Skin biopsy utilization and melanoma incidence among Medicare beneficiaries.

BACKGROUND: Melanoma incidence has increased in recent decades in the U.S.A. Uncertainty remains regarding how much of this increase is attributable to greater melanoma screening activities, potential detection bias and overdiagnosis. OBJECTIVES: To use a cross-sectional ecological analysis to evaluate the relationship between skin biopsy and melanoma incidence rates over a more recent time period than prior reports. METHODS: Examination of the association of biopsy rates and melanoma incidence (invasive and in situ) in SEER-Medicare data (including 10 states) for 2002-2009. RESULTS: The skin biopsy rate increased by approximately 50% (6% per year) throughout this 8-year period, from 7012 biopsies per 100 000 persons in 2002 to 10 528 biopsies per 100 000 persons in 2009. The overall melanoma incidence rate increased approximately 4% (< 1% per year) over the same time period. The incidence of melanoma in situ increased approximately 10% (1% per year), while the incidence of invasive melanoma increased from 2002 to 2005 then decreased from 2006 to 2009. Regression models estimated that, on average, for every 1000 skin biopsies performed, an additional 5·2 (95% confidence interval 4·1-6·3) cases of melanoma in situ were diagnosed and 8·1 (95% confidence interval 6·7-9·5) cases of invasive melanoma were diagnosed. When considering individual states, some demonstrated a positive association between biopsy rate and invasive melanoma incidence, others an inverse association, and still others a more complex pattern. CONCLUSIONS: Increased skin biopsies over time are associated with increased diagnosis of in situ melanoma, but the association with invasive melanoma is more complex.

C16 laminin peptide increases angiotropic extravascular migration of human melanoma cells in a shell-less chick chorioallantoic membrane assay.

BACKGROUND: As distinct from intravascular dissemination, extravascular migratory metastasis (EVMM) has been described as a potential additional mechanism of melanoma spread in which tumour cells migrate along the external surfaces of vessels. Recent experimental studies strongly suggest a correlation of angiotropism of melanoma cells with EVMM. Angiotropic melanoma cells are linked to the endothelium by an amorphous matrix confirmed to contain laminin. OBJECTIVES: To investigate whether laminin plays a role in this extravascular mechanism of tumour spread. METHODS: We tested the effect of the C16 laminin peptide on melanoma spread in a shell-less chick chorioallantoic membrane model. RESULTS: After 3 days, green fluorescent protein-expressing melanoma cells were observed spreading along or in the immediate proximity of vessels. The C16 laminin peptide significantly lengthened the distance of extravascular, angiotropic migration of melanoma cells. Histopathology confirmed the angiotropism of melanoma cells without intravasation, compatible with that observed with human angiotropic melanoma. CONCLUSIONS: The results of this study suggest that the C16 laminin gamma1 chain peptide has angiotropic, extravascular migration-promoting activity on human melanoma cells, and might be a molecular target for preventing melanoma metastasis.

Dysplastic naevi with moderate to severe histological dysplasia: a risk factor for melanoma.

BACKGROUND: The risk of malignant melanoma associated with histologically dysplastic naevi (HDN) has not been defined. While clinically atypical naevi appear to confer an independent risk of melanoma, no study has evaluated the extent to which HDN are predictive of melanoma. OBJECTIVES: To estimate the risk of melanoma associated with HDN. Secondarily, the risk associated with number of naevi and large naevi is estimated. METHODS: We enrolled 80 patients with newly diagnosed melanoma along with 80 spousal controls. After obtaining information on melanoma risk factors and performing a complete cutaneous examination, the most clinically atypical naevus was biopsied in both cases and controls. Histological dysplasia was then assessed independently by 13 dermatopathologists (0, no dysplasia; 1, mild dysplasia; 2, moderate dysplasia; 3, severe dysplasia). The dermatopathologists were blinded as to whether the naevi were from melanoma subjects or controls. Multivariate analyses were performed to determine if there was an independent association between the degree of histological dysplasia in naevi and a personal history of melanoma. RESULTS: In persons with naevi receiving an average score of > 1 (i.e. naevi considered to have greater than mild histological dysplasia), there was an increased risk of melanoma [odds ratio (OR) 2.60, 95% confidence interval (CI) 0.99-6.86] which persisted after adjustment for confounders (OR 3.99, 95% CI 1.02-15.71). Very few dermatopathologists reliably graded naevi of subjects with melanoma as being more dysplastic than naevi of control subjects. Among the entire group, the interobserver reliability associated with grading histological dysplasia in naevi was poor (weighted kappa 0.28). CONCLUSIONS: HDN do appear to confer an independent risk of melanoma. However, this result may add more to our biological understanding of melanoma risk than to clinical assessment of risk, because HDN assessed by a single pathologist generally cannot be used to assess risk of melanoma. Future studies should be directed at establishing reproducible, predictive criteria for grading naevi.

Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas.

In the recently revised melanoma staging system proposed by the American Joint Committee on Cancer (AJCC), ulceration assessment by the pathologist is a pivotal parameter. Patients upstaged because of ulceration might be included in adjuvant trials conducted in AJCC stage II melanoma patients. Therefore, accuracy based on interobserver reproducibility for melanoma ulceration assessment is crucial for proper clinical management. In some cases, it is extremely difficult, even for an experienced pathologist, to distinguish between trauma-induced ulceration, artifact and tumoral ulceration. Whether this difficulty may be resolved by the use of a more precise definition of ulceration has not been evaluated. Therefore, we have proposed a refined definition of melanoma ulceration and we tested whether this definition might improve the interobserver interpretative reproducibility of ulceration in primary cutaneous melanomas. The results of this study support the need for a more precise definition of melanoma ulceration that rules out biopsy trauma or processing artifact and could be incorporated into a standardised pathology worksheet for reporting primary melanomas.

Epidermal hyperplasia overlying human melanoma correlates with tumour depth and angiogenesis.

The aim of this study was to determine whether epidermal hyperplasia overlying cutaneous human melanoma is associated with increased tumour angiogenesis, tumour growth and the potential for metastasis. Forty-two surgical specimens of cutaneous human melanoma of different depths, each containing epidermis present in the tumour-free margin, were analysed by immunohistochemistry for the expression of the pro-angiogenic molecules basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) and the anti-angiogenic molecule interferon-beta (IFN-beta). The epidermis overlying intermediate and thick (1.0-10.0 mm), but not thin (0.5-1.0 mm), melanoma specimens was hyperplastic. Although the expression level of bFGF, VEGF and IL-8 in the epidermis directly overlying the tumour was similar to that in the distant epidermis, the expression of IFN-beta was significantly decreased in keratinocytes overlying intermediate and thick, but not thin, melanomas. The microvessel density was also increased in intermediate and thick specimens. Human melanoma cells were injected subcutaneously into nude mice. The resulting tumours were used to determine the association between overlying epidermal hyperplasia and neoplastic angiogenesis. Similar to human autochthonous melanomas, epidermal hyperplasia was found only over lesions produced by metastatic cells. Although there was no change in the expression of the pro-angiogenic molecules, the expression of IFN-beta was significantly decreased in the hyperplastic epidermis. Conditioned medium collected from cultures of the metastatic cell line induced in vitro proliferation of mouse keratinocytes, whereas conditioned medium collected from cultures of the non-metastatic cell line did not. Collectively, the data demonstrate that metastatic melanoma cells induce keratinocyte proliferation, leading to decreased expression of the negative regulator of angiogenesis, IFN-beta, and hence to increased angiogenesis.

Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas.

