decreased number of melanocytes. Phototherapy was discontinued in four patients, of whom three showed a partial or complete disappearance of the IGH-lesions. The other three patients are still receiving phototherapy, with no change in their IGH-like lesions. CONCLUSIONS: Phototherapy may induce an eruption bearing similar clinical and histopathological features to IGH. The eruption is rare, appears to emerge only after prolonged therapy and seems to be reversible upon discontinuation of phototherapy. IGH-like eruption should be added to the list of side-effects of phototherapy.

Juvenile onset of primary low-grade cutaneous B-cell lymphoma.

BACKGROUND: Cutaneous lymphomas rarely occur in children and adolescents, and are mostly of the T-cell lineage. Low-grade primary cutaneous B-cell lymphoma (CBCL) is extremely rare in individuals under 18 years old. Only 11 patients under 20 years old have been reported in the literature. OBJECTIVES: To evaluate the number of patients younger than 18 years with primary CBCL diagnosed at our centre and to investigate its clinicopathological features, treatment and course in this age group. METHODS: We reviewed the files of all 90 patients with primary CBCL who attended the Department of Dermatology of our tertiary care university-affiliated centre from 1992 to 2007. RESULTS: Four patients who met study criteria were identified: three girls and one boy. Mean age at diagnosis was 16.6 years (range 16-17). Three patients had cutaneous marginal zone lymphoma (CMZL), and one had a spindle-cell (sarcomatoid) lymphoma, most probably follicular centre cell type. All were treated with the standard regimen used in adults. The mean duration of follow up was 45 months. No extracutaneous progression was noted. At present two of the four patients are in complete clinical remission. CONCLUSIONS: In Israel, primary CBCL apparently occurs more often in young patients than reported in the literature. CMZL is the most frequent type. Long follow up is mandatory to assess the biological behaviour of CBCL in the paediatric/adolescent age group.

Sclerosing peritonitis associated with bilateral luteinized thecoma, linked to anticonvulsant therapy.

OBJECTIVE: To present a new case of sclerosing peritonitis associated with bilateral luteinized thecoma of the ovaries, linked to anticonvulsant therapy. CASE: A 22-year-old patient, receiving carbamazepine for seizures and anxiety attacks presented with shortness of breath, abdominal pain, nausea and vomiting. Clinical and imaging examinations revealed bilateral ovarian masses with massive ascites. At emergency surgery, bilateral ovarian luteinized thecoma with sclerosing peritonitis was found. Due to recurrent, postoperative episodes of small bowel obstruction she was treated with nasogastric suction, intravenous fluids and electrolyte replacement. Total parenteral nutrition was introduced. Since only partial improvement was achieved tamoxifen was administered with resolution of the bowel obstruction. CONCLUSIONS: This is the 19th case of sclerosing peritonitis associated with luteinized thecoma of the ovaries and the 3rd to be associated with anticonvulsant therapy. Treatment should be aimed at relief of bowel obstruction symptoms, preferably with conservative methods. Tamoxifen for downregulation of TGF-beta production should be considered as a treatment modality, as it proved to be very helpful in the presented patient.

Ewing Sarcoma tumor cells express CD34: implications for autologous stem cell transplantation.

The significance of tumor cell contamination in marrow and peripheral blood stem cell (PBSC) collections of patients with solid tumors remains controversial. Various methods have been developed to purge tumor cells from autologous stem cell products, including CD34+ selection. PBSC harvests from patients with Ewing family of tumors (EFT) were analyzed for contaminating tumor cells prior and after CD34+ selection using reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC) analyzes. The expression of CD34 was studied by RT-PCR and FC in 14 primary tumors and 13 PBSC harvests, respectively. Tumor cells were identified in the harvests by both methods. In two patients, contaminating tumor cells were evident by RT-PCR only after positive selection. FC analysis confirmed a higher level of tumor cells in the CD34+ fraction. In an attempt to explore this finding, expression of CD34 was detected in 93% of primary tumors and 67% of contaminated harvests. As CD34 is expressed on EFT cells, these cells may be enriched following CD34+ selection of harvests, although the total number of tumor cells is reduced. Other methods of purging, rather than CD34+ selection, should be explored in patients with EFT undergoing autologous stem cell transplantation.

