Medical Diagnosis: Lymph node metastases of right groin from melanoma in the epigastric region.

Excision of supraumbilical nevoid lesion on (approx 7-8 months before this report) for which the histological diagnosis gives evidence for: "malignant melanoma growing vertically, Clark level III, 0.10 Breslow thickness. The edges of the surgical resection cover the entire lesion (approximately 0.1 – 0. cm)."

Subsequently, further tests were performed that turned out to be negative for metastases, specifically: Chest X-ray; echo tomography soft tissue of axillary and inguino-crural areas; full body CAT scan.

Following performance of lymph scintigraphy, the patient underwent an operation to enlarge the previous nevus resection and a sentinel node biopsy of the right groin was performed at the Regional Reference Centre for Cutaneous Melanoma – IOV – Padua. After removing 4 lymph nodes in the right groin area, one resulted positive for sub capsular and intraparenchymal micrometastasis of melanoma with multiple foci (maximum diameter 0.61 mm, SII Starz sec).

Revision in Padua of the first histological test with class worsening: Superficial-extension malignant melanoma, in vertical-growth phase, non-ulcerated, with low mitotic index (o mitosis/mm²), with plentiful brisk type lymphocytic infiltrate and areas of regression, Clark level IV, maximum thickness of the lesion under Breslow 1.14 mm. Edges of resection undamaged.

Given the positivity of the sentinel node, on--- (approx. 5 months before report) the patient underwent a surgical right inguinal-iliac-obturator lymphadenoidectomy, which resulted negative (21 lymph nodes removed). The post-operative course was complicated by the appearance of significant lymphocoele that gradually reduced toward the end of --- (approx. 2 months later).

In consideration of the stage of the disease (pT2a N1a -> IIIA), an adjuvant treatment with Interferon as part of the Mel. A. The study was proposed to the patient. This treatment began on --- (approx 4 months before report), and the patient was assigned to Arm A (IFN with high intensified doses), with a protocol schedule of 4 cycles, each lasting 1 month, with intervals of 1 month of suspension as in the calendar provided below:

Cycle start date Last dose date

1st cycle ev., (4 months before report) (approx 1 month later)

2nd cycle ev. (2 months before) (1 month later)

3rd cycle ev. (several weeks before) (patient almost through)

4th cycle ev. (this treatment to begin shortly and last for month)

On---(towards the end of the first cycle), the specialized oncological examination during the 1st cycle found out that the patient showed good tolerance to the treatment, so that no reduction in dose was required.

A marked edema appeared on the right leg, for which the patient presented for examination on---- (between first and second treatment cycles); the oncology specialist interpreted this edema as the direct result of the procedure to empty the right inguinal-iliac-obturator, however recommended, as a precaution, a venous echo Doppler of the lower limb that excluded a deep venous thrombosis.

Follow-up blood tests were performed during the treatment with IFN, the results are enclosed (53, 54, 55, 59, 64).

On---(approx 2 months before report), excision of another nevoid lesion on the right thigh giving histological evidence for "compound freckled nevus with moderate degree of dysplasia – entire lesion within the borders of the resection".

The ultrasound of the lower abdomen on, shows at the level of the inguinal regions:

“On the right oedematous thickening of the soft tissues in relation to recent results of surgery."

No lymphadenomegalies.

Some lymph nodes were found in the left inguinal area, in the medial planes, the largest measuring 1.6 – 1.8 cm.

Due to the worsening of the lymphedema, the patient underwent an additional oncological examination on ----(11/2 month before report), with recommendation to repeat a venous Doppler that confirms a "situation likely secondary to a serious lymphostasis, provoked by inteventions in the lymphatic system, although at this time it is not possible to exclude components related to the primary pathology." Therefore a cycle of manual lymphatic drainage is recommended with elasto-compressive bandage performed by the patient.

The most recent available tests concern blood tests (earlier the same month)(attachments 78, 79, 80) and left groin ultrasound: "significant numerous lymph node formations with reactive character and maximum diameter of 18 mm. No evidence of nodular-type aspects").

Questions:

1) What do you think about the experimental treatment with interferon?

2) Any further alternative treatments to prevent metastases and/or relapses of the disease?

3) Therapy recommended for the lymphedema?

4) What is the prognosis?

Medical Report:

 

The patient is a 47 year old male who was found to have stage IIIA (pT2aN1aMo) superficial malignant melanoma of the trunk (supra-umbilical area). It was originally resected on ----(7-8 months before report). The tumor measurement was unclear, but the lesion was fully excised, and was seen to be without ulceration, with a low miotic index (0 mitoses per mm2). There was evidence of lymphocytic infiltration and areas of tumor regression. The extension was Clark´s level IV, with a maximum Breslow thickness of 1.14. The patient initially underwent a sentinel lymph node biopsy on ---(5 months before report), that revealed one of four lymph nodes involved with multi-focal microscopic (maximum diameter 0.61 mm), subcapsular tumor. Subsequently, a right groin lymphadenectomy was performed, removing 21 lymph nodes from the inguinal, iliac and obturator regions. None of the lymph nodes had any evidence of metatastic melanoma. Additional staging studies included an ultrasound examination of the groin and axilla, a full body CT scan and chest x-ray. None of these imaging studies revealed evidence of metastic disease.

