A literature overview of primary cervical malignant melanoma: An exceedingly rare cancer
Introduction
Malignant melanoma (MM) involving mucosal membranes (mucosal melanoma) represents an exceedingly uncommon neoplasm which can occur in a variety of mucosal sites, including the oral cavity, esophagus, anus, conjunctiva and gynecological tract [1]. Altogether, mucosal melanomas account for 0.03% of all newly diagnosed cancers and, as far as the female genital apparatus is concerned, they represent less than 2% of all MM [2]. The majority of them arises in the vulva and in the vagina and, more rarely, in the uterine cervix, with an incidence five times lower as compared to primary vaginal or vulvar mucosal melanomas [3], [4], [5]. Clinical history usually includes abnormal genital bleeding and discharge, and gynecological physical examination at diagnosis often reveals an exophytic cervical mass, either pigmented or amelanotic, involving the vaginal fornix in more than 50% of cases [6]. Diagnostic substantiation is made by histological examination and immuno-histochemical staining [7]. Even though outcomes are not particularly encouraging and satisfactory, the management of primary cervix MM includes radical surgery, radiation therapy and chemo- or immuno-therapy. Prognosis is poor and is characterized by survival times ranging from a minimum of a few days to a maximum of 14 years [8].
A literature survey drawn from NCBI Pub Med Medline database, which excluded all cases of metastatic melanoma of the cervix, has indicated that from 1889 to date only 78 cases of primary cervical MMs have been reported. Apart from two early, brief and poorly documented reports by Johnson in 1889, who described a macroscopically “black cancer” of the cervix, and by Schickele in 1923, the first well-documented case was reported by Taylor and Tuttle in 1944 [9], [10], [11]. Based on this scenario encompassing more than one century of literature survey on primary MMs of the uterine cervix (Table 1, Table 2), updated information regarding epidemiology, pathology, clinical presentation and behavior, staging, diagnostic work-up, therapeutic procedures, survival and prognosis are here below reported, and possible new perspectives are argued.
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Incidence and risk factors
Contrary to cutaneous melanoma, whose incidence is continuously increasing, cases of mucosal melanomas have remained relatively stable over the years: currently, 2.8 cases per million women and 1.5 cases per million men have been recorded annually [4], [5]. The higher incidence among women can be ascribable to the higher rates of genital tract mucosal melanomas which predominantly occur in the vulva (76.7%), in the vagina (19.8%) and more rarely in the uterine cervix (3–9%) [5], [12].
Despite
Pathogenesis
Ethio-pathogenesis of MM uterine cervix has not yet been completely elucidated. The existence of primary cervical MM was called into question in the past based on the belief that there was a total lack of melanocytes in the uterine cervix. The first proof of the presence of melanocytic cells in the cervical mucosa dates back to 1959, when Cid evidenced basal melanocytes in 3.5% of the examined cervical biopsies. Subsequently, in 1967, Goldman and Friedman described three cases of melanocytic
Histology
There is a broad spectrum of histological features of cervical MM, the most common displaying spindle-shaped cells (desmoplastic variant), epithelioid cells and, seldom, round or clear cells (Table 1). Lesions may consist of spindle cells showing intra-cytoplasmic melanin, nests of large cells with rare eosinophilic cytoplasms and large hyper-chromatic nuclei with prominent nucleoli, or of large pleomorphic cells with abundant cytoplasm, large typical vesicular nuclei and prominent abnormal
Clinical presentation and behaviors
The natural evolution of cervix MM is similar to that of other gynecological malignancies. With the exception of few patients in whom diagnosis is occasionally made during routine vaginal examination, most cases are symptomatic. The main symptoms consist of vaginal bleeding or vaginal discharge of various degrees and duration (often short), abdominal pain, dyspareunia and post-coital bleeding. Weight loss and hematuria may represent other complaints (Table 2) [34], [37], [38]. Cervical MM
Staging
