Assessing health-related quality of life using the Wound-QoL-17 and the Wound-QoL-14-Results of the cross-sectional European HAQOL study using item response theory.

For assessing health-related quality of life in patients with chronic wounds, the Wound-QoL questionnaire has been developed. Two different versions exist: the Wound-QoL-17 and the Wound-QoL-14. For international and cross-cultural comparisons, it is necessary to demonstrate psychometric properties in an international study. Therefore, the aim of this study was to test both questionnaires in a European sample, using item response theory (IRT). Participants were recruited in eight European countries. Item characteristic curves (ICC), item information curves (IIC) and differential item functioning (DIF) were calculated. In both questionnaires, ICCs for most items were well-ordered and sufficiently distinct. For items, in which adjacent response categories were not sufficiently distinct, response options were merged. IICs showed that items on sleep and on pain, on worries as well as on day-to-day and leisure activities had considerably high informational value. In the Wound-QoL-14, the item on social activities showed DIFs regarding the country and age. The same applied for the Wound-QoL-17, in which also the item on stairs showed DIFs regarding age. Our study showed comparable results across both versions of the Wound-QoL. We established a new scoring method, which could be applied in international research projects. For clinical practice, the original scoring can be maintained.

How does a chronic wound change a patient's social life? A European survey on social support and social participation.

Chronic wounds can severely limit patient's social life. This cross-sectional study investigated quantitatively social support of patients with chronic wounds, its association with health-related quality of life as well as qualitatively changes in social participation of these patients. Overall, 263 patients from seven countries participated. The most frequent wound class was leg ulcer (49.2%). Results revealed generally high levels of social support (mean global score: 5.5) as measured with the Multidimensional Scale of Perceived Social Support. However, individuals differed considerably (range 1.0-7.0). All dimensions of social support differed by patients' family and living situations (p < 0.001 to p = 0.040) and were positively correlated with generic health-related quality of life (r = 0.136-0.172). Having children, living with others and being in a relationship were significant predictors of having higher global social support. Patients reported great support from family members. Many participants reported no changes in relationships with friends. Wound care managers took an important role and provided additional emotional support. Patients reported a range of discontinued activities. Despite the high overall level of social support, inter-individual differences should be acknowledged. The importance of family carers should be acknowledged to be able to reduce caregiver burden and to ensure high-qualitative wound care.

Validation of the Wound-QoL-17 and the Wound-QoL-14 in a European sample of 305 patients with chronic wounds.

The Wound-QoL assesses the impact of chronic wounds on patients' health-related quality of life (HRQoL). A 17-item and a shortened 14-item version are available. The Wound-QoL-17 has been validated for multiple languages. For the Wound-QoL-14, psychometric properties beyond internal consistency were lacking. We aimed to validate both Wound-QoL versions for international samples representing a broad range of European countries, including countries for which validation data had yet been pending. Patients with chronic wounds of any aetiology or location were recruited in Austria, Lithuania, the Netherlands, Poland, Slovakia, Spain, Switzerland and Ukraine. Psychometric properties were determined for both Wound-QoL versions for the overall sample and, if feasible, country-wise. We included 305 patients (age 68.5 years; 52.8% males). Internal consistency was high in both Wound-QoL-17 (Cronbach's α: 0.820-0.933) and Wound-QoL-14 (0.779-0.925). Test-retest reliability was moderate to good (intraclass correlation coefficient: 0.618-0.808). For Wound-QoL-17 and Wound-QoL-14, convergent validity analyses showed highest correlations with global HRQoL rating (r = 0.765; r = 0.751) and DLQI total score (r = 0.684; r = 0.681). Regarding clinical data, correlations were largest with odour (r = -0.371; r = -0.388) and wound size (r = 0.381; r = 0.383). Country-wise results were similar. Both Wound-QoL versions are valid to assess HRQoL of patients with chronic wounds. Due to its psychometric properties and brevity, the Wound-QoL-14 might be preferrable in clinical practice where time is rare. The availability of various language versions allows for the use of this questionnaire in international studies and in clinical practice when foreign language patients are being treated.

The World of Melanoma: Epidemiologic, Genetic, and Anatomic Differences of Melanoma Across the Globe.