For adjuvant treatment, to reduce the risk of recurrent disease, the patient was enrolled in the MelA study, and initiated treatment with high dose interferon A (doses not specified) on ----(see schedule above). Four monthly cycles, given over the course of 6 months, were planned. The first cycle went well. Laboratory evaluation revealed an unremarkable complete blood count and liver function tests. In ---(3 months before report), the patient had a reduction in his absolute neutrophil count to 1150 (date), and 1680 (1 week later), with no reports of neutropenic fever. There was a mild increase in liver function tests at that time.

Unfortunately, the patient developed marked lymphedemia of the right lower extremity that was evaluated on ---(2 months before). There was no evidence of deep vein thrombosis by Doppler Ultrasound, a test that was repeated on ---(within a couple of weeks). The evaluating physicians felt that the lymphedemia was a consequence of extensive lymphadectomy, and recommended physical therapy.

The most recent reported imaging study was a left groin ultrasound revealing benign/ inflammatory- appearing lymph nodes, none greater than 18 mm. Of note the patient also had a compound nevoud removed from his right thigh on ---(3 months before).

Comments:

Comments are requested regarding the adjuvant treatment strategy with interferon and any available alternatives; therapeutic recommendations for the lymphedema; and a request for prognosis.

Interferon alfa (IFNa) in the adjuvant treatment of patients with lymph- node positive malignant melanoma

For patients with stage III melanoma, who have a life expectancy more than 10 years and no other life- threatening disease, high dose Interferon A is the standard post-operative treatment. The typical dose, as reported in ECOG 1604 was 20 million units per m2 intravenously, 5 days per week for 4 weeks, followed by 10 million units per m2 subcutaneously three times weekly for the next 11 months, for a total of one year treatment. Patients who received interferon tended to live longer, and if there disease did recur, it recurred later than those patients who did not receive treatment. Due to the toxicity of IFNa, which includes fever, fatigue, nausea, neutropenia, reversible hepatoxicity, and thyroid dysfunction, other treatment modalities are undergoing investigation, but none have shown the benefit seen from adjuvant IFNa. At this time, numerous studies are trying to improve upon IFNa by using by using bio-chemotherapy (IFNa with interleukin-2, cisplatin, vinblastine and dacrbazine), vaccines and GM-CSF. Unconjugated monoclonal antibodies and GD2 and GD3, IL-2 fusion proteins, anti CTLA-4 monoclonal anti-bodies, dendetric cell vaccine therapy and heat shock protein (HSP) vaccines are all in different stages of clinical development. However, I would hesitate to recommend anything other than interferon Alfa outside of clinical trial.

Treatment of lower extremity lymphedema

Grated compression garments remain the mainstay of lymphedema treatments. Complex decongestive therapy (manual drainage, bandaging and exercises) may add some benefit, but the addition of electrically stimulated lymphatic drainage, pneumatic compression pumps, laser treatment, electrical stimulation, Cryotherapy, microwave therapy or therapeutic ultrasound has not shown a reproducible, statistically significant result in most patients with lymphedema. Patients with lymphedema are encouraged to moisturize and maintain scrupulously clean skin, avoid local heating pads, keep their ideal body weight, exercise judiciously and promptly treat any and all skin infections.

Prognosis

In patients with melanoma, the thickness of the primary tumor and the presence or absence of ulceration, as well as the existence and number of lymph node mestasis are the primary factors influencing the prognosis. Patients who have stage IIIa malignant melanoma have 1-3 microscopically involved lymph nodes and a tumor that was not ulcerated. In the US, prognosis is based on 2 validated data bases: the AJCC validated data base (17,600 patients) and the Surveillance, Epidemiology, and End Results (41,417 melanoma patients). The 10 year survival rate for patients with stage III melanoma were 35% and 46% respectively. In this patient´s case, he has factors associated with better prognosis: his tumor was not ulcerated, it had a low mitotic rate, tumor-infiltrating lymphocytes were seen, as evidence of primary tumor regression. That coupled with the fact that the patient is receiving adjuvant IFNa, should improve his chances of longer progression free survival.

Thank you for the opportunity to consult in this case.

If I can be of any further help to the patient, please contact me through Medical Opinion.

Sincerely,

Dr---

Associate Professor of Clinical Medicine