Melanoma: Johnson TM

Houghton AN, Coit DG, Daud A, Dilawari RA, Dimaio D, Gollob JA, Haas NB, Halpern A, Johnson TM, Kashani-Sabet M, Kraybill WG, Lange JR, Martini M, Ross MI, Samlowski WE, Sener SF, Tanabe KK, Thompson JA, Trisal V, Urist MM, Walker MJ, Anonymous00370. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #16884669 No free full text.

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Sober AJ, Chuang TY, Duvic M, Farmer ER, Grichnik JM, Halpern AC, Ho V, Holloway V, Hood AF, Johnson TM, Lowery BJ, Anonymous00178. · No affiliation provided · J Am Acad Dermatol. · Pubmed #11568750 No free full text.

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Schwartz JL, Mozurkewich EL, Johnson TM. · No affiliation provided · Cancer. · Pubmed #12712462 links to  free full text

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Schmalbach CE, Johnson TM, Bradford CR. · Wilford Hall Medical Center, San Antonio, TX, USA. · Curr Probl Surg. · Pubmed #17112819 No free full text.

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Johnson TM, Sondak VK, Bichakjian CK, Sabel MS. · Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA. · J Am Acad Dermatol. · Pubmed #16384752 No free full text.

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Puleo CA, Messina JL, Riker AI, Glass LF, Nelson C, Cruse CW, Johnson TM, Sondak VK. · Cutaneous Oncology Division, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. · Cancer Control. · Pubmed #16258494 links to  free full text

Abstract: BACKGROUND: As the incidence of melanoma increases, thin melanomas are being diagnosed at an increasingly frequent rate. Currently available prognostic factors are limited in their ability to reliably discriminate which patients will manifest regional nodal metastasis and would be identified early through sentinel node biopsy. METHODS: We summarized our experience with sentinel node biopsy for patients with cutaneous melanomas less than 1.00 mm in Breslow thickness, with evaluation of Clark level as a predictor of positive sentinel node metastasis. RESULTS: Among the 409 patients identified, micrometastases were found in the sentinel node in 20 patients, for an overall incidence of nodal progression of 4.9%. A total of 252 (62%) were Clark level II or III (11 of whom had a positive sentinel node) and 157 (38%) were Clark level IV (9 of whom had a positive sentinel node). We reviewed the literature to identify reliable indicators that might be helpful in determining which patients with "thin melanomas" would be likely to manifest regional progression to warrant routinely undergoing a preoperative lymphoscintigraphy followed by a sentinel node biopsy. CONCLUSIONS: Based on available data, patients with melanomas between 0.75 and 1.00 mm are appropriate candidates to be considered for sentinel node biopsy after discussing the likelihood of finding evidence of nodal progression, the risks of sentinel node biopsy (including the risk of a false-negative result), and the lack of proven survival benefit from any form of surgical nodal staging.

Wechter ME, Gruber SB, Haefner HK, Lowe L, Schwartz JL, Reynolds KR, Johnston CM, Johnson TM. · Department of Obstetrics and Gynecology, University of Michigan Health System, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0314, USA. · J Am Acad Dermatol. · Pubmed #15034504 No free full text.

Abstract: BACKGROUND: Vulvar melanoma is the second most common vulvar malignancy and represents a significant women's health issue. OBJECTIVE: To report experience with 21 cases of vulvar melanoma in 20 patients and to review the literature about the condition. METHODS: Parameters retrospectively reviewed included age at diagnosis, family history of melanoma, location on the vulva, atypical nevi, Breslow depth, ulceration status, histologic pattern, presenting signs and symptoms, and the results of sentinel lymph node biopsy. Molecular characterization of the melanocortin type 1 receptor was performed in 1 patient. RESULTS: A family history of cutaneous melanoma was present in 15% of cases. The mean Breslow depth was 2.8 mm (range, 0.0-11.0 mm). Ten patients successfully underwent sentinel lymph node biopsy, results of which were positive in 2 (20%). Reported for the first time is that one patient had a germline mutation in the melanocortin type 1 receptor. CONCLUSION: Vulvar and cutaneous melanoma behave similarly despite their unique pathogeneses. Sentinel lymph node biopsy can be performed successfully for vulvar melanoma.

