Orbit, 2014; 33(2): 139–141 ! Informa Healthcare USA, Inc. ISSN: 0167-6830 print / 1744-5108 online DOI: 10.3109/01676830.2013.851708
C ASE REPORT
Spontaneous Regression of a Conjunctival Malignant Melanoma Christina V. Miller1, Ian S. Cook2, Rama Jayaramachandran1, and Anthony G. Tyers1 1
Department of Ophthalmology, Salisbury District Hospital, NHS Foundation Trust, Salisbury, United Kingdom and 2Department of Pathology, Salisbury District Hospital, NHS Foundation Trust, Salisbury, United Kingdom
ABSTRACT Introduction: Conjunctival malignant melanoma (MM) is a rare malignancy and accounts for 2% of all ocular malignancies. We describe what we believe to be the first reported case of complete spontaneous regression of a conjunctival malignant melanoma. Methods: A 75-year-old female presented with a large, pigmented lesion in her left lower fornix. Histopathology revealed a mixed cell type MM. The tumour regressed spontaneously. Now, 6 years after she first presented, she remains well and there is no sign of recurrence or metastasis. Conclusion: Spontaneous regression is not always synonymous with complete cure from the underlying disease but may represent a temporary regression due to host protective mechanisms. In our patient regression and cure were complete. Keywords: Conjunctiva, histopathology, malignant melanoma, regression
INTRODUCTION
it arose in Primary Aquired Melanosis, (ConjunctivalMelanocytic Intraepithelial Neoplasia, C-MIN) (Figure 1).2 An incisional biopsy confirmed the initial diagnosis of a mixed cell type MM. The tumour was too advanced for local excision and an orbital exenteration was offered. The patient refused any treatment. She was assessed by an oncologist and metastatic spread was excluded. No treatment was given. The tumour regressed spontaneously over several months. The patient has been reviewed every few months to date. Now, 6 years after she first presented, she remains well and there is no sign of recurrence or metastasis. Histopathological examination of the incisional biopsy revealed a nodular malignant melanoma arising from the conjunctiva. This was composed predominantly of epithelioid melanocytes with a lesser population of plump spindle shaped melanocytes. The tumour cells had irregular vesicular nuclei and prominent eosinophilic nucleoli. There was no maturation towards the deep aspect of the lesion.
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Conjunctival malignant melanoma (MM) is a rare malignancy and accounts for 2% of all ocular malignancies.1,2 The incidence is increasing and varies between 0.2–0.8% per year in the Caucasian population. It may be pigmented or non-pigmented, single or multifocal. Tumour recurrence is reported to occur in more than 50% of cases, metastases develop in 20–30% of the patients and tumour mortality rate ranges from 18% to 44%.3–5 We describe what we believe to be the first reported case of complete spontaneous regression of a conjunctival malignant melanoma.
Case Report A 75-year-old female was referred with a large, pigmented lesion in her left lower fornix. It extended from the inferior fornix up to the limbus of the cornea and to just below the eyelid margin and
Received 20 August 2013; Accepted 30 September 2013; Published online 19 November 2013 Correspondence: Dr. Christina V. Miller, Department of Ophthalmology, NHS Foundation Trust, Salisbury District Hospital, Odstock Road, Salisbury, SP2 8BJ, United Kingdom. E-mail: [email protected]
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140 C. V. Miller et al.
FIGURE 1. Photograph showing malignant melanoma at presentation (left) and at 6 years following regression (right).
There were frequent mitoses (16 per square mm). A Ki-67 proliferation marker showed positive staining throughout the full thickness of the tumour with a proliferation fraction of over 50%. The adjacent conjunctiva showed melanosis with atypia. The tumour cells showed diffuse positive immunohistochemical staining with HMB45. The tumour had a thickness of 6.0 mm (Jacobiek modification of Breslow thickness) and was in vertical growth phase. There was surface ulceration (ulcer diameter 4.5 mm) and brisk tumour infiltrating lymphocytes with large areas of regression within the tumour with accumulation of pigment laden melanophages (Figure 2). The lymphocytes present were predominantly CD4 positive cells, with a lesser population of CD8 positive T-lymphocytes. There was no staining with CD56 (a marker for natural killer cells). There was no lymphovascular or perineural invasion. Tumour extended to all margins of the incisional biopsy.
COMMENT By definition, spontaneous regression is the partial or complete disappearance of a malignant tumour in the absence of all treatment or the presence of an adequate therapy to alter significantly the natural course of the malignancy.6,7 This phenomenon is well accepted in the natural course of cancer. Spontaneous regression is a frequent event in malignant melanomas of the skin.8,9 The literature research on spontaneous regression of malignant melanoma showed it to be a frequent event in the natural history of skin melanoma. However, to our knowledge it has not previously been described in conjunctival MM. It is postulated that spontaneous regression of skin melanoma may occur when the immune system is triggered by certain factors. These include: operative trauma, infection and immunologic factors.8 Surgery may interrupt the tumour’s blood supply and may lead to stronger immunological resistance against the
FIGURE 2. Photomicrograph showing malignant melanoma with brisk tumour infiltrating lymphocytes and evidence of regression (on the right-hand side of photomicrograph) with accumulation of deeply pigmented melanophages (H&E, 200).
tumour growth. The postoperative inflammation or infection could enhance the host immune system and augment the natural defences against the malignant melanoma. Finally, an unknown immunologic response similar to the pathophysiology in skin melanoma which elicits cytotoxic T-lymphocytes (CD8 positive) and natural killer cells (CD 56 positive), which play a leading role in this host-immune response. It has been suggested that natural killer cells are the first cells to play a role in regression of cutaneous melanomas. They in turn may stimulate a subtype of T-helper cells which may then account for the recruitment of cytotoxic T-lymphocytes.10 The same mechanisms may have occurred in our patient. In summary, the exact mechanism of spontaneous regression of malignant melanoma is still unknown. Identification of specific histological features may predict a potential for spontaneous regression. However, this phenomenon is not always synonymous with complete cure from the underlying disease Orbit
Regression of Conjuctival Melanoma but may represent a temporary regression due to host protective mechanisms. In our patient regression and cure were complete. It is possible that identifying the exact mechanisms by which regression occurs could lead to more effective and targeted therapies.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Lim LA, Madigan MC, Conway RM. Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol 2013;6:521–531. 2. Kenawy N, Lake SL, Coupland SE, Damato BE. Conjunctival melanoma and melanocytic intra-epithelial neoplasia. Eye 2013;27(2):142–152.
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3. Paridaens AD, McCartney AC, Minassian DC, Hungerford JL. Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol 1994;78(7):520–528. 4. Paridaens AD, Minassian DC, McCartney AC, Hungerford JL. Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. Br J Ophthalmol 1994;78(4):252–259. 5. Mudhar HS, Rennie IG. Local conjunctival metastases from primary conjunctival melanoma: clinico-pathological correlation and implications. Br J Ophthalmol 2013;97(1): 33–39. 6. Everson TC, Cole WH. Spontaneous regression of malignant disease. J Amer Med Asso 1959;169(15):1758–1759. 7. Stewart FW. Experiences in spontaneous regression of neoplastic disease in man. TX Repts Biol Med 1952; 10(1):239–253. 8. Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melan Res 2009;19(5):275–282. 9. Nathanson L. Spontaneous regression of malignant melanoma: a review of the literature on incidence, clinical features, and possible mechanisms. Natl Cancer Instit Monogr 1976;44:67–76. 10. McKay K, Moore PC, Smoller BR, Hiatt KM. Association between natural killer cells and regression in melanocytic lesions. Human Pathol 2011;42(12):1960–1964.
Copyright of Orbit is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
C ASE REPORT
Spontaneous Regression of a Conjunctival Malignant Melanoma Christina V. Miller1, Ian S. Cook2, Rama Jayaramachandran1, and Anthony G. Tyers1 1
Department of Ophthalmology, Salisbury District Hospital, NHS Foundation Trust, Salisbury, United Kingdom and 2Department of Pathology, Salisbury District Hospital, NHS Foundation Trust, Salisbury, United Kingdom
ABSTRACT Introduction: Conjunctival malignant melanoma (MM) is a rare malignancy and accounts for 2% of all ocular malignancies. We describe what we believe to be the first reported case of complete spontaneous regression of a conjunctival malignant melanoma. Methods: A 75-year-old female presented with a large, pigmented lesion in her left lower fornix. Histopathology revealed a mixed cell type MM. The tumour regressed spontaneously. Now, 6 years after she first presented, she remains well and there is no sign of recurrence or metastasis. Conclusion: Spontaneous regression is not always synonymous with complete cure from the underlying disease but may represent a temporary regression due to host protective mechanisms. In our patient regression and cure were complete. Keywords: Conjunctiva, histopathology, malignant melanoma, regression
INTRODUCTION
it arose in Primary Aquired Melanosis, (ConjunctivalMelanocytic Intraepithelial Neoplasia, C-MIN) (Figure 1).2 An incisional biopsy confirmed the initial diagnosis of a mixed cell type MM. The tumour was too advanced for local excision and an orbital exenteration was offered. The patient refused any treatment. She was assessed by an oncologist and metastatic spread was excluded. No treatment was given. The tumour regressed spontaneously over several months. The patient has been reviewed every few months to date. Now, 6 years after she first presented, she remains well and there is no sign of recurrence or metastasis. Histopathological examination of the incisional biopsy revealed a nodular malignant melanoma arising from the conjunctiva. This was composed predominantly of epithelioid melanocytes with a lesser population of plump spindle shaped melanocytes. The tumour cells had irregular vesicular nuclei and prominent eosinophilic nucleoli. There was no maturation towards the deep aspect of the lesion.
20 14
Conjunctival malignant melanoma (MM) is a rare malignancy and accounts for 2% of all ocular malignancies.1,2 The incidence is increasing and varies between 0.2–0.8% per year in the Caucasian population. It may be pigmented or non-pigmented, single or multifocal. Tumour recurrence is reported to occur in more than 50% of cases, metastases develop in 20–30% of the patients and tumour mortality rate ranges from 18% to 44%.3–5 We describe what we believe to be the first reported case of complete spontaneous regression of a conjunctival malignant melanoma.
Case Report A 75-year-old female was referred with a large, pigmented lesion in her left lower fornix. It extended from the inferior fornix up to the limbus of the cornea and to just below the eyelid margin and
Received 20 August 2013; Accepted 30 September 2013; Published online 19 November 2013 Correspondence: Dr. Christina V. Miller, Department of Ophthalmology, NHS Foundation Trust, Salisbury District Hospital, Odstock Road, Salisbury, SP2 8BJ, United Kingdom. E-mail: [email protected]
139
140 C. V. Miller et al.
FIGURE 1. Photograph showing malignant melanoma at presentation (left) and at 6 years following regression (right).
There were frequent mitoses (16 per square mm). A Ki-67 proliferation marker showed positive staining throughout the full thickness of the tumour with a proliferation fraction of over 50%. The adjacent conjunctiva showed melanosis with atypia. The tumour cells showed diffuse positive immunohistochemical staining with HMB45. The tumour had a thickness of 6.0 mm (Jacobiek modification of Breslow thickness) and was in vertical growth phase. There was surface ulceration (ulcer diameter 4.5 mm) and brisk tumour infiltrating lymphocytes with large areas of regression within the tumour with accumulation of pigment laden melanophages (Figure 2). The lymphocytes present were predominantly CD4 positive cells, with a lesser population of CD8 positive T-lymphocytes. There was no staining with CD56 (a marker for natural killer cells). There was no lymphovascular or perineural invasion. Tumour extended to all margins of the incisional biopsy.
COMMENT By definition, spontaneous regression is the partial or complete disappearance of a malignant tumour in the absence of all treatment or the presence of an adequate therapy to alter significantly the natural course of the malignancy.6,7 This phenomenon is well accepted in the natural course of cancer. Spontaneous regression is a frequent event in malignant melanomas of the skin.8,9 The literature research on spontaneous regression of malignant melanoma showed it to be a frequent event in the natural history of skin melanoma. However, to our knowledge it has not previously been described in conjunctival MM. It is postulated that spontaneous regression of skin melanoma may occur when the immune system is triggered by certain factors. These include: operative trauma, infection and immunologic factors.8 Surgery may interrupt the tumour’s blood supply and may lead to stronger immunological resistance against the
FIGURE 2. Photomicrograph showing malignant melanoma with brisk tumour infiltrating lymphocytes and evidence of regression (on the right-hand side of photomicrograph) with accumulation of deeply pigmented melanophages (H&E, 200).
tumour growth. The postoperative inflammation or infection could enhance the host immune system and augment the natural defences against the malignant melanoma. Finally, an unknown immunologic response similar to the pathophysiology in skin melanoma which elicits cytotoxic T-lymphocytes (CD8 positive) and natural killer cells (CD 56 positive), which play a leading role in this host-immune response. It has been suggested that natural killer cells are the first cells to play a role in regression of cutaneous melanomas. They in turn may stimulate a subtype of T-helper cells which may then account for the recruitment of cytotoxic T-lymphocytes.10 The same mechanisms may have occurred in our patient. In summary, the exact mechanism of spontaneous regression of malignant melanoma is still unknown. Identification of specific histological features may predict a potential for spontaneous regression. However, this phenomenon is not always synonymous with complete cure from the underlying disease Orbit
Regression of Conjuctival Melanoma but may represent a temporary regression due to host protective mechanisms. In our patient regression and cure were complete. It is possible that identifying the exact mechanisms by which regression occurs could lead to more effective and targeted therapies.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Lim LA, Madigan MC, Conway RM. Conjunctival melanoma: a review of conceptual and treatment advances. Clin Ophthalmol 2013;6:521–531. 2. Kenawy N, Lake SL, Coupland SE, Damato BE. Conjunctival melanoma and melanocytic intra-epithelial neoplasia. Eye 2013;27(2):142–152.
!
2014 Informa Healthcare USA, Inc.
141
3. Paridaens AD, McCartney AC, Minassian DC, Hungerford JL. Orbital exenteration in 95 cases of primary conjunctival malignant melanoma. Br J Ophthalmol 1994;78(7):520–528. 4. Paridaens AD, Minassian DC, McCartney AC, Hungerford JL. Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. Br J Ophthalmol 1994;78(4):252–259. 5. Mudhar HS, Rennie IG. Local conjunctival metastases from primary conjunctival melanoma: clinico-pathological correlation and implications. Br J Ophthalmol 2013;97(1): 33–39. 6. Everson TC, Cole WH. Spontaneous regression of malignant disease. J Amer Med Asso 1959;169(15):1758–1759. 7. Stewart FW. Experiences in spontaneous regression of neoplastic disease in man. TX Repts Biol Med 1952; 10(1):239–253. 8. Kalialis LV, Drzewiecki KT, Klyver H. Spontaneous regression of metastases from melanoma: review of the literature. Melan Res 2009;19(5):275–282. 9. Nathanson L. Spontaneous regression of malignant melanoma: a review of the literature on incidence, clinical features, and possible mechanisms. Natl Cancer Instit Monogr 1976;44:67–76. 10. McKay K, Moore PC, Smoller BR, Hiatt KM. Association between natural killer cells and regression in melanocytic lesions. Human Pathol 2011;42(12):1960–1964.
Copyright of Orbit is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
