Diagnosis of Oral Pathology

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Oral pigmentation: Case report and review of malignant melanoma with flow charts for diagnosis and treatment Anuradha Pai, MDS

  n 

Shesha Prasad, BDS

  n 

Bharati A. Patil, MDS

  n 

The color of the human oral mucosa is not uniform. Chromatic variations can occur, depending on the degree of keratinization, melanogenic activity, number of melanocytes, vascularization, and type of submucosal tissue.1 If a pathological pigmentation is suspected, its benign or malignant nature will guide the treatment plan. This article presents a rare case of malignant melanoma of

A

Sujatha Dyasanoor, MDS

  n 

Sushmini Hegde, MDS

the anterior maxilla with asymptomatic palatal pigmentation and regional lymph node metastasis. Flow charts for the diagnosis and treatment of pigmented lesions (with special emphasis on treatment of primary and metastatic melanoma) are included. Received: October 20, 2011 Accepted: February 9, 2012

58-year-old man sought treatment for swelling in the maxillary anterior that had begun six months earlier. One year before the swelling began, the patient noticed a small brown discoloration in the palatal area that was flat and asymptomatic. It had gradually increased in size over a period of six months and reached its present size after becoming exophytic. The patient complained of throbbing, continuous pain, and difficulty with

speech. Seven months before seeking treatment, the patient was told he had “a mole” that did not require further treatment. The patient had suffered from hypertension and diabetes for seven years and was taking medication for both. He had also smoked 20 bidis per day for the last 20 years. On examination, the patient was sthenic and moderately nourished with a blood pressure of 130/80, and all vital signs were within normal

limits. A diffuse extraoral swelling was seen in the mid-facial region (between the nose and the upper lip). The swelling was soft in consistency and slightly tender on palpation. Intraoral examination revealed a grayish black exophytic growth in the anterior maxilla, which extended in a mediolateral direction from the labial vestibule (tooth No. 6) to the contralateral region (tooth No. 13) and posteriorly up to the midpalatal region. The growth measured

Fig. 1. A 58-year-old man with a malignant melanoma extending into the anterior and midpalatal region.

Fig. 2. Anterior extension of the melanoma.

Fig. 3. The patient in Figure 1, showing lateral drifting of teeth.

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Fig. 4. Histology reveals atypical melanocytes (H&E stain, 40X magnification).

approximately 6 cm x 5 cm and had a lobulated surface (Fig. 1–3). On palpation, the lesion bled and was tender with a firm consistency. The solitary left submandibular lymph node was enlarged (measuring approximately 3 cm x 2 cm), firm in consistency, and mobile. Based on the clinical appearance, a provisional diagnosis of malignant melanoma involving the palate and a differential diagnosis of Kaposi sarcoma was considered. Fine needle aspiration cytology of the left submandibular lymph node yielded a brown fluid, suggesting metastatic malignant melanoma (Fig. 4). Orthopantomograph revealed a large, ill-defined radiolucency in the anterior maxilla with complete loss of bone structure and trabecular pattern in relation to teeth No. 7–10, which gave them the appearance of floating with displacement (Fig. 5). To rule out distant metastasis, a chest radiograph and an abdomen ultrasound were performed; no abnormalities were found in either. Computed tomography (CT) with three-dimensional reconstruction showed a soft tissue mass arising from the roof of the oral cavity, resulting in erosion of the hard palate and the lowest portion of the nasal septum (Fig. 6). A complete hemogram, plasma proteins, alkaline phosphatase, serum creatinine, urea,

Fig 5. Orthopantomograph revealing anterior maxillary bone loss.

