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Pigmented Squamous Cell Carcinoma In Situ of the Conjunctiva in 5 Cases
Pigmented Squamous Cell Carcinoma In Situ of the Conjunctiva in 5 Cases Carol L. Shields, MD, Ajay Manchandia, MD, Rajeeve Subbiah, MD, Ralph C. Eagle, Jr, MD, Jerry A. Shields, MD Purpose: To describe 5 patients with pigmented conjunctival squamous cell carcinoma in situ. Design: Retrospective noncomparative case series. Participants: Five patients. Methods: Clinical and histopathologic features were reviewed. Main Outcome Measures: Relationship of clinical and histopathologic features to carcinoma pigmentation. Results: All 5 patients were male. Two were Hispanic, 2 were Caucasian, and 1 was Asian Indian. Localized racial melanosis was evident in 3 cases and no case showed diffuse racial melanosis. The tumor showed leukoplakia (n ⫽ 1) and was at the temporal limbus (n ⫽ 4) or nasal limbus (n ⫽ 1). The mean tumor basal dimension was 9.2 mm and mean thickness was 3.2 mm. Brown pigment was present deep within the tumor in all 5 cases, involving 50% to 90% of the mass. In each case, pigmented squamous cell carcinoma was suspected; melanoma was a second possibility. Histopathology revealed in situ squamous cell carcinoma (conjunctival intraepithelial neoplasia) with pigmented dendritic melanocytes in all 5 cases. Pigment was also found within neoplastic cells (n ⫽ 2). After surgical resection, there was no recurrence over mean follow-up of 23 months. Conclusions: Squamous cell carcinoma in situ can manifest as a pigmented tumor, resembling melanoma, in both Caucasians and non-Caucasians, primarily due to intratumoral pigmented dendritic melanocytes. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008;115:1673–1678 © 2008 by the American Academy of Ophthalmology.
Squamous cell carcinoma is among the more common malignancies of the conjunctiva.1–5 In an analysis of 1643 conjunctival tumors, squamous cell carcinoma (in situ and invasive) represented 11% of all tumors and was diagnosed at a median age of 69 years, generally in Caucasians (90%) and in males (81%).1 This malignancy classically manifests as a gelatinous, nonpigmented, yellow-pink conjunctival mass with prominent feeder vessels and intrinsic papillary vascular pattern. Some of the major considerations in the differential diagnosis include pingueculum, pterygium, papilloma, and conjunctival melanoma. Conjunctival melanoma is a more dangerous malignancy with a higher rate of metastasis of 26% by 10 years6 compared with squamous cell carcinoma metastasis of ⬍1%.1 The clinical differentiation of these 2 malignancies is based on several features, but the presence of pigment is a strong indicator of melanoma.1,2,5 Despite this accepted dictum, we describe herein 5 patients who displayed prominent intrinsic brown pigment within squamous cell carcinoma.
Case Reports (Table 1) Case 1 A 27-year-old Hispanic man developed a limbal mass with a papillary configuration and feeder vessels. Approximately 75% of the tumor displayed brown pigmentation (Fig 1A, B) There was no conjunctival racial melanosis. After resection, histopathology revealed in situ squamous cell carcinoma of the conjunctiva with © 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
parakeratosis and focal papillomatous configuration. Pigmented dendritic melanocytes were observed within the tumor.
Case 2 A 44-year-old Hispanic man developed a limbal mass with a nonpapillary configuration and prominent feeder vessels (Fig 1C, D) Approximately 50% of the tumor displayed brown pigment and fine dusted intraepithelial melanosis was noted along the inferior tumor margin (Fig 1). After complete resection, histopathology confirmed in situ squamous cell carcinoma of the conjunctiva with parakeratosis, and reactive inflammation. Pigmented dendritic melanocytes were observed within the epithelial tumor.
Case 3 A 69-year-old Italian-American man (previously reported)7 developed a pigmented, papillomatous vascular conjunctival mass with feeder vessels. Approximately 85% of the tumor displayed brown intrinsic pigment (Fig 1E, F). There was no local or diffuse conjunctival racial melanosis. After resection, histopathology confirmed in situ squamous cell carcinoma with papillomatous configuration. Pigmented dendritic melanocytes were observed superficially within the epithelial tumor.
Case 4 A 78-year-old Italian-American man (previously reported)8 developed a limbal vascular mass with prominent feeder vessels. Approximately 90% of the tumor displayed brown intrinsic pigmentation and fine dusted intraepithelial melanosis was noted along the ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.01.020
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Ophthalmology Volume 115, Number 10, October 2008 Table 1. Clinical and Histopathologic Features of 5 Cases of Clinical Features
Case
Age/Race/ Gender
1
Leukoplakia
Racial Melanosis at Tumor Site
Racial Melanosis Elsewhere on Conjunctiva
3
No
No
No
11
2
Yes
Yes
No
Temp
6
3
No
No
No
Limbus
Temp
7
4
No
Yes
No
Limbus
Temp
12
4
No
Yes
No
Immunosuppression
Tumor Location
Tumor Quadrant
Tumor Base
Tumor Thickness
27/H/M
No
Limbus
Nasal
10
2
44/H/M
HIV
Limbus
Temp
3
69/C/M
No
Limbus
4
78/C/M
No
5
54/I/M
No
Follow-up (mos) No recur (4) No recur (15) No recur (5) No recur (76) No recur (13)
C ⫽ Caucasian; H ⫽ Hispanic; HIV ⫽ human immunodeficiency virus; I ⫽ Indian; M ⫽ male; recur ⫽ recurrence; temp ⫽ temporal.
inferior tumor margin (Fig 1G, H). After resection, histopathology confirmed in situ squamous cell carcinoma, with some neoplastic cells showing intracytoplasmic pigment granules. In addition, pigmented dendritic melanocytes were scattered within the epithelial tumor.
