Topical mitomycin chemotherapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: 12 years’ experience

Clinical Investigation

Abstract

Purpose

To report 12-year follow-up experience with topical mitomycin chemotherapy for diffuse and multifocal primary acquired melanosis (PAM) with atypia and conjunctival melanoma.

Methods

Interventional case series of 16 patients. Mitomycin was a primary treatment for residual epithelial disease in ten patients (eight with PAM with atypia and two with conjunctival melanoma) and as an adjuvant to excision and cryotherapy in six with conjunctival malignant melanoma. Primary treatments consisted of mitomycin 0.04% qid for 28 days (two 14-day cycles) and for 7 consecutive days as adjuvant therapy. Patients were followed for both local recurrence and metastatic disease.

Results

Sixteen patients were followed for a mean 81 months (range 13–144 months) after treatment. All tumors responded to chemotherapy. Recurrence was noted in eight (three adjuvant and five primary treatment patients). Three underwent orbital exenteration. The remaining five were treated conservatively. The mean time to recurrence was 36.9 months. The short-term mitomycin-related complications included transient keratoconjunctivitis (n=14), severe keratoconjunctivitis (n=1) and one corneal abrasion with scar formation. The long-term complications included pannus (n=2) and corneal haze (n=1). Visual acuity was maintained within two lines in 14 patients (including measurements just prior to exenteration). Three patients died, one of metastatic conjunctival melanoma.

Conclusions

Conjunctival melanoma and PAM responded to mitomycin 0.04% topical chemotherapy; subepithelial nests appeared resistant to treatment. Treatment-related complications were acceptable. In this series, as primary and adjuvant therapy, topical mitomycin yielded an overall recurrence rate of 50%.

Introduction

Malignant melanoma of the conjunctiva is a rare tumor whose incidence has been increasing [35]. Conjunctival melanomas can arise from primary acquired melanosis (PAM) with atypia, from malignant transformation of a conjunctival nevus or de novo [16, 30]. These tumors can be nodular, diffuse or multifocal.

The treatment plan depends on the size, thickness, location and histopathologic features of the tumor [3, 9, 12, 18, 20, 23, 30, 33]. Local recurrences have been found to occur with all conservative eye- and vision-sparing treatments. Typically, when the pigmented margin is used to define the extent of resection, the tumor’s edges may not be completely excised [4]. This explains the current interest in and widespread use of adjuvant therapies (e.g., cryotherapy and topical chemotherapy) [8, 15]. Loss of local control leads to multifocal disease that carries a greater risk for metastatic disease and death [30].

Mitomycin is an alkylating agent and binds to DNA during any phase of the cell cycle, leading to irreversible cross-linking and inhibition of DNA synthesis and function. Adjunctive mitomycin has been used both intraoperatively and postoperatively to prevent pterygium recurrence and to prevent scarring associated with glaucoma filtration surgery [6, 21, 34]. It has also been used to treat squamous conjunctival neoplasia, sebaceous gland carcinoma with conjunctival epithelial invasion, recurrent conjunctival papilloma and ocular pemphigoid [7, 11, 22, 32, 35, 38].

In 1992, Finger et al. first used topical mitomycin 0.04% to induce regression of conjunctival melanoma and PAM with atypia [3, 9]. No permanent ocular toxicity was noted. This 12-year study presents the follow-up of 16 patients treated with topical mitomycin chemotherapy for diffuse, multifocal PAM with atypia and conjunctival melanoma.

Methods

This study was an interventional case series where 16 consecutive patients with multifocal PAM and/or conjunctival malignant melanoma were treated with 0.04% topical mitomycin (Table 1).
Table 1

Patient demographics and treatment results

Pt

Age

Sex

Diffuse

Multifocal

Nodular

Histopathology

TNM

Duration of treatment

Response

Local control

Side effects

Cyro/symbl

Metastases

Death

Vision

Follow up (months)

Recurrence (months)

Treatment after recurrence

Partial

Complete

Short term

Long term

Pretreatment

Recent

Adjuvant chemotherapy group

1

71

F

No

Yes

Yes

Conjuctival MM

T4NOMO

7 days

Adjuvant

Adjuvant

Noa

KC

None

No

No

No

20

25

107

72

Excision & Cryotherapy

2

45

F

Yes

No

Yes

Conjuctival MM

T4NOMO

7 days

Adjuvant

Adjuvant

Yes

KC

None

No

No

No

20

16

118

None

 

