Published Ahead of Print on December 14, 2009 as 10.1200/JCO.2009.24.7734 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/jco.2009.24.7734 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Pathology Review of Thin Melanoma and Melanoma in Situ in a Multidisciplinary Melanoma Clinic: Impact on Treatment Decisions Alfredo A. Santillan, Jane L. Messina, Suroosh S. Marzban, Gema Crespo, Vernon K. Sondak, and Jonathan S. Zager From the Department of Surgery, Section of Surgical Oncology, University of Texas Health Science Center at San Antonio; Section of Surgical Oncology, Audie L. Murphy Veterans Affairs Hospital, San Antonio, TX; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute; and Departments of Oncologic Sciences, Dermatology, and Surgery, University of South Florida College of Medicine, Tampa, FL. Submitted June 25, 2009; accepted September 22, 2009; published online ahead of print at www.jco.org on December 14, 2009. Presented in part at the 7th World Congress on Melanoma/5th Congress of the European Association of Dermato-Oncology, May 12-16, 2009, Vienna, Austria. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Jonathan S. Zager, MD, 12902 Magnolia Dr, SRB4.24012, Tampa, FL 33602; e-mail: jonathan.zager@moffitt.org. 2009 by American Society of Clinical Oncology A B S T R A C T Purpose Patients with thin melanoma ( 1.0 mm) and melanoma in situ (MIS) represent the majority of newly diagnosed melanoma. We estimated the impact of expert review of outside pathology material on the staging and thus treatment decisions affecting patients referred to a multidisciplinary clinic with early-stage melanoma. Patients and Methods We studied patients with a diagnosis of thin melanoma or MIS referred to H. Lee Moffitt Cancer Center from 2006 to 2009. After comparing the referring laboratory and in-house dermatopathologic interpretations, we calculated any differences in diagnosis and tumor staging and the potential impact of differences in diagnosis and staging on prognosis and surgical treatment using the National Comprehensive Cancer Network clinical guidelines. Results The overall pathologic discordance rate in diagnosis was 4% (15 of 420 patients; 95% CI, 2% to 6%). The overall change in tumor staging rate was 24% (97 of 405 patients; 95% CI, 20% to 28%). Pathology review led to changes in surgical excision margins in 12% of patients (52 of 420 patients; 95% CI, 9% to 16%) and in the decision about whether to perform a sentinel lymph node biopsy in 16% of patients (67 of 420 patients; 95% CI, 13% to 20%). Key pathologic factors, particularly mitotic rate, were frequently missing from outside pathology reports. Conclusion Our data suggest that review of thin melanoma or MIS by an expert dermatopathologist results in frequent, clinically meaningful alterations in diagnosis, staging, prognosis, and surgical treatment. Referral of these patients to a multidisciplinary melanoma clinic is appropriate, and management of such patients should include review of the biopsy whenever feasible. J Clin Oncol 27. 2009 by American Society of Clinical Oncology 0732-183X/09/2799-1/$20.00 DOI: 10.1200/JCO.2009.24.7734 INTRODUCTION The incidence of malignant melanoma is increasing rapidly worldwide, even in countries with historically low incidence rates. 1 Melanoma now represents the sixth most common cancer in the United States, with an average lifetime risk of one in 39 men and one in 58 women. 2 Furthermore, according to the American Joint Committee on Cancer (AJCC), stage I melanomas make up approximately 78% of all newly diagnosed cutaneous melanomas reported to the National Cancer Institute s Surveillance, Epidemiology, and End Results cancer registry. Of these, 81% are thin lesions (Breslow thickness of 1.0 mm). 3 Clinical visits for evaluation and management of both MIS and thin melanomas are expected to increase in the future as a result of populationbased melanoma education programs that, in turn, will likely result in a reduction of the median melanoma thickness at the time of diagnosis. 4-6 The growing incidence of melanoma has resulted in the need to optimize patient care. As a result, multidisciplinary cancer clinics have become increasingly prevalent in the management of patients with melanoma and other malignancies. Although the multidisciplinary approach is favored and in fact funded by the National Cancer Institute as part of the care provided by its comprehensive cancer centers, its impact on care has yet to be established. 7,8 Currently, most multidisciplinary melanoma care focuses on patients with advanced disease. 9 Patients with early-stage melanoma may be treated in the community and potentially overlooked in a group treatment/discussion approach. 2009 by American Society of Clinical Oncology 1 Copyright 2009 by American Society of Clinical Oncology
