Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions.

BACKGROUND: Risk indicators of indolent systemic mastocytosis (ISM) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa (UP)] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid (MIMA) and methylhistamine (MH) to select patients for bone marrow investigations to diagnose ISM. METHODS: Retrospective data analysis of all adults, in whom bone marrow investigations were performed to diagnose ISM, was carried out. RESULTS: In total, 142 patients were included. SM was absent in all 44 patients with tryptase <10 µg/l, in 45 of 98 (46%) patients with tryptase ≥10 µg/l and in 18 of 52 patients (35%) with tryptase >20 µg/l. Above 43 µg/l, all patients had ISM (n = 11). Male gender, insect venom anaphylaxis as presenting symptom, tryptase, MIMA, and MH were independent ISM predictors. If tryptase was ≥10 µg/l, the diagnostic accuracy of MIMA and MH was high (areas under the ROC curve 0.92). CONCLUSIONS: In suspected patients without UP, the ISM risk is very low (if present at all) if tryptase is <10 µg/l. If tryptase is ≥10 µg/l, this risk depends on MIMA and MH, being low if these are normal, but high if these are elevated. Male gender and insect venom anaphylaxis are additional risk indicators. We recommend refraining from bone marrow examinations in suspected patients without UP if tryptase is <10 µg/l. Our results question the reliability of the minor diagnostic World Health Organization criterion of tryptase >20 µg/l.

Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients.

PURPOSE: Although patients with primary cutaneous B-cell lymphoma (CBCL) and localized skin lesions are generally treated with radiotherapy and have an excellent prognosis, the clinical behavior and optimal treatment of CBCL presenting with multifocal skin lesions are less well defined. In this study, we evaluated the clinical behavior of and results of treatment for multifocal CBCL in 29 patients, and we formulated therapeutic guidelines. PATIENTS AND METHODS: The study group included 16 patients with primary cutaneous follicular center-cell lymphoma (PCFCCL), eight with primary cutaneous immunocytoma (PCI), and five with primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL of the leg). RESULTS: Only one of the 24 patients with multifocal PCFCCL or PCI developed extracutaneous disease, and no patient died from lymphoma (median follow-up, 54 months). In patients with PCFCCL, treatment with either multiagent chemotherapy (nine patients) or radiotherapy directed toward all skin lesions (five patients) proved equally effective in terms of complete remission, relapse, and survival. In contrast, all five patients with PCLBCL of the leg developed extracutaneous disease, and four of the five died from systemic lymphoma, 8 to 36 months (median, 21 months) after diagnosis. CONCLUSION: The results of these preliminary studies suggest that patients with PCFCCL or PCI presenting with multifocal skin lesions have the same excellent prognosis that patients with localized PCFCCL or PCI have and that radiotherapy directed toward all skin lesions is as effective as multiagent chemotherapy. Patients with PCLBCL of the leg have a more unfavorable prognosis, particularly patients presenting with multifocal skin lesions. This last group should always be treated with multiagent chemotherapy.

Primary cutaneous marginal zone B-cell lymphoma: clinical and therapeutic features in 50 cases.

BACKGROUND: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) is a low-grade B-cell lymphoma that originates in the skin, with no evidence of extracutaneous disease. Studies focusing on the optimal treatment of PCMZL have not been published thus far. We describe 50 patients with PCMZL to further characterize clinical characteristics and outcome and, in particular, to evaluate our current therapeutic approach. OBSERVATIONS: The majority of the patients (36/50 [72%]) presented with multifocal skin lesions, and 14 patients (28%) presented with solitary or localized lesions. The initial treatment of patients with solitary lesions consisted of radiotherapy or excision, whereas patients with multifocal lesions received a variety of initial treatments, most commonly radiotherapy and chlorambucil therapy. Cutaneous relapses developed in 19 (48%) of 40 patients who had complete remission and were more common in patients with multifocal disease. After a median period of follow-up of 36 months, 2 patients developed extracutaneous disease, but none of the patients died of lymphoma. CONCLUSIONS: Patients with PCMZL who have solitary lesions can be treated effectively with radiotherapy or excision. For patients with PCMZL who have multifocal lesions, chlorambucil therapy and radiotherapy are suitable therapeutic options. In case of cutaneous relapses, the beneficial effects of treatment should carefully be weighed against the potential adverse effects.

