Case report
Metastatic melanoma of the tongue: a case report with immunohistochemical profile ^ nica Ghislaine O. Alves1, Luciene R. Chagas2, Yasmin R. Carvalho1, Luiz A. G. Cabral1, Mo Ricardo D. Coletta3 and Janete D. Almeida1 Department of Biosciences and Oral Diagnosis, S~ ao Jos e dos Campos Dental School, UNESP – Univ. Estadual Paulista, S~ao Jose dos Campos, S~ ao Paulo, Brazil; 2Nursing Course, Health Sciences School, Universidade do Vale do Paraıba, S~ao Jose dos Campos, S~ao Paulo, Brazil; 3Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, Piracicaba, S~ao Paulo, Brazil 1
doi: 10.1111/ger.12032 Metastatic melanoma of the tongue: a case report with immunohistochemical profile Background: Melanoma of the skin is characterised by a high metastatic potential, but reports of metastasis to the tongue are rare. We report a case of skin melanoma with metastasis to the lymph nodes, tongue and brain. Objectives: This report highlights the clinical and histological features of oral metastatic melanoma. Case report: A 72-year-old man was seen with a nodule on the tongue. The differential diagnosis included salivary gland tumour, lymphoma and metastatic melanoma. His medical history revealed treatment for melanoma in the periumbilical region and micrometastases in the inguinal lymph nodes. An incisional biopsy was obtained and histological analysis showed the presence of a solid, epithelioid malignant tumour of monotonous appearance infiltrating the skeletal musculature. Immunohistochemistry showed reactivity of neoplastic cells to anti-HMB45, anti-melan A and anti-S100 antibodies and negativity for anti-PAN cytokeratin, confirming the diagnosis of metastatic melanoma. Conclusion: The present findings highlight the importance of a complete medical evaluation of the patient by anamnesis to identify possible oral repercussions of primary diseases in other organs and/or systems. Keywords: oral mucosa, melanoma, oral cancer, skin cancer, immunohistochemistry Accepted 16 November 2012
Introduction The incidence of melanoma has increased over recent years. This skin cancer is characterised by high metastatic potential to multiple organs1. In general, metastases in the maxillomandibular complex and associated organs are rare, with only 7.8% of melanomas developing metastases to these regions2. Metastatic melanoma of the tongue is rare3. We report here the case of a patient with melanoma who developed metastases to the lymph nodes, tongue and brain.
Case report A 72-year-old white man was seen at a stomatology outpatient clinic with a nodule on the 314
tongue. The patient reported the formation of a haematoma after trauma to the region 2 months earlier, followed by the formation of a nodular lesion. The patient had no pain symptoms. His medical history revealed the presence of nodular melanoma in the periumbilical region, classified as Clark invasion level IV and with a Breslow depth of 2.5, accompanied by 1-mm micrometastases in the right inguinal lymph nodes. The patient underwent surgical treatment and inguinal lymph node drainage and remained without clinical signs of the disease for 15 months. Extraoral clinical examination showed irregular, hard, mobile and painless cervical lymph nodes on the left side (level IV) measuring on average 1 cm. Computed tomography revealed round nodules and heterogeneous enhancement. Intraoral examination revealed a submucosal nodular
© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
Metastatic melanoma of the tongue
lesion on the dorsum of the tongue. The lesion measured approximately 2.5 cm in its major diameter, was consistent upon palpation and infiltrated underlying tissue. Tongue mobility was preserved (Fig. 1). The differential diagnosis included salivary gland tumour, lymphoma and metastatic melanoma. An incisional biopsy was obtained, and the material was sent for histochemical and immunohistochemical analysis.
315
Histopathological examination revealed mucosa lined with squamous epithelium and the presence of a solid, epithelioid malignant tumour of monotonous appearance infiltrating the skeletal musculature. The cells contained clearly visible nucleoli and moderately eosinophilic cytoplasm (Fig. 2). The mean number of mitoses in 10 highpower fields was 20.6 per mm2. Immunohistochemistry by the streptavidin-biotin-peroxidase
(a)
(b)
Figure 1 Clinical findings. (a) Lateral view of the tumour. (b) Tumour seen in the region of the ventral tongue.
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(b)
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(d)
Figure 2 Histopathological findings (HE stain). (a) Mucosal fragment lined with stratified pavement epithelium showing no dysplastic alterations. Note the presence of a nodule deep in the lamina propria separated by a band of connective tissue (259). (b) Poorly circumscribed nonencapsulated tumour infiltrating connective tissue and muscle (1009). (c) Scarce stroma and connective tissue septa conferring an alveolar appearance to the tumour (2009). (d) Presence of mainly round tumour cells containing poorly delimited cytoplasm and a round nucleus. The nucleus was hyperchromatic, pyknotic or contained clearly visible nucleoli. Loss of cohesion and areas of red blood cell extravasation (4009). © 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
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method showed reactivity of the neoplastic cells to primary antibodies against HMB45, melan A and S100 and negativity for PAN cytokeratin (Dako Corporation, Carpinteria, CA, USA), confirming the diagnosis of metastatic melanoma (Fig. 3). Chest and abdominal multislice computed tomography and brain magnetic resonance imaging were performed to rule out the presence of other distant metastases and were negative at that time. The patient was submitted to partial resection of the tongue and showed good immediate postoperative evolution, being oriented and in good general condition. After 2 months, the patient started to present disorientation, headache and dizziness. Brain magnetic resonance imaging revealed the presence of multiple secondary lesions. The patient died 30 days after the diagnosis of brain metastases. Immunohistochemical analysis of cell proliferation markers (Ki67, MCM2, MCM5 and geminin – Novocastra Laboratories, Newcastle upon Tyne, UK) was performed to better characterise the tumour. Abundant nuclear reactivity to all markers was observed in the tumour cells (Fig. 4).
Discussion Melanoma is the sixth most frequent cancer among men and the seventh most common among women4. The median age at the time of diagnosis is 59 years, and the mean age of death due to this cancer is 68 years5. The present
(a)
(b)
(c)
(d)
patient was 72 years old and was within the expected age range. The main risk factor for the development of melanoma of the skin is ultraviolet radiation. An increased risk is observed in patients with a family history of the disease and those with specific subtypes of nevic lesions5. Certain phenotypic characteristics such as red hair and skin with freckles are also associated with a higher risk of melanoma6. Furthermore, sun damage at a younger age can increase the risk of melanoma7. The present patient was white and reported no excessive sun exposure during his life. The most common type of melanoma in the head and neck region is superficial spreading melanoma, corresponding to 70% of diagnosed cases. Nodular melanoma accounts for 15–30% of cases, whereas mucosal melanoma is relatively rare. The desmoplastic variant mainly affects the head and neck region. In addition, there is lentigo maligna melanoma or melanoma in situ, a precursor of melanoma8. In the present case, both the primary tumour and the tongue metastases were of the nodular type. The tumour-nodule-metastasis stage of melanoma is classified using a combination of criteria (Breslow’s depth, Clark level of invasion and presence of ulceration) to characterise the primary tumour. The Breslow depth is measured in millimetre: 1.0 mm (T1), 1.01–2.0 mm (T2), 2.01– 4.0 mm (T3), and >4.0 (T4). The Clark level describes the depth of invasion: level I, tumour cells limited to the epidermis (in situ); level II,
Figure 3 Immunohistochemistry. (a) Anti-HMB45 positive (4009). (b) Anti-melan A positive (4009). (c) Anti-S100 positive (4009). (d) Anti-Pan cytokeratin negative. © 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
Metastatic melanoma of the tongue
Figure 4 Immunohistochemistry showing reactivity to the cell proliferation markers Ki67 (a), MCM2 (b), MCM5 (c) and geminin (d).
(a)
(b)
(c)
(d)
penetration into the underlying dermis; level III, invasion into the papillary dermis; level IV, invasion into the reticular dermis, and level V, invasion into subcutaneous fat. The presence of ulceration is evaluated by histological examination. Ulcerations are important since they indicate a higher risk of metastases5. In the present case, the Breslow depth was 2.5 mm, corresponding to T3, and the Clark level of invasion was level IV, involving the reticular dermis. No ulceration was observed in the skin lesion or oral mucosa. Melanomas can histologically mimic a wide variety of neoplasms, including lymphomas, poorly differentiated carcinomas and sarcomas. Microscopically, melanomas are characterised by larger than normal, atypical melanocytes that exhibit nuclear pleomorphism and hyperchromatism. The tumour cells are generally epithelioid and/or spindle shaped and are arranged in nests, spirals, trabeculae, nodules, rosettes and papillary projections9. In the present case, there was a predominance of round cells with a poorly delimited cytoplasm. The nuclei were round and hyperchromatic, pyknotic or contained clearly visible nucleoli. The cells were arranged in nests separated by thin connective tissue septa that conferred an alveolar appearance to the tumour. Furthermore, the mean number of mitoses in 10 high-power fields was high, and the patient died 30 days after the diagnosis of metastases. This agrees with Thompson et al.10 who concluded that a high mitotic rate is associated with poor survival.
317
Immunohistochemistry is widely used to differentiate melanoma from other tumours9. In the present case, the tumour cells were positive for HMB45, melan A, S100, Ki67, MCM2, MCM5 and geminin. HBM45 is expressed in melanocytic tumours, but not on normal adult melanocytes. This marker shows a higher specificity and lower sensitivity than S-100, with the observation of an irregular and diffusely positive staining pattern11. The sensitivity of HBM45 is reduced in metastatic melanoma lesions and a combination of markers is therefore required for the identification of these lesions9. Melan A is a marker of melanocytic differentiation that is used to distinguish melanomas from nonmelanocytic lesions. The sensitivity and specificity of this marker for the diagnosis of melanoma are similar to those of HMB45, but the resulting staining pattern is intense and more diffuse12. S-100 stains cells of the central and peripheral nervous system, as well as Langerhans cells. In addition, this marker shows high sensitivity for nevic and melanoma cells, but is less specific than HMB-4511 and should therefore be used in combination with other markers for the diagnosis of melanoma9. Protein Ki67 is expressed during all phases of the cell cycle, except G0, and is an important biomarker of cell proliferation. Expression of Ki67 is related to the presence of metastases and therefore indicates a poor prognosis13. Minichromosome maintenance proteins (MCM) are essential for the process of DNA replication and regulate the entry into the S phase of the cell cycle14. The presence of these proteins in
© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
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malignant tumours has been associated with a high degree of cellular atypia and a poor prognosis15. Six members of this protein family (MCM2 to 7) have been documented. These proteins interact with one another, forming a complex16. Geminin plays an important role in the monitoring of cell cycle progression and cell proliferation17. This protein is overexpressed in melanomas18. In the present case, the immunohistochemical panel led to the diagnosis of malignant melanoma characterised by intensive cell proliferation and a poor prognosis. Melanomas are characterised by a high metastatic potential. Therefore, an excisional biopsy comprising the full thickness of the lesion with margins of 1–3 mm is preferred5,8. In the present case, the first biopsy met these criteria, whereas the surgical objective of the tongue lesion biopsy was to collect material for definition of the diagnosis. Despite recent advances treatment of metastatic melanoma remains a challenge. The main treatment for primary melanoma is surgery consisting of wide local excision with free margins1,5,8. Adjuvant therapy, such as radiation, chemotherapy, immunotherapy or a combination of these therapies, is reserved for metastatic disease19. Melanoma first spreads through the sentinel lymph node of the regional nodal basin. The presence or absence of metastases in the sentinel lymph node is closely correlated with their presence or absence in the residual lymph node basin5. As a consequence, a sentinel lymph node biopsy is a minimally invasive technique to evaluate the need for complete regional lymph node resection and has become an important tool for melanoma staging1,5,20,21. This approach permits individual treatment planning for each patient20. Nevertheless, some investigators alert to the risk of false-positive results22,23. In the present case, the skin lesion was accompanied by 1 mm micrometastases in the right inguinal lymph nodes detected by sentinel lymph node biopsy. Most distant metastases of melanoma first occur in the skin, subcutaneous tissue or regional lymph nodes24. Photographic assessment has been used at various centres for skin analysis in patients with melanoma21. After the skin and lymphatic system, the lungs are the site most frequently affected by metastases. Periodic chest X-rays are therefore important, although false-positive results have been reported21. The present patient was submitted to clinical evaluation, chest X-ray, abdominal and liver ultrasound, and cranial tomography to rule out the presence of other
distant metastases and the exams were negative at that time. Metastatic melanoma lesions on the tongue are rare3. In a survey conducted in 2007, Meleti et al.24 detected 13 metastatic melanoma lesions in the oral region, one of them on the tongue. Metastatic oral melanoma is associated with advanced disease and a poor prognosis25. Brain metastases generally occur relatively late during the course of the disease. Most patients with brain metastases experience headache or other symptoms, such as weakness, dormancy, loss of balance and loss of vision, as result of an increased intracranial pressure due to a mass effect26. In the present case, the patients started to show disorientation, headache and dizziness after 2 months, and the presence of brain metastases was confirmed. The patient died 30 days after this diagnosis.
Conclusion The present findings highlight the importance of a complete medical evaluation of the patient by anamnesis to identify possible oral repercussions of primary diseases in other organs and/or systems.
Acknowledgements The authors thank the Laboratory of Diagnostic Medicine CIPAX, Instituto de Oncologia do Vale (IOV) and Dr Da´rcio Kitakawa for their collaboration. Ethics Committee approval number 015/ 2010 - PH/CEP.
Funding source None declared.
Conflict of interests None declared.
References 1. Kingham TP, Karakousis G, Ariyan C. Randomized clinical trials in melanoma. Surg Oncol Clin N Am 2010; 19: 13–31. 2. Shen ML, Kang J, Wen YL et al. Metastatic tumors to the oral and maxillofacial region: a retrospective study of 19 cases in West China and review of the Chinese and English literature. J Oral Maxillofac Surg 2009; 67: 718–737. 3. Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58: 71–96. 4. Cho YR, Chiang MP. Epidemiology, staging (new system), and prognosis of cutaneous melanoma. Clin Plast Surg 2010; 37: 47–53.
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5. Veierod MB, Weiderpass E, Th€ orn M et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst 2003; 95: 1530–1538. 6. Larson DL, Larson JD. Head and neck melanoma. Clin Plast Surg 2010; 37: 73–77. 7. Fagundo E, Rodrıguez-Garcıa C, Rodrıguez C, Gonz alez S, S anchez R, Jim enez A. Analysis of phenotypic characteristics and exposure to UV radiation in a group of patients with cutaneous melanoma. Actas Dermosifiliogr 2011; 102: 599–604. 8. Ohsie SJ, Sarantopoulos GP, Cochran AJ, Binder SW. Immunohistochemical characteristics of melanoma. J Cutan Pathol 2008; 35: 433–444. 9. Yu CH, Chen HH, Liu CM et al. HMB-45 may be a more sensitive maker than S-100 or Melan-A for immunohistochemical diagnosis of primary oral and nasal mucosal melanomas. J Oral Pathol Med 2005; 34: 540–545. 10. Thompson JF, Soong SJ, Balch CM et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol 2011; 29: 2199–2205. 11. Zubovits J, Buzney E, Yu L, Duncan LM. HMB45, S-100, NK1/C3, and MART-1 in metastatic melanoma. Hum Pathol 2004; 35: 217. 12. Gimotty PA, Van Belle P, Elder DE et al. Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma. J Clin Oncol 2005; 23: 8048–8056. 13. Tye BK. MCM proteins in DNA replication. Annu Rev Biochem 1999; 68: 649–686. 14. Korkolopoulou P, Givalos N, Saetta A et al. Minichromosome maintenance proteins 2 and 5 expression in muscle-invasive urothelial cancer: a multivariate survival study including proliferation markers and cell cycle regulators. Hum Pathol 2005; 36: 899–907. 15. Giaginis C, Vgenopoulou S, Vielh P, Theocharis S. MCM proteins as diagnostic and prognostic tumor markers in the clinical setting. Histol Histopathol 2010; 25: 351–370. 16. McGarry TJ, Kirschner MW. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 1998; 93: 1043–1053.
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17. Winnepenninckx V, Lazar V, Michiels S et al. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst 2006; 98: 472–482. 18. Treisman J, Garlie N. Systemic therapy for cutaneous melanoma. Clin Plast Surg 2010; 37: 127–146. 19. Wilson LL. Sentinel lymph node biopsy from the vantage point of an oncologic surgeon. Clin Dermatol 2009; 27: 594–596. 20. Lifchez SD, Kelamis JA. Melanoma: workup and surveillance. Clin Plast Surg 2010; 37: 55–63. 21. Brennick JB, Yan S. False-positive cells in sentinel lymph nodes. Semin Diagn Pathol 2008; 25: 116– 119. 22. Thomas JM. Prognostic false-positivity of the sentinel node in melanoma. Nat Clin Pract Oncol 2008; 5: 18–23. 23. Huang CL, Provost N, Marghoob AA, Kopf AW, Levin L, Bart RS. Laboratory tests and imaging studies in patients with cutaneous malignant melanoma. J Am Acad Dermatol 1998; 39: 451–463. 24. Meleti M, Leemans CR, Mooi WJ, van der Waal I. Oral malignant melanoma: the Amsterdam experience. J Oral Maxillofac Surg 2007; 65: 2181– 2186. 25. Bonan PR, Laranjeira AL, Martelli-J unior H, Guimar~ aes AL, Vargas PA, Coletta RD. Synchronous metastatic melanoma presenting as gingival and facial swelling: a case report and review of the literature. J Periodontol 2008; 79: 2371–2377. 26. Sloan AE, Nock CJ, Einstein DB. Diagnosis and treatment of melanoma brain metastasis: a literature review. Cancer Control 2009; 16: 248–255.
Correspondence to: M^ onica Ghislaine Oliveira Alves, Department of Biosciences, and Oral Diagnosis, S~ao Jose dos Campos Dental School, S~ao Jose dos Campos, UNESP - Univ Estadual Paulista, S~ao Paulo, Brazil. 777 Engenheiro Francisco Jose Longo Avenue, S~ao Dimas. S~ ao Jose dos Campos, SP, Brazil. Zip code: 12245-000. Tel.: +55 1232072962/ + 55 1288278200 Fax: +55 1239479010 E-mail: [email protected]
© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
Metastatic melanoma of the tongue: a case report with immunohistochemical profile ^ nica Ghislaine O. Alves1, Luciene R. Chagas2, Yasmin R. Carvalho1, Luiz A. G. Cabral1, Mo Ricardo D. Coletta3 and Janete D. Almeida1 Department of Biosciences and Oral Diagnosis, S~ ao Jos e dos Campos Dental School, UNESP – Univ. Estadual Paulista, S~ao Jose dos Campos, S~ ao Paulo, Brazil; 2Nursing Course, Health Sciences School, Universidade do Vale do Paraıba, S~ao Jose dos Campos, S~ao Paulo, Brazil; 3Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, Piracicaba, S~ao Paulo, Brazil 1
doi: 10.1111/ger.12032 Metastatic melanoma of the tongue: a case report with immunohistochemical profile Background: Melanoma of the skin is characterised by a high metastatic potential, but reports of metastasis to the tongue are rare. We report a case of skin melanoma with metastasis to the lymph nodes, tongue and brain. Objectives: This report highlights the clinical and histological features of oral metastatic melanoma. Case report: A 72-year-old man was seen with a nodule on the tongue. The differential diagnosis included salivary gland tumour, lymphoma and metastatic melanoma. His medical history revealed treatment for melanoma in the periumbilical region and micrometastases in the inguinal lymph nodes. An incisional biopsy was obtained and histological analysis showed the presence of a solid, epithelioid malignant tumour of monotonous appearance infiltrating the skeletal musculature. Immunohistochemistry showed reactivity of neoplastic cells to anti-HMB45, anti-melan A and anti-S100 antibodies and negativity for anti-PAN cytokeratin, confirming the diagnosis of metastatic melanoma. Conclusion: The present findings highlight the importance of a complete medical evaluation of the patient by anamnesis to identify possible oral repercussions of primary diseases in other organs and/or systems. Keywords: oral mucosa, melanoma, oral cancer, skin cancer, immunohistochemistry Accepted 16 November 2012
Introduction The incidence of melanoma has increased over recent years. This skin cancer is characterised by high metastatic potential to multiple organs1. In general, metastases in the maxillomandibular complex and associated organs are rare, with only 7.8% of melanomas developing metastases to these regions2. Metastatic melanoma of the tongue is rare3. We report here the case of a patient with melanoma who developed metastases to the lymph nodes, tongue and brain.
Case report A 72-year-old white man was seen at a stomatology outpatient clinic with a nodule on the 314
tongue. The patient reported the formation of a haematoma after trauma to the region 2 months earlier, followed by the formation of a nodular lesion. The patient had no pain symptoms. His medical history revealed the presence of nodular melanoma in the periumbilical region, classified as Clark invasion level IV and with a Breslow depth of 2.5, accompanied by 1-mm micrometastases in the right inguinal lymph nodes. The patient underwent surgical treatment and inguinal lymph node drainage and remained without clinical signs of the disease for 15 months. Extraoral clinical examination showed irregular, hard, mobile and painless cervical lymph nodes on the left side (level IV) measuring on average 1 cm. Computed tomography revealed round nodules and heterogeneous enhancement. Intraoral examination revealed a submucosal nodular
© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
Metastatic melanoma of the tongue
lesion on the dorsum of the tongue. The lesion measured approximately 2.5 cm in its major diameter, was consistent upon palpation and infiltrated underlying tissue. Tongue mobility was preserved (Fig. 1). The differential diagnosis included salivary gland tumour, lymphoma and metastatic melanoma. An incisional biopsy was obtained, and the material was sent for histochemical and immunohistochemical analysis.
315
Histopathological examination revealed mucosa lined with squamous epithelium and the presence of a solid, epithelioid malignant tumour of monotonous appearance infiltrating the skeletal musculature. The cells contained clearly visible nucleoli and moderately eosinophilic cytoplasm (Fig. 2). The mean number of mitoses in 10 highpower fields was 20.6 per mm2. Immunohistochemistry by the streptavidin-biotin-peroxidase
(a)
(b)
Figure 1 Clinical findings. (a) Lateral view of the tumour. (b) Tumour seen in the region of the ventral tongue.
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(b)
(c)
(d)
Figure 2 Histopathological findings (HE stain). (a) Mucosal fragment lined with stratified pavement epithelium showing no dysplastic alterations. Note the presence of a nodule deep in the lamina propria separated by a band of connective tissue (259). (b) Poorly circumscribed nonencapsulated tumour infiltrating connective tissue and muscle (1009). (c) Scarce stroma and connective tissue septa conferring an alveolar appearance to the tumour (2009). (d) Presence of mainly round tumour cells containing poorly delimited cytoplasm and a round nucleus. The nucleus was hyperchromatic, pyknotic or contained clearly visible nucleoli. Loss of cohesion and areas of red blood cell extravasation (4009). © 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
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method showed reactivity of the neoplastic cells to primary antibodies against HMB45, melan A and S100 and negativity for PAN cytokeratin (Dako Corporation, Carpinteria, CA, USA), confirming the diagnosis of metastatic melanoma (Fig. 3). Chest and abdominal multislice computed tomography and brain magnetic resonance imaging were performed to rule out the presence of other distant metastases and were negative at that time. The patient was submitted to partial resection of the tongue and showed good immediate postoperative evolution, being oriented and in good general condition. After 2 months, the patient started to present disorientation, headache and dizziness. Brain magnetic resonance imaging revealed the presence of multiple secondary lesions. The patient died 30 days after the diagnosis of brain metastases. Immunohistochemical analysis of cell proliferation markers (Ki67, MCM2, MCM5 and geminin – Novocastra Laboratories, Newcastle upon Tyne, UK) was performed to better characterise the tumour. Abundant nuclear reactivity to all markers was observed in the tumour cells (Fig. 4).
Discussion Melanoma is the sixth most frequent cancer among men and the seventh most common among women4. The median age at the time of diagnosis is 59 years, and the mean age of death due to this cancer is 68 years5. The present
(a)
(b)
(c)
(d)
patient was 72 years old and was within the expected age range. The main risk factor for the development of melanoma of the skin is ultraviolet radiation. An increased risk is observed in patients with a family history of the disease and those with specific subtypes of nevic lesions5. Certain phenotypic characteristics such as red hair and skin with freckles are also associated with a higher risk of melanoma6. Furthermore, sun damage at a younger age can increase the risk of melanoma7. The present patient was white and reported no excessive sun exposure during his life. The most common type of melanoma in the head and neck region is superficial spreading melanoma, corresponding to 70% of diagnosed cases. Nodular melanoma accounts for 15–30% of cases, whereas mucosal melanoma is relatively rare. The desmoplastic variant mainly affects the head and neck region. In addition, there is lentigo maligna melanoma or melanoma in situ, a precursor of melanoma8. In the present case, both the primary tumour and the tongue metastases were of the nodular type. The tumour-nodule-metastasis stage of melanoma is classified using a combination of criteria (Breslow’s depth, Clark level of invasion and presence of ulceration) to characterise the primary tumour. The Breslow depth is measured in millimetre: 1.0 mm (T1), 1.01–2.0 mm (T2), 2.01– 4.0 mm (T3), and >4.0 (T4). The Clark level describes the depth of invasion: level I, tumour cells limited to the epidermis (in situ); level II,
Figure 3 Immunohistochemistry. (a) Anti-HMB45 positive (4009). (b) Anti-melan A positive (4009). (c) Anti-S100 positive (4009). (d) Anti-Pan cytokeratin negative. © 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
Metastatic melanoma of the tongue
Figure 4 Immunohistochemistry showing reactivity to the cell proliferation markers Ki67 (a), MCM2 (b), MCM5 (c) and geminin (d).
(a)
(b)
(c)
(d)
penetration into the underlying dermis; level III, invasion into the papillary dermis; level IV, invasion into the reticular dermis, and level V, invasion into subcutaneous fat. The presence of ulceration is evaluated by histological examination. Ulcerations are important since they indicate a higher risk of metastases5. In the present case, the Breslow depth was 2.5 mm, corresponding to T3, and the Clark level of invasion was level IV, involving the reticular dermis. No ulceration was observed in the skin lesion or oral mucosa. Melanomas can histologically mimic a wide variety of neoplasms, including lymphomas, poorly differentiated carcinomas and sarcomas. Microscopically, melanomas are characterised by larger than normal, atypical melanocytes that exhibit nuclear pleomorphism and hyperchromatism. The tumour cells are generally epithelioid and/or spindle shaped and are arranged in nests, spirals, trabeculae, nodules, rosettes and papillary projections9. In the present case, there was a predominance of round cells with a poorly delimited cytoplasm. The nuclei were round and hyperchromatic, pyknotic or contained clearly visible nucleoli. The cells were arranged in nests separated by thin connective tissue septa that conferred an alveolar appearance to the tumour. Furthermore, the mean number of mitoses in 10 high-power fields was high, and the patient died 30 days after the diagnosis of metastases. This agrees with Thompson et al.10 who concluded that a high mitotic rate is associated with poor survival.
317
Immunohistochemistry is widely used to differentiate melanoma from other tumours9. In the present case, the tumour cells were positive for HMB45, melan A, S100, Ki67, MCM2, MCM5 and geminin. HBM45 is expressed in melanocytic tumours, but not on normal adult melanocytes. This marker shows a higher specificity and lower sensitivity than S-100, with the observation of an irregular and diffusely positive staining pattern11. The sensitivity of HBM45 is reduced in metastatic melanoma lesions and a combination of markers is therefore required for the identification of these lesions9. Melan A is a marker of melanocytic differentiation that is used to distinguish melanomas from nonmelanocytic lesions. The sensitivity and specificity of this marker for the diagnosis of melanoma are similar to those of HMB45, but the resulting staining pattern is intense and more diffuse12. S-100 stains cells of the central and peripheral nervous system, as well as Langerhans cells. In addition, this marker shows high sensitivity for nevic and melanoma cells, but is less specific than HMB-4511 and should therefore be used in combination with other markers for the diagnosis of melanoma9. Protein Ki67 is expressed during all phases of the cell cycle, except G0, and is an important biomarker of cell proliferation. Expression of Ki67 is related to the presence of metastases and therefore indicates a poor prognosis13. Minichromosome maintenance proteins (MCM) are essential for the process of DNA replication and regulate the entry into the S phase of the cell cycle14. The presence of these proteins in
© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
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malignant tumours has been associated with a high degree of cellular atypia and a poor prognosis15. Six members of this protein family (MCM2 to 7) have been documented. These proteins interact with one another, forming a complex16. Geminin plays an important role in the monitoring of cell cycle progression and cell proliferation17. This protein is overexpressed in melanomas18. In the present case, the immunohistochemical panel led to the diagnosis of malignant melanoma characterised by intensive cell proliferation and a poor prognosis. Melanomas are characterised by a high metastatic potential. Therefore, an excisional biopsy comprising the full thickness of the lesion with margins of 1–3 mm is preferred5,8. In the present case, the first biopsy met these criteria, whereas the surgical objective of the tongue lesion biopsy was to collect material for definition of the diagnosis. Despite recent advances treatment of metastatic melanoma remains a challenge. The main treatment for primary melanoma is surgery consisting of wide local excision with free margins1,5,8. Adjuvant therapy, such as radiation, chemotherapy, immunotherapy or a combination of these therapies, is reserved for metastatic disease19. Melanoma first spreads through the sentinel lymph node of the regional nodal basin. The presence or absence of metastases in the sentinel lymph node is closely correlated with their presence or absence in the residual lymph node basin5. As a consequence, a sentinel lymph node biopsy is a minimally invasive technique to evaluate the need for complete regional lymph node resection and has become an important tool for melanoma staging1,5,20,21. This approach permits individual treatment planning for each patient20. Nevertheless, some investigators alert to the risk of false-positive results22,23. In the present case, the skin lesion was accompanied by 1 mm micrometastases in the right inguinal lymph nodes detected by sentinel lymph node biopsy. Most distant metastases of melanoma first occur in the skin, subcutaneous tissue or regional lymph nodes24. Photographic assessment has been used at various centres for skin analysis in patients with melanoma21. After the skin and lymphatic system, the lungs are the site most frequently affected by metastases. Periodic chest X-rays are therefore important, although false-positive results have been reported21. The present patient was submitted to clinical evaluation, chest X-ray, abdominal and liver ultrasound, and cranial tomography to rule out the presence of other
distant metastases and the exams were negative at that time. Metastatic melanoma lesions on the tongue are rare3. In a survey conducted in 2007, Meleti et al.24 detected 13 metastatic melanoma lesions in the oral region, one of them on the tongue. Metastatic oral melanoma is associated with advanced disease and a poor prognosis25. Brain metastases generally occur relatively late during the course of the disease. Most patients with brain metastases experience headache or other symptoms, such as weakness, dormancy, loss of balance and loss of vision, as result of an increased intracranial pressure due to a mass effect26. In the present case, the patients started to show disorientation, headache and dizziness after 2 months, and the presence of brain metastases was confirmed. The patient died 30 days after this diagnosis.
Conclusion The present findings highlight the importance of a complete medical evaluation of the patient by anamnesis to identify possible oral repercussions of primary diseases in other organs and/or systems.
Acknowledgements The authors thank the Laboratory of Diagnostic Medicine CIPAX, Instituto de Oncologia do Vale (IOV) and Dr Da´rcio Kitakawa for their collaboration. Ethics Committee approval number 015/ 2010 - PH/CEP.
Funding source None declared.
Conflict of interests None declared.
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© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
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Correspondence to: M^ onica Ghislaine Oliveira Alves, Department of Biosciences, and Oral Diagnosis, S~ao Jose dos Campos Dental School, S~ao Jose dos Campos, UNESP - Univ Estadual Paulista, S~ao Paulo, Brazil. 777 Engenheiro Francisco Jose Longo Avenue, S~ao Dimas. S~ ao Jose dos Campos, SP, Brazil. Zip code: 12245-000. Tel.: +55 1232072962/ + 55 1288278200 Fax: +55 1239479010 E-mail: [email protected]
© 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd Gerodontology 2014; 31: 314–319