Johnson TM, Bradford CR, Gruber SB, Sondak VK, Schwartz JL. · Department of Dermatology, University of Michigan Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor 48109-0314, USA. · Arch Dermatol. · Pubmed #14732667 No free full text.

Abstract: OBJECTIVES: To clarify and update workup and follow-up strategies based on fundamental principles and current data, and to discuss new and current concepts regarding sentinel lymph node biopsy (SLNB), particularly in relation to the staging workup. DATA SOURCES: Studies conducted from 1995 to 2003 were identified by PubMed search. Additional searches included workup for reference lists of retrieved articles when applicable, and PubMed-related articles. STUDY SELECTION: Contemporary studies with good design, conclusions based on sound methods, and results pertaining to staging workup, SLNB, and follow-up tests were critically reviewed. DATA EXTRACTION: Data and conclusions based on the above studies were incorporated into a review. DATA SYNTHESIS: Routine tests have marginal to no efficacy and are not cost-efficient for detecting occult disease in asymptomatic patients with localized melanoma. The only staging test that has relatively high sensitivity and specificity and provides tissue diagnosis is SLNB; moreover, SLNB has revolutionized our understanding of lymphatic pathways. The concepts of interval nodes and unexpected lymphatic drainage pathways have been addressed by several recent reports. There are no data that demonstrate any significant difference in overall survival for detection of asymptomatic vs symptomatic stage IV melanoma. CONCLUSIONS: An initial workup is useful for staging and prognosis to identify occult disease, with potential outcome benefit if treated early; and, by detecting distant occult disease (stage IV), to obviate the need for an extensive surgical procedure and thereby avoid associated increased morbidity. The foundation for the workup and follow-up remains thorough history taking and a physical examination, combined with a low index of suspicion for symptom-directed tests.

Altman JF, Lowe L, Redman B, Esper P, Schwartz JL, Johnson TM, Haefner HK. · Department of Dermatology, University of Michigan, 1910 Taubman Center, Ann Arbor, MI 48109-0314, USA. · J Am Acad Dermatol. · Pubmed #14639405 No free full text.

Abstract: Metastasis of maternal malignant tumor to the products of conception is a rare event. Melanoma is the most common maternal malignant tumor to metastasize to the placenta and the fetus. We report the case of a 28-year-old woman with melanoma during pregnancy. At parturition, histologic evaluation of the placenta revealed metastatic melanoma, and multiple organ metastasis developed. The infant was free of disease. Metastasis to products of conception portends a poor prognosis for the mother. To our knowledge, this report is the first of a patient with melanoma metastasis to the placenta to survive more than 7 months after parturition. As caretakers of patients with melanoma, dermatologists are in a position to coordinate and direct the care and follow-up treatment of affected patients.

Johnson TM, Sondak VK. · Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109-0314, USA. · Arch Dermatol. · Pubmed #15381557 No free full text.

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Swetter SM, Layton CJ, Johnson TM, Brooks KR, Miller DR, Geller AC. · No affiliation provided · Arch Dermatol. · Pubmed #19380679 No free full text.

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Geller AC, Johnson TM, Miller DR, Brooks KR, Layton CJ, Swetter SM. · Department of Dermatology, Boston University School of Medicine, 720 Harrison Ave, DOB 801A, Boston, MA 02118, USA. · Arch Dermatol. · Pubmed #19380662 No free full text.