BACKGROUND: The Intergroup Melanoma Surgical Trial began in 1983 to examine the optimal surgical margins of excision for primary melanomas of intermediate thickness (i.e., 1-4 mm). There is now a median 10-year follow-up. METHODS: There were two cohorts entered into a prospective multi-institutional trial: (1) 468 patients with melanomas on the trunk or proximal extremity who randomly received a 2 cm or 4 cm radial excision margin and (2) 272 patients with melanomas on the head, neck, or distal extremities who received a 2 cm radial excision margin. RESULTS: A local recurrence (LR) was associated with a high mortality rate, with a 5-year survival rate of only 9% (as a first relapse) or 11% (anytime) compared with an 86% survival for those patients who did not have a LR (P < .0001). The 10-year survival for all patients with a LR was 5%. The 10-year survival rates were not significantly different when comparing 2 cm vs. 4 cm margins of excision (70% vs. 77%) or comparing the management of the regional lymph nodes (observation vs. elective node dissection). The incidences of LR were the same for patients having a 2 cm vs. 4 cm excision margin regardless of whether the comparisons were made as first relapse (0.4% vs. 0.9%) or at anytime (2.1% vs. 2.6%). When analyzed by anatomic site, the LR rates were 1.1% for melanomas arising on the proximal extremity, 3.1% for the trunk, 5.3% for the distal extremities, and 9.4% for the head and neck. The most profound influence on LR rates was the presence or absence of ulceration; it was 6.6% vs. 1.1% in the randomized group involving the trunk and proximal extremity and was 16.2% vs. 2.1% in the non-randomized group involving the distal extremity and head and neck (P < .001). A multivariate (Cox) regression analysis showed that ulceration was an adverse and independent factor (P = .0001) as was head and neck melanoma site (P = .01), while the remaining factors were not significant (all with P > .12). CONCLUSION: For this group of melanoma patients, a local recurrence is associated with a high mortality rate, a 2-cm margin of excision is safe and ulceration of the primary melanoma is the most significant prognostic factor heralding an increased risk for a local recurrence.

The biology of melanoma micrometastases.

The biology and significance of micrometastases remain poorly understood. Whether such deposits represent hypothetical "dormant" metastases, simply the earliest metastases recognizable, or both has not been resolved. Attempting to answer the latter question among many others, we carried out studies on the rates of proliferation, and microvessel counts in melanoma micrometastases taken from sentinel lymph nodes as compared to conventional melanoma lymph node macrometastases. We found that these micrometastases were not vascularized and had low (and comparable) rates of both proliferation and apoptosis, suggesting a steady or dormant state. On the other hand, the macrometastases were fully vascularized and more proliferative, i.e., they had rates of proliferation that were significantly higher compared to the micrometastases and rate of apoptosis. How micrometastases develop is also poorly understood. Tumor cells are thought to arrive in lymph nodes and other sites through the blood and lymphatic circulation and to extravasate. However, in addition to the latter explanation, another mechanism may be operable which we have proposed as extravascular migratory metastasis. In studies of metastatic melanoma we have identified melanoma cells positioned on the surface of endothelial cells both by light and electron microscopy. We have also identified ultrastructurally the presence of an amorphous matrix interposed between the latter two cell types that shows immunostaining for laminin and, recently, the beta-2 chain of laminin. Thus, we currently believe that the latter form of "free" laminin may play a role in this proposed mechanism of metastasis and thus in the formation of micrometastases.

Evaluation of the relative contributions of various structures in chronic low back pain.

An attempt was made to determine the relative contribution of various structures to chronic low back pain, including facet joint(s), disc(s), and sacroiliac joint(s) in a prospective evaluation. Precision diagnostic blocks, including disc injections, facet joint blocks, and sacroiliac joint injections, are frequently used. In contrast, selective nerve root blocks or transforaminal epidural injections are used occasionally to evaluate persistent or recurrent low back pain in patients without appropriate radiologic or neurophysiologic diagnosis. One hundred and twenty patients with a chief complaint of low back pain were evaluated with precision diagnostic injections, which included medial branch blocks, provocative discography and sacroiliac joint injections. In 40% (95% CL, 31%, 49%), of the patients, facet joint pain was diagnosed; and in 26% (95% CL, 18%, 34%) of the patients discogenic pain was diagnosed; and 2% of the patients were diagnosed with sacroiliac joint pain.

Caudal epidural injections with sarapin or steroids in chronic low back pain.

