The diagnostic value of skin biopsies in Sneddon syndrome.

BACKGROUND: Sneddon syndrome (SS) is defined by widespread livedo reticularis (LR) and stroke. There is no single diagnostic test for SS and diagnosis can be solely based on clinical features. This cross-sectional case-control study aimed to determine the diagnostic value of skin biopsies in SS patients. MATERIALS AND METHODS: We studied skin biopsies from patients with a clinical diagnosis of SS or isolated LR. We also studied controls with vitiligo or normal skin. Biopsies were considered standardized if 3 biopsies were taken from the white centre of the livedo and reached until the dermis-subcutis border. Biopsies were scored for features of an occlusive microangiopathy without knowledge of the clinical features. Sensitivity and specificity of the biopsy findings were calculated with the clinical criteria as the reference standard. RESULTS: We included 34 SS patients, 14 isolated LR patients and 41 control patients. Biopsies of 17 patients with SS (50%), 4 with isolated LR (31%) and 10 control patients (24%) showed at least one artery in the deep dermis with a thickened vessel wall combined with recanalization or neovascularization (sensitivity 50% and specificity 69% with LR as reference). Standardized biopsies increased the sensitivity to 70%. In a post hoc analysis the combination of an occlusive microangiopathy and the presence of a livedo pattern in the superficial dermis increased the specificity to 92%. CONCLUSIONS: Standardized skin biopsies can support the clinical diagnosis of SS. An occlusive microangiopathy as the only positive criterion for the diagnosis of SS had insufficient specificity for a definite diagnosis.

Sneddon syndrome: a comprehensive clinical review of 53 patients.

BACKGROUND: The presence of livedo reticularis in patients with ischaemic stroke is associated with Sneddon syndrome (SS). Our objective was to present the clinical features of SS patients and to assess the role of antiphospholipid antibodies (APL). METHODS: Consecutive patients, diagnosed with SS between 1996 and 2017, were retrospectively reviewed for their demographic, neurological, dermatological, cardiac and extracerebral vascular features. Diagnosis of SS was made only if other causes of stroke were excluded. Patients with and without APL were included and compared for their clinical features. RESULTS: Fifty-three patients (79% female) were included, of whom 14 patients were APL-positive. Median age at diagnosis was 40 years. Approximately 60% of the patients had ≥ 3 cardiovascular risk factors. There were 129 previous vascular events (66 ischaemic strokes, 62 TIAs and 1 amaurosis fugax) during a median period of 2 years between the first event and diagnosis of SS. Skin biopsy was positive for SS in 29 patients (67%), mostly showing a thickened vessel wall with neovascularization in the deep dermis. After a median follow-up of 28 months, 4 patients, either on antiplatelet or oral anticoagulation therapy, had a recurrent stroke. There were few statistically significant differences between APL-negative and APL-positive patients, including the number of vascular events before diagnosis. CONCLUSIONS: SS predominantly affects young women with a relatively large number of cardiovascular risk factors. Clinical features of SS are comparable across different studies. We found no differences in the main clinical features between APL-positive and APL-negative patients.

Clinical versus histological grading in the assessment of cutaneous graft versus host disease.

BACKGROUND: Skin biopsies are often used in daily practice for the diagnosis of acute (aGvHD) or chronic graft versus host disease (cGvHD). With the latest understanding in pathogenesis and new National Institute of Health (NIH) classifications for aGvHD and cGvHD, there is a need to evaluate the current prognostic value of histological grading cutaneous GvHD and its correlation to the clinical grade. METHODS: In a retrospective study with 120 skin biopsies (all taken for suspected GvHD) from 110 patients (all classified according to the NIH), biopsies were revised and graded, blinded for clinical information, for either acute of chronic features. Morphological grades were compared for concordance with the clinical grade and survival analyses were done for clinical and histological grading. RESULTS: Correlation for histologic vs. clinical grading was (very) poor for aGvHD and cGvHD (weighted κ - 0.038 and 0.0009, respectively). Patients with clinical aGvHD had worse prognosis compared to cGvHD. However, at time of biopsy neither clinical nor histological grading predicted the eventual survival for either aGvHD (p = 0.9739 and p = 0.0744, respectively) or cGvHD (p = 0.2149 and p = 0.4465, respectively). CONCLUSIONS: Confirming the diagnosis of GvHD is still a valuable reason for taking a skin biopsy, but this study shows that histologic grading of GvHD in the skin biopsy has no additional value for clinicians in current practice.

