- Email: [email protected]
Importance of Pathology Review to Complement Clinical Management of Melanoma
Journal Pre-proof Importance of Pathology Review to Complement Clinical Management of Melanoma Meghan Beatson, BS, Misty G. Eleryan, MD, Jeave Reserva, MD, Bridget Kaufman, MD, Bridget Connelly, MS, Elizabeth Dugan, MD, Arash Radfar, MD, Patricia Lucey, MD, Jeff Harvell, MD, Jag Bhawan, MD, Sekwon Jang, MD, Suraj Venna, MD PII:
S0190-9622(20)30516-8
DOI:
https://doi.org/10.1016/j.jaad.2020.03.093
Reference:
YMJD 14404
To appear in:
Journal of the American Academy of Dermatology
Received Date: 10 September 2019 Revised Date:
10 March 2020
Accepted Date: 30 March 2020
Please cite this article as: Beatson M, Eleryan MG, Reserva J, Kaufman B, Connelly B, Dugan E, Radfar A, Lucey P, Harvell J, Bhawan J, Jang S, Venna S, Importance of Pathology Review to Complement Clinical Management of Melanoma, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2020.03.093. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1 2
3 4
Title: Importance of Pathology Review to Complement Clinical Management of Melanoma (JAAD-D-19-01998R1) Journal Journal of the American Academy of Dermatology (JAAD) Manuscript Type Research Letter Location Fairfax, VA, USA Complete List of Authors Meghan Beatson BS1 Misty G Eleryan MD1 Jeave Reserva MD2 Bridget Kaufman MD3 Bridget Connelly MS4 Elizabeth Dugan MD5 Arash Radfar MD5 Patricia Lucey MD6 Jeff Harvell MD6 Jag Bhawan MD7 Sekwon Jang MD6 Suraj Venna MD6 1 George Washington University School of Medicine, Washington, DC 2 Loyola University, Chicago, IL 3 Mount Sinai Health System, New York City, NY 4 Georgetown University Department of Mathematics and Statistics, Washington, DC 5 Inform Diagnostics, Needham, MA 6 Inova Schar Cancer Institute Melanoma Center, Fairfax, VA 7 Boston University Department of Dermatology, Boston, MA Corresponding Author Meghan Beatson George Washington University School of Medicine Providence VA Medical Center 830 Chalkstone Ave, Providence RI 02908 Phone: 401-273-7100 ext2333 Fax: 401-457-3332 Email: [email protected] Word Count 500 Table Count 2 References 5 Funding and Support This manuscript has no funding source. Conflict of Interests The authors have no conflicts of interest to disclose. Key Words Melanoma, dysplastic nevus Capsule Summary • Skin cancer centers often request a second pathological opinion for patients diagnosed with melanoma before each case is discussed in a multidisciplinary tumor board. • The second opinion creates a holistic approach to each case, allowing for a complete discussion with each patient in the context of their diagnosis.