3

77

M

No

No

No

Conjuctival MM

T1NOMO

7 days

Adjuvant

Adjuvant

Yes

KC

None(cataract)b

No

No

No

25

25

114

None

 

4

41

M

No

No

Yes

Conjuctival MM

T2NOMO

7 days

Adjuvant

Adjuvant

Noa

KC

None

No

No

No

25

25

119

44

Excision & Cryotherapy

5

77

F

No

Yes

Yes

Conjuctival MM

T4NOMO

7 days

Adjuvant

Adjuvant

Noa

KC

None

Yes

No

Yes-MI

50

Prosthesis

100

12

Exenteration

6

70

F

Yes

No

No

Conjuctival MM

T2NOMO

7 days

Adjuvant

Adjuvant

Yes

Corneal Abrasion

Corneal Scar

No

No

No

20

63

13

None

 

Primary chemotherapy group

Conjuctival MM

7

63

F

No

Yes

Yes

Conjuctival MM

T2NOMO

14 days due to allergy

Yes

No

Noa

KC

None

No

No

No

20

Prosthesis

78

30

Exenteration

8

51

F

Yes

Yes

Yes

Conjuctival MM

T3NOMO

28 days

Yes

No

Noa

KC

None

No

Yes

Yes

25

Prosthesis

144

17

Exenteration

PAM with atypia

9

77

M

Yes

Yes

No

PAM with atypia

T2NOMO

28 days

No

Yes

Yes

KC

Pannus

No

No

No

20

20

130

None

 

10

82

F

Yes

Yes

No

PAM with atypia

T1NOMO

14 days due to KC

No

Yes

Noa

KC-severe

None

No

No

No

20

32

69

54

Excision & Cryotherapy

11

61

M

Yes

Yes

No

PAM with atypia

T4NOMO

28 days

No

Yes

Noa

KC

pannus

No

No

No

20

100

94

43

Excision & Cryotherapy

12

55

M

Yes

No

No

PAM with atypia

T4NOMO

28 days

No

Yes

Yes

KC

None

No

No

No

20

20

34

None

 

13

72

F

No

No

No

PAM with atypia

T2NOMO

28 days

No

Yes

Yes

KC

Corneal haze

No

No

Yes-CLL

30

30

31

None

 

14

75

F

Yes

Yes

No

PAM with atypia

T3NOMO

28 days

Yes

No

Yes

KC

None(cataract)b

No

No

No

32

25

26

None

 

15

75

F

No

Yes

No

PAM with atypia

T3NOMO

28 days

No

Yes

Yes

KC

None

No

No

No

20

30

72

None

 

16

68

F

No

Yes

No

PAM with atypia

T2NOMO

28 days

Yes

No

Noa

KC

None

No

No

No

32

40

44

23

Excision & Cryotherapy

                  

Mean

81

36.9

 

TNM=AJCC classification at diagnosis

KC=keratoconjunctivitis

symbl=symblepharon

MI=myocardial infarction

CLL=chronic lymphocytic leukemia

anot attributed to mitomycin

bsubconjunctival/orbital recurrence

Internal review board and pharmacy committee approvals at the New York Eye and Ear Infirmary were obtained for the purpose of investigating topical mitomycin chemotherapy for the treatment of conjunctival and corneal surface neoplasia. This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

Sixteen patients (11 women and 5 men) with biopsy-proven conjunctival melanoma (eight patients) and PAM with atypia (eight patients) were treated with 0.04% mitomycin (Bristol Laboratories, Princeton, NJ) after they had given informed consent. The mean age of these patients was 66 years (range 41–82 years). The mean duration of follow-up was 81 months (range 13–144 months). Topical mitomycin was used as the primary and only treatment in eight patients with PAM with atypia and in two patients with conjunctival malignant melanoma and as an adjuvant to excision and cryotherapy in six patients with conjunctival melanoma. The tumors were staged according to the AJCC classification for conjunctival melanomas, and regression was defined as reduction in the size of the tumor or of the area of pigmentation on clinical examination and on comparison with the pretreatment clinical photographs. It was not possible to document the size of most of the tumors due to their diffuse and multifocal nature.

