This document provides an overview of malignant melanoma of the head and neck. It begins with an introduction that defines malignant melanoma and notes its rarity in mucosal tissues. It then covers the epidemiology, etiology and pathogenesis, subtypes, clinical manifestations including oral manifestations, diagnosis, staging, treatment and prognosis. Key points include that mucosal melanomas have a poorer prognosis than cutaneous melanomas, risk factors are unknown for mucosal melanomas, and the main treatment is complete surgical resection though prognosis remains poor with few long term survivors.

1. Malignant Melanoma of the head and neck
JOURNAL CLUB PRESENTATION
PRESENTED BY
Dr. CHITHRA P
Senior Lecturer
Dept of Oral Medicine & Radiology
Malabar Dental College & Research Centre, Manoor
Chekannoor Road, Mudur PO, 679578,

2. CONTENTS
• Introduction
• Definition
• Epidemiology
• Etiopathogenesis
• Subtypes
• Clinical manifestations
• Oral manifestations
• Differential diagnosis
• Diagnosis
• Staging
• Treatment and Prognosis
Critical analysis of the
article
• Why was the article
chosen
• Aim/objective
• Major references cited
• Method
• Results
• Strong points
• Weak points
• New terms learnt
• References

3. INTRODUCTION
• Malignant melanoma (MM) is a malignancy of pigment
producing cells (melanocytes), which are located primarily
in the skin, but also found in the ears, gastrointestinal tract,
eyes, oral and genital mucosa and leptomeninges.
• Malignant melanoma is least common but most deadly of all
primary skin cancers.
• Mucosal melanomas are exceedingly rare tumors which
comprise a small subset of all melanomas. Poorer prognosis
than their cutaneous counterparts.

4. • Acc to Burket’s 12th edition:
• Malignant melanoma is included among endogenous
focal melanocytic pigmented lesions.

5. DEFINITION
“Malignant melanoma is a type of cancer arising from the
melanocyte cells of the skin. Melanocytes are cells in the skin
that produce a pigment called melanin. Malignant melanoma
develops when the melanocytes no longer respond to normal
control mechanisms of cellular growth. They may then
invade nearby structures or spread to other organs in the body
(metastasis), where again they invade and compromise the
function of that organ.”
Gale Encyclopedia of Medicine. 2008
“a highly malignant tumor that starts in melanocytes of
normal skin or moles and metastasizes rapidly and widely.”
Merriam-Webster's Learner's Dictionary.2010

6. ETIOPATHOGENESIS
• Melanocytes are dendritic cells originate from the neural
crest cells.
• located amongst the basal layer of the epidermis, mucosal
epithelium, hair bulb, eyes, ears, and meninges .

7. • Melanocyte migration to the
epidermis, function, and its
survival are all dependant on
expression of the tyrosine
kinase receptor c-kit gene
• Melanin pigment is produced
by melanocytes in their
specific cytoplasmic
organelles called
melanosomes.
•
ETIOPATHOGENESIS

8. • Melanin pigment synthesized by each melanocyte is
transferred to an average of 36 keratinocytes.
• PAR-2 on the keratinocyte surface is a key receptor in
this transfer .
• The transferred melanin then forms a cap at the top of
nucleus of mitotically active basal cells and prevents
the ultraviolet injurious effects on nucleus.
ETIOPATHOGENESIS

9. • The sequence of events in which normal melanocytes
transform into melanoma cells (melanomagenesis) is
poorly understood.
• a multistep process of progressive genetic mutations
that (1) alter cell proliferation, differentiation, and
death and (2) impact susceptibility to the carcinogenic
effects of ultraviolet radiation.
ETIOPATHOGENESIS

10. • The development of melanoma is multifactorial and
appears to be related to multiple risk factors,
• fair complexion/sun sensitivity,
• excessive childhood sun exposure
• blistering childhood sunburns, an increased number of
common or atypical/dysplastic nevi (moles),
• a family history of melanoma,
• the presence of a changing mole or evolving lesion on the
skin
• older age
• Genetic mutations {eg: 9p21(CDKN2A), 12q15(CDK4),
7q15(BRAF)}
ETIOPATHOGENESIS

11. • Primary cutaneous melanoma may develop (30%) in
precursor melanocytic nevi (ie, common, congenital, and
atypical/dysplastic types).
• Primary mucosal melanomas arise from melanocytes
located in mucosal membranes lining respiratory,
gastrointestinal and urogenital tract.
• Risk factors for mucosal melanomas are unknown
ETIOPATHOGENESIS

12. • Melanoma presents four clinically and
histomorphologically discernable steps in tumor
progression
(1) Malignant Melanoma confined to the epidermis
(melanoma in situ or dysplastic nevus)
(2) Radial Growth Phase (RGP)-confined microinvasive,
which shows some malignant cells present in superficial
papillary dermis.
(3) Vertical Growth Phase (VGP), which means melanoma,
has entered the tumorigenic and/or mitogenic phase.
(4) Metastatic phase.
Bandarchi B,Linglei Ma, Navab R et . From Melanocyte to Metastatic Malignant Melanoma.
Dermatology Research and Practice .2015, Article ID 583748, 8 pages
ETIOPATHOGENESIS

13. TYPES
Melanoma can be classified into 5 different clinical
subtypes (Clark et al and Richard et al):
• Superficial spreading melanoma (SSMM)
• Lentigo maligna melanoma
• Nodular melanoma
• Acral lentiginous melanoma
• Mucosal lentigenous melanoma
• Amelanotic or desmoplastic melanoma.

