Melanoma in a cohort of organ transplant recipients: Experience from a dedicated transplant dermatology clinic in Victoria, Australia

Journal Pre-proof Melanoma in a cohort of organ transplant recipients: Experience from a dedicated transplant dermatology clinic in Victoria, Australia Danit Maor, MBBS, MPH, Claire M. Vajdic, BOptom (Hons I) PhD, Simon Cumming, Vanessa Fahey, MBBS, FRCPA, BMedSci, Harini R. Bala, MBBS, Victoria Snaidr, MBBS FRACGP, Sarah Brennand, MBBS, BSc, FACD, Michelle SY. Goh, MBBS, BMedSci, FACD, Alvin H. Chong, MBBS, M.Med, FACD PII:

S0190-9622(19)33009-9

DOI:

https://doi.org/10.1016/j.jaad.2019.11.009

Reference:

YMJD 13986

To appear in:

Journal of the American Academy of Dermatology

Received Date: 2 October 2018 Revised Date:

15 October 2019

Accepted Date: 3 November 2019

Please cite this article as: Maor D, Vajdic CM, Cumming S, Fahey V, Bala HR, Snaidr V, Brennand S, Goh MS, Chong AH, Melanoma in a cohort of organ transplant recipients: Experience from a dedicated transplant dermatology clinic in Victoria, Australia, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/j.jaad.2019.11.009. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.

Melanoma in organ transplant recipients

Melanoma in a cohort of organ transplant recipients: Experience from a dedicated transplant dermatology clinic in Victoria, Australia Keywords: melanoma; immunosuppression; organ transplant recipients; solid organ transplantation; keratinocyte cancers; multimodal therapy; pigmented cutaneous lesions; transplant dermatology; biopsied pigmented lesions; histopathology; post transplantation

Danit Maor MBBS, MPH1, Claire M. Vajdic BOptom (Hons I) PhD2 , Simon Cumming1, Vanessa Fahey MBBS, FRCPA, BMedSci3, Harini R. Bala MBBS1, Victoria Snaidr MBBS FRACGP1, Sarah Brennand MBBS, BSc, FACD1, Michelle SY Goh MBBS, BMedSci, FACD1,4, Alvin H. Chong MBBS, M.Med, FACD1,4,5 Skin and Cancer Foundation Victoria for Big Data Research in Health, University of New South Wales 3 Melbourne Pathology, Victoria 4 Department of Dermatology, St Vincent’s Hospital Melbourne 5Department of Medicine (Dermatology), St Vincent’s Hospital Clinical School, The University of Melbourne 1

2Centre

Manuscript Word Count (text): 2415 Tables: 2 References: 23

There are no funding sources that have supported our work. There is no publishable conflict of interest. No Human Research Ethics clearance was required.

Corresponding author: A/Professor Alvin Chong E: [email protected] M: (+61) 41 1146 833

1 1

Melanoma in a cohort of organ transplant recipients: Experience from a dedicated

2

transplant dermatology clinic in Victoria, Australia.

3 4

Introduction

5 6

Cutaneous carcinogenesis is an important complication of solid organ transplantation

7

(1). In countries with high UV and a susceptible population, keratinocyte cancers (KC)

8

are the most common post-transplant malignancy in organ transplant recipients (OTR)

9

accounting for 27-37% of all de novo neoplasms (2, 3).

10 11

Melanoma incidence is also increased three-to five-fold compared to the general

12

population (4-6). Furthermore, population based-studies have shown that the

13

prognosis of OTR diagnosed with de-novo invasive melanoma is significantly worse than

14

in the matched immunocompetent population (7, 8).

15 16

We performed a retrospective study of a dedicated Transplant Dermatology Clinic in

17

Victoria, Australia, over a 10-year period. Our findings suggest improved prognosis in

18

our cohort of patients with post-transplant melanomas. We were also able to quantify

19

the benign to malignant ratio of pigmented cutaneous lesions in this cohort.

20 21 22 23 24 25 26 27

2 28

Patients and Methods

29 30

All patients were identified from the database of the dedicated Transplant Dermatology

31

Clinic at the Skin and Cancer Foundation (SCF). Dermatologists with a special interest in

32

transplant medicine run this multidisciplinary clinic with surgical support from

33

dermatological and plastic surgeons.

34 35

Patients are referred to the clinic by transplant physicians, general practitioners and

36

other dermatologists. During their appointment a specialist dermatologist examined

37

each patient using dermoscopy. Suspicious pigmented lesions were excised for

38

histopathological analysis. Lesions which were suspicious for keratinocyte cancers were

39

also biopsied and treated. Patients were given verbal advice on their increased risk of

40

skin cancer and educated on sun-protection measures such as sunscreen, clothing and

41

sun-avoidance. Patients were also advised to present urgently if they had any concerns

42

about a skin lesion, including change in size, shape or colour.

43 44

High-risk patients with multiple KCs are seen every 3-4 months, intermediate risk are

45

seen 6-monthly and low risk patients are reviewed annually. Patients with post-

46

transplant MM (malignant melanoma) were treated and followed up every three months

47

for two years, then every six months thereafter. These intervals are similar to those in

48

clinical guidelines that recommend review and treatment according to individual risk

49

factors (9-13).