Santillan et al Review of referral melanoma in situ (MIS) and thin melanoma histopathologic material at a multidisciplinary tumor board may be of particular benefit to establish correct diagnosis and histopathologic microstaging. This information is critical because it defines the recommended surgical management for early-stage melanoma according to institutional and national guidelines. We sought to examine our experience with patients evaluated at our multidisciplinary melanoma tumor board with MIS and thin melanoma and to determine the impact this had on the surgical recommendations compared with the recommendations received before this evaluation. PATIENTS AND METHODS This is an institutional review board approved retrospective review of data from consecutive patients with biopsy-proven MIS and thin melanoma at outside facilities referred to two surgical oncologists (V.K.S. and J.S.Z.) in the Cutaneous Oncology Program at the H. Lee Moffitt Cancer Center for management of their melanomas between August 2006 and April 2009. All patients in this study had undergone an initial evaluation, biopsy, and recommendations for treatment by community dermatologists, surgeons, or primary care physicians. All medical records, pathology reports, and slides are sent to the clinic before consultation to allow for review and confirmation of diagnosis of the referral biopsy specimens. On the day of consultation, a treatment plan based on pathologic diagnosis and staging obtained after in-house review and according to institutional guidelines and the National Cancer Comprehensive Cancer Network s (NCCN) most current clinical guidelines for MIS and thin melanoma is discussed with the patient and family. 10 The records of 420 consecutive patients with MIS and thin melanoma were reviewed to assess demographic, clinicopathologic, and treatmentrelated factors. We first compared the pathologic diagnosis from the referral facility with the final diagnosis obtained after multidisciplinary tumor board pathology review to establish concordance rates, and then we investigated its potential impact on treatment. To ensure accuracy, a third opinion by an outside dermatopathologist was used for those patients with a discordant diagnosis or diagnostically challenging lesion. Among patients with a concordant diagnosis, significant alterations in the AJCC pathologic staging 11 between the outside pathology and the multidisciplinary tumor board pathology review were recorded. Statistical analysis was performed using the 2 test, Fisher s exact test, and Wilcoxon rank sum test, when appropriate. A twotailed P.05 was considered statistically significant. All statistical analysis was performed using Stata 9 (StataCorp, College Station, TX). RESULTS Pathologic Review A total of 424 lesions from 420 patients were referred to our institution with an outside confirmed pathologic diagnosis of thin melanoma or MIS (Table 1). We assessed the inclusion of several key pathologic findings that should be included in the pathology report according to NCCN guidelines for patients with invasive thin melanoma; these include tumor thickness, ulceration status, mitotic rate, deep margin status, and Clark level (Table 2). The majority (76%) of outside pathology reports indicated that pathologic assessment was performed by a dermatopathologist. Key pathologic findings such as mitotic rate, ulceration status, deep margin status, and Clark level were not reported in 47%, 13%, 29%, and 2% of thin melanoma referral patients, respectively. Among patients referred with a diagnosis of invasive thin melanoma, histopathologic review at the melanoma tumor board resulted in major changes in interpretation for 12 (3%) of 370 patients. Of Table 1. Demographics and Clinical Characteristics of 420 Patients (424 lesions) Referred With the Pathologic Diagnosis of MIS and Thin Melanoma Characteristic MIS Thin Melanoma ( 1.0 mm) Sex Female 30 60 170 46 Male 20 40 200 54 Age, years Mean 64 55 Range 25-85 1-89 20 0 6 2 20-39 6 12 63 17 40-59 15 30 150 40 60-79 27 54 128 35 80 2 4 23 6 Location* Head and neck 8 16 23 6 Trunk 19 38 200 54 Extremity 