14. CLINICAL FEATURES
The American Cancer Society developed the ABCDEs to
serve as a simple guideline of earlymelanoma warning signs.
(i) Asymmetry: half the lesion does not match the other
half.
(ii) Border irregularity: the edges are ragged, notched, or
blurred.
(iii) Color variegation: pigmentation is not uniform and may
display shades of tan, brown, or black; white, reddish, or
blue discoloration is of particular concern.

15. (iv) Diameter: a diameter greater than 6mm is a
characteristic, although some melanomas may have smaller
diameters; any growth in a nevus warrants an evaluation.
(v) Evolving: changes in the lesion over time are a
characteristic; this factor is critical for nodular or
amelanotic (nonpigmented) melanoma, which may not
exhibit the classic criteria above.
CLINICAL FEATURES

16. Asymmetrical lesion with irregular
borders and variegated pigment

18. SUPERFICIAL SPREADING
Brownish black irregular patch on sun exposed skin

19. NODULAR
• Sharply delineated nodule with varying degrees of
pigmentation. Skin of back, head and neck skin.

20. LENTIGO MALIGNA
• Macular lesion on the malar skin with a female predilection

21. ACRAL LENTIGENOUS
irregularly-shaped, hyperpigmented patch surrounding
an ulcera on the side of the foot and extending to the
sole

22. AMELANOTIC / DESMOPLASTIC
• Erythematous or pink eroded nodule.
• Histological examination required for final diagnosis

23. ORAL MANIFESTATIONS
• Uncommon neoplasm
• 0.2-8% of all melanomas
• Male : female= 2:1
• Average age of occurrence=55 years( 40-70 years)
• Predilection for palate and maxillary gingiva/ alveolar
ridge.
• Other sites include mandibular gingiva, buccal mucosa,
tongue, lips and floor of mouth.
• No distinctive clinical appearance.

24. • Asymptomatic ,Macular, plaque like or mass-forming,
well circumscribed or irregular and exhibit focal or
diffuse areas of brown, blue or black pigmentation.
• One-third of oral melanomas are amelanotic.
• Some exhibit both melanotic and amelanotic areas.
• Ulceration can lead to pain,
• tooth mobility or spontaneous exfoliation,root
resorption, bone loss may occur rarely.
ORAL MANIFESTATIONS

25. • Lopez et al. identified five types of oral malignant
melanoma on
• the basis of clinical appearance:
• Pigmented nodular type.
• Nonpigmented nodular type.
• Pigmented macular type.
• Pigmented mixed-type.
• Non pigmented mixed type.
ORAL MANIFESTATIONS

26. A pigmented exophytic growth over the
maxillary anterior region
Palatal extension of the same
lesion
Naik NP, Kiran AR, Samata Y, Kumar AV. Deadliest tumor of oral cavity: A rare case of
intra oral malignant melanoma. J Oral Res Rev 2014;6:49-52.
ORAL MANIFESTATIONS

27. a pink growth measuring 3 cm x 2 cm in dimension, involving
palate, alveolar ridge wrt 16 and maxillary gingiva
ORAL MANIFESTATIONS
Gottipati P, Sangeetha S, Channabasappa B, Deepak V, David MP. Oral mucosal
amelanotic melanoma: A rare case report. IJSS Case Reports & Reviews 2014; 1(6):4-7.

28. RADIOGRAPHIC FEATURES
Intra-oral periapical radiograph in relation to 16, 17 showed edentulous
space and erosion of the bone in relation to 16 region. Bony trabeculae
show enlarged marrow spaces. Floor of maxillary sinus appears
thinned and breach in continuity observed in relation to 16

29. • Any suspicious pigmented lesions must be biopsied to
rule out or rule in melanoma.
• ABCDE rule
• Lesions scoring 3 points or more are suspicious
DIAGNOSIS

30. DIAGNOSIS
• Computed tomography (CT) is used to evaluate the primary
tumor and cervical lymph nodes.
• Magnetic resonance imaging (MRI) is useful to evaluate the
extent of sinonasal tumors, particularly for those that may
involve the skull base and/or exhibit neurotropic spread.
• A chest radiograph is used to detect pulmonary metastases.
• Depending on the patient’s presenting symptoms, additional
studies may be indicated to detect distant metastases
including brain MRI, chest CT, bone scan, and/or position
emission tomography..