[Corticosteroids and the risk of glaucoma]. / Corticosteroïden en het risico van glaucoom.

Corticosteroids are used to treat many diseases and are prescribed by both specialists and general practitioners. One serious side effect of steroid use is glaucoma. This complication, which can cause blindness, is often only discovered at the end stage. Three patients, two women aged 20 and 32 and a man aged 28 developed glaucoma as a result of topical steroid use. It is advisable to examine patients annually if they have a family history of glaucoma and are using steroids regularly in or around the eye. Follow-up should also be considered for patients with a family history of glaucoma who are using systemic steroids regularly, and for all other patients using steroids regularly in or around the eye. All patients on steroids should consult their ophthalmologist speedily if visual symptoms occur.

Defined in situ enumeration of T6 and HLA-DR expressing epidermal Langerhans cells: morphologic and methodologic aspects.

An essential prerequisite for the in situ enumeration of epidermal Langerhans cells (LCs) is the unequivocal identification of the desired cell type. We have examined over 250 cryostat sections of normal human skin to analyze morphologic and methodologic problems underlying the quantification of epidermal LCs, defined by anti-T6 (OKT6) and anti-HLA-DR (OKIal) immunoperoxidase staining. Our findings show that OKT6 reactivity of dendritic processes in cross-sectioned epidermis yields microscopic images which are not easy to analyze objectively. The morphology that we find leads us to categorize dendritic cells into 3 arbitrary types of T6+ LC profiles. In addition we describe criteria for the assessment of OKT6 staining patterns relating to the dendritic state of epidermal LCs. Preliminary quantitative data on this issue are discussed in relation to: epidermal thickness; the thickness of skin tissue sections; and the discrepancy between the number of T6+ and HLA-DR+ LCs. We hope that the principles outlined in this report may serve to overcome potential methodologic problems with quantitation of T6+ epidermal LCs in skin sections.

Homozygous R788W point mutation in the XPF gene of a patient with xeroderma pigmentosum and late-onset neurologic disease.

The second Caucasian xeroderma pigmentosum patient (XP42RO) belonging to complementation group F (XP-F) is described. Mild ocular photophobia was present from childhood, and acute skin reactions occurred upon exposure to sunlight. Basal and squamous cell carcinomas developed after his twenty-seventh year. In his late forties progressive neurologic symptoms emerged, which included intellectual decline, mild chorea and ataxia, and marked cerebral and cerebellar atrophy. Such neurologic abnormalities are very unusual in XP-F. Similar symptoms have been described in only one of 17 other XP-F individuals. His approximately 5-fold reduced activity of nucleotide excision repair in cultured cells, combined with moderately affected cell survival and DNA replication after UV exposure, are typical of XP-F. The recent cloning of the XPF gene allowed a molecular genetic analysis of this unusual patient. XP42RO, representing the second case studied in this respect, turned out to be homozygous for a point mutation in the XPF gene, causing an R788-->W substitution in the encoded protein. Surprisingly, this mutation had also been found in one allele of the other unrelated Caucasian XP-F case. The amount of mutated XPF protein is strongly reduced in cells from XP42RO, presumably due to a conformational change. Biochemical, genetic, and clinical data all indicate the presence of considerable residual repair activity, strongly suggesting that the R788W mutation is leaky.

RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia.

In several families, multiple endocrine neoplasia type 2A (MEN 2A) has been found in association with cutaneous lichen amyloidosis. It has been debated, however, whether the skin amyloidosis found in MEN 2A families, localized exclusively in the interscapular area, represents the same anomaly as that found in autosomal dominant familial cutaneous lichen amyloidosis, which is more generalized. We screened two MEN 2A families with associated skin amyloidosis for germline mutations in the RET gene responsible for the MEN 2A cancer syndrome, and found the same mutation characteristic of MEN 2A in both families. We also screened probands from three pedigrees with familial cutaneous lichen amyloidosis for RET mutations. In none of the RET coding and flanking intronic sequences was a mutation detected. This most probably indicates that skin amyloidosis found in some MEN 2A families and familial cutaneous lichen amyloidosis are different conditions. Consequently, patients with apparent familial cutaneous lichen amyloidosis do not appear to be at risk for MEN 2A.