Abstract: OBJECTIVE: To determine factors associated with physician discovery of early melanoma in middle-aged and older men. DESIGN: Survey. SETTING: Three institutional melanoma clinics. PARTICIPANTS: A total of 227 male participants (aged > or =40 years) with invasive melanoma who completed surveys within 3 months of diagnosis. Intervention Survey. MAIN OUTCOME MEASURES: Factors associated with physician-detected thin melanoma. RESULTS: Patients with physician-detected melanoma were older, 57% were 65 years or older compared with 34% for other-detected (odds ratio [OR], 2.57; 95% confidence interval [CI], 1.19-5.55) and 42% for patient-detected melanoma (P = .07). Physician-detected melanoma in the oldest patients (aged > or =65 years) had tumor thickness equal to that of self-detected melanoma or melanoma detected by other means in younger patients. Back lesions composed 46% of all physician-detected melanoma, 57% of those detected by other means, and 16% of self-detected lesions (physician- vs self-detected: OR, 4.25; 95% CI, 1.96-9.23). Ninety-two percent of all physician-detected back-of-the-body melanomas were smaller than 2 mm compared with 63% of self-detected lesions (P = .004) and 76% of lesions detected by other means (P = .07). CONCLUSIONS: Skin screenings of at-risk middle-aged and older American men can be integrated into the routine physical examination, with particular emphasis on hard-to-see areas, such as the back of the body. "Watch your back" professional education campaigns should be promoted by skin cancer advocacy organizations.

Swetter SM, Johnson TM, Miller DR, Layton CJ, Brooks KR, Geller AC. · Department of Dermatology, Stanford University Medical Center, 900 Blake Wilbur Dr, Room W0069, Stanford, CA 94305, USA. · Arch Dermatol. · Pubmed #19380661 No free full text.

Abstract: OBJECTIVES: To identify factors related to the detection of melanoma and to determine those that differ between thinner vs thicker tumors in middle-aged and older men. DESIGN: Survey. SETTING: Three institutional melanoma clinics. PARTICIPANTS: Men 40 years or older who had newly diagnosed invasive melanoma. MAIN OUTCOME MEASURES: Differences in melanoma awareness, skin examination practices, discovery patterns, and social/medical care factors relative to tumor thickness. RESULTS: Two hundred twenty-seven men completed surveys within 3 months of melanoma diagnosis; 57 (25.1%) had thicker tumors (>2.00 mm). Thicker tumors were associated with nodular histologic features (43.9%), a lack of atypical nevi, having less than a high school education, and patient vs physician (dermatologist or nondermatologist) detection. Knowledge of melanoma (P = .007), attention to skin cancer detection information (P = .02), an interest in health topics (P = .003), and knowing the importance of physician skin examination (P = .05) were more common in those with thin tumors. Tumor thickness did not correlate with age, anatomic location, marital/cohabitation status, prior skin cancer, or sun sensitivity. Overall patient awareness of melanoma warning signs, skin self-examination practices, and Internet use were poor (<20%, <50%, and <14%, respectively). CONCLUSIONS: Physician discovery, the patient's higher level of education and detection-promoting awareness and attitudes, and the presence of clinically atypical nevi were related to thinner melanomas. Innovative outreach strategies and novel educational campaigns incorporating these factors, coupled with sharper messages regarding the importance of physician screening, are needed to improve early detection in middle-aged and older men.

Shackleton MJ, Quintana E, Fullen DR, Sabel MS, Johnson TM. · No affiliation provided · Arch Dermatol. · Pubmed #19289763 No free full text.

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Ludgate MW, Fullen DR, Lee J, Lowe L, Bradford C, Geiger J, Schwartz J, Johnson TM. · Department of Dermatology, University of Michigan Medical School and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA. · Cancer. · Pubmed #19123453 No free full text.