Fig. 6. A three-dimensional reconstruction revealing bone changes in the anterior maxilla

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Diagnosis of Oral Pathology  Oral pigmentation: Case report and review of malignant melanoma

Fig. 7. A palatal view of the tumor after radio-chemotherapy.

and liver function tests were within the normal range. Random blood sugar was 325 mg/dL. The patient tested negative for HIV (ELISA). A final diagnosis of primary malignant melanoma involving the anterior maxilla with regional nodal metastasis (T2 N1 M0) was considered. Actrapid (Novo Nordisk) was administered for diabetic control. Chemotherapy (three cycles of cisplatin, vinblastine, and dacarbazine repeated once over a 21-day period) was initiated by the oncologists to reduce the risk of morbidity. A maxillectomy with deep neck dissection was planned for a later date, after further evaluation. The patient was recalled for further evaluation after three cycles of chemotherapy. Surgery was deferred after initial chemotherapy, as no considerable reduction in tumor size was noted (Fig. 7 and 8). The patient underwent 10 cycles of radiotherapy; at that point, metastasis extending to the contralateral cervical lymph nodes was evident. The patient then received immunochemotherapy with temozolamide and interferon α. The patient was unwilling to undergo surgery, so palliative immunochemotherapy was initiated. He survived for 32 months after the initial diagnosis, dying in September 2011. 412

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Fig. 8. An anterior view of the tumor after radio-chemotherapy.

Discussion Primary malignant melanoma is an aggressive tumor resulting from the uncontrolled growth of melanocytes, which are ectomesenchymally derived dendritic cells found in the basal layer of the oral mucous membranes. It rarely occurs in the oral cavity (estimated at 0.2–8% of all melanomas), occurring more frequently in the maxilla (up to 80%), usually on the palate or alveolar gingiva.1-10 Most oral melanomas arise de novo, from apparently normal mucosa; however, oral pigmentations precede this melanoma (for several months or years) in 30% of these cases, as seen in the present case.1,6,11,12 The etiology of melanoma is unknown. Chronic use of tobacco and mucosal irritation have been mentioned as possible risk factors, but the evidence is weak.2,3,5,11,12 Melanoma rarely occurs among patients under 30 years of age and usually is seen during the sixth or seventh decade of life.3,10 Men are affected 3.5 times more frequently than women.6,7,9-11,13,14 A literature review by Aguas et al discovered survival rates ranging from 6.6% to 15%.2 When the lymph node is involved, the survival time is reduced from 46 months to 18 months.6,11 During the transformation process from a benign melanocytic

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nevus to melanoma, some melanoma-associated antigens become expressed; most are human leukocyte antigen (HLA)-restricted.6 Approximately 66% of patients with oral mucosa melanoma experience alterations in p53 protein.12 A 2007 study reported that a loss of heterozygosity at 12p13 and loss of p27KIP1 protein expression contribute to melanoma progression.6 Alterations in oral melanoma can be deduced using cell lines. SSM-1 was the only cell line reported previously.15 A new cell line (ME) possesses morphological features and differentiation markers of a typical melanoma cell. ME’s other characteristics include rapid replication under culture conditions, strong potential for tumorigenicity, and metastasis in experimental animals, which should be studied further. ME cells could be used to test the efficacy of anti-melanoma drugs.15 The clinical features, histological characteristics, and prognosis of cutaneous and oral melanoma vary; as a result, the 1995 WESTOP Banff workshop recommended a separate classification for oral melanomas.2,4 Descriptive terminologies—such as atypical melanotic proliferation, melanoma in situ, invasive melanoma, and combined

in situ—must be included to describe oral melanomas.2,4,6,16,17 When microscopic evaluation does not yield a definitive diagnosis of melanoma, atypical melanotic proliferation has been suggested as a diagnosis. These lesions have hyperchromatic and angular nuclei and infrequent mitotic figures, which differentiate them from malignant melanoma.2,6

