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September 15, 2008

Importance of Sentinel Lymph Node Biopsy in Patients With Thin Melanoma

Author Affiliations

Author Affiliations: Departments of Surgical Oncology (Drs Wright, Scheri, Faries, Essner, and Morton), Biostatistics (Ms Ye), and Pathology (Dr Turner), John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California.

James E. Goodnight Jr, MD, Sacramento, California: It is certainly an important and correct truism at this point that sentinel lymph node biopsy has revolutionized staging for malignant melanoma and breast carcinoma. The procedures are true, practice-changing events in the management of these patients. The arguments over sentinel lymph node biopsy are now generally how, not whether. By its use, thousands and thousands of patients have been spared the morbidity of lymph node dissection. It is a singular contribution brought about by the leaders of the John Wayne group, certainly Dr Essner being prominent in that group.

Having said that, are you and your colleagues telling me now that no melanoma patient may be spared, that all must undergo sentinel lymph node biopsy? When I was younger, Wallace Clark and Alexander Breslow sort of promised me that some melanomas, the thin ones, don't metastasize. But you are saying this is only mostly true, that at least 1 in 20 thin melanomas actually will show up in the lymph nodes?

If I have to do sentinel lymph node biopsy on all to find these patients, my nuclear medicine people will be happy. So will the isotope salesman. My OR [operating room] schedule will suffer, and I will further deplete the scarce supply of isosulfan blue dye, plus I will create some morbidity. The question is, will I be doing these folks any good? Now actually this complaint is a little tongue in cheek since others have made similar and consistent observations to yours, and I can easily recall in my own cases of patients with lesions in the 0.9-mm range who ultimately showed tumor in the regional lymph nodes and it went on to distant spread and death. So I have liberalized my indications for sentinel lymph node biopsy to include patients with melanomas less than 1 mm in thickness. But the question is, how much less? At this point I don't expect that I will do sentinel lymph node biopsy for patients with melanoma in the 0.5-mm range despite your data. Time may make me change that.

Basically, my obvious major questions are how can we make better identification of patients with thin melanomas who are at risk for occult lymph node metastases? It seems that we ought to be able to get closer to who the baddies are.

My first question actually is why did 631 patients in your database with tumors 1 mm or less actually undergo sentinel lymph node biopsy? Moreover and in particular, why did 178 patients with melanomas less than 0.5 mm undergo sentinel lymph node biopsy? Your surgeons must have had a reason, and do we know what those reasons were, and, in fact, do you still employ those reasons?

The most disturbing finding for me in your data is that Breslow thickness in this large group of thin melanomas was not a guide to risk of occult tumor in the regional nodes. Younger age was suggestive of greater risk, deeper Clark level was suggestive, anatomic site and ulceration were not helpful. I would ask, did you examine mitotic rate or the designation of vertical growth phase as a histologic feature associated with risk?

In this series of thin melanomas, one-half of your patients with a positive sentinel lymph node biopsy had a shave biopsy of the primary lesion. We all know the problems with a shave biopsy. Is shave biopsy in fact a risk factor in thin melanomas that would impel us to do a sentinel lymph node biopsy?

My final question is, what clinical approach to thin melanomas and sentinel lymph node biopsy do you recommend from your study? Are you in fact doing them all?

So I am going to close with a brief digression. In your manuscript, very nicely done, there are 5 patients in your series who had a positive sentinel lymph node biopsy but did not go on to complete lymph node dissection. Only 1 of those patients went on to progression of disease. This is in contrast to your very cogent observation that in this group of thin melanomas, ulceration of the primary and anatomic location in the head and neck does confer an adverse survival risk, but it does not predict for sentinel lymph node biopsy. So basically, this dichotomy, that is, a positive sentinel lymph node patient not progressing vs an anatomic factor and histologic factor that predict for survival but don't predict for sentinel lymph nodes, I think simply underscores the vagaries and variable genome of this exasperating disease.

Dr Essner: As Dr Goodnight has discussed already, the concept of sentinel node dissection not being new anymore has revolutionized the care of our melanoma patients, allows us to stage them with a minimum morbid procedure, and with increasing surgical experience has become an outpatient procedure done often in the main OR, occasionally in a surgery center setting, or even under local anesthesia alone.

Nevertheless, the question of the biology of melanoma continues to confound us as we struggle with determining which factors are predictive of patient outcome, and in the era of molecular biology, we have failed to learn much about the primary tumors; because of their small size, we have little access to fresh tumor tissue. Nevertheless, we examined this group of 631 patients from our institution who underwent sentinel node biopsy as a follow-up from a paper that we published in 2003 when we noted the observation of about a 5% incidence of tumor-positive sentinel nodes in the thin primary group. Yet in this initial study, there were essentially no patient deaths, which suggested the biology of lymph node metastases from thin primaries varied from thicker lesions. Nevertheless, in this study, it is clear that these patients with thin primary melanomas and tumor-positive lymph nodes do have a long-term prognosis similar to patients with thicker lesions, suggesting that the biology is more indolent but equally dangerous with thin primaries than thicker lesions.