Abstract: BACKGROUND: Atypical Spitz tumors (AST) are rare spitzoid melanocytic proliferations with an uncertain malignant potential. ASTs have overlapping features of both Spitz nevi and spitzoid melanoma, and consequently generate controversy with diagnosis and management. Sentinel lymph node biopsy (SLNB) has been proposed as a possible means to gain additional insight into the true biologic potential of these tumors; however, previous reports on the use of SLNB in ASTs have been limited by small numbers of patients and short durations of follow-up. METHODS: The authors extracted data from their institution's prospective melanoma database, collected between 1994 and 2007, for all patients with ASTs of uncertain biologic potential. They reviewed the clinical features of these patients, including the sentinel lymph node status, and the histological features of the tumors. RESULTS: A total of 67 patients with ASTs were identified, with a median age of 23.7 years. The mean depth was 2.4 mm. Of these, 57 had a SLNB performed, with 27 (47%) having a positive sentinel lymph node. SLNB-positive cases had a significantly lower mean age than SLNB-negative cases (17.9 vs 28.7 years; P = .013); however, no other significant differences were observed. All 27 patients with a positive SLNB were alive and disease free with median follow-up of 43.8 months. One patient who did not receive a SLNB developed recurrent disease with regional and distant metastases. CONCLUSIONS: ASTs do not appear to behave like conventional melanoma. There is a high incidence of microscopic lymph node deposits in SLNBs, but despite this finding, patients have a favorable prognosis. Our findings raise several questions regarding the malignant potential of ASTs, and the role of SLNB in their management.

Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. · Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA. · Nature. · Pubmed #19052619 links to  free full text

Abstract: A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells (0.1-0.0001%) form tumours when transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, the extent to which NOD/SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg(-/-)) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.

Demirci H, Johnson TM, Frueh BR, Musch DC, Fullen DR, Nelson CC. · Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA. · Ophthalmology. · Pubmed #18692248 No free full text.

Abstract: OBJECTIVE: To evaluate the outcome of the square procedure, a multidisciplinary, staged excision technique using standard formalin-fixed, vertically oriented sections for periocular cutaneous melanoma. DESIGN: Observational, retrospective, case series. PARTICIPANTS: Forty patients with periocular cutaneous melanoma treated with the square procedure. METHODS: Demographic features, tumor data, and recurrence rate were reviewed retrospectively for 40 patients with periocular cutaneous melanoma treated with the square procedure. MAIN OUTCOME MEASURE: Local recurrence rate. RESULTS: Of 40 patients, 26 (65%) had lentigo maligna melanoma in situ (MIS), 12 (30%) had lentigo maligna melanoma, and 2 (5%) had superficial spreading melanoma. Tumor-free margins were reached within a mean margin of 13 mm for patients with MIS and of 16 mm for patients with invasive melanoma. There was no statistical difference for the margin width in patients with MIS and invasive melanoma. The lesion size and margin width were significantly correlated. Recurrence was observed in 1 (2.5%) patient at 8 months after the square procedure, and a Kaplan-Meier survival curve estimated a local recurrence rate of 2.5% at 8 years. CONCLUSIONS: The square procedure is an effective procedure for management of periocular lentigo maligna melanoma in situ and lentigo maligna melanoma with a low local recurrence rate of 2.5% at 8 years. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Frankel TL, Griffith KA, Lowe L, Wong SL, Bichakjian CK, Chang AE, Cimmino VM, Bradford CR, Rees RS, Johnson TM, Sabel MS. · Department of Surgery, University of Michigan Health System, Ann Arbor, MI, USA. · Ann Surg Oncol. · Pubmed #18626721 No free full text.

