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Metastatic melanoma

Sub Title: 
Metastatic melanoma stage IIIC
Short summary: 

A 58 year-old woman who first presented for evaluation of a bleeding pigmented lesion on the back. An excisional biopsy was performed and revealed a nodular melanoma. A wide excision was performed and no residual melanoma was identified. After a sentinel lymph node biopsy found to be positive, a completion of node dissection was performed and on pathological evaluation, total 6 of 17 lymph nodes contained melanoma.
Staging studies included whole body PET/CT scan and a head CT. FDG uptake by PET was noted in the left axilla only, with no evidence of more distant metastatic disease.

Patient's question: 
1) Do you confirm the therapy carried out? 2) Is there any further recommended therapy? 3) Prognosis? 4) Are there any centers of excellence in Italy?
Medical background: 

A 58 years old female. The patieant was first presented for evaluation of a bleeding pigmented lesion on the back.
Dermatological check up:
Melanocytic nevi without any atypia in all the examined regions. During the same session, the traumatized nevus coagulation was planned for the same night, bleeding on the dorsal region (recommended home therapy with Fudicin cream in the evening for 7-10 days).
Dermatological check up 8 months later:
Reassessment of the homogeneous pigmented neoplasia on the dorsal region, already traumatized, covered by a recent hematic scab. Upon enlargement detection reported by the relatives, a surgical excision was indicated.

One month later, the surgical excision of the lesion was carried out and defined as: “Radical skin removal 864°”,as described in the following surgery report: “elliptical excision of skin and underskin. Hemostasis and suture in layers".
The relevant histological examination was indicative of:
“Pigmented nodular malignant melanoma with epithelioid and spindled cells (HMB45 +, MART1 +), locally ulcerated, infiltrating into the reticular dermis (maximum thickness 5.8 mm). The lesion shows a high mitotic index (61 mitosis x 10 HPF; proliferation index assessed with Mib-1: 50%), poor perilesional lymphoplasmocytic infiltrate with sparse melanophages. No evident appearance of neoplastic endovascular angiolymphatic infiltration. Resection edges in a healthy tissue (minimum distance 3mm; pT4b according to TNM; Clark level IV, thickness of the upper lesion at 4 mm according to Breslow).”

Two weeks later, the patient underwent a follow-up examination at the melanoma surgery department, where assessed that: “the histological features of the lesion (Clark IV, Breslow over 4 mm) require a completion of the surgical treatment through enlargement of the previous scar (2 cm per side) and biopsy of the sentinel lymph node”.
The patient also underwent the FDG PET/CT exam for surgical restaging. The medical report was indicative of: “the PET/CT study of the body shows a focal pathological hyperaccumulation of FDG in correspondence to the lymphadenopathy in the left axillary armpit, with suspect metastases. Within the limits of sensitivity and specificity of the method (lesions < 5 mm or phlogosis), there are proofs of relevant pathological hyperaccumulation of metabolic tracer in the remaining explored body regions.”

One month later, the patient was hospitalized at the department of surgical oncology to undergo the surgical operation of radicalization of the previous excision at the dorsal level and a biopsy of the sentinel lymph node of the left axillary armpit.
Histological exam with assessment of the following elements:
A) Skin and underskin: “Skin with a little residual dermal nevus in the central part of the lozenge, associated to diffuse fibre-collagen presence on the dermis, granuloma with multinucleated giant cells of foreign body type, frequently around the inert material (stitches), and lymphoid inflammatory infiltrate at a perianexial and perivascular level”.
B) Sentinel lymph node of 2.3 cm, totally removed in 3 fragments: “Metastasis of pigmented malignant neoplasia, originating from a melanoma, and reported in 68 sections of the sentinel lymph node, completely examined in 75 sections”;
C) Adjacent weakly capturing lymph node with max diameter of 0.6 cm, totally removed in 2 fragments: “Lymph node in non-specific reactive hyperplasia, undamaged by neoplastic infiltration”
pN1 (sn) TNM.

The patient underwent a CT scan of the brain with contrast medium, with negative result.
Due to the finding of a positive left axillary armpit sentinel lymph node, pN1 (sn), the patient, at last, underwent a lymphadenectomy surgery of the left axillary armpit. The relevant histological examination reported: Metastasis from neoplasia referred to the known pathology in anamnesis (melanoma) in 5 of the total 15 axillary lymph nodes examined. The pathologic stage as for the N parameter is: pN3 according to TNM.

