[Swiss clinical practice guidelines for skin cancer in organ transplant recipients]

Swiss clinical practice guidelines for skin cancer in organ transplant recipients Transplant patients have increased over the last decades. As a consequence of long-term immunosuppression, skin cancer, in particular squamous cell carcinoma (SCC), has become an important problem. Screening and education of potential organ transplant recipients (OTRs) regarding prevention of sun damage and early recognition of skin cancer are important before transplantation. Once transplanted, OTRs should be seen yearly by a dermatologist to ensure compliance with sun avoidance as well as for treatment of precancerosis and SCC. Early removal is the best treatment for SCC. Reduction of immunosuppression, switch to mTOR inhibitors and chemoprevention with acitretin may reduce the incidence of SCC. The dermatological follow-up of OTRs should be integrated into a comprehensive post-transplant management strategy.

Destruction of lymphoid organ architecture and hepatitis caused by CD4+ T cells

Immune responses have the important function of host defense and protection against pathogens. However, the immune response also causes inflammation and host tissue injury, termed immunopathology. For example, hepatitis B and C virus infection in humans cause immunopathological sequel with destruction of liver cells by the host's own immune response. Similarly, after infection with lymphocytic choriomeningitis virus (LCMV) in mice, the adaptive immune response causes liver cell damage, choriomeningitis and destruction of lymphoid organ architecture. The immunopathological sequel during LCMV infection has been attributed to cytotoxic CD8(+) T cells. However, we now show that during LCMV infection CD4(+) T cells selectively induced the destruction of splenic marginal zone and caused liver cell damage with elevated serum alanin-transferase (ALT) levels. The destruction of the splenic marginal zone by CD4(+) T cells included the reduction of marginal zone B cells, marginal zone macrophages and marginal zone metallophilic macrophages. Functionally, this resulted in an impaired production of neutralizing antibodies against LCMV. Furthermore, CD4(+) T cells reduced B cells with an IgM(high)IgD(low) phenotype (transitional stage 1 and 2, marginal zone B cells), whereas other B cell subtypes such as follicular type 1 and 2 and germinal center/memory B cells were not affected. Adoptive transfer of CD4(+) T cells lacking different important effector cytokines and cytolytic pathways such as IFNγ, TNFα, perforin and Fas-FasL interaction did reveal that these cytolytic pathways are redundant in the induction of immunopathological sequel in spleen. In conclusion, our results define an important role of CD4(+) T cells in the induction of immunopathology in liver and spleen. This includes the CD4(+) T cell mediated destruction of the splenic marginal zone with consecutively impaired protective neutralizing antibody responses.

Extended lymph node dissection: bladder, kidney

To present recent advances in the field of lymph node dissection (LND) in the context of bladder cancer, upper urinary tract urothelial carcinoma and renal cell carcinoma with focus on dissection extent.

Homeodomain-only protein HOP is a novel modulator of late differentiation in keratinocytes

The homeodomain-only protein (HOP) contains an atypical homeodomain which is unable to bind to DNA due to mutations in residues important for DNA binding. Recently, HOP was reported to regulate proliferation/differentiation homeostasis in different cell types. In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Immunohistochemistry of human skin localized HOP to the granular layer in the epidermis. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. Conversely, decreasing HOP expression using small interfering RNA markedly reduced the calcium-induced expression of late markers of differentiation in vitro, with the most prominent effect on profilaggrin (FLG) mRNA. Moreover, mRNA levels of profilaggrin and loricrin were downregulated in the epidermis of HOP knockout mice. Analysis of skin disorders revealed altered HOP expression in lichen planus, psoriasis and squamous cell carcinoma (SCC). Our data indicate that HOP is a novel modulator of late terminal differentiation in keratinocytes.

Acute visual loss after preoperative embolization of an ethmoidal metastasis

An unintentional embolization of retinal arteries is rare and has been documented as a complication after embolization of arteries supplying head and neck tumors. However, occlusion of the central retinal artery with severe loss of vision has never been reported to be a complication from embolization of tumor-supplying ethmoidal branches of the ophthalmic artery. A 40 year-old male patient with a history of right nephrectomy for renal cell carcinoma underwent preoperative radiological embolization of an ethmoidal metastasis after having experienced a life-threatening sinus bleeding. Repeated probing of the ophthalmic artery with an endovascular microcatheter for particle embolization of the tumor-supplying arteries was performed under anticoagulation with heparin. Postoperatively, a standard ophthalmological examination including extended vascular evaluation by angiography was performed. After extended probing of the ophthalmic artery a marked reduction in its blood flow occurred. Despite post-interventional imaging showing persisting perfusion of the central retinal and ciliary arteries, the patient developed complete loss of vision on this side four days later. At this time fundoscopy and fluorescein angiography revealed a recanalized central artery occlusion, while indocyanin angiography showed infarctions of the choroid. Radiological intervention via the ophthalmic artery can result in complete loss of vision, even after limited and transient obstruction of the vessel.