As for other MMs, the clinical staging of cervical MM is still a matter of debate. Generally, the most relevant method for staging MMs is based on tumor thickness, which represents the best prognostic factor, rather than on tumor diameter, tumor aneuploidy and neoplasm ulceration [1], [2]. Unfortunately, the majority of primary MMs of the cervix are detected at a late stage, when they consist of a large and aggressive thick mass and show regional or nodal involvement. Morrow and Di Saia argued
Diagnostic work up
For a reliable detection of a cervical MM, the first step is to exclude its originating from a primary cutaneous melanoma or a metastasis from an ocular melanoma. Given the tendency of these MMs to spread, a critical workup must exclude distant metastases [7]. This includes analysis of serum lactate dehydrogenase, and computed (CT) scan of the brain, chest, abdomen and pelvis or combined computed positron emission tomography/tomography scanning of chest, abdomen and pelvis (PET-CT) [2]. In
Treatment
There is little consensus as to the best approach to the management of MM of the uterine cervix. Several reasons, such as the limited experience deriving from the small number of case reports, the unpredictable biological behavior of the tumor and the large variety of the therapeutic modalities employed, have made it difficult to critically outline the optimal therapy. Therefore, all therapeutic decisions have thus far been based on few anecdotal experiences, where the treatment applied was the
Prognosis and conclusion
Based on data and information drawn from the case series of patients with MM of the uterine cervix, it appears that physicians are dealing with a very rare neoplasm characterized by an extremely poor prognosis. Unquestionably, tumor stage and tumor thickness represent the main prognostic factors. Vascular or lymphatic invasion, presence of lymphocyte infiltration and neovascularisation, however, are additional, important features which may play an important role, since they all strongly
Conflict of interest statement
All authors declare no financial interest and no conflicts of interest.
Reviewers
Michele Maio, M.D., A.O. Universitaria Senese, Department of Medical Oncology, viale bracci n 16, Siena, Italy.
Juan Rosai, M.D., Centro Consulenze Anatomia Patologica Oncologica, Centro, Diagnostico Italiano (CDI), Via Saint Bon,20, I-20147 Milan, Italy.
John M. Kirkwood, M.D., University of Pittsburgh Cancer Institute, Hillman Cancer Center, Melanoma and Skin Cancer Program, Research Pavilion, 5117 Centre Avenue, Pittsburgh, PA 15213-2584, United States.
Ruggero Ridolfi, Istituto Scientifico
Emilio Bajetta Born on 17 August 1943 in Pavia (Italy), Emilio Bajetta graduated in Medicine and Surgery at Pavia University, and his post-graduate education continued with internal medicine and medical oncology specialties. Since 1970 he has been working at the “Istituto Nazionale Tumori” of Milan, and since 1988 is Director of the Medical Oncology Unit 2. He is member of the leading National and International Associations and, in particular, he actively participated in the foundation of the
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Emilio Bajetta Born on 17 August 1943 in Pavia (Italy), Emilio Bajetta graduated in Medicine and Surgery at Pavia University, and his post-graduate education continued with internal medicine and medical oncology specialties. Since 1970 he has been working at the “Istituto Nazionale Tumori” of Milan, and since 1988 is Director of the Medical Oncology Unit 2. He is member of the leading National and International Associations and, in particular, he actively participated in the foundation of the Italian Association of Medical Oncology (AIOM) of which he was president from 2005 to 2007. He is active member of the: American Society of Clinical Oncology (ASCO), American Association for Cancer Research (AACR), European Society for Medical Oncology (ESMO). He is Medical Officer of the WHO Melanoma Programme, where he is involved in experimental medical treatments in advanced melanoma. He is Medical Oncology Professor at the Oncology Institute of the University of Milan Medical School. He published the Manual of Cancer Chemotherapy, edited for the International Union Against Cancer, that is still a fundamental reference point for young oncologists. He has participated all of the main clinical research activities carried out at the Istituto Nazionale Tumori of Milan over the last thirty years. He is involved as main clinical investigator in researches on breast cancer, lymphomas, melanoma, gastrointestinal, pulmonary and neuroendocrine tumors. He published more than 450 articles in peer-reviewed journals and contributed to write many books on cancer.