Fine structure of adrenal cortex in rats harbouring a medullary thyroid carcinoma transfected with a corticotrophin-releasing hormone cDNA expression vector.

We report the light microscopic, transmission and scanning electron microscopic features of the adrenal cortices in rats bearing a medullary thyroid carcinoma cell line transfected with a corticotrophin-releasing hormone (CRH) cDNA expression vector. The animals had elevated CRH, ACTH and corticosterone blood levels, involuted thymuses and markedly enlarged adrenal glands with prominent lipid-depleted cortices and dilated congested capillaries, similar to those of animals treated with ACTH. Using electron microscopy it was found that the enlarged fasciculata and reticularis zones were composed of large, compact cells with abundant smooth endoplasmic reticulum, prominent Golgi complexes, increased number of large mitochondria with focal loss of cristae and cavitation of the internal compartments, numerous lysosomes and prominent elongated microvilli. In addition, small cytoplasmic fragments were seen within the capillary lumina; these structures resembled microvilli that were apparently detached from adrenocortical cells and entered the blood stream via discontinuous endothelium of dilated capillaries. By scanning electron microscopy it was found that the cells had bulging surfaces with scattered pits and numerous long microvilli pointing in different directions. This animal model allows analysis of the effects of protracted CRH excess resembling tumoural CRH-dependent Cushing's syndrome in human patients. Our findings call attention to the role of microvilli in adrenocortical secretion. The increased number and size of microvilli has been thought to lead to an increase in the surface area of adrenocortical cells, thereby facilitating hormone discharge. The detachment of microvilli from adrenocortical cells may represent a form of apocrine secretion and may contribute to hypercorticosteronaemia in CRH excess.

Expression of the apoptosis-related oncogenes bcl-2, bax, and p53 in Merkel cell carcinoma: can they predict treatment response and clinical outcome?

Chemotherapy and radiation therapy act predominantly through the induction of apoptosis in malignancies. Merkel cell carcinoma, an aggressive malignancy with prominent apoptosis, has proved to be sensitive to both modes to a certain degree. We used immunohistochemical methods to examine 25 Merkel cell carcinomas and 8 of their lymph node metastases to assess the status of the antiapoptotic gene bcl-2 and 2 proapoptotic genes, wild-type p53 and bax. All tumors showed prominent bax immunopositivity; 76% were positive for bcl-2, and only 28% were positive for p53, the latter presumably reflecting mutated p53. No statistically significant relationship was found between tumor immunopositivity and therapy response or survival. The widespread bax immunopositivity and the apparently low rate of p53 mutations, as suggested by the low rate of p53 immunopositivity, may be related to the presence of prominent apoptosis in Merkel cell carcinoma. The finding of bcl-2 immunopositivity in 76% of the tumors suggests that some of the tumor cells may be resistant to apoptosis-inducing agents.

HLA-DR and beta 2 microglobulin expression in medullary and atypical medullary carcinoma of the breast: histopathologically similar but biologically distinct entities.