Pre- and posttransplant management of solid organ transplant recipients: risk-adjusted follow-up

Solid organ transplant recipients (SOTR) have an increased risk of skin cancer due to their long-term immunosuppressive state. As the number of these patients is increasing, as well as their life expectancy, it is important to discuss the screening and management of skin cancer in this group of patients. The role of the dermatologist, in collaboration with the transplant team, is important both before transplantation, where patients are screened for skin lesions and the individual risk for skin cancer development is assessed, and after transplantation. Posttransplant management consists of regular dermatological consultations (the frequency depends on different factors discussed below), where early skin cancer screening and management, as well as patient education on sun protective behavior is taught and enforced. Indeed, SOTR are very sensitive to sun damage due to their immunosuppressive state, leading to cumulative sun damage which results in field cancerization with numerous lesions such as in situ squamous cell carcinoma, actinic keratosis and Bowen's disease. These lesions should be recognized and treated as early as possible. Therapeutic options discussed will involve topical therapy, surgical management, adjustment of the patient's immunosuppressive therapy (i.e. reduction of immunosuppression and/or switch to mammalian target of rapamycin inhibitors) and chemoprevention with the retinoid acitretin, which reduces the recurrence rate of squamous cell carcinoma. The dermatological follow-up of SOTR should be integrated into the comprehensive posttransplant care.

Metastatic disease to the parotid gland

OBJECTIVES: The purpose of this study was to review the clinico-pathologic findings and outcome of patients with metastasis to the parotid lymph nodes and gland. METHODS: Retrospective study. Thirty-four out of 520 patients with a parotid mass treated at our institution met the criteria for this study. Age, gender, clinical findings, histopathology, treatment. and outcome were analyzed. RESULTS: Twenty-three patients had metastases to parotid lymph nodes from a squamous cell carcinoma of the skin, seven from a cutaneous malignant melanoma after a mean interval of 15 months, two from a ductal breast carcinoma, one with a metastatic disease from a rhabdomyosarcoma of the lower limb, and one from a Merkel cell carcinoma. The 5-year cause-specific and absolute survival for squamous cell carcinoma was 64% and 48% respectively and 71% and 57% for malignant melanomas. CONCLUSIONS: Metastatic disease to the parotid gland is mostly caused by squamous cell carcinoma. Despite combined treatment modalities long-term survival remains poor.

Oral mucosal lesions diagnosed in a stomatology service. An examination of clinico-pathological findings from the year 2003

During 2003, a total of 258 new patients with oral soft tissue lesions were admitted at the Stomatology Service of the Department of Oral Surgery and Stomatology at the University of Berne. For the present study, 185 patients with clinically and histopathologically verified diagnoses were included. The following data was collected: prevalence of oral mucosal lesions, distribution of benign, precancerous and malign lesions in different age groups, and the concordance of the referral with the working diagnosis at the Stomatology Service. The most frequent pathological soft tissue findings were fibrous hyperplasias (n = 44) and oral lichen planus (n = 30). Precancerous lesions were present in 41 cases (30 patients with oral lichen planus, eleven oral leukoplakias), and ten patients had oral malignomas. Most lesions were found in patients between the age of 40 and 60 years. The referral diagnosis concurred in 36.6% (n = 67) of the cases with the definite diagnosis before initiation of treatment, the working diagnosis in 70% (n = 128) of the cases. Therefore, it can be concluded that a specialised Stomatology Service serves as a center of competence due to large numbers of patients/cases seen and treated, and the resulting high level of clinical experience of the staff. Moreover, it is important in the primary diagnosis of oral squamous cell carcinoma, in collaboration with the referring dentist in private practice.

