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Invited Commentary
Oncology
May 18, 2018

Staging of Cutaneous Melanoma: Is There Room for Further Improvement?

Author Affiliations
  • 1Melanoma Institute Australia, The University of Sydney, Sydney, Australia
  • 2Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia
  • 3Sydney Medical School, The University of Sydney, Sydney, Australia
  • 4Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
  • 5Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston
  • 6Melanoma and Skin Center, The University of Texas MD Anderson Cancer Center, Houston
JAMA Netw Open. 2018;1(1):e180086. doi:10.1001/jamanetworkopen.2018.0086

Elmore and coauthors1 present a study that evaluates the reproducibility and concordance of microstaging of melanoma using the 7th vs 8th editions of the AJCC Cancer Staging Manual.2,3 The authors report modest but significant improvements (up to 10%) in the reproducibility and concordance for both T1a and T1b or greater melanomas when categorized according to the AJCC Cancer Staging Manual, 8th edition (AJCC 8). The authors conclude that AJCC 8 will improve the accuracy of staging of invasive cutaneous melanoma and may have a positive impact on patient care.

At the commencement of 2018, AJCC 8 was implemented in the United States. Among other changes, the definitions of T1a and T1b for primary cutaneous melanomas were refined from the AJCC Cancer Staging Manual, 7th edition (AJCC 7).2,3 Whereas AJCC 7 defined T1a melanomas as being of Breslow thickness 1 mm or less and lacking mitoses (defined using the dermal hotspot approach as either <1/mm2 or ≥1/mm2) and ulceration, AJCC 8 classifies nonulcerated melanomas less than 0.8 mm thick as T1a; T1b is defined as a melanoma 0.8 to 1.0 mm thick or less than 0.8 mm thick with ulceration. While the staging changes in AJCC 8 were data driven, the impact, if any, on reproducibility and concordance of staging was not formally evaluated by the American Joint Committee on Cancer (AJCC) Melanoma Expert Panel.

Elmore et al1 evaluated the effects of the differences between the melanoma staging system in AJCC 7 vs AJCC 8 on reproducibility by analyzing a subset of data compiled from their previously published Melanoma Pathology Study.4 In the Melanoma Pathology Study, 187 pathologists evaluated 240 melanocytic lesions and classified them according to a 5-tiered system called the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis, which includes class I, nevus or mild atypia; class II, moderate atypia; class III, severe atypia or melanoma in situ; class IV, pT1a invasive melanoma (AJCC 7); and class V, pT1b or greater invasive melanoma (AJCC 7). By analyzing the subset of 116 invasive melanomas (ie, those classified as classes IV and V by 3 expert pathologists), the authors attempted to assess the impact of AJCC melanoma staging system changes. While the study methods are not entirely clear, a significant limitation of their approach appears to be that study pathologists were tasked with scoring cases according to the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis system, rather than focusing on classifying them into specific AJCC tumor (T) categories. Based on their classification schema, 7 T subcategories (ie, AJCC 7 T1b-T4b corresponding to Melanoma Pathology Study class V) were grouped together in the current analysis. This approach limits the reader’s interpretation of variability and reproducibility of T1b melanomas, which is important as this is a threshold at which sentinel node biopsy is often recommended.5

Another important revision in AJCC 8 was of the definition of microsatellites, which may also be associated with the reproducibility of components of the melanoma staging system. However, this was not assessed in the study by Elmore and colleagues. Microsatellites are now defined as any microscopic cutaneous and/or subcutaneous metastasis adjacent to or deep to, and completely discontinuous from, a primary melanoma with unaffected stroma occupying the space between, identified on pathological examination of the primary tumor site.2 A microsatellite can therefore upstage a patient’s melanoma to stage III. With recent clinical trial results reporting improvements in outcomes for patients with stage III melanoma receiving adjuvant systemic therapy, accurate diagnosis of microsatellites has become critical for optimal patient care.6,7 Although beyond the scope of the present study, the assessment of microsatellites is an important factor in the overall reproducibility and concordance of staging by the AJCC 8 criteria.

While the reproducibility of staging is critical for patients with melanoma, of perhaps greater importance is the clinical and pathological distinction of melanoma from its mimics. Despite the increasing incidence of melanoma, the histological diagnosis of borderline melanocytic lesions remains poorly reproducible.4 Elmore et al1 showed that tumor classification was also hampered by poor rates of concordance for T1a (54%) and T1b or greater (78%) lesions, and similarly low rates of intraobserver reproducibility. As the participating pathologists in the study by Elmore et al1 ranged from experts in melanocytic skin lesions (42%) to those who reported examining fewer than 5 melanomas per month (44%), it would be of interest to know how the rates of concordance and intraobserver variability aligned with experience among participating pathologists and which staging parameters showed the largest discrepancies. For example, was most of the variability due to the assessment of Breslow thickness or ulceration, or alternatively, the diagnosis of the lesion as melanoma? Previous studies have shown that the reproducibility of mitotic rate assessment is less than that of the other T-category parameters—tumor thickness and ulceration.8 Therefore, were the improvements in concordance and intraobserver variability identified when using AJCC 8 primarily a result of the removal of mitotic rate as a T-category criterion? The Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis study design does not permit specifically addressing this question and represents another limitation of the study. Studies assessing the aforementioned issues may have important ramifications for continuing medical education, referral practice, and the design of future editions of the AJCC melanoma staging system.

