Insect bite-like reaction associated with mantle cell lymphoma: clinicopathological, immunopathological, and molecular studies.

A cutaneous eruption simulating insect bites has been repeatedly described in association with chronic lymphocytic leukemia (CLL). It was only rarely described with mantle cell lymphoma (MCL). Our study was performed to elucidate the clinical, histologic, immunopathological, and molecular characteristics of insect bite like reaction (IBLR) associated with MCL. The clinical presentation and histologic findings in 3 IBLR cases associated with MCL were found to be similar to 3 IBLR cases associated with CLL. The eruptions consisted of itchy erythematous papules, nodules, plaques, and vesicles. Non-vesicular lesions were characterized histologically by normal or mildly spongiotic epidermis. Vesicular lesions were characterized by marked spongiosis and intraepidermal spongiotic vesicles containing eosinophils, or marked subepidermal edema occasionally leading to a dermoepidermal separation. Most of the lesions were characterized by superficial and mid dermal to deep perivascular and interstitial, and occasionally periadnexal, inflammatory-cell infiltrate consisting of mononuclear cells and eosinophils. The densities of the infiltrates varied and the inflammatory-cell infiltrate extended often into the fat lobules. Neutrophils and nuclear dust were found more frequently and abundantly in the IBLR lesions associated with MCL. Immunophenotyping, direct immunofluorescence (DIF) tests, and IgH gene rearrangement studies were performed in the lesions associated with MCL only. The majority of the infiltrating lymphocytes were CD3+, CD5+ and CD43+, more CD4+ than CD8+, and only a small minority was CD20+. The cells did not stain for bcl-1 protein and CD30, and with no evidence of clonality. The DIF test result was negative. The IBLR eruption associated with MCL resembles clinically and histologically IBLR associated with CLL. The eruption seems to be reactive rather than neoplastic, because there is no evidence of MCL involvement in the skin lesions.

Resolution of orofacial granulomatosis with amalgam removal.

A 61-year-old woman presented with a 2-year history of an abnormal erythematous swelling on the upper lip and cheek. Upon examination there were no other physical findings. Histological examination found discreet sarcoidal granulomas in the lower dermis. Routine laboratory studies, chest radiographs and pulmonary functions were all normal. Clinical presentation and histological findings were, therefore, compatible with the diagnosis of orofacial granulomatosis (OFG). The patient was patch tested with an extended standard series that included metal-salt, dental prosthesis, bakery and corticosteroids series. The patch test was positive (score ++) after 48 and 72 h for mercury in the metal-salt and dental prosthesis series. During the past decade the patient had received amalgam fillings of several dental cavities, including one adjacent to the swollen cheek. The unilateral localization of the soft tissue swelling adjacent to the amalgam tooth fillings, along with the positive patch test for mercury, raised the possibility that the OFG was part of a delayed hypersensitive reaction to the fillings. The patient therefore underwent a total amalgam replacement procedure; complete disappearance of the swelling overlying the right cheek was observed within 7 weeks and the swelling of the upper lip subsided completely within 6 months. We propose that mercury in amalgam tooth fillings is another cause of OFG and suggest appropriate patch testing in patients who do not have an apparent cause of OFG.

Epidemiological study of classic Kaposi's sarcoma: a retrospective review of 125 cases from Northern Israel.

BACKGROUND: The morphology of Kaposi's sarcoma is clinically and histologically the same in all clinical forms of the disease. However, there is a difference in the clinical and biological behaviour of the different forms of the disease. The behaviour also differs among individuals with the same form. The factors involved in the initiation and prognosis of the disease are still unknown. The classical form is more common in middle-aged Jews of East European or Mediterranean origin, people of Italian and southern Greek origin. Classic Kaposi's Sarcoma is seen relatively more frequently in Israel than in many other countries. OBJECTIVE: The aim of this study was to examine risk factors that influence the development and course of the disease. METHODS: This retrospective study includes 125 patients with Kaposi's sarcoma, all diagnosed and followed in the Department of Dermatology at Rambam Medical Center in Haifa. RESULTS: The group included 85 (68%) men and 40 (32%) women. Fourteen subjects received corticosteroid therapy and three were kidney transplant recipients. Age at onset of the disease was 21-87 years, with a mean age of 67. A total of 121 patients (96.8%) were Jews and four (3.2%) were non-Jews. A majority (61.6%) were of East European origin. The number of new cases each year was constant in relation to the general population, except for two peaks, one in 1970 and another in 1986-89. The lower limbs were involved in most patients. Extracutaneous involvement was present in 18.4%. Of all the subjects, 28 (22.4%) had diabetes mellitus and 21 (16.8%) had a second primary malignancy. The malignancies were of lymphoreticular origin in 10 patients, four in the urinary bladder, three had carcinoma of the large bowel and one of the pancreas. CONCLUSION: Our study shows similar clinical findings to those described in other series. The relatively high frequency of carcinomas of the colon and urinary bladder was not reported elsewhere. We observed a consistent rate of new cases each year with two peaks in 1970 and 1986-1989, the cause of which deserves explanation. Of interest is the relative rise in the number of females with Kaposi's sarcoma. A relative high risk for developing Kaposi's sarcoma has been found among Jews of Ashkenazi origin compared to those of other ethnic groups. Israeli-born subjects presented a relatively more aggressive course of disease than others.