31. Primary tumor T3 Mucosal disease
T4a Moderately advanced disease. Tumor involving deep softy tissue, cartilage, bone or overlying skin
T4b
Very advanced disease. Tumor involving brain, dura, skull base, lower cranial nerves (IX, X, XI, XII),
masticator space, carotid artery, prevertebral space or mediastinal structures
Regional Lymph Nodes NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases present
Distant metastasis M0 No distant metastasis
M1 Distant metastasis present
Clinical stages Stage III T3 / N0 / M0
Stage IVA T4a / N0 / M0
T3-T4a / N1 / M0
Stage IVB T4b / Any N / M0
Stage IVC Any T / Any N / M1
AJCC Cancer Staging Manual 7th edition (2010)

32. HISTOPATHOLOGIC FEATURES
• Proliferation of neoplastic melanocytes with variable
phenotypes epithelioid, spindle, and plasmacytoid tumor
cells that are arranged in a sheet-like, organoid, alveolar,
solid, or desmoplastic architecture.
• Usually the neoplastic proliferation lies along the junction
between the epithelial and lamina propria, but in
advanced, ulcerated lesions, this might be difficult to be
detected.
• Melanin pigment is noted in almost 90% of lesions

33. 3 histological levels mucosal melanomas
• level 1: in situ melanoma with no evidence of invasion or
with the presence of individual or agglomerated invasive
melanocytes with fewer than 10 atypical melanocytes
near the subepithelial junction
• level 2: melanoma cells, limited to the lamina propria
• level 3, invasion of the deep conjunctive tissue, including
skeletal muscle, bone, or cartilage.
HISTOPATHOLOGIC FEATURES

34. • Immunohistochemical staining positive for protein S-100,
HMB-45, Melan-A, Mart-1 and tyrosinase support
diagnosis of melanoma.
Tumor cell cytoplasmic homatropine
methylbromide (HMB-45) IHC
staining (original magnification, ×40)
Tumor cells shows strong, positive
staining with S-100 protein IHC
stain (original magnification, ×10).

35. TREATMENT
• The mainstay treatment for mucosal melanoma is complete
surgical resection.
• In patients with recurrent disease and without distant
metastasis, a second surgical procedure is considered as the
best option.
• Although malignant melanoma has been regarded as a
radioresistant tumor, radiotherapy has become utilized as
adjuvant treatment, considering the tumor heterogeneity.
• Precise indications for radiotherapy have not been defined
and it is generally used only in advanced and recurrent cases
(Krengli et al., 2008; Wagner et al., 2008).

36. • So far, no systemic therapy has been recognized as effective
for metastatic mucosal melanoma of the head and neck.
• Combinations of cytotoxic chemotherapy with
immunotherapy have shown higher response rates (Bartell
et al., 2008).
• Although interferon-α2b is frequently offered to mucosal
melanoma patients as systemic adjuvant therapy, it has not
been formally studied in this patient population.
TREATMENT

37. • Treatment modalities used for advanced cutaneous
melanoma, such as dacarbazine, temozolomide, the
Dartmouth regimen (dacarbazine, cisplatin, carmustine,
and tamoxifen), biochemotherapy, and high-dose
interleukin-2, have not been systematically studied in
mucosal melanoma.
• Some targeted therapies have been considered as
effective for patients with c-Kit or BRAF gene
mutations (López et al., in press; Warszawik-Hendzel et
al., 2014).
TREATMENT

38. PROGNOSIS
• Mucosal melanoma of the head and neck has a poor
prognosis with few long-term survivors.
• Undifferentiated tumor cell morphology, vascular and
neural invasion, tumor necrosis, thickness of the tumor,
cervical lymph node metastasis are considered to be
independent predictors of outcome (López et al., in press;
Kerr et al., 2012; Prasad et al., 2002).
• Five-year survival rate have been reported to be within
the range of 4.5 to 48.0% (Shuman et al., 2011;
González-García et al., 2005; Rapidis et al., 2003).
• Follow-up for at least 5 years is recommended because
recurrence can occur many years after the original
diagnosis.

39. References
• Burket’s Oral Medicine-12th edition
• Shafer’s Textbook of Oral Pathology- 6th edition
• Lee HY et al. Melanoma: Differences between Asian and
Caucasian Patients. Ann Acad Med Singapore 2012;41:17-
20
• Sharma K et al. Malignant melanoma: A retrospective series
from a regional cancer center in India. J Cancer Res Ther.
2009; 5 (3): 173:180
• H. Gavriel, G. McArthur, A. Sizeland, and M. Henderson,
“Review: mucosal melanoma of the head and neck,”
Melanoma Research, vol. 21, pp. 257–266, 2011.

40. References
• Manolidis S, Donald PJ, “Malignant mucosal
melanoma of the head and neck: review of
the literature and report of 14 patients,”
Cancer.2013; 80 (8): 1373–1386

41. THANK YOU…….