Mid-level and deep melanomas
What are you doing for patients with mid-level and deep melanomas?
I have had several young patients lately with mid-level (over 0.75 mm) or deep melanoma (over 4mm depth). Different oncologists expect me to treat their patients quite differently. After the dermatologists locally excise the lesion, and refer the patient to an oncologist for exam and CT scans, then I see the patient.
One oncologist expects all of his patients to undergo lymph node dissection. These patients have had no palpable or CT visualized lymphadenopathy, their patients’ melanomas have been in the mid back, or one on the mid posterior thigh. He also wants his patients to undergo lymphoscintigraphy (which I have had a very difficult time getting the radiologists to perform, as they say it had been done many years ago and abandoned as not helpful according to them). Another oncology group only wants their patients to have lymphadenectomy if there are palpable or enlarged lymph nodes seen on CT.
How are others treating similar patients with deep or mid-level melanomas? Is patient age a factor in the decision? Any one doing routine lymph node dissections? Any one with a positive experience from lymphoscintigraphy to find a lymph node region to dissect?
In our institution patients with mid-level melanomas and non-enlarged lymph nodes undergo lymphoscintigraphy to mark the sentinel-lymph-node which is then excised and submitted to histopathological examination. If the node is free of tumor cells, the patient is discharged. Oncological controls are performed by the dermatologists. If there are tumor cells, we accomplish lymph node dissection.
Sentinel lymph node mapping is fast becoming the appropriate way to manage patients with intermediate melanomas and clinically negative nodes. We will perform lymphoscintigraphy for truncal and scalp lesions to determine the drainage basin but usually not for extremity lesions. Then we’ll use both blue dye and a radioactiver tracer with a Neoprobe to find the sentinel node as an outpatient. If the sentinel node is negative, we follow the patient. If the sentinel node is positive, they come back for a full dissection, in which case we do a Level III dissection in the axilla and inguinal in the groin. If Cloquet’s node is positive in the groin we’ll do an iliac dissection as well. They then go on a year of biologic therapy per Kirkwood’s protocol.
We are doing PCR of the tyrosinase mRNA to look for occult disease in H & E negative sentinel nodes but that is under an IRB approved research protocol. I would caution you to get your lymphoscintigraphy before someone does a wide local excision, thereby disrupting the lymphatics. It took some time to get our nuclear medicine people up to speed since it was a new concept for them but once they had done a few people, it became routine.
Elective lymph node dissection (ELND,i.e., resection of all the lymph nodes from a hypothetically involved or at least at risk basin) has been the subject of much controversy over the past 30 years. Only retrospective data ever suggested that ELND improved disease free or overall survival, and only in certain subgroups. All randomized prospective trials were negative. In hopes of definitively answering the question, an Intergroup Study was begun, the results of which have been published over the past few years. This study showed definitively that 2 cm margins were as good as 4 cm margins for intermediate thickness melanoma (1-4 mm Breslow thickness, Ann Surg 218:262-269).For over seven years after patient accrual was completed, no data was published on the efficacy of ELND. I saw the data presented at that point at a melanoma conference, and all survival curves were identical. Recently, the data was published, suggesting that younger patients with non-ulcerated melanoma benefitted from the procedure. The problem with their conclusions is that they went outside the randomization stratifiers to subgroup the patients. How valid is a randomized prospective trial when the data must be re-sorted by non-randomized groupings to give you a statistically significant benefit of the experimental treatment?