Mitomycin as primary treatment

Ten patients received topical mitomycin 0.04% therapy as primary and only treatment for a period of 28 days. Treatment was started 2 weeks after biopsy. Eight patients had the histopathological diagnosis of PAM with atypia and two patients had conjunctival malignant melanoma. Six of the eight patients with PAM with atypia had recurrent disease and previously failed treatments (with excision and cryotherapy) and the other two patients had diffuse multifocal disease.

Of the two patients with conjunctival malignant melanoma, one had invasive melanoma with subepithelial infiltration (patient 8). The other patient with conjunctival melanoma had a clinical recurrence with extensive corneal extension (patient 7).

Treatment involved instilling one drop into the superior conjunctival fornix four times a day for 14 days, discontinuing treatment for 14 days and then restarting for a second 14-day course of treatment. The patients and their families were advised to wear latex gloves when handling the medication, and the bottles were returned for disposal.

Mitomycin as adjuvant therapy

Six patients received mitomycin 0.04% as an adjuvant treatment to excision and cryotherapy for the presence of residual disease. All six patients had a histopathological diagnosis of conjunctival malignant melanoma. Mitomycin drops were instilled four times daily for a period of 7 days starting 2 weeks after their primary surgical treatment (to enable wound healing and prevent scleral contact and melt). Excision and cryotherapy was done by the same surgeon (P.T.F.). The technique involved the excision of all pigmented tumors with 2- to 3-mm ‘tumor-free’ margins. If the tumor extended onto the cornea, the affected corneal epithelium plus 2 mm of surrounding normal corneal epithelium was excised. The subjacent corneal tissues were scrubbed with absolute alcohol and then quickly and copiously irrigated [5, 14, 23, 31]. Superficial cryotherapy was applied to the exposed corneal and episcleral tissues within the bed of excision with a double freeze–thaw technique. Additional cryotherapy was applied to enlarge the conjunctival margins after appositional repair.

Patients were followed periodically and evaluated for local recurrence and metastases. Ophthalmic examinations were carried out at intervals of 3–4 months. These included best-corrected EDTRS (COMS type) visual acuity determinations, followed by careful inspection of all conjunctival surfaces and eyelid margins. Palpation of the adnexal structures, pre-auricular and cervical lymph nodes was performed. Slit-lamp biomicroscopy, applanation tonometry, and indirect ophthalmoscopy were also performed. Systemic evaluation for metastatic disease and mitomycin-induced anemia was obtained every 6 months.

Results

Tumor response

Initial regression of the tumor (decrease in size of the tumor or areas of pigmentation documented by clinical examination and photographs) was observed in all 16 patients after treatment (Figs. 1 and 2). Nodular and subepithelial nests of melanoma appeared resistant to topical mitomycin. Over time, five of the ten patients in the primary treatment group (2/2 with conjunctival melanoma and 3/8 with PAM with atypia) and three of six patients in the adjuvant treatment group developed local recurrence at a mean of 36.9 months (range 12–72 months). Three underwent orbital exenteration (one patient with conjunctival melanoma in the adjuvant treatment group and two with conjunctival melanoma in the primary treatment group) and the remaining five were treated with eye-conserving therapy (Table 1).
Fig. 1

Patient 2. a Color photograph of the left eye showing a nodular malignant melanoma inferonasally before treatment. b, c The patient had adjuvant mitomycin C therapy and the tumor had completely regressed with no recurrences by a 9-year follow-up

Fig. 2

Patient 9. a Color photograph of the right eye showing diffuse PAM with atypia present inferiorly. b, c Ten-year follow-up photographs after topical mitomycin therapy showing regression of the tumor with patchy epithelial pigment dusting that had been stable over time

One patient (no. 8) with nodular melanoma in the primary treatment group did not respond to the 28-day mitomycin treatment and had excision and cryotherapy for residual disease; she developed recurrence 17 months later and the eye was exenterated. This patient developed metastatic melanoma 42 months after topical mitomycin therapy and 22 months after orbital exenteration. She died from metastatic malignant melanoma. This patient was the first to be treated with topical mitomycin in our study (12 years ago), and after this we were reluctant to use mitomycin as primary treatment in other patients with melanoma nodules.