23 46 150 40 Previous history of melanoma Yes 4 8 33 10 No 46 92 337 90 Type of biopsy Shave 35 70 242 66 Punch 5 10 54 14 Excisional 5 10 38 10 Unknown 5 10 40 10 Abbreviation: MIS, melanoma in situ. *One patient had two pigmented lesions removed, and the location was not known for this patient s actual invasive thin melanoma with two lesions ambiguously identified. Thus the Location/Then Melanoma column totals 373, not 374. those 12 patients originally diagnosed with thin melanoma, pathologic review led to a change in diagnosis to Spitz nevus (n 3; Appendix Fig A1, online only), compound Clark nevus (n 4), pigmented epithelioid cell nevus (n 1), compound melanocytic nevus (n 1), and atypical melanocytic proliferation (n 3). Histopathologic review of patients referred with MIS resulted in a change in three (6%) of 50 patients to spindle cell nevus of Reed (n 1), atypical junctional Clark nevus (n 1), and junctional dysplastic nevus (n 1; Appendix Fig A2, online only). Overall, 15 (4%; 95% CI, 2% to 6%) of 420 patients referred to our institution with early-stage melanoma were reclassified as having benign lesions. We analyzed clinical factors that potentially could have an impact on misclassification. Among patients with a referral diagnosis of thin melanoma, younger age was significantly associated with a change in diagnosis (P.01, Wilcoxon rank sum test). The median age of diagnosis of patients with misclassification was 35 years (range, 15 to 54 years) compared with 56 years (range, 14 to 89 years) in patients without a change in pathologic interpretation. A similar clinical association was observed among patients with a referral diagnosis of MIS; however, the association was only marginally significant (P.07, Wilcoxon rank sum test). The median age was 48 years (range, 27 to 54 years) in patients with misclassification compared with 64 years (range, 25 to 85 years) in patients without a change in diagnosis. Misclassification was not associated with sex, personal history of melanoma, outside pathology review by a dermatopathologist, location, 2 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Pathology Review of Early-Stage Melanoma Table 2. Referral Pathology Report of 374 Lesions With an Outside Diagnosis of Thin Melanoma Characteristic on Referral Pathology Report Lesions % Outside dermatopathologist review Present 284 76 Absent 21 6 Not reported 69 18 Thickness, mm 0.76 249 67 0.76-1.00 125 33 Clark level II or III 273 73 IV 92 25 Not reported 9 2 Ulceration Present 20 5 Absent 306 82 Not reported 48 13 Regression Present 27 7 Absent 132 35 Not reported 215 58 Angiolymphatic invasion Present 3 1 Absent 187 50 Not reported 184 49 Mitotic rate 0 99 26 1 51 14 Low 41 11 Moderate to high 7 2 Not reported 176 47 Deep margin Positive 119 32 Negative 147 39 Not reported 108 29 or biopsy type in patients with a referral diagnosis of MIS and thin melanoma (Fisher s exact test). We further assessed changes in the AJCC pathologic staging among patients with a diagnosis of melanoma based on our review (Table 3). Twenty-six percent of patients (95% CI, 21% to 31%) who initially were referred with an outside diagnosis of invasive thin melanoma were restaged after review (92 of 358 patients; 92 of 362 lesions). Forty-five patients (13%) were upstaged; reasons for upstaging included findings of ulceration in a T1B lesion 1.0 mm (n 1), change from Clark level II or III to level IV in lesions 1.0 mm (n 28), T2A lesion with a 1.1- to 2.0-mm thickness without ulceration (n 14; Appendix Fig A3, online only), T2B lesion with a 1.1- to 2.0-mm thickness with ulceration (n 1), and T3A lesion with a 2.1- to 4.0-mm thickness with ulceration (n 1). In contrast, 47 patients (13%) were downstaged; reasons for downstaging included change from thin melanoma to MIS (n 15; Appendix Fig A4, online only), change from Clark level IV to level II or III (n 25), and absence of ulceration (n 7). However, 11% of patients (five of 47 patients; 95% CI, 4% to 23%) with an outside diagnosis of MIS were upstaged to thin melanoma (Fig 1). Overall, change in pathologic staging occurred in 24% of patients (95% CI, 20% to 28%) with a diagnosis of early-stage melanoma after pathology review at our multidisciplinary tumor board (97 of 405 patients; 97 of 409 lesions). Surgical Recommendations Pathology review at the tumor board led to changes in the recommended surgical excision margins of the primary lesion in 52 patients (12%; 95% CI, 9% to 16%) based