Reflecting on the 2001 American Joint Committee on Cancer Staging System for Melanoma

Reflecting on the 2001 American Joint Committee on Cancer Staging System for Melanoma Spyros Retsasa and Michael J. Mastrangelob The Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) promulgated in 2001 major revisions of the melanoma tumor-node-metastasis (TNM) categories and stage grouping criteria, for a new staging system of cutaneous melanoma. The Committee invited data analyses relevant to the proposed new melanoma staging for validation of the system. Validation studies that were published subsequently confirmed most of the parameters of the new staging system, identified new prognostic factors that had not been included in the revised AJCC staging, whereas the prognostic power of some parameters could not be confirmed in the data of other institutions. This article provides an in-depth analysis of the current AJCC staging for melanoma, addresses areas of controversy, and offers proposals for consideration at the next revision of the system. Semin Oncol 34:491-497 © 2007 Elsevier Inc. All rights reserved.

I

n 2001, the Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) proposed major revisions of the tumor-node-metastasis (TNM) categories and stage grouping criteria for cutaneous melanoma and proffered a new staging system.1,2 The dominant recommendation among these proposals was that the thickness as well as the presence of ulceration of the primary lesion—as determined by microscopic histopathologic examination—should be used in the tumor (T) classification.2 In the nodal (N) classification, the Committee proposed that the number of lymph node– containing melanoma metastases should be the dominant and independent predictor of outcome and should be used instead of the gross size (dimensions) of nodal metastases. Furthermore, it recommended that ulceration of the primary lesion should be retained as an independent prognostic factor in the classification of any clinically palpable nodal disease. For metastatic disease beyond regional lymph nodes (M), the Committee introduced serum levels of lactate dehydrogenase (LDH) as an independent prognostic factor for survival.2 The revised TNM classification is presented in Table 1. The Committee invited data analyses relevant to the proposed new melanoma staging for validation of the system. Studies that were published subsequently, validated most of the parameters of the new staging system, whereas others aOncology

Centre, Cromwell Hospital, London, UK. Cancer Center, Thomas Jefferson University, Philadelphia, PA. Address correspondence to Spyros Retsas, MD, FRCP, Consultant Medical Oncologist, Oncology Centre, Cromwell Hospital, Cromwell Road, London SW5 0TU, UK. E-mail: [email protected] bKimmel

0093-7754/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2007.09.005

could not be confirmed in the data of other institutions.3,4 Subsequent correspondence has raised concerns about the methodology applied for calculating overall survival times of patients with regional lymph node metastases, an important consideration for the validation of the proposed prognostic parameters.5 This article provides an in depth analysis of the current AJCC staging for melanoma, addresses areas of controversy, and offers proposals for consideration at the next revision of the system.

The Current AJCC Staging System Stages I and II of the current system deal with the grading of the primary lesion (T) and take into consideration the maximum (Breslow) thickness of the primary cutaneous melanoma measured microscopically in millimeters6 and the presence or absence of microscopic ulceration. There is no naturally occurring cut-off point for the thickness of primary melanoma that delineates defined risks of mortality from the neoplasm.1,2 Nevertheless, an improvement of the current system is the use of even integers for the thresholds of the tumor thickness rather than the previously employed threshold of 0.75 mm between T1 and T2 tumors.2 Clark’s level of invasion was found to be an independent predictive factor in thin lesions and is currently used only for tumors with thickness less than 1.00 mm.2 It should be noted, however, that the discriminating power of Breslow thickness in the survival of melanoma is evident 491

S. Retsas and M. Mastrangelo

492 Table 1 Melanoma TNM Classification According to the Current AJCC Staging System T Classification

Thickness

Ulceration Status

T1

<1.0 mm

T2

1.01–2.0 mm

T3

2.01–4.0 mm

T4

>4.0 mm

a: without ulceration and level II/III b: with ulceration or level IV/V a: without ulceration b: with ulceration a: without ulceration b: with ulceration a: without ulceration b: with ulceration

N Classification

No. of Metastatic Nodes

N1

1 node

N2

2–3 nodes

N3

4 or more metastatic nodes, or matted nodes, or in transit met(s)/satellite(s) with metastatic node(s)

Nodal Metastatic Mass a: micrometastasis* b: macrometastasis† a: micrometastasis* b: macrometastasis† c: in transit met(s)/satellite(s) without metastatic nodes

