Update on mucosal melanoma of the head

and neck

Dr Charles Kelly Clinical Oncologist Northern Centre for Cancer Care Freeman Hospital Newcastle upon Tyne

Epidemiology & biology of head and neck mucosal melanoma

Approximately 1 – 2% of melanomas Mucosal melanoma in context

• Head and neck 55% • Anorectal 24% • Vulvo-vaginal 18% • Small intestinal/stomach • Other sites e.g. urinary tract; gallbladder

Incidence increasing but not at same rate as cutaneous melanoma

Mucosal presentation gives a greater proportion of melanoma in non-white races

20% multifocal (< 5% cutaneous melanoma) 40% amelanotic (< 10% cutaneous melanoma)

• Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998; 83:1664.

Aetiology of mucosal melanoma

NOT exposure to UV light Risk factors for cutaneous melanoma

• naevi • UVB • UVA – tanning beds • PUVA treatment • Intense intermittent sun exposure & sunburns • Childhood sun exposure • Occupational sun exposure for H & N skin melanomas • Lack of vitamin D • Endometriosis • Parkinsonism • Previous melanoma • Family history

NO CLEAR RISK FACTORS FOR MUCOSAL MELANOMA

Therefore no prevention or screening unlike cutaneous

Clinical presentation Mucosal melanoma is 10% of head and neck melanoma

(90% cutaneous) Nasal cavity (55%) }nasal obstruction, Sinuses (15%) } epistaxis Oral cavity (25%)

• 60% found incidentally • Painless mass,bleeding, ulcer, dentures not fitting

Other head and neck sites • Pharynx • Larynx • Oesophagus

Courtesy of UC Davis

Staging

Previously stages I, II, III – localised disease; regional nodes; distant metastasis

Now UJCC classification, with staging beginning at stage III to reflect poor prognosis

Head and neck examination plus endoscopic sinus examination

CT/MRI of head and neck, chest and abdomen

Differential diagnosis Oral mucosal melanoma : a malignant trap

Symvoulakis EK et al Head & Face Medicine 2006, 2:7 Melanonosis, Smoking associated melanosis, post-inflammatory pigmentation, medication induced melanosis, melanoplakia, melanoacanthoma,naevi, Addison's disease, Peutz-Jeghers syndrome, amalgam tattoo, Kaposi's sarcoma Amelanotic melanoma – SCC/ Lymphoma

Differential Diagnosis

Oral mucosal melanoma : a malignant trap

Symvoulakis EK et al Head & Face Medicine 2006, 2:7

Open Access

Management - General Mucosal Melanoma of the Head and Neck

David G. Pfister, Kie-Kian Ang, David M. Brizel, Barbara Burtness, Anthony J. Spencer, Andrea Trotti III, Randal S. Weber, Gregory Wolf and Frank Worden Sandeep Samant, Giuseppe Sanguineti, David E. Schuller, Jatin P. Shah, Sharon Martins, Thomas McCaffrey, Bharat B. Mittal, Harlan A. Pinto, John A. Ridge, Ying J. Hitchcock, Merrill S. Kies, William M. Lydiatt, Ellie Maghami, Renato Maura L. Gillison, Robert I. Haddad, Bruce H. Haughey, Wesley L. Hicks, Jr., Cmelak, A. Dimitrios Colevas, Frank Dunphy, David W. Eisele, Jill Gilbert,

2012;10:320-338 J Natl Compr Canc Network Stage III / IVa

• Wide resection and RT to primary / nodes

Stage IV b / c

• Clinical trial • Systemic therapy • Primary radiotherapy • Best supportive care

Management – Surgery

Complete excision with “adequate margin” is advocated • but may be dealing with multifocal disease

Endoscopic resection • Lund VJ, Howard DJ, Harding L, Wei WI. Management options and survival

in malignant melanoma of the sinonasal mucosa. Laryngoscope 1999; 109:208.

• Hanna E, DeMonte F, Ibrahim S, et al. Endoscopic resection of sinonasal cancers with and without craniotomy: oncologic results. Arch Otolaryngol Head Neck Surg 2009; 135:1219.

Craniofacial resection • Ganly I, Patel SG, Singh B, et al. Craniofacial resection for malignant

melanoma of the skull base: report of an international collaborative study. Arch Otolaryngol Head Neck Surg 2006; 132:73.

Lund VJ, Howard DJ, Harding L, Wei WI. Management options and survival in malignant melanoma of the sinonasal mucosa. Laryngoscope 1999; 109:208.