PURPOSE OF REVIEW: As cancer remains an increasing problem in industrial countries, the incidence of melanoma has risen rapidly in many populations during the last decades and still continues to rise. Current strategies aiming to control the disease have largely focused on improving the understanding of the interplay of causal factors for this cancer. RECENT FINDINGS: Cutaneous melanoma shows clear differences in incidence, mortality, genomic profile, and anatomic presentation, depending on the country of residence, ethnicity, and socioeconomic status. Known risk factors are multiple atypical nevi, positive family and/or personal history, immune suppressive diseases or treatments, and fair skin phenotype. Besides new adjuvant therapeutic options, changed attitude toward leisure and sun exposure, primary prevention, and early detection are major contributors to disease control. Melanoma is a disease of multifactorial causality and heterogeneous presentation. Its subtypes differ in origin, anatomical site, role of UV radiation, and mutational profile. Better understanding of these differences may improve prevention strategies and therapeutic developments.

Short- and long-term effects of two emollients on itching and skin restoration in xerotic eczema.

Pruritus is associated with various skin diseases, dry skin, and with it an impaired skin barrier function. The study objective was to investigate short-term and long-term effects of two emollients on symptoms and skin barrier functions in xerotic eczema. Randomized, double-blind, study enrolling females/males, with bilateral itching. Two emollients, containing lactic acid and refined almond oil with/without polidocanol were administered on left versus right body sides. Itching severity, skin moisture, lipid content, and pH were assessed on Day 1, within 30-120 min after first administration, and on Days 7 and 14, and compared with baseline assessments. Severity of itching decreased 30 min after first administration of both emollients compared with baseline (p < .0001) and reached a maximum reduction of 63% (p < .0001) and 69% (p < .0001) on Day 14. Skin moisture and lipid content increased after first application, and further ameliorated within 14 days of treatment (p < .0001). Both emollients were tolerated well, and only a few adverse events were reported. This study confirmed the clinical efficacy of the two study emollients to substantially reduce itching already after first administration, and restore skin barrier integrity and thus should be considered as therapeutic approach for xerotic eczema.

A Prospective Trial Comparing Q-Switched Ruby Laser and a Triple Combination Skin-Lightening Cream in the Treatment of Solar Lentigines.

BACKGROUND: Quality-switched (QS) laser therapy is a safe and well-established treatment option for removing solar lentigines. Triple combination therapy (TCT) with the active pharmaceutical ingredients hydroquinone 5%, tretinoin 0.03%, and dexamethasone 0.03% is often used for skin-lightening. OBJECTIVE: This prospective, open-label trial compares the efficacy and safety of a QS Ruby laser (QSRL) and a TCT in the treatment of solar lentigines. METHODS: In total, 15 patients with symmetrically distributed solar lentigines on the back of both hands were included. The lesions on the back of the right hand were treated in one or 2 sessions with a QSRL, the ones on the back of the left hand with a TCT for 7 weeks accompanied by UV protection. Clinical results were evaluated 4 weeks, 8 weeks, and 20 weeks after baseline. RESULTS: Treatment with QSRL provided significant lightening (p = .01) compared with TCT. Both procedures were generally well-tolerated. Comparing the side effects, the laser produced significantly more crusting and hyperpigmentation than the TCT. CONCLUSION: Both QSRL and TCT were capable in reducing solar lentigines in Fitzpatrick skin Type I to IV with an acceptable side effect profile. The QSRL provides faster, superior, and long lasting lightening compared with TCT.

Topical Timolol for Infantile Hemangiomas: Evidence for Efficacy and Degree of Systemic Absorption.

BACKGROUND: Topical use of timolol for infantile hemangiomas has recently emerged with promising results. It is unknown whether topical ß-blockers act locally or if their effect is partly due to systemic absorption. This study investigates whether topically applied timolol is absorbed and reports on the efficacy of this treatment. METHODS: We treated 40 infants with small proliferating hemangiomas with topical timolol gel 0.5% twice daily and assessed urinary excretion and serum levels in a proportion of patients. Clinical response was evaluated on a visual analog scale of standardized photographs after 1, 2, 3, and 5 months. RESULTS: Forty infants with a median age of 18 weeks (range 2-35 wks) were included; 23 (58%) had superficial and 17 (42%) mixed-type hemangiomas. The median size was 3 cm(2) (range 0.1-15 cm(2) ) and nine hemangiomas were ulcerated. The hemangiomas improved significantly during treatment, with a median increase in visual analog scale of 7 points after 5 months (p < 0.001). Urinalysis for timolol was performed in 24 patients and was positive in 20 patients (83%). In three infants, serum levels of timolol were also measured and were all positive (median 0.16 ng/mL [range 0.1-0.18 ng/mL]). No significant side effects were recorded. CONCLUSION: Topical therapy with timolol is effective for infantile hemangiomas, but systemic absorption occurs. Serum levels in our patients were low, suggesting that using timolol for small hemangiomas is safe, but caution is advised when treating ulcerated or large hemangiomas, very young infants, or concomitantly using systemic propranolol.