Effects of all-trans retinoic acid and sodium lauryl sulphate on the permeability of human skin in vitro.

Recent in vivo investigations have shown that pretreatment with topical all-trans retinoic acid (RA) may diminish the skin response to sodium lauryl sulphate (SLS). This study evaluated the permeation of SLS through human skin after pretreatment with RA, and vice versa, by in vitro methods. The permeability coefficient of SLS (3.24 +/- 0.21 x 10(3) cm/h) and the 24-h cumulative amount of SLS (3.41 +/- 0.6% of dose applied) permeating RA-pretreated skin did not differ significantly from those across untreated skin (control) (P > 0.05). In contrast, the permeability coefficient of RA (0.23 +/- 0.05 x 10(3) cm/h) and its 24-h cumulative amount (0.37 +/- 0.05% of dose applied) penetrating SLS-pretreated skin were significantly greater than those permeating untreated skin (P < 0.05). Thus, an increase in RA penetration was induced by SLS pretreatment; however, pretreating the skin with RA did not inhibit the percutaneous permeation of SLS. Based on previous in vivo findings where RA reduced skin reactions to SLS, one would speculate that RA pretreatment may decrease SLS penetration. However, these penetration data do not necessarily uphold this presumption. Perhaps, other interactions between the substances and the skin, e.g. at cellular levels, may be responsible for the differing skin responses.

Differential irritant skin responses to topical retinoic acid and sodium lauryl sulphate: alone and in crossover design.

Topically applied all-trans retinoic acid (RA) is often associated with skin irritation. A detailed quantification of RA-induced functional changes in stratum corneum is, however, still limited. Using non-invasive bioengineering techniques of measurements of transepidermal water loss (TEWL), stratum corneum hydration and cutaneous blood flow (CBF), we quantified the irritant effects of 0.05% and 0.1% RA in ethanol on normal skin compared with 1% sodium lauryl sulphate (SLS) in water as a model irritant in a 24-h occlusive patch-test assay. Additionally, in order to document data possibly related to the mechanism of action, skin responses to both compounds applied in tandem was also investigated over 18 days. The extent of the irritant response to 0.05 and 0.1% RA, respectively, were similar, implying analogous irritation potency. While RA caused more intense scaling than SLS, other skin responses to RA were significantly weaker than those due to SLS. An increase in TEWL, on day 7, in RA-exposed sites indicates a secondary delayed impairment of the stratum corneum (SC) barrier. In a tandem-design assay, pretreatment with RA appeared to reduce the irritant effects of SLS on SC hydration and CBF. In contrast, pre-exposure to SLS showed a synergestic response in erythema, scaling and TEWL. Our results demonstrate that RA, like SLS, is capable of impairing SC water barrier function, which may be responsible, in part, for the irritation associated with its topical use. However, the distinctive biological responses to these compounds suggest a different mode of action of RA and SLS. In addition, the precise reason for the unique results observed in the tandem-design assays is not clear.

No significant association between HLA antigens and classic Kaposi sarcoma: molecular analysis of 49 Jewish patients.

