Reply to the article "The AJCC staging proposal for cutaneous melanoma: comments by the EORTC Melanoma Group", by D. J. Ruiter et al. (Ann Oncol 2001; 12: 9–11)

C. M. Balch1 and M. C. Mihm2

1Chairman, AJCC Melanoma Staging Committee, Departments of Surgery and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD; 2Member, AJCC Melanoma Staging Committee, Clinical Professor of Pathology, Harvard Medical School/Massachusetts General Hospital, Co Chairman, Pathology Committee, WHO Melanoma Program, USA

The EORTC Melanoma Group has written a thorough analysis of the proposed melanoma staging system published previously by the Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) [1]. The EORTC Melanoma Group leadership have also provided helpful input, some of which contributed to the final revisions of the staging criteria. To validate the accuracy of this proposed staging system, 13 cancer centers and cancer cooperative groups contributed staging and survival data from 17 600 melanoma patients from the United States, Europe and Australia [2]. This analysis, along with advice from melanoma experts, has resulted in a final version which has been formally approved by the AJCC as well as the International Union against Cancer (UICC) TNM Committee. This final version of the melanoma staging system will become official with publication of the 6th edition of the AJCC Cancer Staging Manual in the year 2002.

Specific responses to the suggestions and comments made by Dr Ruiter and colleagues include the following:

The definition of melanoma ulceration has been used for years; it is a histopathological definition where the melanoma tumor invades through the overlying epidermis rather than pushing it upwards, manifesting as an absent epidermis overlying the major portion of the tumor [3]. It can easily be distinguished from artifactual or traumatic disruption of the epidermis. Traumatically induced defects are associated with hemorrhage, brightly eosinophilic fibrin exudation at the site and an architectural defect that usually defines the agent leading to the trauma, such as an insect bite or an excoriation. In fact, the interpretation of melanoma ulceration among pathologists is one of the most reproducible of all the major histopathological features [4, 5]. This definition encompasses spontaneous defects from a total absence of the epidermis overlying the tumor to an excavated area including the epidermis and a portion of the tumor. The surface exhibits scattered debris.
The stage grouping definition of stage now incorporates level of invasion. This is because the data analysis demonstrated that level of invasion was more predictive of survival outcome than tumor ulceration for melanomas <=1.0 mm (T1). The opposite was true for all melanomas thicker than 1.0 mm, where ulceration was clearly the most predictive, and level of invasion ranked below that of patient age and anatomic site of the primary melanoma [2]. In the original study of Clark et al., in which one of us participated, level IV was clearly a recognizable penetration of the reticular dermis by individual cells or nests of cells [6]. A ‘percolation’ of nests or cells for at least a depth of a few fibers was necessary to qualify for this level. Level III was defined as a smooth, sharply expansile nodule deforming the papillary-reticular dermal junction.
The AJCC Melanoma Staging Committee debated thoroughly about the threshold to use for defining T1 versus T2 melanomas, including one at <=0.99 mm as suggested by the authors. The final recommendation of <=1.00 mm was an arbitrary one, since there are no survival differences for melanomas of this small difference in tumor thickness.
We do not recommend incorporating microsatellites into the thickness measurements and are in agreement with the authors.
It is not necessary to measure the dimensions of the nodal metastases for the purposes of staging. Nevertheless, we agree with the authors that the extent of tumor involvement in a sentinel lymph node should be noted (and measured where possible) in order to examine whether future subgroups should account for this.
Intralymphatic metastases are manifested by either the presence of clinical or microscopic satellites around a primary melanoma or in-transit metastases between the primary melanoma and the regional lymph nodes. Both clinical presentations portend a very poor prognosis [79]. The available data show no substantial difference in survival outcome for these two anatomically defined entities [10]. Therefore, they are both assigned to a separate N2c classification in the absence of synchronous nodal metastases. Furthermore, the available data demonstrate that patients with a combination of satellites/in-transit metastases plus nodal metastases have an even worse outcome, so that such patients are assigned to the N3 classification.
We also agree that the pathology report should report both the number of metastatic lymph nodes and the total number of lymph nodes examined. Such comments have been incorporated into the text of the melanoma staging publication.
In patients with distant metastases, the site(s) of metastases and elevated serum levels of lactic dehydrogenase (LDH) were used to delineate the M categories into three groups: M1a (metastases in skin, subcutaneous or distant lymph nodes), M1b (lung) and M1c (all other visceral sites or any site in the presence of an elevated serum LDH). Because the survival differences between the M categories are small, there are no subgroups of stage IV melanoma. An elevated level of serum LDH was among the most predictive independent factors of diminished survival in all published studies of stage IV melanoma when it was analyzed in a multivariate analysis, even after accounting for site and number of metastases [1115].