[Career development of medical school graduates: comparison of medical students from Utrecht, Leiden and Groningen]. / De loopbaan van afgestudeerde artsen.

OBJECTIVE: To gain insight in the career development of Utrecht medical school graduates. DESIGN: Retrospective cohort study. METHOD: In November 2015, we investigated the achieved academic title, occupation and position for 281 graduates who had started their medical education at University Medical Centre Utrecht (UMCU) in the academic year 2003-2004. Information was gathered from the BIG-register for medical professionals, through social media and Google, and if necessary through private messaging. We compared our results to those from previous cohort studies on the career paths of medical graduates from University Medical Centre Groningen (UMCG) and Leiden University Medical Centre (LUMC), both dating back twenty years. RESULTS: On average five years after graduation, 52% of all 281 graduates was in residency, 11% was occupied as general practitioner and 7% was a medical specialist. Among residents, the most frequently chosen specialties were general practice (12%), internal medicine (10%), psychiatry and radiology (both 7%). This distribution of residents amongst these specialties was largely consistent with distributions found in the Groningen and Leiden cohorts. In our cohort, 21% of graduates had achieved a PhD and an additional 16% was a PhD student, whilst only 13% of the Groningen cohort had achieved a PhD. CONCLUSION: A relatively large number of UMCU medical school graduates become a medical specialist. The distribution of UMCU graduates amongst different medical specialty residencies is consistent with the distribution observed nationally. A notable rise in PhD graduates and students is noted in our cohort, when compared to the UMCG cohort analysed 20 years earlier.

Prognostic value of type D personality for 10-year mortality and subjective health status in patients treated with percutaneous coronary intervention.

OBJECTIVE: Given the debate around limitations and controversies in type D personality studies, we aimed to evaluate the prognostic value of 'synergistically' analyzed type D personality (interaction z-scores negative affectivity NA, and social inhibition SI) on 10-year mortality and on 10-year subjective health status in percutaneous coronary intervention (PCI) patients. METHODS: This prospective study comprised a cohort of 1190 consecutive patients who underwent PCI between October 2001 and September 2002 (73% male, mean age: 62years, range [27-90]years). At baseline, type D personality (DS14), and depression/anxiety (HADS) were assessed. Primary endpoint was 10year all-cause mortality; secondary endpoint was 10-year subjective health status (SF-36). RESULTS: After a median follow-up of 10.3years (IQR 9.8-10.8), 293 deaths of any cause (24.6%) were recorded. After adjustment for significant baseline characteristics, personality categories approached and dichotomously approached type D personality were associated with 10-year mortality, p<.05. Synergistically approached type D personality was not associated with all-cause mortality or subjective health status at 10years. In survivors, higher NA was associated with lower subjective health status. Type D was not associated with mortality after adjusting for continuous depression and anxiety in all approaches. CONCLUSIONS: Synergistically analyzed type D was not associated with 10-year all-cause mortality in PCI patients whereas dichotomous type D was. However, after adjustment for depression most of the findings had disappeared. Depression played an important role in this. Type D was not associated with 10-year subjective health status.

Incidence of primary malignant orbital tumours in the Netherlands.