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
DEAR EDITOR, The evaluation of melanocytic lesions is challenging and nuanced. Referral centers for melanoma often request the original biopsy to render a second opinion as part of a multidisciplinary tumor board. We sought to determine the inter-observer agreement between pathologists in the diagnosis of melanoma and discuss the impact on patient management. We expected the vast majority of cases would show agreement in the diagnosis. In the small percentage of cases where there was discordance in the diagnosis, we opened a longer discussion of potential management options with the patient, including seeking a third opinion. The study was approved by the institutional review boards at MedStar Georgetown University and the Inova Schar Cancer Institute. We reviewed all available pathology reports with a diagnosis of melanoma referred to the Melanoma and Skin Oncology Center at the Washington Cancer Institute between July 2009 and October 2014 and the Inova Melanoma and Skin Cancer Center between May 2015 to May 2016. The lesions were staged according to the AJCC 7th edition melanoma staging criteria. Discordance was defined as lack of agreement in diagnosis, clinical stage, or histopathological parameter. Statistical analysis was performed using R (R Core Team, 2013). For categorical variables, Cohen's kappa (κ) statistic was used to measure the agreement between the original dermatopathologist and the consultant rendering the second opinion (Table 1). In total, 777 patients were referred with a biopsy confirmed diagnosis of melanoma or a borderline melanocytic lesion. Of these cases, 623/777 had both initial and second opinion pathology reports available for comparison. The second opinion led to a change in diagnosis or stage in 14% of cases (87/623). Among the melanoma cases, the lesion was upstaged to a higher AJCC stage in 46% of cases (40/87) and downgraded to a lower AJCC stage in 41% of cases (36/87). The lesion was upstaged from dysplastic nevus to melanoma in 5 cases and down-staged from melanoma to dysplastic nevus in 6 cases (Table 2). In all cases of discordance, a third opinion was always offered, though never pursued. We also calculated the number of slides received from the outside lab to render a second opinion: 1 slide was received in 41% of cases. This study agrees with previous studies evaluating inter-observer agreement amongst pathologists in the histopathological diagnosis of melanoma.1-4 This evaluation is limited by the melanoma centers having an inherent bias towards more diagnostically challenging or higher stage lesions. Ideally, all slides should be sent to allow for a comprehensive second opinion. On a practical level, at least 1 slide from the original cut/biopsy and at least 1 deeper and immunohistochemistry if done should be sent. There are significant clinical implications with a change in stage, which dictates the extent of treatment such as whether or not a patient needs a sentinel lymph node biopsy.5 The second opinion allows for a comprehensive assessment of each case. In the few situations where there is discordance, optimal care includes a discussion with the patient and the multidiscipinary team to individualize patient care.
44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61
ACKNOWLEDGEMENTS Author Contributions: Meghan Beatson BS, Misty G Eleryan MD, Jeave Reserva MD, Bridget Kaufman MD, Bridget Connelly MS, Patricia Lucey MD, Sekwon Jang MD, and Suraj Venna MD had full access to the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study Concept and Design: Venna, Beatson. Acquisition, Analysis, and Interpretation of the data: Beatson, Eleryan, Reserva, Kaufman, Connelly. Drafting of the Manuscript: Beatson, Eleryan, Connelly. Critical revision of the manuscript for important intellectual content: Beatson, Venna, Harvell, Jang, Dugan, Radfar, Bhawan. Statistical Analysis: Kaufman, Connelly, Beatson. Administrative, technical, or material support: Venna, Lucey, Jang, Beatson. Study Supervision: Venna. All persons who have contributed substantially to this manuscript are authors. Funding/support: The authors have no funding source to declare. Financial Disclosure: Relationships relevant to this manuscript: None reported. All other relationships: None reported All Financial Interests (including pharmaceutical and device product(s)): None reported. The opinions expressed in this manuscript are those of the authors, not the Inova Schar Cancer Center
62 63 64
REFERENCES
65
and melanocytic nevi between expert pathologists. Hum Pathol. 1996;27(6):528-531.
66
2. Shoo BA, Sagebiel RW, Kashani-Sabet M. Discordance in the histopathologic diagnosis of
67
melanoma at a melanoma referral center. J Am Acad Dermatol. 2010;62(5):751-756.
68
3. Elder DE, Piepkorn MW, Barnhill RL, et al. Pathologist characteristics associated with
69
accuracy and reproducibility of melanocytic skin lesion interpretation. J Am Acad Dermatol.
70
2018;79(1):52-59.
71
4. Elmore JG, Barnhill RL, Elder DE, et al. Pathologists’ diagnosis of invasive melanoma and
72
melanocytic proliferations: Observer accuracy and reproducibility study. BMJ. 2017;357:j2813.
73
5. Scolyer RA, Shaw HM, Thompson JF, et al. Interobserver reproducibility of histopathologic
74
prognostic variables in primary cutaneous melanomas. Am J Surg Pathol. 2003;27(12):1571-
75
1576.
1. Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma
76 77 78 79
TABLES Table 1: Inter-observer Agreement in the Reporting of Histopathological Parameters of Melanoma Parameter Clark Level
Discordance
Any changes in level, including II to III or II to II/III and vice versa Ulceration 1 absent and 1 present Microsatellites 1 absent and 1 present TILS 1 absent and 1 present, or 1 absent and 1 brisk or nonbrisk Regression 1 absent and 1 present Precursor 1 absent and 1 present Mitotic Rateb ≥1/mm2 and 0/mm2 a
Kappa
Level of Agreementa
351
0.57
Moderate
149 447
0.85 0.30
Almost Perfect Fair
296
0.29
Fair
205 288 430
0.59 0.69 0.79
Moderate Substantial Substantial
0-0.19 Poor; 0.2-0.39 Fair; 0.4-0.59 Moderate; 0.60-0.79 Substantial; 0.80-0.99 Almost Perfect; 1.0 Perfect. Mitotic rate kappa evaluated in cases where mitotic rate was reported in mm2 per AJCC guidelines.
b
80
Number of cases
81 82
Table 2: Number and Percent of Concordance and Discordance in the AJCC 7 Melanoma Stage for 623 Lesionsb
a
2B
2C
--
--
--
2nd Op Stage Total 8
--
--
--
74
1 (2%)
--
--
138
7 (11%) 48 (75%) 8 (13%)
1 (2%) 3 (7%) 37 (90%)
--
228
--
56
--
195 (90%) 5 (2%) --
--
45
--
--
--
--
--
73
148
216
64
41
DN
0
1A
2 (29%)b 1 (14%) 2 (29%)
4 (5%) 64 (88%) 4 (5%)
1 (0.7%) 6 (4%) 119 (80%)
1 (0.5%) 3 (1%) 12 (6%)
2A
2 (29%) --
1 (1%) --
22 (15%) --
2B
--
--
2C
--
1st Op Stage Total
7
DNa 0 1A Second Opinion
First Opinion 1B 2A
1B
a
16 16 (100%) 16
Dysplastic Nevus Percent of concordance and discordance calculated as (second opinion stage/1st Op Total). For example, 148 lesions were staged as 1A in the first opinion (1st Op Total). Of those 1A melanomas, 22 lesions were staged as 1B in the second opinion. Therefore, the percent discordance is 15% (22/148). With rounding, values may not add to exactly 100%. b
83
S0190-9622(20)30516-8
DOI:
https://doi.org/10.1016/j.jaad.2020.03.093
Reference:
YMJD 14404
To appear in:
Journal of the American Academy of Dermatology
Received Date: 10 September 2019 Revised Date:
10 March 2020
Accepted Date: 30 March 2020
Please cite this article as: Beatson M, Eleryan MG, Reserva J, Kaufman B, Connelly B, Dugan E, Radfar A, Lucey P, Harvell J, Bhawan J, Jang S, Venna S, Importance of Pathology Review to Complement Clinical Management of Melanoma, Journal of the American Academy of Dermatology (2020), doi: https://doi.org/10.1016/j.jaad.2020.03.093. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
1 2
3 4
Title: Importance of Pathology Review to Complement Clinical Management of Melanoma (JAAD-D-19-01998R1) Journal Journal of the American Academy of Dermatology (JAAD) Manuscript Type Research Letter Location Fairfax, VA, USA Complete List of Authors Meghan Beatson BS1 Misty G Eleryan MD1 Jeave Reserva MD2 Bridget Kaufman MD3 Bridget Connelly MS4 Elizabeth Dugan MD5 Arash Radfar MD5 Patricia Lucey MD6 Jeff Harvell MD6 Jag Bhawan MD7 Sekwon Jang MD6 Suraj Venna MD6 1 George Washington University School of Medicine, Washington, DC 2 Loyola University, Chicago, IL 3 Mount Sinai Health System, New York City, NY 4 Georgetown University Department of Mathematics and Statistics, Washington, DC 5 Inform Diagnostics, Needham, MA 6 Inova Schar Cancer Institute Melanoma Center, Fairfax, VA 7 Boston University Department of Dermatology, Boston, MA Corresponding Author Meghan Beatson George Washington University School of Medicine Providence VA Medical Center 830 Chalkstone Ave, Providence RI 02908 Phone: 401-273-7100 ext2333 Fax: 401-457-3332 Email: [email protected] Word Count 500 Table Count 2 References 5 Funding and Support This manuscript has no funding source. Conflict of Interests The authors have no conflicts of interest to disclose. Key Words Melanoma, dysplastic nevus Capsule Summary • Skin cancer centers often request a second pathological opinion for patients diagnosed with melanoma before each case is discussed in a multidisciplinary tumor board. • The second opinion creates a holistic approach to each case, allowing for a complete discussion with each patient in the context of their diagnosis.