on NCCN guidelines (Table 4). A smaller excision margin was recommended in 30 patients (7%), whereas in 22 patients (5%), a wider excision margin was suggested. We further assessed changes in diagnosis that would lead to changes in the recommendation to perform a sentinel lymph node biopsy (SLNB) after tumor board review (Table 5). Several recommendation criteria were evaluated. First, using tumor thickness as the only criteria for SLNB, we identified that using a tumor thickness 1.0 mm, the multidisciplinary tumor board would have changed the recommendation to perform an SLNB in 16 patients (4%; 95% CI, 2% to 6%). Using a tumor thickness 0.76 mm (which is currently our Breslow depth threshold at H. Lee Moffitt Cancer Center), a change in recommendation in SLNB was observed in 42 patients (10%; 95% CI, 7% to 13%). Alternatively, using the current AJCC staging as a guide to recommend SLNB for those lesions T1B, the multidisciplinary tumor board would have recommended changes (to perform SLNB Table 3. Change in AJCC Tumor Staging After Pathologic Review at the Multidisciplinary Tumor Board in 409 Lesions With a Concordant Diagnosis of Melanoma (thin and MIS) Referral Pathology Tumor Stage T0 T1A T1B Tumor Board Pathology Tumor Stage Lesions % Lesions % Lesions % Lesions % T0 (MIS) 42 89 14 5 1 1 57 14 T1A ( 1.0 mm, Clark II or III, no ulceration) 5 11 211 81 32 31 248 61 T1B ( 1.0 mm, Clark IV or ulceration) 0 0 29 11 58 57 87 22 T2A (1.1-2.0 mm, no ulceration) 0 0 4 2 10 10 14 3 T2B (1.1-2.0 mm, ulceration) 0 0 0 0 1 1 1 0.2 T3A (2.1-4.0 mm, no ulceration) 0 0 1 1 0 0 1 0.2 Total 47 12 260 63 102 25 409 Abbreviations: AJCC, American Joint Committee on Cancer; MIS, melanoma in situ. These numbers indicate concordance between referral diagnosis and internal pathology review. One lesion staged T1A by outside pathology was changed to melanoma dermal nodule with the differential diagnosis of possible recurrent or metastatic melanoma. Total www.jco.org 2009 by American Society of Clinical Oncology 3
Santillan et al Table 5. Changes in Recommended SLNB After Melanoma Tumor Board Review in 420 Patients With Referral Diagnosis of Melanoma SLNB Criteria Not to Perform SLNB Change in Recommendation To Perform SLNB Total Change Thickness only, mm 1.0 0 0 16 4 16 4 0.76 25 6 17 4 42 10 Tumor AJCC staging: T1A v T1B 33 8 34 8 67 16 Mitotic rate: 1mm 2 32 8 38 10 70 18 Fig 1. Lesion with outside diagnosis of melanoma in situ; hematoxylin and eosin (HE) and Melan-A immunostain demonstrate rare dermal nests of tumor (arrow), 0.20 mm in depth (HE and Melan-A, 200). because of upstaging T1A or to avoid SLNB because of downstaging to T1B) in 67 patients (16%; 95% CI, 13% to 20%). Finally, using a mitotic rate 1mm 2 as criteria for SLNB, a change in recommendation would be seen in 70 of 382 patients (18%; 95% CI, 15% to 23%) with available mitotic rate. Of the 352 patients with diagnosis of invasive melanoma after our tumor board review, 82 patients underwent SLNB. Overall, six patients (7%) had positive sentinel lymph nodes. After limiting the analysis to 336 patients with confirmed thin melanoma after local excision of primary tumor (ie, excluding 10 patients who were found to have residual melanoma 1 mm in the wide excision specimen), 72 patients underwent SLNB for a T1 melanoma. Five of these patients (7%) had positive sentinel lymph nodes, of whom two (3%) had a change of a primary tumor factor that led to a recommendation by the multidisciplinary tumor board to perform the SLNB. One patient with a tumor thickness of 0.6 mm was found to have a mitotic rate of 3 mm 2 after tumor board review, which was not reported by outside pathology (Appendix Fig A5, online only). The second patient had an initial thickness by outside pathology of 0.7 mm that was subsequently changed to 0.8 mm by the tumor board review, and therefore, SLNB was recommended. Abbreviations: SNLB, sentinel lymph node biopsy; AJCC, American Joint Committee on Cancer. Outside pathology report of a low mitotic index (41 lesions) was considered as0mm 2, whereas a moderate to high mitotic rate was considered as 1 mm 2 for this analysis. Mitotic rate was not reported in 38 patients with tumor board diagnosis of thin melanoma; therefore, the total patients with available mitotic rate is 382. DISCUSSION Review of histopathologic material by an expert dermatopathologist is commonly performed in multidisciplinary melanoma clinics. Nevertheless, the impact of expert pathology