Abstract: INTRODUCTION: Multiple attempts have been made to identify melanoma patients with a positive sentinel lymph node (SLN) who are unlikely to harbor residual disease in the nonsentinel lymph nodes (NSLN). We examined whether the size and location of the metastases within the SLN may help further stratify the risk of additional positive NSLN. METHODS: A review of our Institutional Review Board (IRB)-approved melanoma database was undertaken to identify all SLN positive patients with SLN micromorphometric features. Univariate logistic regression techniques were used to assess potential significant associations. Decision tree analysis was used to identify which features best predicted patients at low risk for harboring additional disease. RESULTS: The likelihood of finding additional disease on completion lymph node dissection was significantly associated with primary location on the head and neck or lower extremity (P = 0.01), Breslow thickness >4 mm (P = 0.001), the presence of angiolymphatic invasion (P < 0.0001), satellitosis (P = 0.004), extranodal extension (P = 0.0002), three or more positive SLN (P = 0.02) and tumor burden within the SLN >1% surface area (P = 0.004). Sex, age, mitotic rate, ulceration, Clark level, histologic subtype, regression, and number of SLN removed had no association with finding a positive NSLN. Location of the metastases (capsular, subcapsular or parenchymal) showed no correlation with a positive NSLN. Decision tree analysis incorporating size of the metastatic burden within the SLN along with Breslow thickness can identify melanoma patients with a positive SLN who have a very low risk of harboring additional disease with the NSLN. CONCLUSION: Size of the metastatic burden within the SLN, measured as a percentage of the surface area, helps stratify the risk of harboring residual disease in the nonsentinel lymph nodes (NSLN), and may allow for selective completion lymphadenectomy.

Jejurikar SS, Borschel GH, Johnson TM, Lowe L, Brown DL. · Department of Plastic Surgery, Manhattan Eye, Ear and Throat Hospital, New York City, NY, USA. · Plast Reconstr Surg. · Pubmed #17898597 No free full text.

Abstract: BACKGROUND: Peripheral margin control of lentigo maligna and melanoma on the head and neck can be problematic. Frozen sections are unreliable, and conventional histopathology cannot examine the entire margin. Customary treatment involves wide excision and dressing care or skin graft coverage until histopathologic evaluation is complete, as reexcision is frequently required because of positive margins. Wound contraction, donor-site morbidity, and additional procedures before reconstruction are inherent disadvantages to this approach. METHODS: After excisional biopsy of facial lentigo maligna and thin (<1 mm) lentigo maligna melanoma, peripheral margin control was performed in the office by means of excision of 2-mm-wide linear strips of skin, 5 to 10 mm from the biopsy site, combined with simple wound closure. Total margins were evaluated by means of permanent sections. Repeated margin excision was performed until clear. Definitive excision of the lesion was then performed and, with confidence of negative peripheral margins, the optimal reconstructive option was pursued immediately. RESULTS: Fifty-one lesions underwent "square" peripheral margin control, with lentigo maligna melanoma present in nine lesions (average Breslow depth, 0.65 mm). Margins required for clearance of lentigo maligna and lentigo maligna melanoma averaged 1.0 and 1.3 cm, respectively. No recurrences were identified with long-term follow-up. Reconstruction using the optimal procedure was performed immediately in all cases. CONCLUSIONS: Use of the square technique in the management of lentigo maligna and lentigo maligna melanoma improves the certainty of peripheral margin control before definitive excision. Immediate reconstruction can be performed, thereby avoiding temporizing procedures or open wounds and providing for optimal aesthetic and functional results.

Paek SC, Griffith KA, Johnson TM, Sondak VK, Wong SL, Chang AE, Cimmino VM, Lowe L, Bradford CR, Rees RS, Sabel MS. · Department of Dermatology, University of Michigan Health System, Ann Arbor, Michigan, USA. · Cancer. · Pubmed #17146784 links to  free full text