Staging systems are designed to describe primary tumors and the extent of their spread, if any, in a standardized format to stratify patients into prognostic groups that in turn inform clinical decision making and facilitate the design, conduct, and evaluation of clinical trials as well as central registry reporting. The AJCC 8 melanoma staging system was underpinned by analyses from a melanoma database of more than 46 000 patients from 10 centers worldwide diagnosed since 1998.9 Although intraobserver variability and discordance in the diagnosis of melanomas by pathologists, as described by Elmore et al,1 may affect the correlation between histological parameters and outcome in the AJCC data set to some extent, it did not prevent stratification of primary melanomas into prognostic stage groups with statistically significant differences in survival. Furthermore, we have published higher rates of concordance using AJCC 7 criteria, albeit with access to clinical information and reporting by a small number of pathologists with expertise reporting melanomas at a high-volume referral center.10

Overall, Elmore et al1 report modest improvements in reproducibility and concordance using AJCC 8 compared with AJCC 7. Importantly, they also demonstrated that among a large group of pathologists with varying levels of expertise, there is significant opportunity to improve reproducibility and concordance in the pathological staging of melanoma. To address this challenge, future studies could investigate the reproducibility of each parameter required by AJCC 8 or pathological factors proposed for inclusion in subsequent iterations, and how this may be influenced by the experience of the reporting pathologist (eg, by the nature and number of melanocytic cases evaluated per year) and/or the availability of relevant clinical and molecular information. Such studies could potentially inform future editions of the AJCC melanoma staging system and contribute to improved accuracy in the pathological staging of patients with melanoma.

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Article Information

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Ferguson PM et al. JAMA Network Open.

Corresponding Author: Richard A. Scolyer, MD, FRCPA, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Bldg 94, Johns Hopkins Drive, Camperdown, New South Wales, 2050, Australia (richard.scolyer@sydney.edu.au).

Conflict of Interest Disclosures: Dr Gershenwald has served on advisory boards for Merck, Syndax, and Castle Biosciences and is chair of the AJCC Melanoma Expert Panel and a member of the AJCC Executive Committee. No other disclosures were reported.

Funding/Support: This work was supported in part by the Robert and Lynne Grossman Family Foundation, the Michael and Patricia Booker Melanoma Research Endowment, and Melanoma Institute Australia. Dr Ferguson is supported by the Deborah and John McMurtrie Melanoma Institute Australia Pathology Fellowship. Dr Scolyer is supported by an Australian National Health and Medical Research Council Fellowship.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank our colleagues at Melanoma Institute Australia, Royal Prince Alfred Hospital, and MD Anderson Cancer Center.

References
1.
Elmore  JG, Elder  DE, Barnhill  RL,  et al.  Concordance and reproducibility of melanoma staging according to the 7th vs 8th edition of the AJCC Cancer Staging Manual JAMA Netw Open. 2018;1(1):e180083. doi:10.1001/jamanetworkopen.2018.0083Google Scholar
2.
Gershenwald  JE, Scolyer  RA, Hess  KR,  et al. Melanoma of the skin. In: Amin  M, Edge  SB, Greene  FL,  et al, eds.  AJCC Cancer Staging Manual. 8th ed. Cham, Switzerland: Springer; 2017:563-585.
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Balch  CM, Gershenwald  JE, Soong  S-J,  et al.  Final version of 2009 AJCC melanoma staging and classification.  J Clin Oncol. 2009;27(36):6199-6206.PubMedGoogle ScholarCrossref
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Elmore  JG, Barnhill  RL, Elder  DE,  et al.  Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study.  BMJ. 2017;357:j2813.PubMedGoogle ScholarCrossref
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Wong  SL, Faries  MB, Kennedy  EB,  et al.  Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update.  J Clin Oncol. 2018;36(4):399-413.PubMedGoogle ScholarCrossref
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Long  GV, Hauschild  A, Santinami  M,  et al.  Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.  N Engl J Med. 2017;377(19):1813-1823. doi:10.1056/NEJMoa1708539PubMedGoogle ScholarCrossref
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Weber  J, Mandala  M, Del Vecchio  M,  et al; CheckMate 238 Collaborators.  Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.  N Engl J Med. 2017;377(19):1824-1835. doi:10.1056/NEJMoa1709030PubMedGoogle ScholarCrossref
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Scolyer  RA, Shaw  HM, Thompson  JF,  et al.  Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas.  Am J Surg Pathol. 2003;27(12):1571-1576.PubMedGoogle ScholarCrossref
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Gershenwald  JE, Scolyer  RA, Hess  KR,  et al; for members of the American Joint Committee on Cancer Melanoma Expert Panel and the International Melanoma Database and Discovery Platform.  Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.  CA Cancer J Clin. 2017;67(6):472-492.PubMedGoogle ScholarCrossref
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Niebling  MG, Haydu  LE, Karim  RZ, Thompson  JF, Scolyer  RA.  Reproducibility of AJCC staging parameters in primary cutaneous melanoma: an analysis of 4,924 cases.  Ann Surg Oncol. 2013;20(12):3969-3975.PubMedGoogle ScholarCrossref
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    1 Comment for this article
    Melanoma staging via AJCC
    Wolfram Samlowski, MD | Comprehensive Cancer Centers of Nevada/UNLV
    The biggest issue in the AJCC staging system is that Stage IIB deep ulcerated primary melanomas have a worse prognosis than Stage IIIA shallow melanomas with microscopic lymph node involvement. This discrepancy has been carried forward in the 6th, 7th and 8th edition. This is important, since Stage IIB patients are relatively common in clinical practice.

    Unfortunately, high risk T3B N0, T4B N0 stage IIB patients have not been included in most adjuvant therapy studies, making adjuvant treatment hard to justify to insurance companies.
    CONFLICT OF INTEREST: None Reported
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