M Classification

Site

Serum Lactate Dehydrogenase

M1a M1b M1c

Distant skin, subcutaneous, or nodal mets Lung metastases All other visceral metastases Any distant metastasis

Normal Normal Normal Elevated

Reprinted from Balch et al J Clin Oncol 19:3635-3648 2001 with kind permission of the American Society of Clinical Oncology. *Micrometastases are diagnosed after sentinel or elective lymphadenectomy. †Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

even in primary tumors with thickness 1 mm or less as reported by Leiter et al7 and McKinnon et al.8 Reporting for the Sydney Melanoma Unit, McKinnon et al found a 10-year survival of 96.9% for patients with melanomas less than 0.76 mm thick and 84.3% for those with melanomas between 0.76 and 1.0 mm in thickness.8 An important omission in the grading of the primary lesion in the current system is the mitotic count exhibited by the primary melanoma, which reflects the proliferative potential of the lesion at the time of excision. The prognostic importance of mitotic count has been established in other neoplasms9 and has been addressed for some time in the melanoma literature.10-16 More recent studies from Europe and Australia have validated the prognostic significance of this important parameter.3,4 In stage III disease, prognostication is determined by the nodal status. Whereas an earlier World Health Organization staging system addressed nodal disease on development of clinically apparent regional lymph node metastases, the current AJCC system incorporates in the staging microscopically involved lymph nodes detectable with elective lymphadenectomies with or without prior evaluation of the status of the sentinel lymph node at the time of primary diagnosis of the presenting cutaneous lesion. After years of confusion in the literature there is now a clear distinction in the prognostication of clinically occult versus clinically apparent regional lymph node metastases and this distinction has been amply addressed in the current AJCC

system. It should be noted that such differences in the survival of patients with stage III disease may vary by as much as 50%. An important issue here relates to the calculation of overall survival times of patients with metastatic regional lymph nodes and this crucial issue, which may influence the statistical significance of otherwise robust prognostic factors, such as ulceration of the primary lesion, will be addressed in detail later in this article. In stage IV melanoma, metastasis (M), survival risks are defined by the organ(s) involved and the number of metastatic site(s) with soft tissue metastases carrying a relatively better prognosis than pulmonary or visceral metastases. Raised serum levels of LDH also worsen prognosis and this serum marker has now been incorporated as an independent prognostic factor in stage IV melanoma.

Controversies in the Current AJCC System The aggravated prognosis of ulcerated malignant tumors has been known to physicians since antiquity.17 There can be little doubt about the prognostic significance of epidermal ulceration of the primary cutaneous lesion on the risks of relapse and survival of melanoma. Interestingly, the history of bleeding from a primary melanoma prior to excision—a prerequisite of epidermal ulceration— has been reported as a

AJCC staging system for melanoma prognostic factor for survival.3,18 In the case of melanoma, ulceration has been defined as the absence of an intact epidermis overlying a major portion of the primary lesion based on microscopic examination. Although arguments have been raised regarding the reproducible clinical applicability of this definition, the fact remains that the adverse effect on survival of an ulcerated primary cutaneous melanoma has been reported in numerous communications in the past12,13,15,16,19-21 and was confirmed independently in two recent studies of large, single-institution cohorts, from Europe and Australia3,4 and in a population-based database of 36,190 patients studied by Guerry and colleagues, who validated the AJCC melanoma staging system.22 The European study of 1,284 evaluable patients validated the proposal of the AJCC that ulceration of the primary lesion should be used in the tumor classification. However, the same study did not support its inclusion—as recommended by the authors of the current AJCC staging system—in nodal staging, at least in the presence of clinically apparent regional lymph node metastases. This is probably because the core data used by the AJCC for the inclusion of ulceration in nodal staging incorporated studies from the United States and Australia that addressed largely clinically occult regional lymph node metastases detected at elective lymph node dissections and more recently following sentinel node biopsy.3 In these circumstances, survival calculated from detection of lymph node metastases is virtually the same as survival calculated from diagnosis of the primary lesion because resection of such subclinical metastatic regional lymph nodes is likely to take place within a few weeks from primary diagnosis. In contrast, analyses in the European study focused on patients with clinically apparent regional lymph node metastases at initial presentation or at first relapse, the latter potentially occurring many months or years after primary diagnosis. Interestingly both, the European and Australian studies mentioned above found that the mitotic index of the primary lesion—whether investigated as a continuous or categorical variable—was statistically a superior prognostic factor to ulceration and second only to tumor thickness. As mentioned earlier, the mitotic index of the primary lesion is not included in the evaluation of the prognostic parameters of the primary lesion in the current AJCC system. Yet, mitotic activity had been identified as a significant predictor of relapse and survival for cutaneous melanoma as early as 1979.10-16,23,24 A more recent study reported by Gimotty et al found that mitotic rate was an independent predictive factor for thin melanomas ⱕ1.00 mm.25 The appropriate method for evaluation of the number of mitoses/mm2 in the primary lesion has been discussed extensively elsewhere.3,4,10,26 Relevant to these observations is an issue that was recently raised in correspondence by Berd et al.5 It would appear that in the database supporting the current AJCC classification, the overall survival times of patients with stage III disease were calculated from the date of diagnosis of the primary melanoma rather than from the date of documentation of lymph node metastases (usually the date of lymphadenec-