[Tobacco-associated lesions of the oral mucosa]

Consumption of tobacco can result not only in a multitude of different general health problems like carcinoma of the lung, ischaemic cardiac diseases, peripheral vascular diseases, stroke, chronic-obstructive pulmonary diseases or peptic ulcers, but also in pathologic lesions of the oral mucosa. Benign oral lesions from smoking or consumption of smokeless tobacco are the so-called smoker's palate and smoker's melanosis. On the other hand, tobacco-associated lesions like oral leukoplakia or oral squamous cell carcinoma are already potentially life-threatening diseases that in general require active treatment. The following review article will present and discuss the typical lesions of the oral mucosa that result from chronic tobacco consumption. The aim of this article is to demonstrate dental health care providers the needs and benefits of tobacco use cessation in a dental setting, especially regarding stomatologic sequelae and consequences. The present article is the first in a series of articles from the Swiss task force "Smoking - Intervention in the private dental office" on the topic "tobacco use and dental medicine".

[Precancerous and high risk lesions of the oral mucosa--Diagnosis, therapy and follow-up in two cases]

Stomatologic lesions at risk to develop an oral squamous cell carcinoma (OSCC) such as oral leukoplakia, erythroplakia/erythroleukoplakia, or oral lichen planus, need an early detection, diagnosis and a long-term/lifelong follow-up to prevent malignant transformation. In the following report, two patients are presented with oral mucosal lesions, who were referred, diagnosed, treated, and underwent follow-up examinations at the Stomatology Service of the Department of Oral Surgery and Stomatology at the University of Bern. These two cases emphasize the importance of early detection and managment of precancerous lesions or initial stages of OSCC. Additionally, risk factors, such as tobacco and alcohol consumption and their influence on stomatologic lesions and their prognosis, will be discussed.

Interventional management of hypervascular osseous metastasis: role of embolotherapy before orthopedic tumor resection and bone stabilization

OBJECTIVE: The purpose of this study was to evaluate, in relation to intraoperative estimated blood loss (EBL), the effectiveness of preoperative transcatheter arterial embolization of hypervascular osseous metastatic lesions before orthopedic resection and stabilization. MATERIALS AND METHODS: Between June 1987 and November 2007, 22 patients underwent transcatheter arterial embolization of tumors of the long bone, hip, or vertebrae before resection and stabilization. Osseous metastatic lesions from renal cell carcinoma, malignant melanoma, leiomyosarcoma, and prostate cancer were embolized. All patients were treated with a coaxial catheter technique with polyvinyl alcohol (PVA) particles alone or a combination of PVA particles and coils. After embolization, each tumor was angiographically graded according to devascularization (grades 1-3) based on tumor blush after contrast injection into the main tumor-feeding arteries. RESULTS: In patients with complete devascularization (grade 1), mean EBL was calculated to be 1,119 mL, whereas in patients with partial embolization (grades 2 and 3) EBL was 1,788 mL and 2,500 mL. With respect to intraoperative EBL, no significant difference between devascularization grades was found (p > 0.05). Moderate correlation (r = 0.51, p = 0.019) was observed between intraoperative EBL and tumor size before embolization. Only low correlation (r = 0.44, p = 0.046) was found between intraoperative EBL and operating time. Major complications included transient palsy of the sciatic nerve and gluteal abscess in one patient. CONCLUSION: The results of this study support the concept that there is no statistically significant difference among amounts of intraoperative EBL with varying degrees of embolization.

Neoplastic invasion of laryngeal cartilage: reassessment of criteria for diagnosis at MR imaging

PURPOSE: To evaluate whether proposed diagnostic criteria applied to magnetic resonance (MR) images of patients with laryngeal and hypopharyngeal carcinoma may be used to distinguish neoplastic from inflammatory involvement of the laryngeal cartilages. MATERIALS AND METHODS: The radiologic and histopathologic data in 121 consecutive patients with primary squamous cell carcinoma of the larynx (n = 63) or hypopharynx (n = 58) who underwent MR imaging before laryngectomy formed the basis of this retrospective study. Patient consent for retrospective chart review was waived by the institutional review board. All laryngectomy specimens were processed with a dedicated histopathologic whole-organ slice technique. MR images were evaluated by two readers according to established ("old") and proposed ("new") diagnostic criteria on the basis of the signal intensity behavior of cartilage on T2-weighted images and contrast material-enhanced T1-weighted images compared with that of the adjacent tumor. Specifically, with the new criteria, T2-weighted or postcontrast T1-weighted cartilage signal intensity greater than that of the adjacent tumor was considered to indicate inflammation, and signal intensity similar to that of the adjacent tumor was considered to indicate neoplastic invasion. The results of the MR image interpretation were compared with the histologic reference standard. RESULTS: The area under the receiver operating characteristic curve for the new criteria (0.94) was nominally but significantly larger than that for the old criteria (0.92) (P = .01). Overall specificity was significantly improved (82% for new vs 74% for old criteria, P < .001) and was greatest for the thyroid cartilage (75% for new vs 54% for old criteria, P < .001) with the new criteria. The sensitivities of the established and the proposed criteria were identical. CONCLUSION: The proposed MR imaging criteria enable improved differentiation of neoplastic cartilage invasion from peritumoral inflammation.