The other patient with invasive conjunctival malignant melanoma (patient 7) in the primary treatment group had undergone multiple surgeries in the past and did not wish further surgical intervention. She was treated with mitomycin as primary treatment as she had a clinical recurrence with extensive corneal epithelial extension. She developed an allergic reaction to the mitomycin drops, however, and the treatment was discontinued after 14 days. She underwent further excision and cryotherapy 3 months later. This patient developed a recurrence 30 months after topical mitomycin and underwent exenteration. Her most recent metastatic survey was negative at a follow-up of 27 months.

The remaining three patients in the primary treatment group who developed a recurrence had PAM with atypia and were treated conservatively with additional excision and cryotherapy. One of these patients had a history of lid margin involvement and lid resection prior to topical mitomycin therapy. None of these patients have had further recurrences or metastatic disease.

All three patients in the adjuvant therapy group who developed recurrence started with nodular primary tumors. One patient had recurrences at 12 and 36 months. Excision and cryotherapy was performed, but an orbital recurrence developed 5 years later and the patient underwent orbital exenteration. This patient did not develop metastastic disease but died of a myocardial infarction 8 years after the topical mitomycin therapy. The other two patients developed recurrences at 44 and 72 months and were treated with excision and cryotherapy. They have had no further recurrences or evidence of metastatic disease.

Toxic effects

Two patients in the primary treatment group (one conjunctival melanoma and one PAM with atypia) discontinued treatment after 14 days due to severe keratoconjunctivitis and one of them had an allergic reaction to mitomycin. All 16 patients developed transient keratoconjunctivitis after treatment with mitomycin. This took 4–6 weeks to resolve in the primary treatment group. The severity and duration of symptoms in the adjuvant group was milder, perhaps because of the shorter duration of mitomycin treatment. Fourteen of 16 patients (88%) preserved their visual acuity within two lines of their pretreatment vision. This included best-corrected visual acuity measurements prior to exenteration. Cataracts occurred in two patients but could not be attributed to treatment as they developed gradually 2–3 years after topical mitomycin therapy. Intumescent cataract after topical mitomycin for conjunctival melanoma has been reported [27].

Among the 10 patients treated for 28 days, one patient developed a corneal pannus and lost seven lines of vision. No scleral or corneal thinning was seen. Nine of 10 patients treated with topical mitomycin for 28 days maintained their visual acuity within two lines of their pretreatment vision.

In the adjuvant treatment group, postoperative chemotherapy did not prevent wound closure or cause wound dehiscence. One patient developed a corneal abrasion that was thought to be due to dropper tip injury. This led to the development of a central corneal scar and a loss of five lines of vision. One patient developed a corneal pannus and another was noted to have a symblepharon after treatment (attributed to cryotherapy). No scleral toxicity (scleral melt) was noted. Five of six patients maintained their visual acuity within two lines of their pretreatment vision.

Discussion

Excision and cryotherapy is used widely as treatment for conjunctival melanoma and PAM with atypia. This approach provides excellent local control for most solitary, well-circumscribed tumors. Recurrences are typically associated with incomplete excision, corneal involvement and multifocal disease [2, 20, 23, 24, 32].

Frucht-Pery and Pe’er used topical mitomycin C in a patient with primary acquired melanosis with atypia [11]. The tumor regressed and no recurrence was noted at 7 months follow-up. No adverse reaction except mild conjunctival hyperemia was noted. Another report described the dramatic regression of advanced, aggressive PAM with topical mitomycin treatment in a 73-year-old patient [33]. In 2003, Rodriguez-Ares et al. treated two patients, one with PAM with atypia and one with conjunctival melanoma, with topical mitomycin (administered with sponges) [25]. The size and pigmentation of the tumors reduced and atypical melanocytes were found to be absent on histologic studies after treatment. In the patient with PAM with atypia, additional cryotherapy was required. In the patient with conjunctival melanoma, only TMC was used. No recurrence was noted at a follow-up of 3 years in both patients. Conjunctival hyperemia, keratitis and blepharospasm were noted that resolved after stopping mitomycin.