Because of the abundance of the classical form of Kaposi sarcoma (CKS) among Jews and people of Mediterranean origin, studies have been conducted to find an association between CKS and HLA antigens. No conclusive results have been drawn, although in a number of these investigations an increased incidence of HLA-DR5 was reported. In our study 49 CKS patients of Jewish origin were serologically analyzed for HLA class I and class II antigens. We found no significant deviation in serologically defined HLA antigens frequencies between patients and 99 ethnically matched controls. However, a nonsignificant decrease in the frequencies of HLA-DR4, HLA-DR12, and the combination of DR4/DR11 was observed. Then we determined in these patients HLA-DRB1, HLA-DQA1, and DQB1 allelic polymorphism by oligotyping on PCR-amplified DNA. In this molecular analysis the only notable finding was a decreased frequency of the combination HLA-DQA1*0301/DQB1*0301, which appeared in one (2%) patient compared to 13 (13%) of the controls. However, the decrease was not statistically significant. On the basis of both serological and molecular analysis done on a relatively large group of CKS patients, we conclude that there is no significant linkage between HLA antigens and CKS in Jewish population.

Classic and iatrogenic Kaposi's sarcoma. Histopathological patterns as related to clinical course.

The histological findings in the first diagnostic biopsy of 50 patients with Kaposi's sarcoma (KS) were classified and were related to the clinical course. Forty-one patients had the "classic KS," of whom 31 had a benign course and 10 an aggressive disease. Nine patients had iatrogenically induced KS. Histologically the following subtypes were found: mixed type in 18 patients, spindle type in 16, early type in 14, and hemangiomatous and lymphangiomatous types in one each. We did not find any statistical relationship between the histological subtypes, degree of nuclear atypia, number of mitoses, and density of the inflammatory cell infiltrates in the KS lesions, and the clinical types and course of the disease. The results of this study do not support the possibility of a prognostic importance regarding the histological features of the early lesions in patients with classic or iatrogenic Kaposi's sarcoma.

Classic Kaposi's sarcoma: T-lymphocyte subsets, T4/T8 ratio, and NK cell activity.

Lymphocyte function as expressed by T-lymphocyte subsets and natural killer cell activity was evaluated in a group of Israeli patients with classic Kaposi's sarcoma. T-cell subsets were examined in 28 patients, 14 with lesions limited to the lower extremities and 14 with diffuse cutaneous or systemic involvement. CD4 and CD8 lymphocytes and CD4/CD8 ratio were in the normal range in all patients, and mean values of the entire group were similar to a control group. However, CD8 was in the upper limits of the normal range in some patients with diffuse cutaneous or systemic involvement. This factor led to a significantly decreased CD4/CD8 ratio in that group as compared with the group of patients with the disease limited to the lower extremities. Mean values of natural killer cell activity in three effector/target cell ratios were significantly decreased in 13 of the patients with Kaposi's sarcoma with lesions limited to the lower extremities and in all of the patients with normal T-cell subsets and CD4/CD8 ratios.

Kaposi's sarcoma: retrospective study of 67 cases with the classical form.

The records of 67 Israeli patients with classical Kaposi's sarcoma treated at Rambam Medical Center were analyzed retrospectively for clinical and laboratory data. As expected, all except 1 patient were of Jewish origin. There was a male predominance with a ratio of 2.2:1. The age of onset was mostly during the 5th to 7th decades of life. The course of the disease was usually slow and indolent. As has been already noted, we found a higher frequency of diabetes mellitus (16.4%). Although a high frequency of second primary malignancy was seen in our patients, this was less so than that described in an American series, 15% as compared to 37%, respectively. The most frequent second malignancy was that of the lymphoreticular system. No serologic evidence for an association with types of herpes virus infection has been found. No alterations in humoral and cellular immunity were demonstrated. These data show similar clinical findings with those described in other series, besides the lower frequency of a second primary malignancy. Some discordance with that described before concerning the relationship with cytomegalovirus infection and T cells subsets was also noted.

Decreased natural killer cell function in patients with classical Kaposi's sarcoma.

Natural killer (NK) cell activity of peripheral blood lymphocytes was evaluated in a group of 13 patients with classical Kaposi's sarcoma (KS). All patients had a normal T4/T8 ratio, and the disease was confined to the skin of the lower extremities. A group of 5 healthy subjects served as controls. NK cell function was significantly decreased in patients as compared to controls. Our result is similar to that found in another group of patients with AIDS-related KS with lymphadenopathy and an abnormal T4/T8 ratio. This suggests that decreased NK cell function is not a result of a progressive process and might be directly involved in the development of KS.

Elastic tissue changes in generalized granuloma annulare.