Retrospective review 72 patients at Institute of Laryngology & Otology Differing surgical approaches 5YS 28%, 10YS 20%; median survival 21 months No difference in

• Local control if post-op RT • Survival if post-op RT • Survival if post-op chemotherapy • tumour site • Positive nodes • Patient age

Management – Surgery

Elective neck node dissection • Not for Sinonasal– < 10% nodes positive • Possibly for oral cavity – 25% node positive, but bilateral neck node

dissections?

Therapeutic neck node dissection • For improved local control • Gives no increase in five-year survival

Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997; 80:1373.

Sentinel node biopsy • Feasible but not often carried out.

Stárek I, Koranda P, Benes P. Sentinel lymph node biopsy: A new perspective in head and neck mucosal melanoma? Melanoma Res 2006; 16:423.

Recurrence

Local or locoregional recurrence develops in 30 – 80% of patients despite completeness of surgery

Recurrence risk depends on • Tumour size • Incomplete resection • Vascular invasion

Usually first recurrence occurs in the first year after treatment

Most patients still die from metastatic disease

Adjuvant radiotherapy Some studies but not all have shown an improvement in

local control but not overall survival Patel & Shah et al MSK 2002

• Retrospective review of notes 59 patients 1978 – 1998 • 35 sinonasal (15%); and 24 oral (41%). • Only prognostic factors.

Advanced stage at presentation Melanoma thicker than 5 mm vascular invasion. Distant failure. Regional nodal involvement on univariate not multivariate analysis

• Disease-free five-year survival 44% oral; 47% sinonasal

Wu & Shah et al MSK 2008 • Retrospective review of notes 27 patients 1992 – 2007 • 24 sinonasal , 2 oral, 1 oropharynx. • Overall five-year survival 33%

Radical Radiotherapy

Adjuvant chemotherapy

Little evidence but phase II trial from Beijing 2013 Adjuvant chemotherapy after surgery in 189 patients This study needs confirmation and repeating

Management Recurrence free survival (months)

Estimated overall survival (months)

observation 5.4 21 High-dose nterferon for one year

9.4 40

Temozolomide / cisplatin 6x3 weekly

20.8 49

Chemotherapy for metastatic disease Standard as for cutaneous melanoma

• Dacarbazine DTIC, Temozolomide

TARGETED THERAPIES now being investigated • Mitogen activated protein kinase (MAPK) pathway has several targets • B RAF mutations in 50% cutaneous melanoma, 25% mucosal • V 600E mutation predicts response to B RAF or MEK inhibitors

Check B RAF V600 mutation (10% of mucosal melanoma ?)

• B RAF inhibitors – Vemurafenib, Dabrafenib • Immediate response possible PS 3 PS 0—1 in 24 – 40 hours • Fast responders tend to show faster relapse as well • MEK inhibitor - Trametinib

If B RAF wild type check for KIT mutation(25%?) • KIT inhibitor – Imatinib

Immunotherapy for metastatic disease

Ipilimumab Monoclonal antibody directed against CTLA-4 turns off the inhibitory mechanism and allows cytotoxic T

lymphocytes to continue to destroy cancer cells Breaks down the tolerance to tumour associated

antigens in the melanoma 4 infusions at three weekly intervals and there may be

delayed response One study in mucosal melanoma, a retrospective

analysis of 33 patients with non-resectable or metastatic disease : 1CR, 1PR, 5 stable disease, 23 progress of disease at 12 weeks

• Postow MA, Luke JJ, Bluth MJ, et al. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 2013; 18:726.

Some prognostic markers? Heparanase expression correlates with poor survival in oral mucosal melanoma Xin Wang • Weiwei

Wen • Heming Wu •Yi Chen • Guoxin Ren • Wei Guo Med Oncology 2013 30;633 High Low None

Median survival (months)

12 35 62

5YS % 7 36 53

Ki67 Antigen as a Predictive Factor for Prognosis ofSinonasal Mucosal Melanoma Dong-Kyu Kim, Dae Woo Kim, Si Whan Kim, Dong-Young Kim, Chul Hee Lee, Chae-Seo Rhee, Clinical and Experimental Otorhinolaryngology Vol. 1, No. 4: 206-210, December 2008 Better survival if low Ki67 or spindle or mixed cell type on histology

Summary Generally poor outcomes with five-year survival 12 –

30% • “Patients with nasal mucosal melanoma have a 31% 5-year survival rate,

whereas sinus melanoma patients fare poorly, with a 0% rate of 5-year survival. “

• Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997; 80:1373.

Single Institutional reports with limited patient numbers Aetiological factors unknown therefore difficult for

prevention, screening Early disease picked up in the main incidentally Late disease still poor survival despite heroic efforts

at maximising local control Targeted therapies with multiple concurrent drugs and

targets but still only a minority show mutations

Thank you Any questions?

Where`s your robot now Mr Paleri?