review of early-stage melanoma has not been quantified. Our data revealed that review of lesions referred with a diagnosis of thin melanoma and MIS resulted in change in diagnosis in 4% of the patients. Furthermore, change in tumor stage occurred in up to one fourth of patients with early-stage melanoma. This led to alterations in expected prognosis and in the recommended surgical excision margins and SLNB indications in 12% and 16% of patients, respectively. Such data have extensive implications for both patients and physicians. For patients presenting with early-stage melanoma, agreement with the referring diagnoses was excellent at 96%. Although this high rate of concordance is reassuring, 15 (4%) of 420 patients had their referral diagnosis of melanoma or MIS changed to a benign cutaneous Table 4. Changes in Surgical Management After Melanoma Tumor Board Review in 420 Patients With Referral Diagnosis of Early-Stage Melanoma Excision Margin Referral Pathology Tumor Stage T0 (n 50) T1A (n 266) T1B (n 104) Total (N 420) Recommended excision margins Conservative excision 3 6 9 3 3 3 15 4 0.5 cm 42 84 14 5 1 1 57 14 1 cm 5 10 237 89 89 86 331 79 1-2 cm 0 0 4 2 11 10 15 4 2 cm 0 0 2 1 0 0 2 1 Change in excision margins 8 16 29 11 15 14 52 12 Conservative excision was performed among patients with a nonmelanoma diagnosis after tumor board review. One patient staged T1A by outside pathology was changed to melanoma dermal nodule with the differential diagnosis of possible recurrent or metastatic melanoma and was treated with a 2-cm excision margin. 4 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Pathology Review of Early-Stage Melanoma lesion after expert review. Data from the current study further corroborate how a multidisciplinary approach that incorporates routine review of outside pathology can lead to meaningful changes in diagnosis. 12-14 Of interest, younger age was associated with change in diagnosis after expert pathology review. This could be explained by the fact that some benign melanocytic lesions exhibit a wide spectrum of atypical histologic features simulating melanoma and are more frequent in young patients. 15 The identification of this subset of patients who are at particular risk of misdiagnosis strongly supports the concept of referral of pediatric, adolescent, and young adult melanoma patients to a multidisciplinary clinic. Recent NCCN melanoma recommendations are that the pathology report includes Breslow thickness, ulceration status, margin status, and Clark level. Moreover, the NCCN recommends that mitotic rate should be reported because it is emerging as an independent predictor of outcome. 16-18 We identified that outside reports failed to describe at least one of these key pathologic factors in a significant proportion of patients despite being reviewed by a dermatopathologist 76% of the time. These findings could be explained by the fact that many outside pathology reports are not standardized and populated with key pathologic parameters. A recent study demonstrated that key pathologic features of primary cutaneous melanoma are likely to be more completely recorded in synoptic reports. 19 We highly recommend a synoptic format for the pathologic reporting of primary cutaneous melanoma. Our data also provide some insight into how routine review of thin melanoma and MIS pathology might affect patient outcomes even if the melanoma diagnosis was not changed. For 24% of patients with a concordant diagnosis of melanoma, the pathologic staging was changed according to the AJCC staging system. The most common factor that resulted in a change in stage was an alteration from Clark level IV to level II or III or vice versa, which occurred in 51% of the patients. Our findings are in agreement with a recent study that identified Clark level as the major factor leading to a poor T1B stage concordance. 20 The observed change in staging has important connotations for prognostic prediction in melanoma patients. Moreover, increasing pathologic substage is associated with decreasing survival outcomes in melanoma. 21,22 Another advantage of the multidisciplinary tumor board is the ability to evaluate surgical treatment strategies. Pathology review spared unnecessary aggressive treatment in 7% of patients by avoiding wider resections that could need skin grafts or other reconstructive procedures. However, a suboptimal surgical resection was avoided in 5% of patients by performing a wider excisional margin of the primary tumor. We also assessed changes in recommended SLNB after tumor board review. At our institution, patients with melanomas between 0.76 and 1.0 mm are offered SLNB. Furthermore, recent studies have identified mitotic rate as an independent factor for metastasis in SLNB for thin melanomas. 