5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43
DEAR EDITOR, The evaluation of melanocytic lesions is challenging and nuanced. Referral centers for melanoma often request the original biopsy to render a second opinion as part of a multidisciplinary tumor board. We sought to determine the inter-observer agreement between pathologists in the diagnosis of melanoma and discuss the impact on patient management. We expected the vast majority of cases would show agreement in the diagnosis. In the small percentage of cases where there was discordance in the diagnosis, we opened a longer discussion of potential management options with the patient, including seeking a third opinion. The study was approved by the institutional review boards at MedStar Georgetown University and the Inova Schar Cancer Institute. We reviewed all available pathology reports with a diagnosis of melanoma referred to the Melanoma and Skin Oncology Center at the Washington Cancer Institute between July 2009 and October 2014 and the Inova Melanoma and Skin Cancer Center between May 2015 to May 2016. The lesions were staged according to the AJCC 7th edition melanoma staging criteria. Discordance was defined as lack of agreement in diagnosis, clinical stage, or histopathological parameter. Statistical analysis was performed using R (R Core Team, 2013). For categorical variables, Cohen's kappa (κ) statistic was used to measure the agreement between the original dermatopathologist and the consultant rendering the second opinion (Table 1). In total, 777 patients were referred with a biopsy confirmed diagnosis of melanoma or a borderline melanocytic lesion. Of these cases, 623/777 had both initial and second opinion pathology reports available for comparison. The second opinion led to a change in diagnosis or stage in 14% of cases (87/623). Among the melanoma cases, the lesion was upstaged to a higher AJCC stage in 46% of cases (40/87) and downgraded to a lower AJCC stage in 41% of cases (36/87). The lesion was upstaged from dysplastic nevus to melanoma in 5 cases and down-staged from melanoma to dysplastic nevus in 6 cases (Table 2). In all cases of discordance, a third opinion was always offered, though never pursued. We also calculated the number of slides received from the outside lab to render a second opinion: 1 slide was received in 41% of cases. This study agrees with previous studies evaluating inter-observer agreement amongst pathologists in the histopathological diagnosis of melanoma.1-4 This evaluation is limited by the melanoma centers having an inherent bias towards more diagnostically challenging or higher stage lesions. Ideally, all slides should be sent to allow for a comprehensive second opinion. On a practical level, at least 1 slide from the original cut/biopsy and at least 1 deeper and immunohistochemistry if done should be sent. There are significant clinical implications with a change in stage, which dictates the extent of treatment such as whether or not a patient needs a sentinel lymph node biopsy.5 The second opinion allows for a comprehensive assessment of each case. In the few situations where there is discordance, optimal care includes a discussion with the patient and the multidiscipinary team to individualize patient care.