Phototherapy with UVB narrowband, UVA/UVBnb, and UVA1 differentially impacts serum 25-hydroxyvitamin-D3.

BACKGROUND: Ultraviolet (UV) B radiation increases serum 25-hydroxyvitamin-D3 [25(OH)D], but the influence of UVA1 and UVA/narrowband UVB (UVBnb) phototherapy on serum vitamin D is unknown. OBJECTIVE: We sought to investigate the influence of UVBnb, UVA1, and UVA/UVBnb phototherapy on serum levels of 25(OH)D and related parameters in patients with an inflammatory skin condition. METHODS: 25(OH)D, as well as calcium, parathormone, phosphate, and albumin were measured before therapy, 2 weeks after start, and after completion of the phototherapy. Diagnoses were divided in 4 groups: atopic dermatitis, psoriasis, morphea, and others. RESULTS: We surveyed 116 dermatologic patients undergoing phototherapy with UVA1 (n = 38), UVA/UVBnb (n = 30), or UVBnb (n = 48) 2 to 3 times a week for 53 to 90 days. UVBnb phototherapy increased serum 25(OH)D from 22.1 to 39.5 ng/mL after the therapy (P < .001). The lower the baseline 25(OH)D level was, the steeper the increase in 25(OH)D was upon application of UVBnb phototherapy. UVA/UVBnb therapy also increased serum 25(OH)D, from 23.9 to 50.3 ng/mL (P = .003). Conversely, in the UVA1 therapy group, 25(OH)D serum levels decreased significantly from 21.9 to 19.0 ng/mL (P < .001). LIMITATIONS: The study design was open trial without randomization. An influence of a precise skin disease cannot be excluded because of the heterogeneous diagnoses. Bias may have arisen from patient preference for treatment at our center, referral, unrecognized differences in underlying skin disease, and other factors. CONCLUSION: Phototherapy with UVBnb and UVA/UVBnb increased 25(OH)D serum level significantly. UVA1 therapy alone induced a reduction in serum 25(OH)D concentrations.

Management of split-thickness skin graft donor sites: a randomized controlled trial of calcium alginate versus polyurethane film dressing.

BACKGROUND: Split-thickness skin graft (STSG) donor sites sometimes cause more postoperative morbidity for patients than the wound covered with the graft. Yet, there is no consensus on which dressings are best suited to treat these donor sites. OBJECTIVE: To evaluate two commonly used modern wound dressings in the postoperative healing of STSG donor sites in a prospective randomized controlled trial. METHODS: 38 patients were randomly assigned to treatment of an STSG donor site with an alginate dressing or a polyurethane film dressing. The primary outcome measures were postoperative pain scores, secondary outcome variables were time to epithelialization, dressing changes and complications. RESULTS: Postoperative pain on day 1 was significantly lower in the polyurethane film group (2.05 vs. 0.79, p = 0.035) as compared to the alginate group. This difference was not detected on day 5 (0.89 vs. 0.53, p = 0.52). Time to epithelialization did not differ significantly between the two dressing groups. There were more dressing changes in the polyurethane film group and problems with leakage. CONCLUSION: Whereas film dressings resulted in initially lower pain scores, alginate dressings caused fewer additional dressing changes and less leakage.

Dermatofibrosarcoma protuberans in childhood treated with slow Mohs micrographic surgery.