AIMS: To examine the expression of HLA-DR and beta 2 microglobulin in medullary carcinoma and atypical medullary carcinoma of the breast to determine if the effective presentation of tumour antigens to the immune system can differentiate between these two histopathologically similar entities. METHODS: Expression of HLA-DR and beta 2 microglobulin was examined by immunohistochemical methods in five samples of medullary carcinoma of the breast, which has a relatively favourable prognosis, six samples of atypical medullary carcinoma of the breast, which has a prognosis closer to that of regular invasive duct carcinoma, and 20 samples of invasive duct carcinomas, 10 with an accompanying lymphocytic infiltrate. RESULTS: A positive and significant correlation was found between tumour type and both HLA-DR and beta 2 microglobulin expression. Expression was most prominent in medullary carcinoma, followed by atypical medullary carcinoma and invasive duct carcinoma with and without lymphocytic infiltrates. The mean intensity and percentage of HLA-DR tumour immunostaining were significantly higher in medullary carcinoma than in the other three tumour groups, as was the mean intensity of beta 2 microglobulin immunostaining. Mean percentage of beta 2 microglobulin immunostaining was significantly higher in medullary carcinoma than in invasive duct carcinoma without lymphocytic infiltrates, and showed a trend to increase from invasive duct carcinoma with lymphocytic infiltrates to atypical medullary carcinoma and medullary carcinoma. CONCLUSIONS: Medullary carcinoma and atypical medullary carcinoma of the breast differ in their expression of HLA-DR and beta 2 microglobulin. The relatively favourable prognosis of medullary carcinoma of the breast may be related to effective tumour antigen presentation to the immune system through MHC-I and MHC-II expression. Immunotherapy aimed at MHC-I and MHC-II induction might have a beneficial effect in breast cancer.

The long-term predictive value of the zona-free hamster ova sperm penetration assay.

Three hundred sixty-nine infertile couples were followed for 2 to 5 years in a study designed to determine the clinical long-term predictive value of the zona-free hamster ova sperm penetration assay (SPA). Semen analysis (SA), SPA, and a full infertility workup were done in all cases, and only couples in whom the female had no evident cause of infertility were included in the study. During the follow-up period, 106 couples (29%) achieved a pregnancy. Sixteen percent of 131 men who had an SPA of 0%, 23% of 120 men with 1% to 19%, and 48% of 118 men who had a penetration of greater than 19% impregnated their wives 2 to 5 years after the assays. Significant difference in fertility prognosis was found between those who had an SPA greater than 19% and those with an SPA less than 20% (48% versus 20%). Sperm penetration assay greater than 19% was predictive of higher pregnancy rates in both oligospermic (41% versus 17%) and unexplained infertile couples (52% versus 24%). The specificity and positive predictive values of the SPA were higher than those of the SA (77% versus 57% and 48% versus 37%). These findings emphasize the value and importance of the SPA in determining the long-term fertility potential of men.

Migratory ichthyosiform dermatosis with type 2 diabetes mellitus and insulin resistance.

BACKGROUND: In addition to the well-defined hereditary primary ichthyoses, many sporadic or less well-defined keratinization disorders with or without systemic manifestations have been reported. Herein we describe ichthyosiform dermatosis associated with type 2 diabetes mellitus. OBSERVATIONS: The patients were members of a large Arab family with heavy consanguinity. Eighteen members were affected with a variously severe scaly disorder. They showed migratory polycyclic keratotic scaly plaques evolving into diffuse generalized scaling or complete remission. Acanthosis nigricans-like lesions were also noted, and there was an association with type 2 diabetes mellitus. A scarcity of intercorneocyte lamellae and reduction in lamellar body contents were observed. CONCLUSIONS: We could not find a report of a similar dermatosis. Furthermore, an association between ichthyosis and diabetes has not been documented. Therefore, we believe that this may constitute a new entity.

Sentinel-lymph-node biopsy (SLNB) for melanoma is not complication-free.

BACKGROUND AND AIM: Sentinel lymph node biopsy (SLNB) is reportedly associated with insignificant morbidity. The study aims at documenting SLNB-related complications and identifying possible risk factors. METHOD: Data of all melanoma patients who underwent SLNB in our medical center (1994-2002) were analysed. Procedure-related complications were recorded. RESULTS: Three hundred and nine lymphatic basins of 250 patients were explored for SLNB. Overall complication rate was 20%. Sensory morbidity was significantly associated with axillary SLNB (p=0.04) and was more prevalent in younger patients. The use of blue dye alone or combined with a hand-held gamma probe had no statistically significant impact on the identification rate. There were six false-negatives (2.3%), for an overall false-negative rate of 18%. A positive sentinel node was significantly associated with shortened overall survival (p=0.04). CONCLUSION: Wound complications are more frequent than usually reported. Sensory morbidity occurs mostly in the axilla. Neck SLNB is associated with the highest rate of identification failure. Patient age, basin location, and number of excised nodes may serve as prognostic factors of morbidity.