Epidural steroid injections are the most commonly used procedures to manage chronic low back pain in interventional pain management settings. Approaches available to access the epidural space in the lumbosacral spine include the interlaminar, transforaminal, and caudal. The overall effectiveness of epidural steroid injections has been highly variable. This study included 65 patients who underwent diagnostic facet joint nerve blocks utilizing comparative local anesthetic blocks and were shown to be negative for facet joint pain and other problems such as sacroiliac joint pain before enrollment into the study. They were randomly selected from 105 patients negative for facet joint pain allocated into three groups, with Group I consisting of 15 patients comprising a convenience control sample treated conservatively; Group II, consisting of 22 patients treated with caudal epidural with local anesthetic and Sarapin(R); and Group III, consisting of 33 patients treated with caudal epidural with a mixture of local anesthetic, and betamethasone. The study period lasted for 3 years. Results showed that there was significant improvement in patients receiving caudal epidural injections, with a decrease in pain associated with improved physical, functional and mental status; and decreased narcotic intake combined with return to work. The study showed that at 1 month 96% of the patients evaluated showed significant improvement, which declined to 56% at 3 months and 16% at 6 months, with administration of 1 to 3 injections. Cumulative relief with 1 to 12 injections was noted in 96% of the patients at 1 month, 95% at 3 months, 85% at 6 months, and 67% at 1 year. The study also showed cost effectiveness of this treatment, with a cost of $ 2550 for 1-year improvement of quality of life . In conclusion, caudal epidural injections with steroids or Sarapin are an effective modality of treatment in managing chronic, persistent low back pain that fails to respond to conservative modalities of treatments and is also negative for facet joint pain. The treatment is not only effective clinically but also is cost effective.

Prevalence of opioid abuse in interventional pain medicine practice settings: a randomized clinical evaluation.

While drug therapy is one of the most commonly used modalities of treatment in managing persistent or chronic pain, controversy continues with regards to the appropriate use of controlled substances, specifically opioid analgesics, in interventional pain medicine settings. This study included 100 randomly selected patients receiving opioids in an interventional pain medicine setting. The patient's controlled substance profile was evaluated using multiple means. The patients were divided into two groups, with 76 patients in the non-abuse group and 24 patients in the abuse group after data collection. There were no significant differences noted either in demographic characteristics or psychological characteristics, except for a higher prevalence of depression in the abuse group. In conclusion, there was significant abuse of opioids in an interventional pain medicine setting, with an incidence of 24%, with frequent abuse seen in almost half of these patients. Thus, it is important for interventional pain physicians to recognize this possibility and also to recognize that there is no definite physiologic, psychologic or demographic information to suggest abuse, even though depression was more prevalent in abuse patients.

Characteristics of chronic low back pain in patients in an interventional pain management setting: a prospective evaluation.

Chronic low back pain patients are seen in multiple practice settings and managed with a multitude of therapeutic interventions. Studies conducted by various groups have made some generalizations in the literature describing low back pain patients. However, there are no studies evaluating the demographic features of patients presenting to therapeutic interventional pain medicine programs. This prospective study was undertaken to evaluate and explore various demographic features of patients with chronic low back pain presenting to a therapeutic interventional pain medicine program. Two hundred patients were studied, with evaluation of demographic features of age, mode of onset of pain, work status, history of surgery, and pain characteristics. The results showed that, among patients presenting to an interventional pain medicine program, 17% are over 65 years of age: they are predominantly women; two thirds are either overweight or obese; the mean duration of pain is 7 years, predominantly involving multiple regions, with an average pain intensity of 7.6, significant associated psychological conditions; they have undergone multiple interventions, and were seen by, on average, six physicians; and the majority of patients were not employed, with 31% unemployed and 52% disabled or retired.

Contribution of facet joints to chronic low back pain in postlumbar laminectomy syndrome: a controlled comparative prevalence evaluation.