AIMS: To describe the incidence and relative frequencies of primary malignant orbital tumours in the Netherlands from 1989 to 2006. METHODS: All registered primary malignant orbital tumours were extracted from the population-based database of the Netherlands Cancer Registry. Age-adjusted incidence of malignant orbital tumours per 10,000,000 persons per year and the estimated annual percentage change (EAPC) were computed. RESULTS: A total of 367 malignant orbital tumours were registered. The average age-adjusted incidence of malignant orbital tumours is 10.9. Lymphoma has a relative frequency of 67%, rhabdomyosarcoma 12%, adenocarcinoma 6%, and adenoid cystic carcinoma 5%. The incidence of primary malignant orbital tumours has been increasing in the Netherlands (EAPC +2.8%). CONCLUSION: In the Netherlands, lymphoma is the most common primary malignant orbital tumour, followed by rhabdomyosarcoma, adenocarcinoma, and adenoid cystic carcinoma. The relative frequencies of the different histological tumour types are comparable to the frequencies in other parts of the world. The incidence of malignant primary orbital tumours shows a slight increase between 1989 and 2006.

High prevalence of esophageal involvement in lichen planus: a study using magnification chromoendoscopy.

BACKGROUND AND STUDY AIMS: The first cases of squamous cell carcinoma in esophageal lichen planus were recently described. We performed a study to establish the prevalence of endoscopic and histopathologic abnormalities consistent with lichen planus and (pre-) malignancy in a cohort of patients with lichen planus. PATIENTS AND METHODS: A total of 24 patients with lichen planus were prospectively studied using high-magnification chromoendoscopy. Focal esophageal abnormalities were mapped, classified, and biopsied. Biopsies were also taken from normal-appearing esophageal mucosa at three levels (proximal, middle, and distal). The presence of a lymphohistiocytic interface inflammatory infiltrate and Civatte bodies (i. e. apoptotic basal keratinocytes) at histopathologic examination was considered diagnostic for esophageal lichen planus. Symptoms were assessed using validated questionnaires. RESULTS: A total of 38 focal abnormalities were biopsied. These consisted of: layers of mucosa peeling off, hyperemic lesions, papular lesions, submucosal plaques/papules, a flat polypoid lesion, and segments of cylindrical epithelium. No endoscopic signs of dysplasia were present. Esophagitis consistent with gastroesophageal reflux disease was noted in 12 / 24 patients. Histopathology showed chronic inflammation of the esophageal mucosa in the majority (18 / 24) of patients. In 50 % (12 / 24), the diagnosis of esophageal lichen planus was made. Dysplasia was not present. There were no differences in symptoms between patients with and without esophageal lichen planus. CONCLUSIONS: At screening endoscopy a high prevalence (50 %) of esophageal lichen planus was found in patients with orocutaneous lichen planus. No dysplasia was found.

[Mucocutaneous manifestations of amyloidosis]. / Mucocutane manifestaties van amyloyïdose.

Amyloidosis is the collective term for a group ofuncommon metabolic disorders in which insoluble amyloid protein-fibres are deposited in tissues and organs. Mucocutaneous manifestations are frequently found in this disease. The different types ofamyloidosis are divided into a systemic and a non-systemic group. Systemic amyloidosis is characterised by amyloid deposits in several organs. In the most frequent type, amyloid light chain (AL) systemic amyloidosis, the skin is involved in 29-40% of the cases. These mucocutaneous manifestations are sometimes the first clue to the discovery of systemic involvement. The non-systemic group comprises primarily localised amyloid deposits in skin and mucosa. The treatment of localised mucocutaneous amyloidosis is aimed at the local changes themselves. The mucocutaneous manifestations due to systemic amyloidosis may improve when it is possible to treat the underlying disease successfully.

A leg ulcer as manifestation of metastatic squamous cell vaginal carcinoma.

Cutaneous metastasis of vaginal carcinoma is extremely rare. So far, the total number of reported skin metastasis of vaginal carcinoma is only one. We present another case with an unusual manifestation of vagina carcinoma metastasis: skin metastasis presenting as a leg ulcer on the lower leg.

Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low incidence and strong association with acute graft-versus-host disease.

Lung injury limits the success of allogeneic stem cell transplantation (SCT). The overall incidence varies from 30 to 50% and non-infectious causes occur in one-third to one-half of these. We reviewed pulmonary complications in 369 consecutive patients who received a partially T-cell-depleted myeloablative allogeneic hematopoietic SCT at our institution between 1993 and 2003. All patients were treated uniformly with cyclophosphamide followed by total body irradiation. Control subjects were matched on sex, underlying diagnosis, age, type of transplantation and cytomegalovirus (CMV)-serostatus. Sixty-one patients (16.5%) developed pulmonary complications. Twenty-one patients (5.7%) developed infectious pneumonia. Forty patients developed non-infectious complications which were further subclassified as bronchiolitis obliterans (3.5%), bronchiolitis obliterans-organizing pneumonia (0.5%), diffuse alveolar hemorrhage (0.8%), idiopathic pneumonia syndrome (5.5%) or mixed etiology (0.5%). Acute graft-versus-host disease (GVHD) > or =grade II was significantly more common in pulmonary patients than in the controls (36/61 versus 22/61 patients, P=0.02). There was no significant difference in the incidence of chronic GVHD (P=0.09). CMV reactivation was significantly more frequent in patients with lung injury (P=0.02). Median survival was 41 weeks for the pulmonary patients and 350 weeks for the controls (P=0.001). Altogether, the incidence of pulmonary complications is low after T-cell-depleted SCT and is associated with acute GVHD and CMV reactivation.

Identifying subgroups among poor prognosis patients with nonseminomatous germ cell cancer by tree modelling: a validation study.

BACKGROUND: In order to target intensive treatment strategies for poor prognosis patients with non-seminomatous germ cell cancer, those with the poorest prognosis should be identified. These patients might profit most from more intensive treatment strategies. For this purpose, a regression tree was previously developed on 332 patients. We aimed to evaluate the performance and structure of this tree. PATIENTS AND METHODS: The previously developed tree was applied to 456 patients with a poor prognosis as defined by the International Germ Cell Cancer Collaborative Group (IGCCCG). Next, we developed a new tree to evaluate whether a similar structure to the previous tree was found. We assessed the internal validity of the new tree, and compared the 2-year survival estimates of each subgroup together with the discriminative ability for both the previously developed and the new tree. Discriminative ability was measured by a concordance (c) statistic, which varies between 0.5 (no discrimination) and 1.0 (perfect discrimination). RESULTS: The 2-year survival estimates in the IGCCCG data ranged from 33% to 63%. The ordering of the subgroups was different and discriminative ability was lower than originally found (c = 0.56 in the IGCCCG data versus 0.63 originally). The new tree differed considerably from the original tree, and identified poor prognosis subgroups with 2-year survival estimates from 38% to 73%. Internal validation showed similar discriminative ability for the new tree and the original tree (c = 0.59 versus 0.56). CONCLUSIONS: The previously developed tree showed poor validity with respect to discriminative ability and the stability of its structure. The performance of the new tree was also unsatisfactory. Given the low proportion of patients categorised as poor prognosis, it seems that the potential to identify further subgroups with the currently available patient characteristics is limited.

Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning.

The International Germ Cell Consensus (IGCC) classification identifies good, intermediate and poor prognosis groups among patients with metastatic nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site, presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The IGCC classification is easy to use and remember, but lacks flexibility. We aimed to examine the extent of any loss in discrimination within the IGCC classification in comparison with alternative modelling by formal weighing of the risk factors. We analysed survival of 3048 NSGCT patients with Cox regression and recursive partitioning for alternative classifications. Good, intermediate and poor prognosis groups were based on predicted 5-year survival. Classifications were further refined by subgrouping within the poor prognosis group. Performance was measured primarily by a bootstrap corrected c-statistic to indicate discriminative ability for future patients. The weights of the risk factors in the alternative classifications differed slightly from the implicit weights in the IGCC classification. Discriminative ability, however, did not increase clearly (IGCC classification, c=0.732; Cox classification, c=0.730; Recursive partitioning classification, c=0.709). Three subgroups could be identified within the poor prognosis groups, resulting in classifications with five prognostic groups and slightly better discriminative ability (c=0.740). In conclusion, the IGCC classification in three prognostic groups is largely supported by Cox regression and recursive partitioning. Cox regression was the most promising tool to define a more refined classification. British Journal of Cancer (2004) 90, 1176-1183. doi:10.1038/sj.bjc.6601665 www.bjcancer.com Published online 24 February 2004