Clinical features There are no striking features that distinguish malignant oral melanoma from benign oral pigmentations.9 However, when making a diagnosis, it should be noted that any pigmented exophytic lesion (except for amelanotic melanomas) with asymmetry, border irregularities, color variation, and a diameter of more than 6 mm usually indicates melanoma (ABCD system).6,11,12 Rubbing the surface of the lesion results in black or brown stains, due to the presence of melanin pigment on its surface.2,6 Overlying ulcerated mucosa indicates malignancy. The three phases of macule—plaque, nodule, and macroscopic—are seen in most oral melanomas. The nodular form is invasive and aggressive, and represents a vertical growth pattern.2 Rolled out margins are absent in melanoma, as the atypical melanocytes spread in a pagetoid manner.11 Regional lymphadenopathy can be present; distant metastasis often affects the lungs, brain, liver, or bones.1,7 Other signs and symptoms associated with malignant oral melanoma include bleeding, ill-fitting dentures, pain, increased mobility of teeth, and delayed healing of extraction sockets.10 Criteria for diagnosing primary malignant melanoma include the presence of malignant melanoma in the oral mucosa, presence of junctional activity (that is, melanocytes

Table 1. Clinical staging system for oral malignant melanoma with histopathological microstaging.1,5,9 Stage

Level

I

Description Primary tumor present only (any T, N0 M0)

I

I

Pure in situ melanoma without evidence of invasion or in situ melanoma with microinvasion

I

II

Invasion up to the lamina propria

I

III

Deep skeletal tissue invasion into skeletal muscle, bone, or meniscus

II

Tumor metastatic to regional lymph nodes (any T N1 M0)

III

Tumor metastatic to distant sites (any T, any N M1)

Chart 1. Differential diagnosis of pigmented lesions

Pigmented lesions of the oral cavity Racial/physiologic pigmentation

Habit associated Smoker’s melanosis, paan chewer’s mucosa Syndromes Peutz-Jeghers, McCune-Albright, Laugier-Hunziker, PTEN hamartoma tumor Endocrine disorders Addison disease

Postinflammatory Lichen planus Bleeding tendencies Petechiae, purpura, ecchymosis, varix Infection HIV melanosis, Kaposi sarcoma in HIV

Drug-induced Minocycline, phenothiazines, quinidine, bleomycin, busulfan, ketoconazole, and so forth

Vascular lesions Hemangioma, lymphangioma, arteriovenous malformations

Others Benign Melanotic nevi Melanoacanthoma Melanotic macules

along the basal layer of the surface epithelium) in the lesion, and a lack of malignant melanoma at any other primary site.2,5,6 Cebrian Carrettero et al proposed three stages of primary malignant melanoma: a tumor limited to the oral cavity (Stage I), a tumor with www.agd.org

Non-physiologic pigmentation

Metal-induced Lead, graphite, mercury

Malignant Melanoma

lymphatic dissemination (Stage II), and a tumor with distant metastasis (Stage III).2 Table 1 lists a clinical staging system for oral malignant melanoma with histopathological microstaging. The differential diagnosis includes other oral pigmented lesions (Chart 1).2,5,9-12,17,18

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Diagnosis of Oral Pathology  Oral pigmentation: Case report and review of malignant melanoma

Chart 2. Diagnostic and treatment protocol for pigmented lesions. Table 2. Important points to be considered during the diagnosis of melanoma.

Racial/physiologic pigmentation

• Melanomas can initially mimic oral pigmentations.

• Due to the relative inaccessibility of the oral mucosa, patients might not notice the lesion until it reaches a later stage, which can delay diagnosis and complicate the prognosis.

History of smoking, tobacco use, paan chewing, paan smoker’s melanosis

History

No attributable factors or pathology

• 30% of malignant melanomas arise from pre-existing oral pigmentation.

Non-physiologic pigmentation

Medical history History of fillings (amalgam tattoo) Positive for Inflammatory conditions (lichen planus)

• Most oral melanomas are in vertical growth phase, meaning that they have a faster clinical course.

Bleeding history (hematoma, purpura, ecchymosis; varix and thrombus must be ruled out)

• Nodal metastasis must be checked, as it drastically reduces the prognosis

Vascular lesions (hemangioma, lymphangioma, arteriovenous malformations)

Bone loss can be interpreted as radiolucency when conventional radiology is used, particularly when there is a deeper invasion involving the underlying bone.14 CT, MRI, and positron emission tomography can be used to evaluate the primary tumor and regional or distant metastases (Table 2).6 A positive immunohistochemistry for S-100, HMB-45, Melan-A, and vimentin, especially for amelanotic melanomas, confirms the diagnosis.2,5,12,19 Chart 2 provides a diagnostic and treatment protocol based on the present case report.