Postlumbar laminectomy syndrome, or pain following operative procedures of the lumbar spine, is increasingly a common entity in modern medicine. Multiple causes proposed for recurrence of pain after lumbar laminectomy are: epidural fibrosis, recurrent disc herniation, instability, and facet joints. Even though the prevalence of persistent low back pain secondary to the involvement of lumbosacral facet joints has been described in controlled studies from 15% to 45%, the prevalence of facet joint mediated pain in postlumbar laminectomy syndrome has not been studied. This prospective, randomized, controlled comparative evaluation was performed to determine the prevalence of facet joint mediated pain in persistent low back pain in postlumbar laminectomy patients with a comparative non-surgical group. One hundred patients with fifty patients in each group were randomly assigned with group I consisting of fifty patients without history of previous surgery and group II consisting of fifty patients with history of previous surgery. Results showed that the prevalence of facet joint mediated pain in non-surgical patients was 44% compared to 32% in post surgical patients determined by comparative controlled local anesthetic blocks utilizing lidocaine and bupivacaine. This study also showed a false positive rate of 36% in non-surgical group and 24% in post-surgical group. In conclusion, this study shows that facet joint mediated symptomatology in chronic low back pain is prevalent, both in non-surgical as well as post-surgical patients even though prevalence was somewhat higher in the non-surgical group compared to post-surgical group.

Effectiveness of lumbar facet joint nerve blocks in chronic low back pain: a randomized clinical trial.

This randomized clinical trial was designed to determine the effectiveness of therapeutic lumbar facet joint nerve blocks. Two hundred patients were evaluated with controlled diagnostic blocks for the presence of facet joint mediated pain. Eighty four patients, or 42% were determined to have lumbar facet joint mediated pain. These patients were randomly allocated into two groups: Group I receiving therapeutic injections with local anesthetic and Sarapin, and Group II receiving therapeutic injections with a mixture of local anesthetic, Sarapin, and methyl prednisolone. A total of 73 patients were treated with medial branch blocks under fluoroscopy. Results showed that patients underwent multiple procedures over a period of 2(1/2) years. The mean number of procedures or interventions was 2.5 +/- 0.09 from 1 to 3 months, whereas it was 4 +/- 0.13 for 4 to 6 months, 6.1 +/- 0.21 for 7 to 12 months, and 8.4 +/- 0.31 for 13 to 32 months. Cumulative significant relief with one to three injections was 100% up to 1 to 3 months, 82% for 4 to 6 months, 21% for 7 to 12 months, and 10% after 12 months, with a mean relief of 6.5 +/- 0.76 months. There was significant improvement noted in overall health status with improvement not only in pain relief, but also with physical, functional, and psychological status, as well as return-to-work status. In conclusion, the results of this study demonstrate that medial branch blocks with local anesthetic and Sarapin, with or without steroids, are a cost effective modality of treatment, resulting in improvement in pain status, physical status, psychological status, functional status and return to work.

Signs and symptoms of melanoma in older populations.

We conducted a descriptive study to assess the relationship between increasing age and the reporting of melanoma signs/symptoms in 634 hospital-based and 624 population-based incident cases of melanoma. Multivariate logistic regression was used to evaluate the relationship between older age (> or = 50 years) and the reporting of melanoma signs/symptoms. Older patients were less likely to report itching and change in elevation of their lesions (P < 0.05). Change in color was also less likely to be reported by older patients, although not statistically significant. Ulceration of the lesion was reported significantly more by older patients (P < 0.05). Older individuals may be less likely to report itching and change in elevation/color of their lesions, but more likely to report ulceration, a symptom associated with advanced disease and poor prognosis. Further research is necessary to provide a better understanding of the development of melanoma in older populations so that new strategies can be explored to improve early detection in this age group.

Malignant melanoma, dysplastic melanocytic nevi, and Spitz tumors. Histologic classification and characteristics.

The classification and pertinent histopathologic features of cutaneous melanoma, dysplastic melanocytic nevi, and Spitz tumors are presented. A discussion on melanoma emphasizes an objective approach to classification based on histomorphologic features including location in the skin, disposition and frequency of melanocytes, other specific morphologic features, and cell type. Other topics addressed include common and unusual variants of melanoma, the use of immunohistochemistry, and the histopathologic reporting of melanoma.

Adjuvant high-dose interferon alfa-2b in patients with high-risk melanoma.

We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m2/day intravenously (i.v.) for 1 month and 10 mU/m2 three times per week subcutaneously (s.c.) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684.