Experts Opinion: 

The case presentation regards a 58 year-old woman who first presented for evaluation of a bleeding pigmented lesion on the back. In the subsequent months the lesion increased in size. An excisional biopsy was performed. Pathology revealed a nodular melanoma, 5.8 mm in thickness, Clark's level IV, ulceration present and approximately 6 mitoses per high power field, non-brisk tumor infiltrating lymphocytes. A wide excision was performed and no residual melanoma was identified. A sentinel lymph node biopsy identified two sentinel nodes in the left axilla, one of which was found to contain melanoma, the precise dimension of which is not provided, but the description provided suggests that the focus of melanoma was several millimeters in size. A completion node dissection was performed and 15 additional lymph nodes were excised from the left axilla, 5 of which were found to contain melanoma on pathological evaluation. In total, 6 of 17 lymph nodes contained melanoma. Staging studies included a whole body PET/CT scan and a head CT. FDG uptake by PET was noted in the left axilla only, with no evidence of more distant metastatic disease.

This patient has stage IIIC melanoma by the 2009 AJCC classification. Using the melanoma prediction tool which individualizes prognosis based on each of the known prognostic variables in the 2001 AJCC database (http://www.melanomaprognosis.org/Regional.aspx) she is estimated to have an 80% risk of disease recurrence within 10 years, with the vast majority of that risk confined to the first two to three years. With such a high risk of recurrence, consideration of adjuvant therapy is certainly warranted.

Further surgery is not indicated, and radiation therapy to the axilla would generally not be considered strongly, although there is some evidence that it could help to prevent subsequent regional recurrences. This is particularly true for patients with extracapsular extension from an involved lymph node (not described here) or numerous lymph nodes involved (5 nodes involved for this patients, making this a borderline case regarding the consideration of adjuvant radiation).

With regard to systemic therapy, the use of adjuvant interferon in this setting is well-described, and I will only briefly comment on the potential application of interferon for such patients. In the U.S., high-dose interferon is considered the standard-of-care for patients with stage III melanoma. However, this has never been adopted as a standard in Europe. Subset analyses of previously conducted randomized trials suggest that the relapse-free survival benefit of interferon is not as robust in the stage IIIC subset compared to the stage IIIA subset. Some melanoma experts, take this data to mean that high-dose interferon should not be considered as a standard approach for stage IIIC patients.
Intermediate dose interferon, commonly offered in Europe has shown relapse-free survival benefit largely in patients with stage IIIA and IIIB melanoma, thus there is very little evidence regarding these regimens in stage IIIC disease. The toxicity of interferon, and the limited efficacy, particularly in stage IIIC patients permits consideration of investigational therapies in this setting.

There are two international phase III adjuvant trials that include patients with resected stage IIIC melanoma. However, one of the two (MAGE-3 peptide vaccination vs. placebo) requires patients to have clinically palpable lymph node involvement which appears to not be the case here. The other is the ipilimumab vs. placebo trial that is mentioned. This trial is largely based on Europe, but several U.S. centers are also participating. In the U.S, patients are first counseled regarding the available treatment option, interferon. If a patient decides that the efficacy and toxicity of interferon are unattractive, then it is appropriate to consider participation in a placebo or observation controlled trial, as only interferon can be considered a standard option for these patients.

Ipilimumab is a novel immunologic therapy that has been extensively evaluated in patients with metastatic melanoma. The results of two large, randomized trials are still awaited. On the basis of a large phase II trials and the results of a phase III trial with tremelimumab (a very similar agent administered at a distinct dose and schedule compared to ipilimumab) the following statements can be made. Unequivocal evidence of antitumor activity has been observed in patients with metastatic melanoma treated with ipilimumab. Approximately 10% of patients treated have objective tumors responses, the vast majority of which are very long lasting (years in duration). On the basis of uncontrolled trials there is a widely held view among melanoma experts that this therapy is also associated with prolonged disease stabilization and perhaps even survival benefit among patients who have disease progression early in the course of therapy without ever manifesting tumor regression. However, these views cannot be considered evidence until such time as the results of the randomized trials with ipilimumab are available. Some experts believe that as many as 30-40% of patients treated with ipilimumab derive benefit. Despite the lack of data supporting an overall survival or progression-free survival benefit with ipilimumab in the metastatic setting, the aforementioned adjuvant trial was launched. A hypothesized has been advanced by many melanoma experts that an immunologic therapy, such as ipilimumab, might have greater antitumor activity in the adjuvant setting compared to the metastatic setting, though this remains to be seen with any therapy previously evaluated in the both the adjuvant and metastatic setting for melanoma. The toxicities associated with ipilimumab are significant. The primary risk is that patients will develop autoimmune disorders from therapy that typically manifest over the first several months of therapy. Up to 75% of patients have some degree of toxicity, but only a third experience severe manifestation of autoimmunity. Skin and intestine are the most commonly involved organs, although every body site that has been described as being involved by idiopathic autoimmunity in the non-cancer population has been described in some patients receiving ipilimumab. Generally, corticosteroids can ameliorate the autoimmune toxicities, however vigilance is required for the emergence of autoimmunity as some patients can become gravely ill in this setting.

The major center in Italy is the Istituto Nationale Tumori di Milano. The melanoma group there has a global reputation for expertise in the treatment of melanoma and would be considered the premier referral center for challenging cases.