44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61
ACKNOWLEDGEMENTS Author Contributions: Meghan Beatson BS, Misty G Eleryan MD, Jeave Reserva MD, Bridget Kaufman MD, Bridget Connelly MS, Patricia Lucey MD, Sekwon Jang MD, and Suraj Venna MD had full access to the data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study Concept and Design: Venna, Beatson. Acquisition, Analysis, and Interpretation of the data: Beatson, Eleryan, Reserva, Kaufman, Connelly. Drafting of the Manuscript: Beatson, Eleryan, Connelly. Critical revision of the manuscript for important intellectual content: Beatson, Venna, Harvell, Jang, Dugan, Radfar, Bhawan. Statistical Analysis: Kaufman, Connelly, Beatson. Administrative, technical, or material support: Venna, Lucey, Jang, Beatson. Study Supervision: Venna. All persons who have contributed substantially to this manuscript are authors. Funding/support: The authors have no funding source to declare. Financial Disclosure: Relationships relevant to this manuscript: None reported. All other relationships: None reported All Financial Interests (including pharmaceutical and device product(s)): None reported. The opinions expressed in this manuscript are those of the authors, not the Inova Schar Cancer Center
62 63 64
REFERENCES
65
and melanocytic nevi between expert pathologists. Hum Pathol. 1996;27(6):528-531.
66
2. Shoo BA, Sagebiel RW, Kashani-Sabet M. Discordance in the histopathologic diagnosis of
67
melanoma at a melanoma referral center. J Am Acad Dermatol. 2010;62(5):751-756.
68
3. Elder DE, Piepkorn MW, Barnhill RL, et al. Pathologist characteristics associated with
69
accuracy and reproducibility of melanocytic skin lesion interpretation. J Am Acad Dermatol.
70
2018;79(1):52-59.
71
4. Elmore JG, Barnhill RL, Elder DE, et al. Pathologists’ diagnosis of invasive melanoma and
72
melanocytic proliferations: Observer accuracy and reproducibility study. BMJ. 2017;357:j2813.
73
5. Scolyer RA, Shaw HM, Thompson JF, et al. Interobserver reproducibility of histopathologic
74
prognostic variables in primary cutaneous melanomas. Am J Surg Pathol. 2003;27(12):1571-
75
1576.
1. Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma
76 77 78 79
TABLES Table 1: Inter-observer Agreement in the Reporting of Histopathological Parameters of Melanoma Parameter Clark Level
Discordance
Any changes in level, including II to III or II to II/III and vice versa Ulceration 1 absent and 1 present Microsatellites 1 absent and 1 present TILS 1 absent and 1 present, or 1 absent and 1 brisk or nonbrisk Regression 1 absent and 1 present Precursor 1 absent and 1 present Mitotic Rateb ≥1/mm2 and 0/mm2 a
Kappa
Level of Agreementa
351
0.57
Moderate
149 447
0.85 0.30
Almost Perfect Fair
296
0.29
Fair
205 288 430
0.59 0.69 0.79
Moderate Substantial Substantial
0-0.19 Poor; 0.2-0.39 Fair; 0.4-0.59 Moderate; 0.60-0.79 Substantial; 0.80-0.99 Almost Perfect; 1.0 Perfect. Mitotic rate kappa evaluated in cases where mitotic rate was reported in mm2 per AJCC guidelines.
b
80
Number of cases
81 82
Table 2: Number and Percent of Concordance and Discordance in the AJCC 7 Melanoma Stage for 623 Lesionsb
a
2B
2C
--
--
--
2nd Op Stage Total 8
--
--
--
74
1 (2%)
--
--
138
7 (11%) 48 (75%) 8 (13%)
1 (2%) 3 (7%) 37 (90%)
--
228
--
56
--
195 (90%) 5 (2%) --
--
45
--
--
--
--
--
73
148
216
64
41
DN
0
1A
2 (29%)b 1 (14%) 2 (29%)
4 (5%) 64 (88%) 4 (5%)
1 (0.7%) 6 (4%) 119 (80%)
1 (0.5%) 3 (1%) 12 (6%)
2A
2 (29%) --
1 (1%) --
22 (15%) --
2B
--
--
2C
--
1st Op Stage Total
7
DNa 0 1A Second Opinion
First Opinion 1B 2A
1B
a
16 16 (100%) 16
Dysplastic Nevus Percent of concordance and discordance calculated as (second opinion stage/1st Op Total). For example, 148 lesions were staged as 1A in the first opinion (1st Op Total). Of those 1A melanomas, 22 lesions were staged as 1B in the second opinion. Therefore, the percent discordance is 15% (22/148). With rounding, values may not add to exactly 100%. b
83