Herpes zoster-varicella in cutaneous T-cell lymphomas.

The overall frequency of herpes zoster-varicella (HZV) infection in 221 patients with histologically confirmed cutaneous T-cell lymphoma was 10% (22 patients). The frequency of HZV infection and serious complications (viral dissemination, bacteremia) was relatively high in patients with evidence of extracutaneous involvement, especially in patients with Sézary syndrome. The major factors identified to account for this predisposition to HZV infection include intensive treatment with radiation therapy or drugs given for systemic effect and/or immunologic deficiency consequent to advanced disease. These observations are quite similar to those made in patients with Hodgkin's disease.

Primary cutaneous large B-cell lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an intermediate prognosis. Dutch Cutaneous Lymphoma Working Group.

BACKGROUND AND DESIGN: Primary cutaneous follicular center cell lymphomas represent a distinct type of cutaneous B-cell lymphoma, clinically characterized by localized skin lesions on the head or trunk and an excellent prognosis. Histologically similar lymphomas may occur on the legs. The clinical behavior of this group is still undefined, and controversy exists whether these lymphomas should be classified as follicular center cell lymphoma or B-immunoblastic lymphoma. We reviewed the clinical, histologic, and follow-up data of 18 patients with primary cutaneous large B-cell lymphoma of the legs. RESULTS: Primary cutaneous large B-cell lymphoma of the legs generally occurred in elderly patients (median age at diagnosis, 76 years), in particular women (male-female ratio, 7:2), and preferentially affected the lower legs (14 of 18 patients). Radiotherapy and/or systemic polychemotherapy resulted in complete remissions in 16 of 17 patients. Follow-up data demonstrated estimated 2- and 5-year survival rates of 77% and 58%, respectively. Histologic evaluation showed diffuse dermal infiltrates with variable proportions of centroblasts (large noncleaved cells), large centrocytes (large cleaved cells), and B immunoblasts. Seventeen of 18 patients were diagnosed as having primary cutaneous follicular center cell lymphoma; only 1 patient, whose histologic examination showed more than 30% immunoblasts, was diagnosed as having B-immunoblastic lymphoma. CONCLUSIONS: Primary cutaneous large B-cell lymphoma of the legs is a distinct clinicopathologic entity that mainly affects elderly patients and has an intermediate prognosis. Although most cases have a follicular center cell origin, primary cutaneous large B-cell lymphoma is proposed as the most appropriate term for this type of cutaneous lymphoma.

Mycosis fungoides: disease evolution and prognosis of 309 Dutch patients.

OBJECTIVES: To determine the disease course of Dutch patients with mycosis fungoides and to define factors related to disease progression and survival. DESIGN: A multicenter, 13-year, retrospective cohort analysis. SETTING: Eight dermatology departments collaborating in the Dutch Cutaneous Lymphoma Group. PATIENTS: Three hundred nine patients with mycosis fungoides registered between October 1985 and May 1997, including 89 patients with limited patches or plaques (stage Ia), 135 with generalized patches or plaques (stage Ib), 46 with skin tumors (stage Ic), 18 with enlarged but uninvolved lymph nodes (stage II), 18 with lymph node involvement (stage III), and 3 with visceral involvement (stage IV). MAIN OUTCOME MEASURES: Response to initial treatment, sustained complete remission, actuarial disease progression, and overall and disease-specific survival per clinical stage. RESULTS: The median follow-up was 62 months (range, 1-113 months). For the entire group, the actuarial overall and disease-specific survival was 80% and 89% at 5 years, and 57% and 75% at 10 years, respectively. The actuarial 5-year disease-specific survival of patients with stage Ia, Ib, and Ic disease was 100%, 96%, and 80%, respectively, and only 40% for patients with stage III disease. Using multivariate analysis, the presence of extracutaneous disease, the type and extent of skin involvement, the response to initial treatment, and the presence of follicular mucinosis were independently associated with higher disease progression and mortality rates. The calculated risks of disease progression at 5 and 10 years gradually increased from 4% to 10% for those with stage Ia disease, from 21% to 39% for those with stage Ib disease, and from 32% to 60% for those with stage Ic disease; for those with stage III disease, the risk remained at 70% at 5 and 10 years. The overall risk of disease progression at 5 and 10 years was 24% and 38%, respectively, for the total study group. CONCLUSION: At least within the first 10 years after diagnosis, disease progression and mycosis fungoides-related mortality occur in only a subset of patients generally presenting with advanced disease.

Epidermodysplasia verruciformis: Langerhans cells, immunologic effect of retinoid treatment and cytogenetics.

A case study is presented of a 44-year-old negroid male with epidermodysplasia verruciformis (EV), cutaneous carcinomas, and impaired cell-mediated immunity (CMI), infected with human papillomavirus type 8 and 17. Analysis was made of (a) T6+ and HLA-DR+ Langerhans cells (LCs) by immunoperoxidase staining in lesional and clinically normal skin before and during retinoid treatment, (b) the effect of retinoid treatment on CMI in vivo and in vitro, and (c) cytogenetic aspects related to chromosomal instability. The results showed the virtual absence of T6+ and HLA-DR+ LCs in koilocytic areas of epidermis involved with EV. Light-exposed, clinically normal skin also demonstrated microscopic EV lesions largely devoid of T6+ and HLA-DR+ LCs. Retinoid treatment with etretinate (Ro 10-9359) appeared both to increase the CMI response in vitro to T-cell mitogens and to influence the in situ pattern of T6+ and HLA-DR+ LCs. The cytogenetic study did not show evidence of spontaneous or UV-induced chromosomal instability.

Syphilis management and treatment.

Syphilis poses a serious health problem in many developing countries and in some areas of North America and Europe, especially Eastern Europe. This article initially addresses the state of the art regarding the interaction between syphilis and HIV infection and its consequences for management and treatment. Further attention is given to laboratory diagnosis of syphilis and false-positive and false-negative serologic reactions. The diagnosis and management of neurosyphilis, ocular, cardiovascular, and congenital syphilis are addressed, as well as management of syphilis patients allergic to penicillin and the Jarisch-Herxheimer reaction. Finally, the role of partner(s) and contact tracing is discussed.

[Canine scabies in man]. / Hondenscabies bij mensen.

Parasitic prurigo caused by scabies mites from recently acquired puppies is described in two patients and their family members. Because Sarcoptes scabiei var. canis (dog) occasionally survives in man, patients with persisting complaints despite treatment of their dogs should be treated with the topical scabicide lindane for one night.

[Dysplastic nevi and the risk of melanoma: a guideline for patient care. Nederlandse Melanoom Werkgroep van de Vereniging voor Integrale Kankercentra]. / Dysplastische naevi en het risico op melanoom: een richtlijn voor patiëntenzorg. Nederlandse Melanoom Werkgroep van de Vereniging voor Integrale Kankercentra.

Consensus was recently reached in the Netherlands regarding the clinical management of dysplastic naevi and the definitions in clinical and pathological diagnostics. The term 'dysplastic' is reserved for histological diagnostics; the term preferred for clinical use is 'clinically atypical naevus'. A naevus is defined as clinically atypical if it meets three of the following five criteria: > or = 5 mm in diameter, vaguely bordered, asymmetrically shaped, irregularly pigmented and a red hue (erythema). Presence of clinically atypical naevi is a main risk factor for melanoma. Dysplastic naevus syndrome (DNS) is present if a patient has a melanoma and one or several clinically atypical naevi. The diagnosis of 'familial DNS' (familial atypical multiple mole-melanoma syndrome, abbreviation FAMMM syndrome) is made if at least two close relatives (including the patient) are known with a melanoma with or without atypical naevi, while one or several (other) relatives have atypical naevi. The risk of melanoma in a gene carrier of familial DNS is close to 100%, while multiple melanomas develop in 30% of the gene carriers. No DNA diagnostics is yet possible in most DNS/FAMMM families, because of the involvement of genes yet unknown. Accordingly, at present it is still too early for DNA diagnostics. Currently, therefore, the diagnosis is based only on anamnestic, clinical and histological grounds.