18,23 Because indications for SLNB in thin melanomas are complex and evolving, several SLNB recommendation criteria were used to assess the impact of pathology review in SLNB. We identified that SLNB recommendations would have changed after pathology review in 16% of patients by using an AJCC lesion stage T1B, 10% using a tumor thickness 0.76 mm, and 18% using a mitotic rate 1mm 2 as criteria for SLNB. In the present study, sentinel lymph node metastases were identified in six (7%) of 82 patients who underwent SLNB. Importantly, in two of these patients (33% of those with metastatic disease to the lymph nodes), SLNB was recommended after change in pathologic microstaging by the melanoma tumor board. These data emphasize the importance of expert pathology review in assessing key pathologic criteria for SLNB recommendations in patients with thin melanoma. Our study has several limitations. First, pathologic stage could be affected after expert review of recut slides. Mindful of the fact that Breslow depth may be increased by up to 0.16 mm in recut sections in patients for whom recut slides are sent for review and the measured thickness changes the tumor stage, 24 the original slide was requested from the reference laboratory. If this was not available, the original pathologist was contacted by phone to confirm the measured tumor thickness on the original slide, and this depth was used by the multidisciplinary team for staging and management decisions. Second, interobserver variation in the histopathologic reporting of melanoma inherently affects staging. 20,25-28 In particular, Clark level has low levels of concordance. 28,29 In a recent study, a significant level of discordance in pathologic substage T1B was observed (23%), and this was largely a result of poor concordance of Clark level. 20 We also observed that the majority of changes in microstaging were associated with Clark level in patients with thin melanoma, and this suggests that accurate and reliable substage-based prognostic prediction may not be possible in all patients using the current AJCC staging system. Furthermore, because the study was devised to analyze diagnostic changes in patients referred with a diagnosis of melanoma, we cannot comment on how often patients with a benign diagnosis actually prove to have a malignant lesion. Although we occasionally see such patients in our clinic when they experience recurrence locally or in regional or distant sites (all of which were excluded from the current analysis), this is clearly an infrequent event given the large number of benign lesions removed each year in our catchment area. Finally, we have not commented on whether or not survival for patients with MIS or thin melanoma is improved by referral to a multidisciplinary center, but we do consider major changes in diagnosis or treatment to be presumptive evidence that care is improved in this setting. Clearly, a more complex study entailing long-term follow-up of these patients would be necessary to evaluate this possibility. In summary, our data demonstrate that review of thin melanoma or MIS by an expert dermatopathologist results in change in diagnosis in 4% of patients and in pathologic restaging in 24% of patients with a concordant diagnosis of melanoma. Pathology review in the melanoma multidisciplinary clinic had a significant impact on prognosis and clinical care recommendations. Specifically, pathology review resulted in 12% change in the surgical treatment recommendations for the primary lesion and 16% change in SLNB recommendations. Patients with thin melanoma and MIS make up the majority of patients seen today, and referral of these patients to a melanoma multidisciplinary clinic is appropriate and should include review of the biopsy whenever feasible. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about www.jco.org 2009 by American Society of Clinical Oncology 5