Endocrine disorders (Addison disease)

If negative, consider

Benign pigmentations Melanotic nevi Melanoacanthoma Melanotic macules

Malignant melanoma

History of intestinal polyposis (Peutz-Jegher) Other syndromes (LaungierHunziker, McCune-Albright, PTEN hamartoma tumor) HIV (Kaposi sarcoma, HIV melanosis) Metal ingestion/toxicity (lead-, graphite-, or mercury-induced pigmentations) History of drug ingestion (minocycline, quinidine, and others—drug-induced pigmentation)

Diagnosis justified on history

If yes, treat accordingly

If benign, treat if necessary

If no, biopsy

If malignant, treat immediately

Follow-up

Biopsies Studies in the literature have recommended early biopsies to determine the nature of tumors, which can lead to an improved prognosis.8,16 Due to the high malignant potential of these tumors, some authors believe that trauma during incisional biopsies or other surgical procedures prior to excision can cause accidental dissemination (seeding) into the adjacent tissues, blood, or lymphatics.6 414

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The five-year survival rate for patients with oral malignant melanoma remains poor (5–20% postdiagnosis), with a median survival period of 25 months.4,6 Treatment protocols and modalities for melanoma are listed in Charts 3 and 4.4-7,9-12,16,20-23 Table 3 lists newer agents that are being used or considered for treating melanoma.

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Summary Early detection of malignant melanoma is the only key to a possible cure. To reduce diagnostic delays, it is necessary to learn about the possible manifestations and the most frequent locations of oral melanoma. To avoid charges of clinical negligence, dentists must have a thorough understanding of

Chart 3. Treatment modalities for malignant melanoma Table 3. Newer agents used for treating melanoma.

Treatment protocol for malignant melanoma

Lenalidomide (a thalidomide derivative)

Surgery

Radiotherapy

Surgery and combined therapy

Chemotherapy

Immunotherapy

Thalidomide + temozolomide

Others Cancer/testis antigens (CTAs) expression profile for vaccine development

Taxane ABI-007 Sorafenib Anti-Bcl-2 antisense Anti-Bcl-2 antisense + dacarbazine MEDI-522 humanized monoclonal antibody

Gene therapy OK432 (a biologic response modifier)

Curative chemotherapy Dimethyl triazeno imidazole carboxamide (DTIC)

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) Ipilimumab with or without dacarbazine combination

Nimustine hydrochloride (ACNU) Vincristine (VNC)

IL-2 Palliative chemotherapy Dacarbazine

Other cytokines

Platinum analogs Nitrosoureas Microtubular toxins

Chart 4. Drugs used for treatment of metastatic melanoma

Treatment of metastatic melanoma

the differential diagnosis for other pigmented lesions. Once melanoma is diagnosed, treatment should be performed promptly. Various drug regimens have been advocated for melanoma, although these regimens vary for metastatic melanoma. The advantages, disadvantages, and side effects of each drug must be weighed before administration. Periodic evaluation of the selected drug regimen is also important.

Author information Single-agent chemotherapy

Multi-drug combination Nitrosourea + vinca alkaloids + platinum compounds + dacarbazine

Immunotherapies INF-α, IL-2, combination of INF-α + IL-2

Biochemotherapy Dacarbazine + INF-α + IF-2

Dr. Pai is a professor and head of the Department of Oral Medicine and Radiology, Oxford Dental College Hospital & Research Center, Bommanahalli, Bangalore, India, where Dr. Prasad is a postgraduate student.

References

Dacarbazine Temozolomide (DTIC analog)

Nitrosoureas Fotemustine

Others Cisplatin Carboplatin Vinblastine Vindesine

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Published with permission by the Academy of General Dentistry. © Copyright 2012 by the Academy of General Dentistry. All rights reserved.

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