Sentinel-node guided lymph-node dissection for merkel cell carcinoma.

Merkel cell carcinoma is an aggressive neuroendocrine skin tumour. Treatment is still debatable. Merkel cell carcinoma resembles malignant melanoma in its cutaneous presentation and its embryonic origin; both have unpredictable biological behaviour, early regional lymph node involvement, early distant metastases and a high recurrence rate. In light of these common features, we used pre-operative lymphoscintigraphy, intraoperative lymph-node mapping and sentinel-node biopsy-a well-described technique for the treatment of melanoma-in a 60-year-old man with Merkel cell carcinoma in the right buttock. Following frozen section identification of a metastatic first-order sentinel node, radical right groin dissection was performed. All the other lymph nodes in this basin proved to be disease-free, including the second-order sentinel node and Cloquet node. The patient is now being treated with adjuvant chemotherapy and radiotherapy. This case shows that sentinel-node guided dissection is applicable to Merkel cell carcinoma.

HLA-DR expression and lymphocytic infiltration in metastatic and non-metastatic papillary carcinoma of the thyroid.

Thyrocyte HLA-DR expression in association with lymphocytic infiltration has been demonstrated in autoimmune diseases of the thyroid. HLA-DR expression has been noted both in association with lymphocytic infiltration and in its absence. However, no prognostic significance was attributed to these findings. The purpose of this study on papillary carcinoma of the thyroid was to examine how tumour behaviour relates independently to HLA-DR expression and lymphocytic infiltration. Fifty patients with papillary carcinoma with known metastatic status were examined for HLA-DR expression utilizing the immunoperoxidase conjugated indirect method. The patients were divided into three groups: no metastases (n = 16), regional lymph node metastases only (n = 25), and distant haematogenous metastases (n = 9). Overall HLA-DR expression was noted in 6, 36 and 55% of the respective groups. Tumour HLA-DR expression without lymphocytic infiltration was noted in 0, 4 and 33% of the respective groups. Tumour HLA-DR expression with lymphocytic infiltration occurred in 6, 32 and 22% of the respective groups. From these findings we conclude that HLA-DR expression with lymphocytic infiltration occurs more frequently than HLA-DR expression in the absence of infiltration. The concurrence of HLA-DR expression and lymphocytic infiltration is most commonly associated with regional lymph node metastasis. HLA-DR expression in the absence of lymphocytic infiltration occurs in tumours with distant haematogenous metastases and is an uncommon feature of tumours that have not metastasized or have metastasized only to lymph nodes. Tumour HLA-DR expression in the absence of lymphocytic infiltration may indicate the potential for more aggressive behaviour.

Central effects of cycloheximide alone and of its combination with T-2 toxin.

The antibiotic cycloheximide inhibits protein synthesis in eukaryotic cells. This overall effect is similar to that of T-2 toxin, but the mechanism of intoxication by these two inhibitors are different. This is shown here by intracerebral injections of mixtures of T-2 toxin and cycloheximide, leading to potentiation of their toxic effects. The histopathology of cerebral intoxication by the two compounds is similar, but after cycloheximide the lesions appear earlier, and repair is faster.

Genetic analyses of male breast cancer in Israel.

Male breast cancer is a rare disorder, and little is known about the molecular mechanisms associated with the tumorigenic process. We genotyped 31 Jewish Israeli males with breast cancer for the predominant Jewish BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) germline mutations: 11 individuals from high-risk families and 20 patients unselected for family history of cancer. Two patients of the high-risk group (18.2%) displayed germline mutations: one harbored the 185delAG BRCA1 mutation, and the other the 6174delT mutation in BRCA2. None of the unselected patients displayed any mutation. In 2 patients, complete mutation analysis of the BRCA2 gene did not reveal any disease-associated mutations. We conclude that the predominant Jewish germline mutations in BRCA1/BRCA2 contribute to male breast cancer in Israel, primarily in Ashkenazi individuals with a family history of cancer.