Finally, you asked about lymphoscintigraphy, leading to *selective* lymph node dissection. Many physicians who see a significant number of melanoma patients believe that this procedure has already replaced ELND and should be considered the standard of care for all patients with high risk melanoma. Through a combination of lymphoscintigraphy and injection of a blue dye that is avidly adsorbed by the lymphatics, the lymph node(s) that primarily drain the area of a primary tumor are identified. To optimize accuracy, an intraoperative gamma probe must be used to locate these “sentinel” lymph nodes (the Neoprobe 1000, which supposedly costs over $ 20,000 US). The published results suggest that experienced surgeons can identify sentinel nodes almost 100% of the time. The false negative rate is < 5 %, meaning that there are almost never "missed" lymphatic metastases. If a patient has pathologically positive lymph nodes, then a completion lymphadenectomy is performed. Unlike the other respondent, I don't trust frozen section examination, since many of the lymphatic metastases I find during sentinel node harvest are microscopic. I prefer to wait until the final pathology is available, then bring the patient back to the OR if necessary. The advantage of sentinel lymph node mapping and biopsy is that it avoids the significant morbidity of complete lymphadenectomy (lymphedema, wound infection rate, etc.), yet provides enough information to decide who actually needs a complete lymphadenectomy and who doesn't. Conversely, ELND puts all patients at risk for those complications, regardless of whether they end up having lymphatic metastases or not. Sentinel node courses are available at multiple locations. Also, sentinel node mapping occasionally identifies "in-transit" nodes. In one of my first sentinel node cases, we harvested sentinel nodes from the scapular region and from the axilla in a patient with a back melanoma. A scapular node was positive; the axillary nodes were all negative. ELND would have missed this metastasis. The FDA has approved high dose interferon alpha-2B for treatment of patients with high risk melanoma or those with lymphatic recurrence or primary metastases to the lymph nodes (J Clinical Oncology, 14:7-17). This is the only adjuvant treatment ever shown to be effective in melanoma. Although the FDA has approved it for use in all the defined subgroups, only the patients with lymphatic metastases actually benefitted. The patients with high risk primaries without lymphatic spread actually did worse with interferon, although it is a small group. Due to >80% incidence of serious side effects from the medication, leading to dose reduction in most patients, I only recommend it to patients with lymphatic metastases, although many medical oncologists will recommend it for high risk lesions as well, because the FDA has approved it for that indication.
My algorithm would be as follows:
Wide excision if 2 cm margins not obtained
If Breslow thickness >= 1 mm or ulcerated primary, then perform sentinel lymph node mapping and biopsy (can be done as outpt at same time as wide excision)
If lymph node metastases found, perform completion lymphadenectomy
High dose adjuvant interferon for patients with lymphatic mets
No role for ELND. No role for lymphoscintigraphy unless you are going to use it for sentinel node biopsy. Age a factor only in terms of a patient’s ability to tolerate interferon.
I see by the flashing yellow light that my time is up.
As insignificant as it may be, I recall an article published about the time I was an intern by Dan Kenady (DE Kenady) and Kathy Meyer comparing survival of stage IV (and I think Stage V, which makes no sense) melanoma patients with and without regional lymphadenectomy. With lymphadenectomy it was ~20%, without lymphadenectomy it was ~10%. The difference was significant.
I did a literature search on Medline on Kenady DE, and the only relevant article on melanoma was from SGO and was a review article on general melanoma treatment. Is there another one?
I am [still] not aware of any prospective randomized trials that compare therapeutic lymphadenectomy in melanoma with no treatment. It simply has always been done, probably because there has been nothing else to offer the patient. From a clinical perspective, some patients who have lymphatic metastases and have a therapeutic lymphadenectomy do quite well, with long disease free intervals. I have several patients who are more than three years out and are free of disease. They had no further treatments. Other patients, with similar histories and demographics, died within months of their lymphadenectomies with suddenly appearing, rapidly progressive, widespread disease.
All this tells me is that we have much to learn about the biology of melanoma, and that simple lymph node dissection may not have as much impact on survival as we would hope.
I perform a RLND for lesions between 1.51 and 3.99 mm. The approach for lesions between 0.76 and 1.49 mm is the following:RLND of the upper extremities because of the modest morbidity; no RLND for similar depth of lower exts.Lymphoscintigraphy is very useful for uppr back lesions.
We treat them with sampling of enlarged nodes after injection of blue inck in the skin near the lesion in the limb and perform linphadenectomy only in positive cases (EORTC and NCI protocols). Then oncologists will provide to give them interferon or other drugs.Lymphoscintigraphy is unuseful.