The histological picture in granuloma annulare (GA) is well defined. The types of infiltrate and the changes in collagen and elastic tissue have been repeatedly described. This is a preliminary study focused on the elastic tissue changes in lesions of generalized GA. Biopsies from four patients were studied. Specimens of involved and uninvolved skin from both exposed and unexposed parts of the body were compared. Changes of actinic elastosis in the papillary dermis in each patient in different stages were observed only in the exposed skin. The typical GA infiltrate was located beneath, in the upper mid-dermis. In the zone of the infiltrate in all specimens--exposed and unexposed--with no regard to the severity of actinic elastotic changes, absence or a marked reduction of elastic material was noted with engulfment of elastic remnants in giant cells. Giant cells with phagocytosis of elastotic material were mostly located on the periphery of the granuloma in the upper as well as in the deeper portion, where elastic fibers were still present. This might support the suggestion that degenerating elastic fibers promote the granulomatous reaction that leads to the formation of granuloma annulare.

A comparative histopathologic study of generalized and localized granuloma annulare.

We have reviewed the morphologic findings in 41 histologic slides of granuloma annulare (GA), 15 from localized (LGA) and 26 from generalized granuloma annulare (GGA). The most common pattern was the histiocytic infiltrative type, more so in cases with LGA than with GGA. The palisading granuloma pattern was present in 21.9% of patients and its prevalence was almost equal in both clinical types. The least prevalent histologic type in all patients taken together was the epithelioid nodule type. However, the prevalence of this type in LGA was equal to that of the palisading type, in contrast to that in GGA where it accounted for only 11.5%. In addition, a mixed histologic pattern was found in greater than 25% of sections from GGA and in only one section from LGA. Periodic acid-Schiff stain revealed hyalinized capillary basement membrane in most of GGA and only in approximately 50% of LGA sections. The variation in prevalence of the different histologic patterns between sections from LGA and GGA, and the difference between our findings and those observed in other series, are discussed.

[Pemphigus herpetiformis following D-penicillamine in a patient with HLA B8]. / Pemphigus herpetiformis nach D-Penicillamin bei einem Patienten mit HLA B8.

A 57-year-old patient with rheumatoid arthritis, who was being treated with D-penicillamine, developed a bullous eruption 2 months after the onset of treatment. On the basis of the clinical, histological and immunofluorescent findings, the diagnosis of herpetiform pemphigus was made. The eruptions disappeared within 2 weeks after the discontinuation of D-penicillamine treatment. During the 16-month follow-up period there was no recurrence. It is noteworthy that a patch test with potassium iodide was positive and that testing for HLA antigens revealed HLA B8, A1, A2, and BW39.

Immunologic studies in Darier's disease.

Humoral and cellular immunity were evaluated in 10 patients with Darier's disease. The mean levels of serum immunoglobulins, serum complement, peripheral macrophages, and peripheral B and T lymphocytes were within normal limits. Secretory IgA was present in all patients studied. Skin tests for delayed hypersensitivity revealed complete anergy in one of the eight patients tested. Lymphocyte transformation tests revealed statistically significant enhanced responsiveness to both PHA and ConA mitogens in several concentrations studied. These findings may suggest either the existence of alterations in immunoregulation of lymphocyte subpopulations in Darier's disease or may be limited to alterations in membrane functions of certain lymphocyte subpopulations which can be detected only in vitro. The role that such immunologic aberrations may play in the pathogenesis of Darier's disease is still obscure.

Generalized hair follicle hamartoma: the third case report in association with myasthenia gravis.

A 29-year-old woman, referred because of the development of diffuse papules and plaques on the face and progressive hair loss, was found to have generalized hair follicle hamartoma, a very rare condition previously described in only two female patients. All three patients also suffered from myasthenia gravis. The histological appearance of both the involved and uninvolved skin was similar to trichoepithelioma.

Bowel bypass arthritis dermatitis syndrome: a histological and electron microscopical study.

A case of dermal vasculitis with arthralgia after intestinal bypass surgery is reported. A 36-year-old woman developed arthralgia and skin rash, 1 year after an ileo-jejunal bypass operation was performed for overweight (130 kg). Skin biopsy showed leucocytoclastic vasculitis in the dermis. E.M. study showed clumps of platelets around small dermis blood vessels, and polymorphous perivascular infiltration. The symptoms subsided after tetracycline treatment.