Most importantly, we agree with the EORTC Melanoma Group that it is vitally important to distinguish between preoperative clinical staging and postoperative pathological staging. Our own prognostic factors analysis and those from many other institutions have consistently demonstrated that the nodal status is a very significant prognostic feature of melanoma [2, 1618]. Significant differences were identified when survival rates for melanoma patients, who were clinically staged, were compared to those of the same T category whose nodal disease was staged pathologically. The differences were most striking in patients with clinical T2bN0M0, T3aN0M0, T3bN0M0 and T4aN0M0 disease, where 10-year survival rates for the same category of clinically versus pathologically staged patients varied significantly with diminished survival ranging from 20% to 29% (table 6). These results highlight the compelling prognostic value of knowing the nodal status as identified by lymphatic mapping and sentinel lymphadenectomy in those situations where accurate staging is important. The AJCC Melanoma Committee has strongly recommended that all patients with clinical T2N0M0, T3N0M0 and T4N0M0 melanomas have pathological nodal staging with sentinel lymphadenectomy prior to entry into melanoma clinical trials.

We thank the authors and the Annals of Oncology for the opportunity to respond to this article so promptly.

C. M. Balch & M. C. Mihm

Chairman, AJCC Melanoma Staging Committee, Departments of Surgery and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD; Member, AJCC Melanoma Staging Committee, Clinical Professor of Pathology, Harvard Medical School/Massachusetts General Hospital, Co Chairman, Pathology Committee, WHO Melanoma Program, USA

References

1. Balch CM, Buzaid AC, Atkins MB et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 2000; 88: 1484–1491.[ISI][Medline]

2. Balch C, 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 Oncology 2001; 19: 3622–3634.[Abstract/Free Full Text]

3. Balch CM, Wilkerson JA, Murad TM et al. The prognostic significance of ulceration of cutaneous melanoma. Cancer 1980; 45: 3012–3017.[ISI][Medline]

4. Lock-Andersen J, Hou-Jensen K, Hansen JP et al. Observer variation in histological classification of cutaneous malignant melanoma. Scand J Plast Reconstr Surg Hand Surg 1995; 29: 141–148.[ISI][Medline]

5. 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 1996; 14: 1218–1223.[Abstract]

6. Clark WH Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Research 1969; 29: 705–727.[ISI][Medline]

7. Cascinelli N, Bufalino R, Marolda R et al. Regional non-nodal metastases of cutaneous melanoma. Eur J Surg Oncol 1986; 12: 175–180.[ISI][Medline]

8. Leon P, Daly JM, Synnestvedt M et al. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg 1991; 126: 1461–1468.[Abstract]

9. Harrist TJ, Rigel DS, Day CL Jr et al. "Microscopic satellites" are more highly associated with regional lymph node metastases than is primary melanoma thickness. Cancer 1984; 53: 2183–2187.[ISI][Medline]

10. Buzaid AC, Ross MI, Balch CM et al. Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol 1997; 15: 1039–1051.[Abstract]

11. Deichmann M, Benner A, Bock M et al. S100-Beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from non-progressive American Joint Committee on Cancer stage IV melanoma. J Clin Oncol 1999; 17: 1891–1896.[Abstract/Free Full Text]

12. Eton O, Legha SS, Moon TE et al. Prognostic factors for survival of patients treated systemically for disseminated melanoma. J Clin Oncol 1998; 16: 1103–1111.[Abstract]

13. Franzke A, Probst-Kepper M, Buer J et al. Elevated pretreatment serum levels of soluble vascular cell adhesion molecule 1 and lactate dehydrogenase as predictors of survival in cutaneous metastatic malignant melanoma. Br J Cancer 1998; 78: 40–45.[Medline]

14. Keilholz U, Conradt C, Legha SS et al. Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Oncol 1998; 16: 2921–2929.[Abstract]

15. Sirott MN, Bajorin DF, Wong GY et al. Prognostic factors in patients with metastatic malignant melanoma. A multivariate analysis. Cancer 1993; 72: 3091–3098.[ISI][Medline]

16. Gershenwald JE, Prieto V, Colome-Grimmer MI et al. The prognostic significance of microscopic tumor burden in 925 melanoma patients undergoing sentinel lymph node biopsy. Proc Am Soc Clin Oncol 2000; 19: 551a.

17. Gershenwald JE, Thompson W, Mansfield PF et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 1999; 17: 976–983.[Abstract/Free Full Text]

18. Gershenwald JE, Colome MI, Lee JE et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 1998; 16: 2253–2260.[Abstract]





This Article
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Balch, C. M.
Articles by Mihm, M. C.
PubMed
PubMed Citation
Articles by Balch, C. M.
Articles by Mihm, M. C.