493 tomy). Berd and colleagues point out that the statement that the survival of stage III patients was calculated from the time of diagnosis of the primary melanoma was found in the published article,1 as well as in the companion paper.2 However, such calculations would substantially increase the survival rates of patients with clinically evident regional lymph node metastases (stages IIIB and IIIC) and could conceivably alter the relative significance of the prognostic factors evaluated in the system. In reply to this observation, Balch et al27 stated that the survival times for patients with stage III melanoma were actually calculated from either the date of documented lymph node metastases or the date of lymphadenectomy and added some parenthetic remarks suggesting that the descriptions of the survival calculations were inadvertently misplaced in the text. This is a reassuring clarification but still leaves some difficulties in the interpretation of survival data of a subgroup analysis of 396 patients with four positive nodes marked as either micro or macrometastatic (Table 2).2 The crucial issue of the method of calculating survival times should be readdressed and unambiguously clarified in the next revision of the AJCC staging system. Moreover, a closer review of Table 2 identifies additional discrepancies that are difficult to explain. For example, the 10-year survival of 563 patients with a T4a primary tumor (⬎4.0 mm) without ulceration and without nodal metastases (current AJCC stage IIB disease) is said to be about 54%. Yet, the 10-year survival of 252 patients with a higher AJCC stage IIIA melanoma (harboring microscopic nodal metastases) is reportedly 63%. Similar discrepancies are noted for AJCC stage IV M1b and M1c disease.2 It is conceivable that subsequent systemic treatments may have been responsible for these differences, but that seems extremely unlikely.

Potential New Prognostic Factors for Consideration in the Next Revision NCOA3 (also known as AIB1 or SRC-3) is a member of the steroid receptor coactivator family enhancing transcriptional activation. Overexpression of this molecule in the primary tumors of 353 patients studied by Rangel et al retrospectively, using tissue microarrays, indicated a significant association with reduced relapse-free and overall survival. High NCOA3 levels were predictive of sentinel lymph node metastases.28 If confirmed with further studies, NCOA3 may prove to be a novel independent prognostic marker for melanoma and may have to be considered as such in the next revision of the AJCC staging system. Ki67 is a biomarker of proliferation, as well as of mitotic rate, characteristics that were found to be independent prognostic factors in thin melanomas ⱕ1.00 mm.25 S100, a dimeric, 21-kd acidic, calcium-binding protein found in tissue of neuroectodermal origin, incorporates two major protein subunits, ␣ and ␤.29 It is an established immu-

494

Table 2 Survival Rates for Melanoma TNM and Staging Categories Pathologic Stage IA IB IIA IIB IIC IIIA IIIB

IIIC

IV

Total

TNM

Thickness (mm)

Ulceration

No. ⴙ Nodes

Nodal Size

Distant Metastasis

No. of Patients

T1a T1b T2a T2b T3a T3b T4a T4b N1a N2a N1a N2a N1b N2b N1b N2b N3 M1a M1b M1c

1 1 1.01–2.0 1.01–2.0 2.01–4.0 2.01–4.0 >4.0 >4.0 Any Any Any Any Any Any Any Any Any Any Any Any

No Yes or level IV, V No Yes No Yes No Yes No No Yes Yes No No Yes Yes Any Any Any Any

0 0 0 0 0 0 0 0 1 2–3 1 2–3 1 2–3 1 2–3 4 Any Any Any

— — — — — — — — Micro Micro Micro Micro Macro Macro Macro Macro Micro/macro Any Any Any

— — — — — — — — — — — — — — — — — Skin, SQ Lung Other Visceral

4,510 1,380 3,285 958 1,717 1,523 563 978 252 130 217 111 122 93 98 109 396 179 186 793 17,600