[Follow-up after malignant tumours of the uterus (cancer of the uterine corpus / cervical cancer)]

Malignant uterine tumours can affect the corpus or the cervix. The endometrial carcinoma with its different histological subtypes counts for most of the malignomas of the uterine body. But the rare category of uterine sarcomas (carcinosarcomas, leiomyosarcomas as well as endometrial stromal sarcomas) also belongs to this group. Cervical cancer presents an own entitity, regarding both histology and therapeutic options. Endometrial cancer is the most common genital malignoma in Northern Europe and North America. Histologically, the endometrial cancer can be subdivided in two groups: type I is hormonal sensitive and well differentiated, type II represents an undifferenciated aggressive tumour with poor prognosis. In general, the patient is elderly. Due to the main symptom - abnormal vaginal bleeding - endometrial cancer is detected in an early stage in about 75% of all patients. First choice in therapy is stage related surgery. Follow-up schemes have not proved yet to improve survival, therefore clear guidelines are missing. National and international groups recommend regular follow-up visits to detect the early vaginal vault relapse which is curable. Cervical cancer is mainly a squamous cell carcinoma and oncogenic Human Papilloma Virus (HPV) associated. Surgery is only indicated up to stage IIA, advanced stages should be treated by radio-chemotherapy. Several studies have shown that follow-up visits can improve survival rates. Intention is the detection of the curable local relapse.

Comparison of outcome and recurrence-free survival after sentinel lymph node biopsy and lymphadenectomy in vulvar cancer

OBJECTIVES: Lymph node status is an important prognostic factor in patients with squamous cell carcinoma (SCC) of the vulva. Complete inguinofemoral lymph node dissection (ILND) is accompanied by a high morbidity. Sentinel lymph node biopsy (SLNB) was established for less invasive lymph node (LN) staging. The aim of this study was to evaluate safety of SLNB in terms of accuracy and outcome in a clinical routine setting. METHODS: We retrospectively reviewed the data of patients who underwent SLNB and/or ILND for vulvar SCC in the years 1990-2007. Clinical follow-up was evaluated for histological nodal-negative patients with tumor stage T1 or T2. The false negative rate of SLNB was determined in patients who underwent both SLNB and ILND. RESULTS: Preoperative sentinel lymph node (SLN) visualization by scintigraphy was successful in 95% of all patients. SLNB was false negative in 1/45 inguinae (2.2%). All SLN were detected intraoperatively. During the follow-up period (median 24 months for SLNB and 111 months for ILND), no groin recurrences in initially nodal negative patients occurred (n=34, 59 inguinae). Transient lymph edema occurred in 7/18 patients after ILND (39%) and 2/16 patients (13%) after SLNB. No persistent edemas were found after SLNB and ILND. CONCLUSION: According to our experience SLNB is feasible and accurately predicts LN status of vulvar SCC under clinical routine conditions. SLNB in vulvar cancer seems to be a safe alternative to ILND in order to reduce morbidity of surgical treatment.

MET Y1253D-activating point mutation and development of distant metastasis in advanced head and neck cancers

We investigated if the MET-activating point mutation Y1253D influences clinical outcomes in patients with advanced squamous cell carcinoma of the head and neck (HNSCC). The study population consisted of 152 HNSCC patients treated by hyperfractionated radiotherapy alone or concomitant with chemotherapy between September 1994 and July 2000. Tumors were screened for the presence of the MET-activating point mutation Y1253D. Seventy-eight patients (51%) received radiotherapy alone, 74 patients (49%) underwent radiotherapy concomitant with chemotherapy. Median patient age was 54 years and median follow-up was 5.5 years. Distant metastasis-free survival, local relapse-free survival and overall survival were compared with MET Y1253D status. During follow-up, 29 (19%) patients developed distant metastasis. MET Y1253D was detected in tumors of 21 out of 152 patients (14%). Distant metastasis-free survival (P = 0.008) was associated with MET Y1253D. In a multivariate Cox regression model, adjusted for T-category, only presence of MET Y1253D was associated with decreased distant metastasis-free survival: hazard ratio = 2.5 (95% confidence interval: 1.1, 5.8). The observed association between MET Y1253D-activating point mutation and decreased distant metastasis-free survival in advanced HNSCC suggests that MET may be a potential target for specific treatment interventions.