In our study, with respect to local control, conjunctival melanoma and PAM with atypia clearly responded initially to topical 0.04% mitomycin therapy (Figs. 1 and 2). However, nodular and subepithelial nests of melanoma appeared to be resistant to treatment. Our overall recurrence rate was 50% (n=8) at up to 12 years’ follow-up (mean 81 months, range 13–144 months) and 62.5% (n=5) of these patients had nodular disease. Seven of ten (70%) patients with multifocal disease developed a recurrence. The recurrence rate in patients with conjunctival melanoma treated with mitomycin as primary treatment was 100% (2/2); in conjunctival melanoma treated with mitomycin as adjuvant therapy, 50% (3/6); and in PAM with atypia treated with mitomycin as primary treatment, 37.5% (3/8). This compares with a recurrence rate of 60% after simple excision with 9.9 years mean follow-up [17], with 40% (PAM with atypia) and 90% (multifocal melanoma) after excision and cryotherapy at 3.3 years mean follow-up [10], and with 46% (PAM with atypia) and 47% (conjunctival melanoma) at 11.2 years mean follow-up after excision and radiation therapy [20].

We also noted that recurrence typically originated in the deeper layers of the substantia propria and orbital tissues. This finding was consistent with the clinical experience that topical mitomycin was most effective for superficial or intraepithelial disease. Multifocal and nodular disease was associated with a higher recurrence rate. The small number of patients in the study precluded calculation of the statistical significance of this association. In addition, tumor resistance to topical mitomycin may be due to the inhibition of intracellular bioreduction of mitomycin required for its activation by polymorphisms (inherited or occur as a result of new mutations) in the NADP (H): quinone oxidoreductase 1 enzyme [29].

The use of topical mitomycin on the eye has been reported to produce tear film disturbances, corneal edema, corneal perforation, scleral melting, punctal canalicular stenosis and cataract formation [1, 5, 7, 14, 34]. In contrast, no severe ocular toxicity (such as scleral or corneal melting as seen in the treatment of pterygia and in glaucoma surgery) was noted in our patients [10, 13, 25]. It is our impression that an intact conjunctival and corneal surface provides a protective barrier against mitomycin penetrating into the deeper tissues and causing severe toxicity. Two patients developed pannus and we attribute this to limbal stem cell deficiency following extensive surgical treatment in the past. The treatments described in this study induced no severe ocular toxicity that would prevent their use in patients with PAM with atypia (diffuse, superficial, intraepithelial disease) and conjunctival melanoma.

This study suggests that topical mitomycin offers a method to treat the entire conjunctival surface with less dependence on the determination of tumor margins; it treats the ‘conjunctiva at risk’ for the presence of occult disease. Topical mitomycin has been used as a primary treatment for intra-epithelial disease, as an adjuvant after excision and cryotherapy in patients with conjunctival melanoma and as an alternative for patients who do not consent to or are unable to have surgery. Most importantly, topical mitomycin has been associated with acceptable ocular toxicity, particularly in comparison with the alternative treatments.

We suggest that topical mitomycin should be considered as an alternative primary treatment in PAM with atypia (particularly in cases of diffuse, superficial or intraepithelial disease) and as an adjuvant therapy for nodular disease. Topical mitomycin therapy is not recommended as primary treatment for patients with nodular melanoma. In our experience, multifocal and nodular tumors had a higher incidence of recurrence.

Lastly, it is important to note that this study has investigated only one strength (0.04%) and two durations of treatment (28 and 7 days). We have not (as yet) injected mitomycin beneath the conjunctiva as Donnenfeld et al. have done for ocular pemphigoid [7]. Further research to evaluate different cycles and methods of treatment (or alternative chemotherapeutic agents) would be reasonable.

Notes

Acknowledgements

This work is supported by The EyeCare Foundation, Inc., and Research to Prevent Blindness, New York City, NY, USA.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  1. 1.The New York Eye Cancer CenterNew YorkUSA
  2. 2.The New York Eye and Ear InfirmaryNew YorkUSA
  3. 3.New York University School of MedicineNew YorkUSA

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