[Chlamydia trachomatis diagnosis in women: the value of serological studies and of culture of cervical and urethral swabs]. / Chlamydia trachomatis-diagnostiek bij de vrouw: de waarde van serologisch onderzoek en van kweek van materiaal uit cervix en urethra.

We studied the value of the determination of the serum IgM antibody level for the diagnosis of genital Chlamydia trachomatis infection in women and the value of the urethra in addition to the cervix as a sampling site for the diagnosis of C. trachomatis infection by culture and direct immune-fluorescence (IF) test. Of 205 women, mean age 26 years (range 14-56), who visited the Sexually Transmitted Disease clinic of the University Hospital Groningen from July 1985 until November 1987, single serum samples were obtained for the determination of IgM and IgG anti-C. trachomatis antibodies using FITC conjugates, in addition to swabs of cervix and urethra for culture and direct IF test. In women with a negative culture and positive IgM serology the culture was repeated. The culture was used as golden standard. In 17/205 (36%) women positive C. trachomatis IgM serology (greater than or equal to 1:32) and in 190/205 (93%) positive IgG serology (greater than or equal to 1:40) was found. In 67/205 (33%) women the C. trachomatis culture of cervix and (or) urethra was positive. The positive and negative predictive values of C. trachomatis IgM serology were 41% and 72%. In 3/20 women with negative culture results and positive IgM serology a second culture was positive. In 176 women, of whom samples from both cervix and urethra were available, the only C. trachomatis positive site by culture was the urethra in 7/54 (13%) and by direct IF in 3/42 (7%). The increase in the prevalence obtained by collecting material not only from the cervix but also from the urethra was 4% by culture and 2% by direct IF.2+n

[Chlamydia trachomatis infection in women and the use of oral contraceptives]. / Chlamydia trachomatis-infectie bij de vrouw en het gebruik van orale anticonceptiva.

We determined the prevalence of genital Chlamydia trachomatis infection in women who visited a clinic for sexually transmitted diseases (STD) and the influence of the number of partners and the use of oral contraceptives (OC), with special attention to the recognition of pelvic inflammatory disease (PID) and to the results of therapy. Of 217 women, with a mean age of 26 years (range 14-56), who visited the STD clinic of the University Hospital of Groningen from July 1985 until November 1987, anamnestic data were collected as well as the results of swabs from cervix and urethra taken for culture and direct immunofluorescence test of C. trachomatis and for gonococcal culture. The influence of the number of partners (1 versus greater than 1) and OC on the prevalence of C. trachomatis infection was evaluated by logistic regression analysis. PID was excluded in coöperation with the department of gynaecology. C. trachomatis-infected women were treated by doxycycline orally (day 1 2 x 100 mg, day 2-7 1 x 100 mg) according to the dosage scheme advised by the Dutch Health Council in 1986. A control culture was taken 2-3 weeks after treatment. C. trachomatis was detected in 72/217 (33%) women by culture and (or) direct IF test and in 22/41 (54%) women with gonorrhoea. In connection with the number of partners in the year preceding the examination, the following prevalences were found: 18/74 (24%) (1 partner), 43/108 (40%) (2-5 partners) and 10/27 (greater than 5 partners).(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: The authors determined the prevalence of genital Chlamydia trachomatis infection in women who visited a clinic for sexually transmitted diseases (STDS) and the influences of the number of partners and of the use of oral contraceptives (OCs), with special attention paid to the recognition of pelvic inflammatory disease (PID) and to the results of therapy. Of 217 women with a mean age of 26 years (range 14-56), who visited the STD clinic of the University Hospital of Groningen from July 1985-November 1987, anamnestic data were collected as well as the results from swabs of the cervix and urethra taken for culture and direct immunofluorescence (IF) test of C. trachomatis and for gonococcal culture. The influence of the number of partners (1 vs 1) and OCs on the prevalence of C. trachomatis infection was evaluated by logistic regression analysis. PID was excluded in cooperation with the department of gynecology. C. trachomatis-infected women were treated by doxycycline orally (day 1, 2x 100 mg, days 2-7, 1x 100 mg) according to the dosage scheme advised by the Dutch Health Council in 1986. A control culture was taken 2-3 weeks after treatment. C. trachomatis was detected in 72/217 (33%) of the women by culture and/or direct IF test and in 22/41 (54%) women with gonorrhea. In connection with the number of partners in the year preceding the examination, the following prevalences were found: 18/74 (24%, 1 partner), 43/108 (40%, 2-5 partners), and 10/27 (5 partners). The prevalence among OC-using women was significantly higher (p0.05) than in non-OC using women: 44.101 (44%) vs 21/93 (23%). This was also true when OC users were compared to sterilized women (9/47, 19%), regardless of number of partners and age. Active PID was found in 2 women, both infected. After treatment with positive C. trachomatis cultures, control cultures were negative in 39/40 (98%). A relatively high prevalence of genital C. trachomatis infection is found in women visiting STD clinics, as well as in women with only 1 partner during the year preceding the examination. This study supports the hypothesis of OC use being a risk factor. How OC use influences PID risk is not fully understood. Within the framework of reliable contraception and prevention of STD complications, the combination of OC + a barrier method should be advised to women without a steady partner. Further study is necessary to determine whether preventive antibiotic treatment of asymptomatic adolescents with anamnestic risk factors for C. trachomatis infection is indicated at the start of a new relationship. (author's modified)