The first question was regarding how we found these 631 patients to be considered for sentinel node dissection. It represents about half of the patients we saw during this era, and in fact many of the patients present to our institution for a variety of reasons. The first is because of our wide range of referrals we get from all over the country and occasionally from abroad. The second is that we have had a number of adjuvant therapy trials during this time, and patients would undergo sentinel lymph node dissection to be considered for entry into adjuvant therapy studies. Occasionally, patients noted our work on using molecular profiling of the sentinel nodes and would find their way to our institution for molecular staging, although it was not performed on these patients. So there was a rather large group of patients not generally considered for sentinel node dissection yet nevertheless made it to our institution and ultimately had a sentinel node biopsy.

The second question was regarding the 178 patients with very thin primaries. A lot of these patients wanted to have their lymph nodes evaluated, although the risk of metastases was relatively low.

As you can see from the data, there are a number of factors predictive of sentinel node positivity, including female gender, younger age, and increasing Clark level; these factors have been shown in other reports to be relevant. Yet as Dr Goodnight pointed out, prognosis of our patients related to the sentinel node status, head and neck primary site, and ulceration. We and others have examined these factors and found that head and neck primaries seem to be underrepresented for the total number of positive sentinel nodes, yet many of the patients will develop distant disease as did some of our patients with thin primaries or those who had ulcerated primaries. While ulceration is not very common in this group, it does predict poor outcome.

Another point was raised regarding mitotic rate and vertical growth factor of the primary. The group from the University of Pennsylvania has used mitotic rate and vertical growth phase to classify the risk of metastases for thin primaries and found these factors to be predictive. Yet, we have not found mitotic rate and vertical growth phase to be reproducible factors or always relevant when evaluating the primary tumors.

Indeed, about half of the patients had shave biopsies. This is very common in our melanoma patient population as many dermatologists refer patients after shave biopsies. In fact, a number of papers suggest that a shave biopsy is an adverse prognostic factor because in many cases it underestimates the true primary thickness. So it's not the shave biopsy itself, but it's in fact this method of excising the nevus which may cause the pathologist to underestimate the metastatic potential of the primary.

Our recommendation currently at this point is that we recommend doing sentinel node biopsy in patients with thin primaries who are younger, are female, and have an increasing Clark level. We didn't use regression of the primary with as much certainty. Patients with nonulcerated primaries and non-head and -neck lesions should be considered for sentinel node biopsy.

So the question is, what is the true biology of melanoma? Well, I think we are only starting to learn, and certainly in patients who have a thin primary melanoma and have a negative sentinel node, the prognosis is so good we may change our methods of following up these patients, ie, we rarely use blood work, and examination by chest x-ray may be the only imaging that is necessary. There is no defined role for whole-body PET [positron emission tomographic] scanning or other costly scanning techniques for these patients. It also appears that patients with a tumor-positive sentinel node in this thin group may not require completion dissection, as the risk of nonsentinel lymph nodes containing metastases is reportedly low.

Arch Surg. 2008;143(9):892-900. doi:10.1001/archsurg.143.9.892

Hypothesis  The status of the sentinel node (SN) confers important prognostic information for patients with thin melanoma.

Design, Setting, and Patients  We queried our melanoma database to identify patients undergoing sentinel lymph node biopsy for thin (≤1.00-mm) cutaneous melanoma at a tertiary care cancer institute. Slides of tumor-positive SNs were reviewed by a melanoma pathologist to confirm nodal status and intranodal tumor burden, defined as isolated tumor cells, micrometastasis, or macrometastasis (≤0.20, 0.21-2.00, or >2.00 mm, respectively). Nodal status was correlated with patient age and primary tumor depth (≤ 0.25, 0.26-0.50, 0.51-0.75, or 0.76-1.00 mm). Survival was determined by log-rank test.

Main Outcome Measures  Disease-free and melanoma-specific survival.

Results  Of 1592 patients who underwent sentinel lymph node biopsy from 1991 to 2004, 631 (40%) had thin melanomas; 31 of the 631 patients (5%) had a tumor-positive SN. At a median follow-up of 57 months for the 631 patients, the mean (SD) 10-year rate of disease-free survival was 96% (1%) vs 54% (10%) for patients with tumor-negative vs tumor-positive SNs, respectively (P < .001); the mean (SD) 10-year rate of melanoma-specific survival was 98% (1%) vs 83% (8%), respectively (P < .001). Tumor-positive SNs were more common in patients aged 50 years and younger (P = .04). The SN status maintained importance on multivariate analysis for both disease-free survival (P < .001) and melanoma-specific survival (P < .001).

Conclusions  The status of the SN is significantly linked to survival in patients with thin melanoma. Therefore, sentinel lymph node biopsy should be considered to obtain complete prognostic information.