2-Year

5-Year

10-Year

99.7 ⴞ 0.1 99.8 ⴞ 0.1 99.5 ⴞ 0.1 98.2 ⴞ 0.5 98.7 ⴞ 0.3 95.1 ⴞ 0.6 94.8 ⴞ 1.0 89.9 ⴞ 1.0 95.9 ⴞ 1.3 93.0 ⴞ 2.4 93.3 ⴞ 1.8 92.0 ⴞ 2.7 88.5 ⴞ 2.9 76.8 ⴞ 4.4 77.9 ⴞ 4.3 74.3 ⴞ 4.3 71.0 ⴞ 2.4 59.3 ⴞ 3.7 57.0 ⴞ 3.7 40.6 ⴞ 1.8

99.0 ⴞ 0.2 98.7 ⴞ 0.3 97.3 ⴞ 0.3 92.9 ⴞ 0.9 94.3 ⴞ 0.6 84.8 ⴞ 1.0 88.6 ⴞ 1.5 70.7 ⴞ 1.6 88.0 ⴞ 2.3 82.7 ⴞ 3.8 75.0 ⴞ 3.2 81.0 ⴞ 4.1 78.5 ⴞ 3.7 65.6 ⴞ 5.0 54.2 ⴞ 5.2 44.1 ⴞ 4.9 49.8 ⴞ 2.7 36.7 ⴞ 3.6 23.1 ⴞ 3.2 23.6 ⴞ 1.5

95.3 ⴞ 0.4 90.9 ⴞ 1.0 89.0 ⴞ 0.7 77.4 ⴞ 1.7 78.7 ⴞ 1.2 63.0 ⴞ 1.5 67.4 ⴞ 2.4 45.1 ⴞ 1.9 69.5 ⴞ 3.7 63.3 ⴞ 5.6 52.8 ⴞ 4.1 49.6 ⴞ 5.7 59.0 ⴞ 4.8 46.3 ⴞ 5.5 29.0 ⴞ 5.1 24.0 ⴞ 4.4 26.7 ⴞ 2.5 18.8 ⴞ 3.0 6.7 ⴞ 2.0 9.5 ⴞ 1.1

87.9 ⴞ 1.0 83.1 ⴞ 1.5 79.2 ⴞ 1.1 64.4 ⴞ 2.2 63.8 ⴞ 1.7 50.8 ⴞ 1.7 53.9 ⴞ 3.3 32.3 ⴞ 2.1 63.0 ⴞ 4.4 56.9 ⴞ 6.8 37.8 ⴞ 4.8 35.9 ⴞ 7.2 47.7 ⴞ 5.8 39.2 ⴞ 5.8 24.4 ⴞ 5.3 15.0 ⴞ 3.9 18.4 ⴞ 2.5 15.7 ⴞ 2.9 2.5 ⴞ 1.5 6.0 ⴞ 0.9

S. Retsas and M. Mastrangelo

Reprinted from Balch et al J Clin Oncol 19:3635-3648 2001 with kind permission of the American Society of Clinical Oncology.

Survival ⴞ SE 1-Year

AJCC staging system for melanoma V & D

10

495

Vinorelbine & Taxol

8 6 S100 μg/l

4 2 0 15-Apr-03

04-Jun-03 01-Sep-03

Figure 1 Serum S100␤ protein levels in relation to disease-status and treatment of a patient with disseminated melanomatosis (AJCC stage IV; M1c disease). Metastases progressed clinically in the face of first-line treatment with four courses of vindesine and dacarbazine. On introduction of second-line treatment with vinorelbine and paclitaxel (Taxol, Bristol-Myers Squibb), there was a dramatic clinical response to five courses of this combination with a corresponding precipitous fall of serum S100␤ levels towards normal values (⬍20 ␮g/L).

nohistochemical marker in the histopathological diagnosis of melanoma.30,31 The S100␤ subunit also has been evaluated as a serum tumor marker in clinical practice.32 The relationship between circulating S100␤ and staging in melanoma has been established.33-37 It is of limited or no prognostic value in stages I–IIIA melanoma. However, raised serum S100␤ values in the presence of, or following complete resection of clinically apparent regional lymph node metastases stage IIIB or IIIC, should raise concern about systemic metastases requiring elaborate imaging, preferably with computed tomography (CT)/positron emission tomography (PET). The main value of S100␤ is in monitoring the course of and response to treatment of stage IV disease. Serum levels of S100␤ protein have been found to be a better indicator of disease activity than LDH and an independent prognostic factor of survival.38,39 Whereas LDH is nonspecifically raised in a number of metastatic neoplasms, S100␤ shows a specificity of 93% with a sensitivity of 68% in melanoma.39 An example of serum S100␤ levels in relation to treatment and clinical response to different chemotherapy regimens is shown in Fig 1.