[Standardized multidisciplinary diagnosis of cow's milk protein allergy in children. Work Group Cow's Milk Protein Allergy of the Groningen Academic Hospital]. / Gestandaardiseerde multidisciplinaire diagnostiek van koemelkeiwitallergie bij kinderen. Werkgroep Koemelkeiwitallergie van het Academisch Ziekenhuis Groningen.

OBJECTIVE: Evaluation of standardized multidisciplinary diagnostic procedures for cow's milk allergy (CMA) in children. DESIGN: Prospective standardized study. SETTING: Beatrix Children's Hospital, Department of Allergology, Dermatology and Dietetics, University Hospital Groningen, the Netherlands. METHODS: From August 1991 until May 1993, 114 children suspected of CMA for the first time were investigated according to the protocol for diagnosis of CMA, together with 23 children, previously diagnosed as CMA, in whom CMA was re-evaluated. Of 114 children with first suspicion of CMA, 66 improved on a cow's milk-free diet. The remaining 48 were excluded from the study because of no improvement on a cow's milk free diet, no diet given, insufficient data or no follow-up. The protocol was evaluated by questionnaire sent to 10 representatives of the departments involved. RESULTS: In 26/66 (39%) children, the diagnosis of CMA was confirmed by cow's milk challenge. The eosinophilic granulocytes were higher (p = 0.04), both IgE RAST and Skin Prick Test (SPT) for cow's milk were more often positive (both p = 0.01) in CMA than in non-CMA. The sensitivity and specificity were 50%-82% for IgE RAST and 60%-84% for the SPT, respectively. Four of the 23 children still had CMA at re-evaluation. In three of them, a SPT was performed, which was positive in all. In 12 of the 19 children, without CMA at re-evaluation, a SPT was performed, which was negative in all. At 1, 2, 3 and 4 years of age 13%, 48%, 74% and 78%, respectively, of the re-evaluation CMA patients had developed tolerance for cow's milk. The use of the protocol was found important by the representatives involved, although some practical difficulties remain. CONCLUSION: A multidisciplinary approach of CMA is possible. Improvement on a cow's milk-free diet by itself is not sufficient to diagnose CMA. Cow's milk challenge is obligatory. Laboratory investigations are of limited value. Re-evaluation of CMA after one year of age is necessary in view of the temporary character of CMA. When the SPT for cow's milk is positive, postponement of re-evaluation may be considered.

[Epithelioid sarcoma as cause of ulcus cruris]. / Epithelioïd sarcoom als oorzaak van ulcus cruris.

In two young men, 22 and 23 years old, with non-healing leg ulcers, epithelioid sarcoma was diagnosed. This malignancy may be mistaken for a benign process. Better awareness may result in earlier diagnosis and improved prognosis. Both patients developed lymphogenic metastases.