Dermatofibrosarcoma protuberans (DFSP) in childhood is a rare tumor with high recurrence rates. Wide local excision can result in disfiguring mutilation, whereas Mohs micrographic surgery (MMS) reduces surgical margins. MMS in children is not performed routinely, as the required infrastructures such as a histopathology lab in close proximity to the operating room is often lacking. We retrospectively reviewed children diagnosed with DFSP treated at our hospital over 2 years. We recorded surgical treatment details, including margins, duration of inpatient stay, outcome, follow-up, and molecular genetic tumor tissue analysis. Four children with a median age of 6.8 years (range 6.0-8.8 years) were identified who had a diagnostic delay of a median of 2.5 years (range 0.5-4.0 years); all underwent complete tumor excision using the slow MMS technique using vacuum-assisted closure systems between repeated excisions and before wound closure. The median maximal safety margins were 1.5 cm (range 1.0-3.0 cm). By using vacuum-assisted closure systems, no dressing changes were needed, pain was limited, and full mobility was maintained in all children. The median total time in the hospital was 11 days (range 10-14 days). No relapses occurred during a median follow-up of 25.8 months (range 11.3-32.6 months). Collagen 1A1/platelet-derived growth factor B (COL1A1/PDGFB) translocation on chromosomes 17 and 22 was detected in all three analyzable specimens. Lesions suspected of being DFSP warrant prompt histologic evaluation; interdisciplinary management is mandatory in particular for children. Micrographic surgery allows smaller surgical margins than wide excision and should be considered as the treatment of choice in children with DFSP. The interim usage of vacuum-assisted closure systems increases patient comfort. Translocations in the COL1A1/PDGFB gene imply susceptibility to targeted treatment modalities for therapy-resistant cases.

Long-term recurrence rate of large and difficult to treat cutaneous squamous cell carcinomas after superficial radiotherapy.

BACKGROUND: Surgical excision is the gold standard for cutaneous squamous cell carcinoma (cSCC), however its application is limited in specific cases. Superficial radiotherapy (RTx) is an alternative treatment option, but long-term follow-up data are limited. OBJECTIVE: To determine the outcome of superficial RTx of cSCC in correlation to histological differentiation grade and tumor localization. METHODS: The outcome of 180 large cSCCs after superficial RTx between 1960 and 2004 was retrospectively reviewed. RESULTS: Mean tumor size was 3.5 cm(2) (SD 7.5) and mean follow-up period was 4.9 years (SD 4.7). Relapse-free survival was 95.8 and 80.4% after 1 and 10 years. Two-year relapse-free survival was 94.8% for good, 88.9% for moderate and 85.7% for poor differentiated tumors. Five-year relapse-free survival was highest in cSCCs located around the eyes (100%) and cheeks (90.9%). CONCLUSION: Superficial RTx is an effective alternative for cSCC if surgery is difficult due to localization or concomitant disease.

Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions.

We have investigated the staining patterns of primary and metastatic melanoma lesions using F8, L19 and F16. These three clinical-stage antibodies are currently being studied in clinical trials for the pharmacodelivery of cytokines or therapeutic radionuclides to neoplastic sites in patients with cancer. Frozen sections of 24 primary and 29 metastatic melanoma lesions were stained, using immunofluorescence procedures, with biotinylated preparations of the F8, L19 and F16 antibodies, which are specific to the alternatively spliced extra domain A and extra domain B domains of fibronectin and A1 domain of tenascin-C, respectively. Blood vessels were costained using von Willebrand factor-specific antibodies. In primary cutaneous melanoma lesions, F16 and F8 (but not L19) strongly stained the basal lamina at the interface between epidermis and dermis, with a strikingly complementary pattern. By contrast, metastatic melanoma lesions displayed a strong and diffuse pattern of immunoreactivity with all three antibodies. It was found that the extracellular matrix in melanoma undergoes extensive remodelling during the transition from primary to metastatic lesions. The intense staining of metastatic melanoma lesions by the F8, L19 and F16 antibodies provides a strong rationale for the use of these antibodies and their derivatives for the treatment of melanoma patients and possibly for the personalized choice of the best performing antibody in individual patients.

Facial blaschkitis: case and review.

We report on a 15-year-old female with a 3-month history of a pruritic, erythematous cutaneous eruption on the right cheek and perioral area. The lesion had a linear distribution following the lines of Blaschko. Histopathological findings and direct immunofluorescence were compatible with chronic cutaneous lupus erythematosus (LE). Treatment with topical steroids and systemic antimalarial agents over 2 months showed hardly any improvement contrary to similar cases reported in the literature in the past. Histological findings move this case close to LE. However, the unusual clinical presentation as well as the resistance to antimalarial drugs do not fully allow to confirm this suspicion. Therefore, we recommend to call this new entity LE-like facial Blaschkitis of the adult.