Abstract: BACKGROUND: In addition to Breslow depth, the authors previously described how increasing mitotic rate and decreasing age predicted sentinel lymph node (SLN) metastases in patients with melanoma. The objectives of the current study were to verify those previous results and to create a prediction model for the better selection of which patients with melanoma should undergo SLN biopsy. METHODS: The authors reviewed 1130 consecutive patients with melanoma in a prospective database who underwent successful SLN biopsy. After eliminating patients aged <16 years and patients who had melanomas that measured <1 mm, 910 remaining patients were reviewed for clinical and pathologic features and positive SLN status. Univariate association of patient and tumor characteristics with positive SLN status was explored by using standard logistic regression techniques, and the best multivariate model that predicted lymph node metastases was constructed by using a backward stepwise-elimination technique. RESULTS: The characteristics that were associated significantly with lymph node metastasis were angiolymphatic invasion, the absence of regression, increasing mitotic rate, satellitosis, ulceration, increasing Breslow depth, decreasing age, and location (trunk or lower extremity compared with upper extremity or head/neck). Previously reported interactions between mitotic rate and age and between Breslow depth and age were confirmed. The best multivariate model included patient age (linear), angiolymphatic invasion, the number of mitoses (linear), the interaction between patient age and the number of mitoses, Breslow depth (linear), the interaction between patient age and Breslow depth, and primary tumor location. CONCLUSIONS: Younger age, increasing mitotic rate (especially in younger patients), increasing Breslow depth (especially in older patients), angiolymphatic invasion, and trunk or lower extremity location of the primary tumor were associated with a greater likelihood of positive SLN status. The current results support the use of factors beyond Breslow depth to determine the risk of positive SLN status in patients with cutaneous melanoma.

Schmalbach CE, Johnson TM, Bradford CR. · Wilford Hall Medical Center, San Antonio, TX, USA. · Curr Probl Surg. · Pubmed #17112818 No free full text.

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Denoyelle C, Abou-Rjaily G, Bezrookove V, Verhaegen M, Johnson TM, Fullen DR, Pointer JN, Gruber SB, Su LD, Nikiforov MA, Kaufman RJ, Bastian BC, Soengas MS. · Department of Dermatology and Comprehensive Cancer Center, University of Michigan, 1500E Medical Center Drive, 4217 CCGC, Ann Arbor, MI 48109, USA. · Nat Cell Biol. · Pubmed #16964246 No free full text.

Abstract: Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRAS(G12V)) but not its downstream target BRAF (BRAF(V600E)), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16(INK4a) nor classical senescence markers--such as foci of heterochromatin or DNA damage--were able to account for the specific response of melanocytes to HRAS(G12V). Instead, HRAS(G12V)-driven senescence was mediated by the ER-associated unfolded protein response (UPR). The impact of HRAS on the UPR was selective, as it was poorly induced by activated NRAS (more frequently mutated in melanoma than HRAS). These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control.

McHugh JB, Su L, Griffith KA, Schwartz JL, Wong SL, Cimmino V, Chang AE, Johnson TM, Sabel MS. · Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Ann Surg Oncol. · Pubmed #16952026 No free full text.

Abstract: BACKGROUND: Truncal melanoma involving metastases to multiple lymph node basins has a much worse prognosis than tumor involvement of a single lymph node basin. Recent results also suggest that, independently of the status of lymph node involvement, patients with multiple lymphatic basin drainage (MLBD) on lymphoscintigraphy have an increased risk of lymph node metastasis and a worse prognosis than those with a single lymphatic drainage basin. Because published reports have conflicting results, the authors compared their experience at the University of Michigan Comprehensive Cancer Center with recently published findings. METHODS: The authors searched a prospectively maintained melanoma database at the University of Michigan for patients with primary truncal melanoma who underwent lymphoscintigraphy and sentinel lymph node biopsy between 1997 and 2004. The association of MLBD with the clinical and pathologic characteristics collected and the presence of regional metastases was tested by using contingency tables and the chi(2) test statistic and by using the Fisher's exact test statistic when cell frequencies were small. The product-limit method of Kaplan and Meier was used to estimate disease-free and overall survival probabilities. RESULTS: Of 423 patients with primary truncal melanoma who underwent sentinel lymph node biopsy, 123 (29%) had a positive result, and 98 patients (23.2%) had MLBD. Patients with tumors located in the middle of the trunk and tumor ulceration were more likely to have MLBD (P < .0001 and P = .045, respectively). Patients with a single lymphatic drainage basin and MLBD had a similar risk of lymph node metastasis and similar disease-free and overall survival. CONCLUSIONS: Patients with truncal melanomas tend to have MLBD when the tumor is located in the middle of the trunk or when ulceration is present. In our experience, drainage to multiple lymphatic basins was not an independent risk factor for sentinel lymph node metastasis and has no independent prognostic significance.

Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, Redman B, Thomas NE, Gruber SB. · Department of Epidemiology, University of Michigan, Ann Arbor, Michigan 48109-2200, USA. · Melanoma Res. · Pubmed #16845322 No free full text.

Abstract: In this report, we investigated BRAF/NRAS mutations in samples from a case-control study of melanoma and a series of benign melanocytic nevi. We evaluated potential associations between BRAF mutations and histopathologic and pigmentary characteristics of melanoma. Mutations in BRAF and NRAS were detected by sequencing microdissected/laser-captured DNA from 18 in-situ melanomas, 64 primary melanomas, and 51 nevi. Nevi showed the highest frequency of BRAF mutations (82%). BRAF mutations were identified in 29% of invasive melanomas and in only 5.6% of in-situ melanomas. Mutations in NRAS were found in 5.2% of primary melanomas, 5.9% of nevi and no NRAS mutations were seen in in-situ melanomas. A majority of the BRAF mutations observed in primary invasive melanoma were seen in superficial spreading melanoma (15/17), and melanomas with BRAF mutations were also more likely to be found on a body site that was likely to be exposed to intermittent sun exposure compared with chronic or no sun exposure (P=0.02). Tumors with BRAF mutations were also significantly more likely to occur in association with a contiguous nevus (odds ratio 3.49, 95% confidence interval 1.06-11.46), although a contiguous nevus was not found in all melanomas with a BRAF mutation. Our data support the evidence that the mitogen-activated protein kinase pathway is upregulated in a large percentage of melanocytic lesions, but these mutations are not sufficient for malignant transformation. We suggest that BRAF mutations contribute to benign melanocytic hyperplasia, but are likely to contribute to invasive melanoma only in conjunction with other mutations.

Fullen DR, Poynter JN, Lowe L, Su LD, Elder JT, Nair RP, Johnson TM, Gruber SB. · Department of Pathology, University of Michigan, Ann Arbor, MI 48109-0602, USA. · Mod Pathol. · Pubmed #16799476 links to  free full text

Abstract: BRAF mutations are common events in a variety of melanocytic nevi and primary cutaneous melanomas. We have previously found BRAF mutations in 82% of nevi, consisting of congenital, common acquired and dysplastic types, and 33% of primary cutaneous melanomas other than the spitzoid type, similar to other published reports. A small number of studies have evaluated Spitz nevi and have failed to detect any lesions possessing a BRAF mutation. Only one study included categories of atypical Spitz nevus and borderline lesions suspected to be spitzoid melanomas, along with classic Spitz nevi and spitzoid melanomas. We examined a spectrum of spitzoid lesions that included 48 Spitz nevi, some with atypical features, seven atypical (borderline) Spitz tumors, and 13 spitzoid melanomas. BRAF mutations were detected in 12 of 68 spitzoid lesions, of which two were spitzoid melanomas and 10 were Spitz nevi. Five of the 10 Spitz nevi with BRAF mutations were altered by more than usual cytologic atypia and/or architectural atypia overlapping with dysplastic nevi, or irritation/inflammation; one desmoplastic Spitz nevus had a BRAF mutation. These results indicate that a small subset of Spitz nevi, some with atypical histologic features, possess BRAF mutations. Therefore, the BRAF mutational status does not separate all Spitz nevi from spitzoid melanomas and non-Spitz types of melanocytic proliferations, contrary to previous reports.