[Nephrogenic fibrosing dermopathy]. / Nefrogene fibroserende dermopathie.

A 58-year-old man with renal insufficiency, who was being treated by haemodialysis, developed progressive skin lesions. He had thickening and hardening of the skin at the extremities and swelling of the toes and fingers with flexion contractures. His face was not affected. Laboratory evaluation was unremarkable and a skin biopsy [table: see text] showed an increase of collagen and mucin, without an inflammatory infiltrate. These clinical features resemble a recently reported new disorder: nephrogenic fibrosing dermopathy. This disorder manifests as scleromyxedema-like cutaneous skin lesions without associated paraproteinemia, occurring in the setting of renal disease. The histopathologic features of nephrogenic fibrosing dermopathy, i.e. thickened collagen and mucin deposition, are unique. The incidence, prevalence and cause of the disease are unknown and there is currently no effective treatment. The Centers for Disease Control and Prevention (CDC) in the USA are calling on physicians who have encountered patients suffering from this type of lesions to contact the CDC for an intended control study.

[Five patients with metastasized basal-cell carcinoma]. / Vijf patiënten met een gemetastaseerd basaalcelcarcinoom.

During the period 1986-2001, a metastasised basal-cell carcinoma of the head was diagnosed in five patients (a 35-year-old woman and four men aged 40, 44, 54 and 54 years) at the Utrecht University Medical Centre, the Netherlands. Metastases were found in the cervical lymph nodes, the skeleton, the parotid region and the lungs. The tumours were all of the morphoeic or 'wispy' type. The treatment consisted of excision and sometimes radiotherapy. Two patients died, one of whom of a cause unrelated to the tumour, two patients were free of symptoms 24 months after the last treatment and one patient was still being treated with radiotherapy. It is often assumed that basal-cell carcinomas do not metastasised, but a frequency of 0.0028-0.55% is reported in the literature. An important risk factor is the size of the tumour. Surgical excision or Mohs' micrographic surgery is the preferred method of treatment because this allows histological inspection of the excised margins. Due to the low incidence, there are no clear therapeutic guidelines for the treatment of patients with metastasised basal-cell carcinoma.

Differential diagnosis of skin lesions after allogeneic haematopoietic stem cell transplantation.

Allogeneic haematopoietic stem cell transplantation (i.e. bone marrow or peripheral blood stem cell transplantation) is a common procedure in the treatment of various haematological disorders such as aplastic anaemia, (pre)leukaemias, some malignant lymphomas, multiple myeloma and immunodeficiency states. Many of these patients develop erythematous skin lesions following transplantation. Although graft- versus-host disease is the major differential diagnosis in these situations, many other causes of erythema are encountered. The large number of transplant patients means that more and more pathologists are confronted with the challenging problem of making a correct diagnosis in these situations. In this review article we therefore describe the different causes of erythema and their differential diagnoses. In most cases the clinical presentation is related to the microscopical features. Besides acute and chronic graft-versus-host disease, we discuss the (common) drug reactions and non-specific features such as Sweet's syndrome, erythema nodosum and eosinophilic folliculitis. In addition, we deal with the recurrence of original diseases and infections. With this knowledge every pathologist should feel comfortable when looking at skin biopsies of patients after haematological stem cell transplantation.