Case 5 A 54-year-old Asian Indian man developed a limbal vascular mass with prominent feeder vessels. Approximately 70% of the tumor displayed brown intrinsic pigmentation and intraepithelial melanosis was noted surrounding the tumor (Fig 1I, J). A vascular papillomatous nodule extended from the tumor onto the cornea. After resection, histopathology confirmed in situ squamous cell carcinoma, with scattered pigmented dendritic melanocytes and some neoplastic cells with fine intracytoplasmic pigment granules. The dendritic cells stained positive for melan A (cytoplasmic melanocytic stain) and microphthalmia transcription factor nuclear melanocytic stain, suggesting that the cells were of melanocytic origin (Fig 2). Additionally, there were small, round, nondendritic cells with cytoplasmic pigment within the tumor that simulated epithelial cells or small macrophages morphologically, but positive staining with melan A and microphthalmia transcription factor suggested that the cells were of melanocytic and not epithelial origin. A deep stromal nevus was found underlying the carcinoma.
Discussion Classic squamous cell carcinoma (in situ and invasive) of the conjunctiva appears as a nonpigmented epibulbar mass typically at the nasal or temporal corneoscleral limbus.2–5 Rare variants include mucoepidermoid, spindle cell, and pigmented carcinoma. Pigmented squamous cell carcinoma has been found mostly in patients with darkly pigmented complexion. Noyes9 is credited with the first published case of pigmented squamous cell carcinoma of the conjunctiva in 1879, in which he described a 48-year-old man of “dark complexion” who was found histopathologically to have a “melanotic epithelioma.” In that report, there were no illustrations of the tumor or the histopathology. Previous publications of pigmented squamous cell carcinoma of the conjunctiva have been single case reports.7–14
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It is believed that this tumor occurs more often in patients of African descent.10,11,13 In 1967, Templeton10 reviewed 312 tumors of the eye and adnexa in Uganda, Africa, over a 5-year period and found 54 cases of conjunctival squamous cell carcinoma. Without providing specific details, the author commented that this tumor was “usually gray but sometimes black,” affecting males in 80% of cases and at an average age of 48 years. Histopathologically, Templeton observed that “melanocytic hyperplasia was sometimes seen deep to the tumor.” In the United States, pigmented squamous cell carcinoma of the conjunctiva is rare. In our experience with 305 consecutive eyes with conjunctival squamous cell carcinoma on the Ocular Oncology Service at Wills Eye Institute, only 5 cases (1.6%) of pigmented squamous cell carcinoma have been found and are reported herein (Shields CL, Manchandia A, Subbiah R, et al. Conjunctival squamous cell carcinoma in 305 consecutive cases. Presented in part at the American Academy of Ophthalmology, New Orleans, November 2007). In our 5 cases, the patient race was Hispanic (2 cases), Asian Indian (1 case), and Caucasian (2 cases). The histopathology and electron microscopy of a pigmented squamous cell carcinoma of the conjunctiva in a 47 year-old black man was evaluated by Jauregui and Klintworth.11 Using Masson–Fontana stain, they found that melanin granules were present in the neoplastic squamous cells, Langerhans cells, macrophages, and stellate cells (dendritic melanocytes). Using transmission electron microscopy, they commented that mature melanosomes were present in the squamous cells within membrane-bound vesicles, vacuoles, or free within the cytoplasm. The melanosomes in the Langerhans cells were within lysosomal-like vesicles and those in the macrophages and the stellate cells were within vesicles. Premelanosomes were not observed in any cells. It was speculated that the neoplastic squamous cells, Langerhans cells, and macrophages acquired the melanin granules through phagocytosis of the tips of the melanosome-packed dendrites of melanocytes and/or by digestion of free melanin granules. A later report on transmission electron microscopy in a 57-year-old black man with pigmented squamous cell carcinoma disclosed melanosomes within squamous
Shields et al 䡠 Pigmented Squamous Cell Carcinoma In Situ Pigmented Squamous Cell Carcinoma of the Conjunctiva Histopathologic Features Squamous Cell Carcinoma In Situ
Pigment in Dendritic Melanocytes (Fellow Travelers)
Pigment in Neoplastic Cells
Racial Melanosis at Tumor Site
Yes
Yes
No
No
No
Yes
Yes
No
Yes
No
Yes
Yes
No
No
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
neoplastic cells, macrophages, and dendritic melanocytes.12 Unlike the previous report,11 premelanosomes were identified within the dendritic melanocytes and macrophages.12 The dendritic melanocytes were labeled “fellow travelers” because they were apparently nonneoplastic, innocent cells within the tumor.12 In all of our 5 cases, the tumor was a thick mass at the corneoscleral limbus, classified as in situ squamous cell carcinoma. Pigmented conjunctival squamous cell carcinoma, like the nonpigmented counterpart, has a tendency to occur at the corneoscleral limbus.7–14 All 5 patients showed brown pigment deep within the mass and 3 had clinically evident localized racial melanosis at the site of the tumor. There were no patients with diffuse racial or primary acquired melanosis elsewhere on the conjunctiva. The brown tumor pigment was clinically visible throughout 50% to 90% of the neoplasm, but none appeared “black.” Perhaps the adjacent localized melanosis was coincidently involved with the neoplasm and proliferated as a response to the tumor or possibly the pigmentation developed from a combination of factors including darker skin complexion, a response to ultraviolet light at the limbus, and a response to the localized tissue trauma induced by the in situ carcinoma. It is recognized that solar ultraviolet irradiation promotes increased pigmentation within cutaneous wounds.15 Furthermore, animal and human studies have shown that laser-damaged skin exposed to solar ultraviolet irradiation induced localized cutaneous hyperpigmentation and the degree of pigmentation was greater in individuals with darker constitutive skin color, but was found even in albinos.16 In our series, histopathology revealed melanin pigment predominantly within pigmented dendritic melanocytes in all 5 cases. Fine intracytoplasmic pigment was noted within neoplastic epithelial cells in 2 cases. There were small, round, nondendritic cells with cytoplasmic pigment within the tumor that simulated epithelial cells or small macrophages morphologically, but positive staining with melan A (cytoplasmic melanocytic stain) and microphthalmia transcription factor nuclear melanocytic stain suggested that the cells were of melanocytic and not epithelial origin (Fig 2).
Nevus at Tumor Site
In case 5, a deep stromal nevus was noted underlying the malignancy. Cutaneous tumors such as squamous cell carcinoma, basal cell carcinoma, seborrheic keratosis, and sweat gland tumors can manifest pigmentation and simulate cutaneous melanoma. In these cases, dendritic melanocytes, melanincontaining neoplastic cells, and pigmented-laden macrophages are found within the tumor.17–22 In an analysis of 46 791 archived cases of cutaneous squamous cell carcinoma, only 5 (0.01%) were pigmented.20 All 5 tumors grew rapidly. A matched group of 31 clinically nonpigmented tumors showed no histopathologic evidence of unsuspected intratumoral melanocytes, even when stained for S-100 and HMB-45. Most studies on pigmented cutaneous squamous cell carcinoma indicate that the long-term prognosis is similar to conventional nonpigmented squamous cell carcinoma.20 Pigmented cutaneous squamous cell carcinoma has been reported as single case reports at various sites including the thigh, forehead, external auditory canal, breast,uterine cervix, and scrotum.19,21,23–26 In 2000, Matsumoto et al19 commented that only 13 cases of pigmented squamous cell carcinoma had been reported in the English-language literature, mostly in the oral mucosa or conjunctiva. Within the mouth, pigmented squamous cell carcinoma has been recognized on the lower lip and alveolar ridge.27,28 Pigmented melanocytes in cutaneous squamous cell carcinoma have been postulated to arise from either a divergent matrix stem cell17 or, more likely, serendipitously; melanocytes randomly populate the tissue that leads to squamous cell carcinoma.20 Some authors have speculated that the pigmentation might be acquired from a surrounding pigmented lesion.19,29 Matsumoto et al19 described a pigmented squamous cell carcinoma of the scrotum that had adjacent lentigo and they conjectured that melanocytes from the lentigo might have been activated during enlargement of the squamous neoplasia, resulting in melanocytic colonization of the tumor. Jurado et al29 described a case of cutaneous pigmented squamous cell carcinoma of the forehead associated with an adjacent melanocytic nevus and pigmented solar keratosis. In our series, 3 cases had visible
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Figure 1. Clinical appearance and histopathology findings of 5 cases of pigmented squamous cell carcinoma in situ of the conjunctiva. A, B, Case 1. C, D, Case 2. E, F, Case 3. G, H, Case 4. I, J, Case 5. Note the intratumoral dendritic melanocytes dispersed among the neoplastic cells (B, D, F, H, J).
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Shields et al 䡠 Pigmented Squamous Cell Carcinoma In Situ
Figure 2. Case 5: Immunohistochemical staining 5 revealing pigmented dendritic cells with positive staining for melan A (A; cytoplasmic stain for melanocytes) and microphthalmia transcription factor (MITF; B), a nuclear stain for melanocytes, indicating cells of melanocytic origin. Small, round cells showed similar positive staining for Melan A (C) and MITF (D), indicating cells of melanocytic origin.
racial melanosis immediately adjacent to the tumor, and resected30 with the tumor, but no case showed diffuse racial or primary acquired melanosis. Case 5 manifested a deep stromal nevus adjacent to the malignancy.
References 1. Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643 melanocytic and nonmelanocytic tumors of the conjunctiva. Ophthalmology 2004;111:1747–54. 2. Shields CA, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol 2004;49:3–24. 3. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39:429 –50. 4. Cha SB, Shields JA, Shields CL, Wang MX. Squamous cell carcinoma of the conjunctiva. Int Ophthalmol Clin 1993;33: 19 –24. 5. Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors. An Atlas and Textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008:283–305.
6. Shields CL, Shields JA, Gunduz K, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol 2000;118:1497–507. 7. Shields JA, Shields CL, Luminais S, Eagle RC Jr. Differentiation of pigmented conjunctival squamous cell carcinoma from melanoma. Ophthalmic Surg Lasers Imaging 2003;34:406 – 8. 8. Shields JA, Shields CL, Eagle RC Jr, et al. Pigmented conjunctival squamous cell carcinoma simulating a conjunctival melanoma. Am J Ophthalmol 2001;132:104 – 6. 9. Noyes HD. Report of a case of melanotic epithelioma upon the front of the eye: extirpation of the tumor and preservation of the globe and of sight. Arch Ophthalmol 1879;8:145– 63. 10. Templeton AC. Tumors of the eye and adnexa in Africans of Uganda. Cancer 1967;20:1689 –98. 11. Jauregui HO, Klintworth GK. Pigmented squamous cell carcinoma of cornea and conjunctiva: a light microscopic, histochemical, and ultrastructural study. Cancer 1976;38:778 – 88. 12. Salisbury JA, Szpak CA, Klintworth GK. Pigmented squamous cell carcinoma of the conjunctiva: a clinicopathologic ultrastructural study. Ophthalmology 1983;90:1477– 81.
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Ophthalmology Volume 115, Number 10, October 2008 13. Adefule AO, Mordi VP. Squamous cell carcinoma of the limbal conjunctiva with corneal involvement and racial melanosis in a Nigerian woman [letter]. Am J Ophthalmol 1983; 96:106 –7. 14. Kremer I, Sandbank J, Weinberger D, et al. Pigmented epithelial tumours of the conjunctiva. Br J Ophthalmol 1992;76:294 – 6. 15. Due E, Rossen K, Sorensen LT, et al. Effect of UV irradiation on cutaneous cicatrices: a randomized, controlled trial with clinical, skin reflectance, histological, immunohistochemical and biochemical evaluations. Acta Derm Venereol 2007;87: 27–32. 16. Haedersdal M. Cutaneous side effects from laser treatment of the skin: skin cancer, scars, wounds, pigmentary changes, and purpura— use of pulsed dye laser, copper vapor laser, and argon laser. Acta Derm Venereol Suppl (Stockh) 1999;207: 1–32. 17. Kossard S, Cook D. Pigmented squamous cell carcinoma with dendritic melanocytes. Australas J Dermatol 1997;38:145–7. 18. Jurado I, Saez A, Luelmo J, et al. Pigmented squamous cell carcinoma of the skin: report of two cases and review of the literature. Am J Dermatopathol 1998;20:578 – 81. 19. Matsumoto M, Sonobe H, Takeuchi T, et al. Pigmented squamous cell carcinoma of the scrotum associated with a lentigo. Br J Dermatol 1999;141:132– 6. 20. Morgan MB, Lima-Maribona J, Miller RA, et al. Pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases. J Cutan Pathol 2000;27: 381– 6.
21. Chapman MS, Quitadamo MJ, Perry AE. Pigmented squamous cell carcinoma. J Cutan Pathol 2000;27:93–5. 22. Saxena A, Kasper DA, Campanelli CD, et al. Pigmented Bowen’s disease clinically mimicking melanoma of the nail. Dermatol Surg 2006;32:1522–5. 23. Stante M, de Giorgi V, Massi D, et al. Pigmented Bowen’s disease mimicking cutaneous melanoma: clinical and dermoscopic aspects. Dermatol Surg 2004;30:541– 4. 24. Kamiya M, Maehara R, Iizuka S, et al. Pigmented squamous cell carcinoma with dendritic melanocyte colonization in the external auditory canal. Pathol Int 1999;49:909 –12. 25. Pizzichetta MA, Canzonieri V, Massarut S, et al. Pigmented mammary Paget’s disease mimicking melanoma. Melanoma Res 2004;14:S13–5. 26. Masuzawa N, Kishimoto M, Takahashi Y. Pigmented squamous cell carcinoma of the uterine cervix. Int J Gynecol Pathol 2003;22:285– 8. 27. Biediger TL, Grabski WJ, McCollough ML. Bilateral pigmented Bowen’s disease of the lower lip. Int J Dermatol 1995;34:116 – 8. 28. Kuwabara H, Uda H, Miyaguchi M, et al. Pigmented squamous cell carcinoma of the alveolar ridge in the oral mucosa. Oral Surg Oral Med Oral Pathol 1994;77:61–5. 29. Jurado I, Saez A, Luelmo J, et al. Pigmented squamous cell carcinoma of the skin: report of two cases and review of the literature. Am J Dermatopathol 1998;20:578 – 81. 30. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997;115:808 –15.
Footnotes and Financial Disclosures Originally received: November 6, 2007. Final revision: January 15, 2008. Accepted: January 16, 2008. Available online: April 18, 2008.
Manuscript no. 2007-1443.
From the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Dr Carol Shields has had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Financial Disclosure(s): The authors have no conflict of interests relative to the article. Support provided by the Retina Research Foundation of the Retina Society,
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Cape Town, South Africa (CLS); the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS); a donation from Michael, Bruce, and Ellen Ratner, New York, New York (JAS, CLS); Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (CLS); the LuEsther Mertz Retina Research Foundation, New York, New York (CLS); and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS). Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: carol.shields@ shieldsoncology.com.
Squamous cell carcinoma is among the more common malignancies of the conjunctiva.1–5 In an analysis of 1643 conjunctival tumors, squamous cell carcinoma (in situ and invasive) represented 11% of all tumors and was diagnosed at a median age of 69 years, generally in Caucasians (90%) and in males (81%).1 This malignancy classically manifests as a gelatinous, nonpigmented, yellow-pink conjunctival mass with prominent feeder vessels and intrinsic papillary vascular pattern. Some of the major considerations in the differential diagnosis include pingueculum, pterygium, papilloma, and conjunctival melanoma. Conjunctival melanoma is a more dangerous malignancy with a higher rate of metastasis of 26% by 10 years6 compared with squamous cell carcinoma metastasis of ⬍1%.1 The clinical differentiation of these 2 malignancies is based on several features, but the presence of pigment is a strong indicator of melanoma.1,2,5 Despite this accepted dictum, we describe herein 5 patients who displayed prominent intrinsic brown pigment within squamous cell carcinoma.
Case Reports (Table 1) Case 1 A 27-year-old Hispanic man developed a limbal mass with a papillary configuration and feeder vessels. Approximately 75% of the tumor displayed brown pigmentation (Fig 1A, B) There was no conjunctival racial melanosis. After resection, histopathology revealed in situ squamous cell carcinoma of the conjunctiva with © 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
parakeratosis and focal papillomatous configuration. Pigmented dendritic melanocytes were observed within the tumor.
Case 2 A 44-year-old Hispanic man developed a limbal mass with a nonpapillary configuration and prominent feeder vessels (Fig 1C, D) Approximately 50% of the tumor displayed brown pigment and fine dusted intraepithelial melanosis was noted along the inferior tumor margin (Fig 1). After complete resection, histopathology confirmed in situ squamous cell carcinoma of the conjunctiva with parakeratosis, and reactive inflammation. Pigmented dendritic melanocytes were observed within the epithelial tumor.
Case 3 A 69-year-old Italian-American man (previously reported)7 developed a pigmented, papillomatous vascular conjunctival mass with feeder vessels. Approximately 85% of the tumor displayed brown intrinsic pigment (Fig 1E, F). There was no local or diffuse conjunctival racial melanosis. After resection, histopathology confirmed in situ squamous cell carcinoma with papillomatous configuration. Pigmented dendritic melanocytes were observed superficially within the epithelial tumor.
Case 4 A 78-year-old Italian-American man (previously reported)8 developed a limbal vascular mass with prominent feeder vessels. Approximately 90% of the tumor displayed brown intrinsic pigmentation and fine dusted intraepithelial melanosis was noted along the ISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.01.020
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Ophthalmology Volume 115, Number 10, October 2008 Table 1. Clinical and Histopathologic Features of 5 Cases of Clinical Features
Case
Age/Race/ Gender
1
Leukoplakia
Racial Melanosis at Tumor Site
Racial Melanosis Elsewhere on Conjunctiva
3
No
No
No
11
2
Yes
Yes
No
Temp
6
3
No
No
No
Limbus
Temp
7
4
No
Yes
No
Limbus
Temp
12
4
No
Yes
No
Immunosuppression
Tumor Location
Tumor Quadrant
Tumor Base
Tumor Thickness
27/H/M
No
Limbus
Nasal
10
2
44/H/M
HIV
Limbus
Temp
3
69/C/M
No
Limbus
4
78/C/M
No
5
54/I/M
No
Follow-up (mos) No recur (4) No recur (15) No recur (5) No recur (76) No recur (13)
C ⫽ Caucasian; H ⫽ Hispanic; HIV ⫽ human immunodeficiency virus; I ⫽ Indian; M ⫽ male; recur ⫽ recurrence; temp ⫽ temporal.
inferior tumor margin (Fig 1G, H). After resection, histopathology confirmed in situ squamous cell carcinoma, with some neoplastic cells showing intracytoplasmic pigment granules. In addition, pigmented dendritic melanocytes were scattered within the epithelial tumor.
Case 5 A 54-year-old Asian Indian man developed a limbal vascular mass with prominent feeder vessels. Approximately 70% of the tumor displayed brown intrinsic pigmentation and intraepithelial melanosis was noted surrounding the tumor (Fig 1I, J). A vascular papillomatous nodule extended from the tumor onto the cornea. After resection, histopathology confirmed in situ squamous cell carcinoma, with scattered pigmented dendritic melanocytes and some neoplastic cells with fine intracytoplasmic pigment granules. The dendritic cells stained positive for melan A (cytoplasmic melanocytic stain) and microphthalmia transcription factor nuclear melanocytic stain, suggesting that the cells were of melanocytic origin (Fig 2). Additionally, there were small, round, nondendritic cells with cytoplasmic pigment within the tumor that simulated epithelial cells or small macrophages morphologically, but positive staining with melan A and microphthalmia transcription factor suggested that the cells were of melanocytic and not epithelial origin. A deep stromal nevus was found underlying the carcinoma.
Discussion Classic squamous cell carcinoma (in situ and invasive) of the conjunctiva appears as a nonpigmented epibulbar mass typically at the nasal or temporal corneoscleral limbus.2–5 Rare variants include mucoepidermoid, spindle cell, and pigmented carcinoma. Pigmented squamous cell carcinoma has been found mostly in patients with darkly pigmented complexion. Noyes9 is credited with the first published case of pigmented squamous cell carcinoma of the conjunctiva in 1879, in which he described a 48-year-old man of “dark complexion” who was found histopathologically to have a “melanotic epithelioma.” In that report, there were no illustrations of the tumor or the histopathology. Previous publications of pigmented squamous cell carcinoma of the conjunctiva have been single case reports.7–14
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It is believed that this tumor occurs more often in patients of African descent.10,11,13 In 1967, Templeton10 reviewed 312 tumors of the eye and adnexa in Uganda, Africa, over a 5-year period and found 54 cases of conjunctival squamous cell carcinoma. Without providing specific details, the author commented that this tumor was “usually gray but sometimes black,” affecting males in 80% of cases and at an average age of 48 years. Histopathologically, Templeton observed that “melanocytic hyperplasia was sometimes seen deep to the tumor.” In the United States, pigmented squamous cell carcinoma of the conjunctiva is rare. In our experience with 305 consecutive eyes with conjunctival squamous cell carcinoma on the Ocular Oncology Service at Wills Eye Institute, only 5 cases (1.6%) of pigmented squamous cell carcinoma have been found and are reported herein (Shields CL, Manchandia A, Subbiah R, et al. Conjunctival squamous cell carcinoma in 305 consecutive cases. Presented in part at the American Academy of Ophthalmology, New Orleans, November 2007). In our 5 cases, the patient race was Hispanic (2 cases), Asian Indian (1 case), and Caucasian (2 cases). The histopathology and electron microscopy of a pigmented squamous cell carcinoma of the conjunctiva in a 47 year-old black man was evaluated by Jauregui and Klintworth.11 Using Masson–Fontana stain, they found that melanin granules were present in the neoplastic squamous cells, Langerhans cells, macrophages, and stellate cells (dendritic melanocytes). Using transmission electron microscopy, they commented that mature melanosomes were present in the squamous cells within membrane-bound vesicles, vacuoles, or free within the cytoplasm. The melanosomes in the Langerhans cells were within lysosomal-like vesicles and those in the macrophages and the stellate cells were within vesicles. Premelanosomes were not observed in any cells. It was speculated that the neoplastic squamous cells, Langerhans cells, and macrophages acquired the melanin granules through phagocytosis of the tips of the melanosome-packed dendrites of melanocytes and/or by digestion of free melanin granules. A later report on transmission electron microscopy in a 57-year-old black man with pigmented squamous cell carcinoma disclosed melanosomes within squamous
Shields et al 䡠 Pigmented Squamous Cell Carcinoma In Situ Pigmented Squamous Cell Carcinoma of the Conjunctiva Histopathologic Features Squamous Cell Carcinoma In Situ
Pigment in Dendritic Melanocytes (Fellow Travelers)
Pigment in Neoplastic Cells
Racial Melanosis at Tumor Site
Yes
Yes
No
No
No
Yes
Yes
No
Yes
No
Yes
Yes
No
No
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
neoplastic cells, macrophages, and dendritic melanocytes.12 Unlike the previous report,11 premelanosomes were identified within the dendritic melanocytes and macrophages.12 The dendritic melanocytes were labeled “fellow travelers” because they were apparently nonneoplastic, innocent cells within the tumor.12 In all of our 5 cases, the tumor was a thick mass at the corneoscleral limbus, classified as in situ squamous cell carcinoma. Pigmented conjunctival squamous cell carcinoma, like the nonpigmented counterpart, has a tendency to occur at the corneoscleral limbus.7–14 All 5 patients showed brown pigment deep within the mass and 3 had clinically evident localized racial melanosis at the site of the tumor. There were no patients with diffuse racial or primary acquired melanosis elsewhere on the conjunctiva. The brown tumor pigment was clinically visible throughout 50% to 90% of the neoplasm, but none appeared “black.” Perhaps the adjacent localized melanosis was coincidently involved with the neoplasm and proliferated as a response to the tumor or possibly the pigmentation developed from a combination of factors including darker skin complexion, a response to ultraviolet light at the limbus, and a response to the localized tissue trauma induced by the in situ carcinoma. It is recognized that solar ultraviolet irradiation promotes increased pigmentation within cutaneous wounds.15 Furthermore, animal and human studies have shown that laser-damaged skin exposed to solar ultraviolet irradiation induced localized cutaneous hyperpigmentation and the degree of pigmentation was greater in individuals with darker constitutive skin color, but was found even in albinos.16 In our series, histopathology revealed melanin pigment predominantly within pigmented dendritic melanocytes in all 5 cases. Fine intracytoplasmic pigment was noted within neoplastic epithelial cells in 2 cases. There were small, round, nondendritic cells with cytoplasmic pigment within the tumor that simulated epithelial cells or small macrophages morphologically, but positive staining with melan A (cytoplasmic melanocytic stain) and microphthalmia transcription factor nuclear melanocytic stain suggested that the cells were of melanocytic and not epithelial origin (Fig 2).
Nevus at Tumor Site
In case 5, a deep stromal nevus was noted underlying the malignancy. Cutaneous tumors such as squamous cell carcinoma, basal cell carcinoma, seborrheic keratosis, and sweat gland tumors can manifest pigmentation and simulate cutaneous melanoma. In these cases, dendritic melanocytes, melanincontaining neoplastic cells, and pigmented-laden macrophages are found within the tumor.17–22 In an analysis of 46 791 archived cases of cutaneous squamous cell carcinoma, only 5 (0.01%) were pigmented.20 All 5 tumors grew rapidly. A matched group of 31 clinically nonpigmented tumors showed no histopathologic evidence of unsuspected intratumoral melanocytes, even when stained for S-100 and HMB-45. Most studies on pigmented cutaneous squamous cell carcinoma indicate that the long-term prognosis is similar to conventional nonpigmented squamous cell carcinoma.20 Pigmented cutaneous squamous cell carcinoma has been reported as single case reports at various sites including the thigh, forehead, external auditory canal, breast,uterine cervix, and scrotum.19,21,23–26 In 2000, Matsumoto et al19 commented that only 13 cases of pigmented squamous cell carcinoma had been reported in the English-language literature, mostly in the oral mucosa or conjunctiva. Within the mouth, pigmented squamous cell carcinoma has been recognized on the lower lip and alveolar ridge.27,28 Pigmented melanocytes in cutaneous squamous cell carcinoma have been postulated to arise from either a divergent matrix stem cell17 or, more likely, serendipitously; melanocytes randomly populate the tissue that leads to squamous cell carcinoma.20 Some authors have speculated that the pigmentation might be acquired from a surrounding pigmented lesion.19,29 Matsumoto et al19 described a pigmented squamous cell carcinoma of the scrotum that had adjacent lentigo and they conjectured that melanocytes from the lentigo might have been activated during enlargement of the squamous neoplasia, resulting in melanocytic colonization of the tumor. Jurado et al29 described a case of cutaneous pigmented squamous cell carcinoma of the forehead associated with an adjacent melanocytic nevus and pigmented solar keratosis. In our series, 3 cases had visible
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Figure 1. Clinical appearance and histopathology findings of 5 cases of pigmented squamous cell carcinoma in situ of the conjunctiva. A, B, Case 1. C, D, Case 2. E, F, Case 3. G, H, Case 4. I, J, Case 5. Note the intratumoral dendritic melanocytes dispersed among the neoplastic cells (B, D, F, H, J).
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Figure 2. Case 5: Immunohistochemical staining 5 revealing pigmented dendritic cells with positive staining for melan A (A; cytoplasmic stain for melanocytes) and microphthalmia transcription factor (MITF; B), a nuclear stain for melanocytes, indicating cells of melanocytic origin. Small, round cells showed similar positive staining for Melan A (C) and MITF (D), indicating cells of melanocytic origin.
racial melanosis immediately adjacent to the tumor, and resected30 with the tumor, but no case showed diffuse racial or primary acquired melanosis. Case 5 manifested a deep stromal nevus adjacent to the malignancy.
References 1. Shields CL, Demirci H, Karatza E, Shields JA. Clinical survey of 1643 melanocytic and nonmelanocytic tumors of the conjunctiva. Ophthalmology 2004;111:1747–54. 2. Shields CA, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol 2004;49:3–24. 3. Lee GA, Hirst LW. Ocular surface squamous neoplasia. Surv Ophthalmol 1995;39:429 –50. 4. Cha SB, Shields JA, Shields CL, Wang MX. Squamous cell carcinoma of the conjunctiva. Int Ophthalmol Clin 1993;33: 19 –24. 5. Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors. An Atlas and Textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2008:283–305.
6. Shields CL, Shields JA, Gunduz K, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol 2000;118:1497–507. 7. Shields JA, Shields CL, Luminais S, Eagle RC Jr. Differentiation of pigmented conjunctival squamous cell carcinoma from melanoma. Ophthalmic Surg Lasers Imaging 2003;34:406 – 8. 8. Shields JA, Shields CL, Eagle RC Jr, et al. Pigmented conjunctival squamous cell carcinoma simulating a conjunctival melanoma. Am J Ophthalmol 2001;132:104 – 6. 9. Noyes HD. Report of a case of melanotic epithelioma upon the front of the eye: extirpation of the tumor and preservation of the globe and of sight. Arch Ophthalmol 1879;8:145– 63. 10. Templeton AC. Tumors of the eye and adnexa in Africans of Uganda. Cancer 1967;20:1689 –98. 11. Jauregui HO, Klintworth GK. Pigmented squamous cell carcinoma of cornea and conjunctiva: a light microscopic, histochemical, and ultrastructural study. Cancer 1976;38:778 – 88. 12. Salisbury JA, Szpak CA, Klintworth GK. Pigmented squamous cell carcinoma of the conjunctiva: a clinicopathologic ultrastructural study. Ophthalmology 1983;90:1477– 81.
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Ophthalmology Volume 115, Number 10, October 2008 13. Adefule AO, Mordi VP. Squamous cell carcinoma of the limbal conjunctiva with corneal involvement and racial melanosis in a Nigerian woman [letter]. Am J Ophthalmol 1983; 96:106 –7. 14. Kremer I, Sandbank J, Weinberger D, et al. Pigmented epithelial tumours of the conjunctiva. Br J Ophthalmol 1992;76:294 – 6. 15. Due E, Rossen K, Sorensen LT, et al. Effect of UV irradiation on cutaneous cicatrices: a randomized, controlled trial with clinical, skin reflectance, histological, immunohistochemical and biochemical evaluations. Acta Derm Venereol 2007;87: 27–32. 16. Haedersdal M. Cutaneous side effects from laser treatment of the skin: skin cancer, scars, wounds, pigmentary changes, and purpura— use of pulsed dye laser, copper vapor laser, and argon laser. Acta Derm Venereol Suppl (Stockh) 1999;207: 1–32. 17. Kossard S, Cook D. Pigmented squamous cell carcinoma with dendritic melanocytes. Australas J Dermatol 1997;38:145–7. 18. Jurado I, Saez A, Luelmo J, et al. Pigmented squamous cell carcinoma of the skin: report of two cases and review of the literature. Am J Dermatopathol 1998;20:578 – 81. 19. Matsumoto M, Sonobe H, Takeuchi T, et al. Pigmented squamous cell carcinoma of the scrotum associated with a lentigo. Br J Dermatol 1999;141:132– 6. 20. Morgan MB, Lima-Maribona J, Miller RA, et al. Pigmented squamous cell carcinoma of the skin: morphologic and immunohistochemical study of five cases. J Cutan Pathol 2000;27: 381– 6.
21. Chapman MS, Quitadamo MJ, Perry AE. Pigmented squamous cell carcinoma. J Cutan Pathol 2000;27:93–5. 22. Saxena A, Kasper DA, Campanelli CD, et al. Pigmented Bowen’s disease clinically mimicking melanoma of the nail. Dermatol Surg 2006;32:1522–5. 23. Stante M, de Giorgi V, Massi D, et al. Pigmented Bowen’s disease mimicking cutaneous melanoma: clinical and dermoscopic aspects. Dermatol Surg 2004;30:541– 4. 24. Kamiya M, Maehara R, Iizuka S, et al. Pigmented squamous cell carcinoma with dendritic melanocyte colonization in the external auditory canal. Pathol Int 1999;49:909 –12. 25. Pizzichetta MA, Canzonieri V, Massarut S, et al. Pigmented mammary Paget’s disease mimicking melanoma. Melanoma Res 2004;14:S13–5. 26. Masuzawa N, Kishimoto M, Takahashi Y. Pigmented squamous cell carcinoma of the uterine cervix. Int J Gynecol Pathol 2003;22:285– 8. 27. Biediger TL, Grabski WJ, McCollough ML. Bilateral pigmented Bowen’s disease of the lower lip. Int J Dermatol 1995;34:116 – 8. 28. Kuwabara H, Uda H, Miyaguchi M, et al. Pigmented squamous cell carcinoma of the alveolar ridge in the oral mucosa. Oral Surg Oral Med Oral Pathol 1994;77:61–5. 29. Jurado I, Saez A, Luelmo J, et al. Pigmented squamous cell carcinoma of the skin: report of two cases and review of the literature. Am J Dermatopathol 1998;20:578 – 81. 30. Shields JA, Shields CL, De Potter P. Surgical management of conjunctival tumors. The 1994 Lynn B. McMahan Lecture. Arch Ophthalmol 1997;115:808 –15.
Footnotes and Financial Disclosures Originally received: November 6, 2007. Final revision: January 15, 2008. Accepted: January 16, 2008. Available online: April 18, 2008.
Manuscript no. 2007-1443.
From the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Dr Carol Shields has had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. Financial Disclosure(s): The authors have no conflict of interests relative to the article. Support provided by the Retina Research Foundation of the Retina Society,
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Cape Town, South Africa (CLS); the Paul Kayser International Award of Merit in Retina Research, Houston, Texas (JAS); a donation from Michael, Bruce, and Ellen Ratner, New York, New York (JAS, CLS); Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania (CLS); the LuEsther Mertz Retina Research Foundation, New York, New York (CLS); and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS, JAS). Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: carol.shields@ shieldsoncology.com.