Santillan et al ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Vernon K. Sondak, Schering-Plough (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Alfredo A. Santillan, Jane L. Messina, Vernon K. Sondak, Jonathan S. Zager Provision of study materials or patients: Jane L. Messina, Vernon K. Sondak, Jonathan S. Zager Collection and assembly of data: Alfredo A. Santillan, Jane L. Messina, Suroosh S. Marzban, Gema Crespo, Vernon K. Sondak, Jonathan S. Zager Data analysis and interpretation: Alfredo A. Santillan, Jane L. Messina, Suroosh S. Marzban, Gema Crespo, Vernon K. Sondak, Jonathan S. Zager Manuscript writing: Alfredo A. Santillan, Jane L. Messina, Vernon K. Sondak, Jonathan S. Zager Final approval of manuscript: Alfredo A. Santillan, Jane L. Messina, Vernon K. Sondak, Jonathan S. Zager REFERENCES 1. Ries LA, Wingo PA, Miller DS, et al: The annual report to the nation on the status of cancer, 1973-1997, with a special section on colorectal cancer. Cancer 88:2398-2424, 2000 2. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2009. CA Cancer J Clin 59:225-249, 2009 3. Gimotty PA, Botbyl J, Soong SJ, et al: A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 23:8065-8075, 2005 4. Johnson TM, Dolan OM, Hamilton TA, et al: Clinical and histologic trends of melanoma. J Am Acad Dermatol 38:681-686, 1998 5. Aitken JF, Janda M, Elwood M, et al: Clinical outcomes from skin screening clinics within a community-based melanoma screening program. J Am Acad Dermatol 54:105-114, 2006 6. Abbasi NR, Shaw HM, Rigel DS, et al: Early diagnosis of cutaneous melanoma: Revisiting the ABCD criteria. 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Sondak VK, Taylor JM, Sabel MS, et al: Mitotic rate and younger age are predictors of sentinel lymph node positivity: Lessons learned from the generation of a probabilistic model. Ann Surg Oncol 11:247-258, 2004 19. Karim RZ, van den Berg KS, Colman MH, et al: The advantage of using a synoptic pathology report format for cutaneous melanoma. Histopathology 52:130-138, 2008 20. Murali R, Hughes MT, Fitzgerald P, et al: Interobserver variation in the histopathologic reporting of key prognostic parameters, particularly Clark level, affects pathologic staging of primary cutaneous melanoma. Ann Surg 249:641-647, 2009 21. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:3622-3634, 2001 22. Balch CM, Soong SJ, Atkins MB, et al: An evidence-based staging system for cutaneous melanoma. CA Cancer J Clin 54:131-149, 2004 23. Kesmodel SB, Karakousis GC, Botbyl JD, et al: Mitotic rate as a predictor of sentinel lymph node positivity in patients with thin melanomas. Ann Surg Oncol 12:449-458, 2005 24. Patrick RJ, Corey S, Glass LF: The use of sequential serial sectioning of thin melanomas in determining maximum Breslow depth. J Am Acad Dermatol 57:S127 S128, 2007 (suppl 5) 25. Colloby PS, West KP, Fletcher A: Observer variation in the measurement of Breslow depth and Clark s level in thin cutaneous malignant melanoma. J Pathol 163:245-250, 1991 26. Krieger N, Hiatt RA, Sagebiel RW, et al: Interobserver variability among pathologists evaluation of malignant melanoma: Effects upon an analytic study. J Clin Epidemiol 47:897-902, 1994 27. Corona R, Mele A, Amini M, et al: Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol 14:1218-1223, 1996 28. Scolyer RA, Shaw HM, Thompson JF, et al: Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas. Am J Surg Pathol 27:1571-1576, 2003 29. McDermott NC, Hayes DP, al-sader MH, et al: Identification of vertical growth phase in malignant melanoma: A study of interobserver agreement. Am J Clin Pathol 110:753-757, 1998 6 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Pathology Review of Early-Stage Melanoma Appendix Fig A1. Lesion from 23-year-old woman with outside diagnosis of melanoma (Clark level III, 0.57 mm) found to be consistent with compound Spitz tumor (hematoxylin and eosin, 100 and 200). Fig A2. Lesion with outside diagnosis of melanoma in situ was found to represent junctional dysplastic nevus on review (hematoxylin and eosin and Melan-A immunostain, 200). 1.4 mm Fig A3. Lesion had outside diagnosis of 0.80-mm melanoma. Tumor thickness at pathologic review was found to be 1.4 mm (hematoxylin and eosin, 100). www.jco.org 2009 by American Society of Clinical Oncology 7
Santillan et al Fig A4. Lesion diagnosed as invasive melanoma was found on review to be melanoma in situ with involvement of adnexal units (hematoxylin and eosin, 200). Fig A5. Sentinel lymph node with subcapsular micrometastasis (arrow) in a patient with primary lesion was found on review to be 0.6-mm invasive melanoma, Clark level III, with at least 3 mitoses/mm 2 (hematoxylin and eosin, 400). 8 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY