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Metastatic Melanoma of Unknown Primary: A Unique Entity?
November 2012
TITLE: Metastatic Melanoma of Unknown Primary: A Unique Entity?
SOURCE: Grand Rounds Presentation, Department of Otolaryngology
The University of Texas Medical Branch (UTMB Health)
DATE: November 28, 2012
RESIDENT PHYSICIAN: Benjamin Walton, MD
FACULTY PHYSICIAN: Susan McCammon, MD
SERIES EDITOR: Francis B. Quinn, Jr., MD
ARCHIVIST: Melinda Stoner Quinn, MSICS
"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate
Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its
present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express
or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current
or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting
appropriate literature sources and informed professional opinion."
Introduction
Malignant melanoma is a cancer arising from pigment cells in the skin called
melanocytes. Melanoma is a primary skin cancer whose incidence is rising at a faster rate than
any other malignancies, except for lung cancer. A recent study from Europe has shown that
while the mortality for melanoma stayed relatively stable, the incidence has increased
exponentially. The incidence is highest in the countries Australia and New Zealand, followed by
North America and Northern Europe. According to the US National Cancer Institute
Surveillance Epidemiology and Results database, there is an estimation that 68,130 individuals
will be diagnosed with melanoma worldwide in 2010 and that in the US alone, 8700 people will
die from melanoma. There are many risk factors associated with the development of cutaneous
melanoma. These are generally broken up into environmental and genetic risk factors.
Environmental risk factors generally include: an inability to tan, fair complex, blue/green eyes,
blonde/red hair, freckling, history of peeling sun burns, immunosuppression, teenage outdoor
summer jobs, and a history of tanning booth exposure. Genetic and past medical causes include
CDKN2A (p16) mutation, family history of melanoma, history of a prior melanoma, actinic
keratoses, non-melanoma skin cancer, xeroderma pigmentosa, atypical nevus, and giant
congenital melanocytic nevus. Melanocytes derive from neural crest cells. During embryo
genesis, the precursors for melanocytes migrate from the neural crest to the skin, uvea,
leptomeninges, and mucous membranes. These are all sites where melanoma can occur.
Generally, they remain undifferentiated until they are stimulated where they begin to produce
melanin and become melanocytes. Recent studies have looked into the pathways involved in
melanoma. Probably, the most important and most researched intracellular signaling pathway is
the RAS/RAF/ MEK/MAPK pathway. In this pathway, the BRAF protein has been found to be
mutated in up to 66% of all melanoma. Also the N-RAS protein is found to be mutated in 15%
of melanoma.
There are several histological classifications in melanoma. Superficial spreading
melanoma is the most common form of melanoma and arises in a pre-existing nevus. Nodular
melanoma is generally regarded as a second most common form of melanoma. Lentigo maligna
is an in situ melanoma and is generally a precursor for invasive lentigo malignant melanoma.
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Desmoplastic melanoma is a somewhat atypical form of melanoma. 73% are amelanotic, and
this often leads to delay in diagnosis. Often this can lead to cranial nerve and skull base
involvement. Mucosal melanoma is somewhat different in both its nature and incidence. It is
most commonly in the head and neck which presents up to 40-50% of all incidence. However, it
is less than 2% of all melanomas. The peak incidence for mucosal melanoma is generally during
the 6th and 7th decade. Within the head and neck, the nasal cavity is the most commonly
involved site. Generally, the anterior septum is the most likely location followed by the middle
and inferior turbinate. The second most common site is the oral cavity, with the hard palate and
the maxillary alveolar gingival being the most common subsites. Mucosal melanomas generally
do not present with regional spread as only 18.7% will have regional spread at the time of
diagnosis. Also ocular melanoma can occur and is usually subdivided into choroidal or
conjunctival melanoma.
Staging
Due to the unique nature of melanoma, staging system differs to other head and neck
cancers and cutaneous malignancies. Two important classifications one should understand are
the Clark and Breslow microstaging systems. The Breslow microstaging system is based on the
microscopic depth of invasion of the melanoma in millimeters. The Clark level is based on a one
through five level depth of invasion and based on the separate levels of the skin. A Clark level I
is confined to the epidermis while Clark level II is a melanoma in both the epidermis and through
the basal lamina. Clark level III is a melanoma infiltrating through the papillary dermis while
Clark level IV is a melanoma invading the reticular dermis. Clark level V is when the melanoma
has infiltrated through the subcutaneous fat. The AJCC revised their staging in 2009 after multivariate analysis of 30,946 patients with stage I, 2, and 3 melanoma and 7,9722 patients with
stage IV melanoma. The T staging is based on the thickness of the melanoma. Due to the multivariate analysis showing prognostic differences, ulceration and number of mitoses were added.
A T1 tumor is less than 1.0 mm thick. A T2 tumor is 1.01-2.00 mm thick, and a T3 tumor is
2.01-4.00 mm thick. A T4 tumor is greater than 4.00 mm thick. Sub-dividing these further,
ulceration will upstage each of these classifications as this is been found to be a poorer
prognostic factor. N staging is based on the number of metastatic nodes. N1 classification is
one metastatic node, and N2 is 2-3 number of metastatic nodes. N3 disease is 4+ metastatic
nodes or nodes that are matted or in transit metastases/solid metastases with metastatic nodes.
Microscopic examination is now being used as part of the staging system. M staging is
classified based on number of metastases. These are M0, M1a, M1b, or M1c. LDH is used as
well in the staging system. An elevated LDH will increase the staging to M1c. The differences
most notably from the 6 addition to the seventh addition (2009) of the melanoma staging system
include the addition of mitotic rate in T1 melanomas. Also, the immunochemical detection of
nodal metastases has not been included for nodal classification. Prior to the latest addition, there
was a lower threshold for staging N-positive disease. Classification changes now include all
nodal metastases with isolated tumor cells or tumor deposits less than 0.1 mm. This will meet
criteria for histologic or immunohistochemical detection of melanoma as N- positive.
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Treatment Options
Melanoma is primarily a surgical disease as radiation and chemotherapy have not been
found to be sufficient in treatment. Standard approaches include wide local excision, wide local
excision with sentinel lymph node biopsy, wide local excision with elective lymphadenectomy,
radiation therapy, and/or systemic therapy. Sentinel lymph node biopsy has become more widely
accepted as a standard care for patients with melanoma. Multiple studies have shown the
efficacy of sentinel lymph node biopsy if identifying occult metastases. This aids in the staging
and prognosis of patients.
Lymphatic Drainage
In understanding both malignant melanoma and melanoma of unknown primary, one
must understand the lymphatic drainage patterns of the head and neck region and their
unpredictability. A study out at M.D. Anderson by Ow et el specifically looked at melanoma
and its drainage pathways. They found highly variable drainage pathways but found that the
majority of the face, forehead, and cheek drained into the parotid lymph nodes. The parotid
gland severs as a major drainage pathway from the face and scalp before draining into the upper
jugular nodes. Ow et al also looked at different nodal fields and a number of instances where
melanoma drained into multiple lymph node fields. They found that 42% of head and neck
melanomas drained into greater than one nodal field. This differed from non-head and neck
melanomas which generally drained into one nodal field. Another study out of Croatia sought to
examine areas where there was discordance between the primary site and the predicted nodal
fields involved. They found that the posterior scalp and upper neck were the most discordant
with their projections on drainage. Of the sites examined, the coronal scalp had the highest
predictable drainage patterns. Understanding the lymphatic drainage pathways can help focus
the search for a primary site in occult disease.
Melanoma of Unknown Primary
Melanoma of unknown primary (MUP) is unique in many accounts which will be
discussed in further detail. It was first described in 1952 by Pack et al. Dasgupta first described
diagnostic criteria for this unique entity in 1963. MUP generally accounts for 1-8% of all
melanomas. It can be divided into 2 clinical groups. These are: metastatic involvement to
lymph nodes or non-lymph node disease. There are many theories on the origin of this unique
entity. Some theorize it is an unrecognized completely regressed primary melanoma that
metastasized prior to regression. Lee et al have speculated that this is the most probable
explanation. Other theories include a previous excised undiagnosed melanoma, concurrent and
undetected melanoma, a melanoma arising from benign nevus cells found in lymph nodes, or a
de-novo malignant transformation. Anbari et al set analyzed their clinical experience with
melanoma of unknown primary site. They analyzed 40 patients and found that 22.5% of their
patients had a clinically dysplastic nevus prior to developing a MUP. 20% of their patients had a
history of regressed skin lesion that was never diagnosed.
Regression in melanoma is well documented with a postulated frequency of 3.7-8.7%.
This is thought to be more common in men. Theories on this gender inequality include sun
exposure and ignorance for pigmented lesions by men. Some authors believe men will ignore a
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Metastatic Melanoma of Unknown Primary: A Unique Entity?
November 2012
lesion for a long enough period to allow for total regression. Melanoma is one of the most
common tumors to undergo regression and only 2 other tumors share this characteristic. These
are neuroblastoma and hypernephroma. Studies differ on whether regression is found to be a
positive or negative prognostic factor. In fact some studies have shown that in primary
cutaneous melanoma, regression can be a worse prognosis. There is plenty of experimental data
on immunologic studies which support endogenous anti-melanoma immune response. Mauer et
al identified circulating factors potentiating lymphocytic cytotoxicity in regressed melanomas.
There are also increased lymphocytic infiltrates found in many regressed melanomas. Some
studies have shown there is a favorable prognosis associated with the presence of tumor
infiltrating lymphocytes and melanoma.
Since 1963, there have been changes to the original diagnostic criteria is set by Dasgupta.
Current diagnostic criteria include a metastatic melanoma confirmed clinically, histologically, or
immunohistochemically, an absence of a previous cutaneous tumor, pigmentedor not, which has
been destroyed or excised without histology. There is also an exclusion of unusual primary sites,
including areas in the urogenital, otolaryngologic, or ophthalmologic sites. Diagnositc
recommendations for evaluation for patient presenting with melanoma of unknown a primary are
based on these criteria. Patients should have a review of the previous skin biopsies, a full skin
evaluation, CT or MRI imaging of the brain, CT imaging of the chest, abdomen and pelvis, a full
ENT examination, and ophthalmologic examination, and a Wood's UV lamp examination. The
Woods UV lamp reveals areas of depigmentation or regressed melanomas. This appears to be a
fairly strenuous evaluation and has been questioned as being redundant. Tos et al reviewed 103
patients from 1986-2006. 61% of their patients presented with lymph node metastases. Each of
their patients underwent a full examination including otoscopy, rhinoscopy, laryngoscopy,
ophthalmologic exam, sigmoidoscopy or proctoscopy, and gynecological examination when
relevant. Of the 103 patients, only one was found with a possible primary on examination. This
patient was thought to have an ocular melanoma; however, this was never proven. The study
recommended against multiple special examinations in the workup for metastatic melanoma with
unknown primary, but suggested a focused search based on history and physical. PET imaging
has also been recently added and the workup for metastatic melanoma with unknown primary. It
unfortunately has not been very good at finding unknown primaries as in squamous cell
carcinoma. Kole et al study 20 patients of which 8 were melanoma of unknown primary site.
None of hese patients had a primary site identified after PET imaging. O’neill et al also
examined 40 patients diagnosed with a melanoma of unknown primary site, all of which
underwent PET imaging. None of these patients had an identification of a primary site. While
PETimaging has not been shown to help evaluate for a primary site, it has be useful in O’neill’s
study at identifying further metastatic disease. PET imaging is especially limited in the brain and
scalp due to high background activity of the brain.
Due to the unique nature of melanoma of unknown primary site, the staging system is
slightly different and only takes into account the N and M staging. Melanoma of unknown
primary site is classified as stage III or stage IV disease. Any metastatic disease automatically
upstages the patient to stage IV. Although theories for the nature of this unique disease cannot
be fully explained, it has been shown that this disease has a similar, if not improved, outcome
compared to cutaneous melanomas with lymph node metastases. Experts theorize that immune
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November 2012
responses causing regression of the primary tumor incur improved regional and distant control of
the disease. With the unusual nature of melanoma of unknown primary site, Pfeil et al sought to
determine whether the AJCC 2009 melanoma classification was suitable for melanoma of
unknown primary site. They also sought to determine prognostic factors in this patient
population. Of the 8897 patients, 172 patients had a melanoma of unknown primary site or a
1.9% incidence. The study, comparing patient based on staging found survival rate significantly
different. The survival differences included staging as defined by lymph node metastases,
number of satellite or in-transit metastases, the size of satellite/in-transit metastases, the number
of regional lymph node metastases, number of distant metastases, the total number of metastases
, the M classification at diagnosis, and LDH level at diagnosis. Independent significant
prognostic factors in these patients included : age less than 60 years old, stage at diagnosis, the
total number of metastases, and the LDH level. Patients with regional metastatic disease had a
significantly better overall survival when compared to those with distant metastases. The number
of metastatic regional lymph nodes also proved to be a significant factor in multi-variate
analysis. An elevated LDH was found to be strongest predictor of unfavorable survival in
patients with stage IV disease.
Prognosis
The prognosis of melanoma of unknown primary site appears to be better, or similar, to
patients with a cutaneous melanoma with metastases. Katz et al reviewed 19 separate case series
from 1952 to 2001. The overall percentage of melanoma of unknown primary site in each study
was between 1.2-8.1%. There was also consistent ratio of male greater than female. Of the 19
case series, 7 studies showed a better prognosis. Nine studies showed a similar or better
prognosis. Only one study from 1952 showed a worse prognosis. A study from M.D. Anderson
performed a Cox regression analysis looking for disease-free survival, disease-specific survival,
and overall survival in patients comparing melanoma of unknown primary site with a metastatic
melanoma with a known site (MKP). Overall survival was significantly different between the
patients with unknown primary site and with melanoma of known primary site. There was a
statistically significant difference between male and female patients as well. Also, overall
survival was statistically significant for patients with N3 disease. In patients with N1b disease,
overall and disease-free survival was better in MKP subjects. However, in each of the other
stages patients with melanoma of unknown primary source had both improve disease-free and
overall survival. There are many theories on the cause of such improved prognosis. Many
theories are based on immune responses to the primary lesion with a likely complete regression.
There are also theories based on the melanoma originating from benign melanocytes in lymph
nodes. With regards to treating the disease, the surgeon is able to rid the occult primary with a
nodal dissection. Pathological studies of lymph nodes have found benign melanocytes in lymph
nodes.
Treatment
The treatment options for patients with melanoma of unknown primary site include
surgery, radiation, and/or systemic therapy. The mainstay surgery for these patients is a
lymphadenectomy or lymph node dissection. Lee et al found improved survival in patients after
lymphadenectomy from a nodal metastasis from an unknown primary melanoma. Their research
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November 2012
showed a 5 year survival of 55% in patients after lymph node dissection compared at 27% in
patients without lymph node dissection. Their conclusions include most patients with melanoma
of unknown primary site can generally expect long-term survival after an adequate
lymphadenectomy. They matched patients based on tumor burden and showed improved overall
survival in the patients with melanoma of unknown primary site compared to those with
cutaneous melanoma. Also, patients with stage IV disease were examined by Lee et al. They
found the patients did not have an improved prognosis and M1a disease but otherwise had a
significant improvement in overall survival in patients with an unknown primary site versus
those with a known primary site.
There's controversy on the use of radiation in patients with melanoma and with a
melanoma of unknown primary site. Most believe the melanoma, in general, is not radio
sensitive. Ballo et al at M.D. Anderson showed positive data for local and regional control after
surgical treatment in patients with melanoma. They found regional control rates of 89% at 5 and
10 years in patients with stage I or stage II melanoma. They concluded that radiation is a useful
adjunct especially in patients in whom lymph node dissection or systemic therapies are not
options. The suggested indications for adjuvant radiotherapy include evidence of extracapsular
spread, multiple lymph nodes, large lymph nodes greater than 3 cm, or recurrent disease.
Extracapsular spread incurs a 5% higher regional recurrence rate in patients. Ballo et al found
that adjuvant radiotherapy reduced regional recurrence. However, this was not statistically
significant. Bastiannet et al performed a systemic review and found that radiotherapy improved
locoregional control without improving overall survival. Moncrief et al have suggested that the
most important factor preventing locoregional recurrence of melanoma is the primary surgical
clearance of the nodal field. Extracapsular spread and large or multiple nodes indicate a higher
risk of distant spread and overall mortality. Both appear to remain unaffected by the use of
adjuvant radiotherapy. Adjuvant treatments including chemotherapy and systemic therapy have
been looked on. Most of these have suggested no improvement in comparing patients with
melanoma of unknown primary site with those of a known primary site. As studies continued to
look at gene-targeted therapy and melanoma, new drugs are being tested to help in a fight to cure
melanoma. Most of these medications are now in either phase I or phase II trials. There is hope
then the next several years there will be new adjuvant treatments available for patients with
melanoma both of unknown and a known primary site.
Conclusion
Metastatic melanoma of unknown primary site continues to be unique entity in head and
neck cancer. Due to its unique presentation and differences with its counterpart, melanoma of
unknown primary site should be treated aggressively. A thorough workup is required in the
diagnosis of this disease. Surgery is the main treatment option for these patients, and an
aggressive surgical approach will yield the best results. Questions continue on whether there is a
really improved prognosis compared to cutaneous melanoma with metastases. Most present
studies would agree that a melanoma of unknown primary site does incur a better prognosis.
There continues to be limited data on adjuvant therapy on patients with a melanoma of unknown
primary site. Further studies are currently being done evaluating the role of different genetic
markers and protein mutations in melanoma. Melanoma requires a multidisciplinary
management team led by the surgeon
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