Discussion There can be little doubt that the current AJCC staging system has improved the prognostication of the various stages in the clinical evolution of cutaneous melanoma (Table 3). Yet, it has generated new challenges as well with, for example, the introduction into the nodal staging of the micrometastatic status of the sentinel node. Sentinel node biopsy has not been shown to date to add protection to the patient or convincingly influence disease outcome. In the latest report by Morton et al, no overall survival advantage could be demonstrated for the group of patients who underwent sentinel node biopsy versus the group ran-

domized to nodal observation.40 Furthermore, the predictive value of the sentinel node status has not been ascertained against all the prognostic resources available from the primary lesion individually, or against their collective, algorithmic prognostic power. An example of this is the mitotic rate, which has been omitted from the current AJCC staging system. The argument that sentinel node biopsy selects patients for adjuvant treatment is also untenable because there is no universally endorsed adjuvant treatment effective in clinically occult metastases harboured in regional lymph nodes.41 Furthermore, any new adjuvant treatment of value in the current state of play should address hierarchically surgically resectable metastases in stage IV and stage IIIB–C disease rather than just the occult micrometastases in regional lymph nodes, detectable with the sentinel node biopsy or indeed for the high-risk localized primary melanoma. In the light of these arguments the following proposals merit consideration for their simplicity and ease of application in the next revision of the AJCC staging system: ●

●

●

Clearly and unambiguously defined survival times for patients with clinically detectable nodal metastases in relation to analyses of prognostic factors. Inclusion of mitotic rate of the primary lesion (/mm2) in the tumor classification in a universally reproducible and agreed manner. In parallel with LDH the inclusion in stage IV disease of serum S100␤ protein as a prognostic factor.

Whether functional imaging with PET/CT using (18)Ffluorodeoxyglucose (FDG) FDG PET/CT scan should be incorporated in the revised system of the AJCC staging for melanoma is at this point arguable. Reihardt et al evaluated retrospectively this imaging modality in the nodal and metastasis staging of 250 patients with cutaneous melanoma. They report that PET/CT imaging provided significantly more accurate interpretations regarding overall nodal and metastasis staging than PET alone and CT alone. More importantly, change of treatment according to PET/CT findings occurred in 121 patients (48.4%).42 Although this modality is increasingly used for staging in cancer referral centers, it is not generally available and its cost remains prohibitive. A

Table 3 Improvements Introduced Into the 2001 AJCC Melanoma Staging System T

Use of even integers in the expression of tumour thickness Introduction of the prognostic significance of ulceration Limitation of the prognostic value of level of invasion to lesions <1.00 mm N The prognostic significance of the number of metastatic lymph nodes The prognostic discrimination between clinically occult and clinically apparent regional lymph node metastases M Introduction of the discriminating power of serum LDH levels

S. Retsas and M. Mastrangelo

496 Table 4 Proposals for Consideration in the Next Revision of the Melanoma Staging System T N

M

Inclusion of mitotic rate of the primary lesion (/mm2) Address the presence of extracapsular extension of nodal metastases Address unambiguously survival times from detection of regional nodal involvement as they differ considerably for occult versus apparent metastases Retain serum LDH but include also serum S100␤ levels Functional imaging and volumetric quantization of metastases desirable

cancer staging system should be universally applicable and as simple and practical as possible in its implementation in every day clinical practice. It also should be in constant evolution, exploiting and accommodating newer developments on the biology of the disease especially from the explosive growth of molecular and genetic science. There is every reason to expect that these challenges will be addressed in the next revision of the melanoma AJCC staging system (Table 4).

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497 41. Spitler LE: Adjuvant therapy of melanoma. Oncology (Williston Park) 16:40-48, 2002 (suppl 1) 42. Reinhardt MJ, Joe AY, Jaeger U, et al: Diagnostic performance of whole body dual modality 18 F-FDG PET/CT imaging for N- and M-staging of malignant melanoma: Experience with 250 consecutive patients. J Clin Oncol 24:1178-1187, 2006