Spitzoid melanoma and micrometastases in two lymph node regions: a critical situation.

Atypical Spitz tumors can hardly be differentiated from spitzoid melanoma. CGH might help in the differential diagnosis. An 8 year old child with an atypical Spitz tumor (with a CGH pattern compatible with melanoma) of 8.0 mm Breslow thickness and micrometastases in two lymph node regions was seen at our department. The management and prognosis of atypical Spitz tumors is controversial, and aggressive procedural steps similar to melanoma are usually not recommended. Even performing sentinel lymph node biopsy has been questioned. After extensive interdisciplinary consultations, we did not recommend resection of both lymph node regions and chose instead to follow-up with regular whole-body MRI and adjuvant treatment with pegylated interferon. Treatment decisions for atypical Spitz tumors are a major medical and ethical challenge due to the limited available data.

Clinical and Molecular Features of Skin Malignancies in Muir-Torre Syndrome.

BACKGROUND: We investigated the mutational landscape of skin tumors in patients with Muir-Torre Syndrome (MTS) a hereditary autosomal dominant mismatch repair disorder of increased cancer susceptibility, and examined mutations other than in the DNA mismatch repair (MMR) genes. METHODS: This retrospective single-center case series included seven patients with the diagnosis of Muir-Torre Syndrome with precise medical history and family history. Mutational analysis of tumor samples Formalin-fixed paraffin-embedded tissue blocks of skin lesions associated with Muir-Torre Syndrome were used for further analysis. All skin tumors were analyzed with the Oncomine Comprehensive Assay v3 (Life Technologies), which includes 161 of the most relevant cancer driver genes. RESULTS: Eleven skin neoplasms (nine sebaceous tumors, one melanoma, one cutaneous squamous cell carcinoma) were diagnosed in seven patients. In two patients, visceral malignancies preceded the diagnosis of the skin tumors and one patient was diagnosed with a visceral malignancy after a sebaceous tumor. History of familial cancer of Lynch Syndrome (LS) was reported in three patients. The most frequently detected mutation was in the MSH2 gene, followed by mutations in the NOTCH1/2 and TP53 gene. Conclusion, this study provides a molecular analysis of Muir-Torre Syndrome associated and non-associated skin tumors in patients with Muir-Torre Syndrome. Patients with sebaceous lesions should undergo microsatellite instability analysis and accurate evaluation of personal and family history to detect a possible Muir-Torre syndrome. As secondary malignancies may appear years after the first occurrence of sebaceous tumors, lifelong screening is mandatory.

Results of a 10-year web-based health promotion campaign against skin cancer in Switzerland.

Skin cancer is the most common malignancy with rising incidence. Although early detection can be lifesaving, prevention programmes are under-utilized. In 2008, a group of board-certified dermatologists in Switzerland established a website aimed at educating about skin cancer risk factors and providing guidance on self-assessment. To present the data of this programme over the last 10 years with regards to representation of the targeted groups and sustained impact on primary skin cancer prevention. A comprehensive web-based health promotion campaign was established for education and guidance on self-assessment. Teledermatological evaluation was offered and participants were then interviewed. In total, 11,171 digital photos were evaluated during 2008-2018; 54.3% (n = 6,067) from females and 45.7% (n = 5,104) from males. In 26.7% (n = 2,983), clinical examination was recommended. Of the participants, 1,874 replied revealing 103 malignancies (9.2% of the lesions were presented to a physician): 34 melanomas in situ, six squamous cell carcinomas, 53 basal cell carcinomas and 10 malignant lesions (not further specified). Of the participants, 40.5% (n = 683) changed their attitude towards sun exposure, 48.7% (n = 820) used more sunscreen, and 57.5% (n = 966) improved sunscreen measures. Web-based educational programmes raise public awareness, enhance prevention, and support early diagnosis of skin cancer. Teledermatology might contribute to reducing skin cancer mortality rates.

Frequency, Treatment and Outcome of Immune-Related Toxicities in Patients with Immune-Checkpoint Inhibitors for Advanced Melanoma: Results from an Institutional Database Analysis.

Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs), which may result in treatment discontinuation. We sought to describe the onset, frequency, and kinetics of irAEs in melanoma patients in a real-life setting and to further investigate the prognostic role of irAEs in treatment outcomes. In this retrospective single-center cohort study, we included 249 melanoma patients. Onset, grade, and resolution of irAEs and their treatment were analyzed. A total of 191 (74.6%) patients in the non-adjuvant and 65 (25.3%) in the adjuvant treatment setting were identified. In the non-adjuvant setting, 29 patients (59.2%) with anti-CTLA4, 43 (58.1%) with anti-PD1, and 54 (79.4%) with anti-PD1/anti-CTLA4 experienced some grade of irAE and these had an improved outcome. In the adjuvant setting, the frequency of irAEs was 84.6% in anti-CTLA4 and 63.5% in anti-PD1, but no correlation with disease relapse was observed. Patients with underlying autoimmune conditions have a risk of disease exacerbation. Immunomodulatory agents had no impact on treatment efficacy. IrAEs are correlated with increased treatment efficacy in the non-adjuvant setting. Application of steroids and immunomodulatory agents, such as anti-TNF-alpha or anti-IL6, did not affect ICI efficacy. These data support irAEs as possible prognostic markers for ICI treatment.

Internet based health promotion campaign against skin cancer - Results of www.skincheck.ch in Switzerland.

Conventional skin cancer prevention programs appeal to limited populations, and the middle aged male population responds less frequently. Our objective was to establish a complementary health promotion campaign tool for skin cancer prevention. Internet-based education, instruction for self assessment and teledermatological evaluation of skin lesions by an expert commission of dermatologists was used. Compliance and clinical diagnosis was assessed in a subgroup. 12,000 users visited the educational website. There was strong interest among the middle aged male population (53% (N = 262): male; mean age: 42). 28.5% of examined lesions (N = 494) were considered suspicious. Email requests, sent to the group whose lesions where considered suspicious, were answered by 46.0% of females (N = 29) and 59.7% of males (N = 46) with a female distribution predominantly in younger ages (52.6% of females with known age: < 30 years). Males were predominantly represented over 30 years (86.2% of all males). According to user's declarations, at least 8 (8.5%) malignant lesions (1 melanoma in situ, 1 squamous cell carcinoma, 4 basal cell carcinomas, 2 malignant lesions without declared diagnosis) were finally diagnosed by physicians. We conclude that internet-based, interactive, educational programs, in addition to existing health promotion campaigns, can enhance public participation in the middle aged male population in skin cancer prevention.

Vitamin D, ultraviolet exposure, and skin cancer in the elderly.

Ultraviolet (UV) radiation has both beneficial and harmful effects on the human body. Its most important beneficial effect may be vitamin D production in the skin, also known as vitamin D photosynthesis. This is of particular interest for the elderly who often show vitamin D-deficiency. Intentional UV exposure has been recommended by different institutions in order to increase vitamin D levels. Nevertheless, UV radiation directly causes DNA damage and is verifiably responsible for carcinogenesis, potentially resulting in lethal skin cancers. Unfortunately, skin cancer incidence is rising worldwide, and there is still a lack of appropriate treatment for metastasized types. The only proven and avoidable risk factor is UV radiation. It has been shown that the earlier UV protection is started, the greater the benefit in terms of skin cancer prevention. Nevertheless, even if UV protection is started at older ages, individuals will benefit measurably. Because UV radiation is neither a reliable nor a safe method of achieving healthy vitamin D levels, intentional UV radiation is not recommended to increase vitamin D levels. In order to prevent skin cancer, UV protection is to be conducted as commonly recommended, by minimizing sun exposure, and especially sunburn, with appropriate sun protective behaviors, e.g. usage of sunscreen and clothing (hat, sunglasses, long sleeves, and pants). Infants must be protected with extra care. Tanning beds must be avoided.

Ectopic axillary breast cancer in a male patient.

Ectopic breast tissue can persist in the axilla due to lack of involution of mammary glands along the mammary lines. It is rare in men, and the malignant transformation to breast cancer has occasionally been described. Differential diagnosis of any axillary tumor should include breast cancer arising at ectopic sites.