50 51

Demographic, clinical and histopathological data are entered prospectively into the SCF

52

database. We reviewed the database and histopathology reports for all consecutive

53

patients under the care of the SCF dedicated Transplant Dermatology clinic between

54

January 1st 2006 and December 31st 2015 (120 months).

3 55 56

Data collected included the age at transplant, age at melanoma diagnosis, the time

57

interval between transplant and melanoma (taken from the first transplant where there

58

were more than one), type and dose of immunosuppressive therapy at melanoma

59

diagnosis and site of occurrence of melanoma. Other relevant data collected included

60

history of other skin malignancies including atypical naevi and previous biopsies

61

performed, skin phototype and history of excessive sun exposure. In addition patients

62

were asked about history of previous melanomas and their family history of both

63

melanoma and non-melanoma skin cancers.

64 65

We also performed an audit of all biopsied pigmented skin lesions in OTRs to determine

66

the ratio of benign to malignant excised pigmented lesions. We extracted age at biopsy,

67

anatomical location of biopsied lesion, histopathological diagnosis and the type of

68

biopsy.

69 70

All histopathological diagnoses were made or confirmed by consultant pathologists with

71

an interest in dermatopathology. All melanoma histology reports were subsequently

72

reviewed by an experienced dermatopathologist (V.F). The characteristics of each

73

melanoma was documented and included the histological subtype, Breslow thickness,

74

Clark level, regression, tumour-infiltrating lymphocyte (TIL), ulceration, mitoses and

75

contiguous nevus. Other information extracted from the database included diagnoses of

76

cutaneous lesions such as keratinocyte cancers, whether there was recurrence of

77

melanoma, whether immunosuppression was changed after the melanoma diagnosis,

78

and the total follow-up period. Short term monitoring had not been used to diagnose

79

any of the melanomas.

80 81

Results

4 82 83

A total of 327 OTRs were included in the study; 285 (87%) renal, 18 (5.5%) heart, eight

84

pancreatic islet cell (2.5%), six lung (1.8%; double or single), five (1.5%) liver, and four

85

(1.2%) pancreas. One patient had a hand transplant.

86 87

There were 212 (65%) men and 115 (35%) women. The mean age at first presentation

88

to the clinic was 50.3 years (±13.5 years). The mean age at first transplantation was 43.0

89

years (±14.8 years). The mean duration of immunosuppression to the end of the study

90

period was 13.9 years (±8.7). The mean number of visits to the clinic was 8.2 (±8.9)

91

(median 12, range 1-43). For those recipients with more than 1 visit (n=275), the mean

92

duration of follow up was 4.7 years (±3.2 years, range 0.1-9.8).

93 94

A total of 11 incident primary melanomas were diagnosed in 10 patients (one patient

95

had two primary melanomas); five were in-situ and six were invasive. The male to

96

female ratio was 8:2 (Table 1). Nine of the 10 patients (90%) were renal transplant

97

recipients and one a heart recipient.

98 99

The melanoma locations were the upper limbs (n=4), the head and neck (n=3), trunk

100

(n=2), and lower limbs (n=2). The mean interval between first transplant and diagnosis

101

of melanoma was 5.5 years (range 0-19 years). The mean duration of follow up after

102

melanoma diagnosis was 7.5 years (range 2.0-9.7 years).

103 104

Other clinical characteristics of the OTRs diagnosed with melanoma such as age at

105

melanoma diagnosis and immunosuppressive treatment at melanoma diagnosis are

106

recorded in Table 1. Fifty percent of those with a melanoma diagnosis had concurrent

107

dysplastic nevi and 92% had a keratinocyte cancer.

108

5 109

Table 1: Clinical characteristics of solid organ transplant recipients diagnosed with

110

melanoma at the SCF Transplant Dermatology Clinic.

111 112

Immunosuppressive treatment varied greatly in the melanoma patients. The doses and

113

combinations varied for each patient in accordance with the clinical practice of the

114

treating physicians.

115 116

After melanoma diagnosis, seven of the ten patients had modifications to their

117

immunosuppression regimen with the advice of both the transplant physician and the

118

treating dermatologist. This included a decrease in dosage, removing one of the drugs

119

from a three-drug regimen or changing a calcineurin inhibitor to an mTOR inhibitor.

120

Four of the 10 patients who were on a calcineurin inhibitor-based three-drug regimen

121

had the calcineurin inhibitor changed to an mTOR inhibitor. Three patients had the dose

122

of calcineurin inhibitor decreased and two patients had the dose of mTOR inhibitor

123

decreased. In three patients the immunosuppression therapy was unchanged.

124 125

Only one patient had been on azathioprine; four patients had oral acitretin as part of

126

chemoprophylaxis of keratinocyte cancers. None of the patients had received other

127

photosensitizing medications such as thiazides or voriconazole.

128 129

The patient who had two primary melanomas had a negative sentinel lymph node

130

biopsy (SLNB) at first diagnosis. She had local adjuvant postoperative radiotherapy to

131

the site of her primary desmoplastic melanoma (1.04mm thick) following wide local

132

excision. This was a decision of the treating melanoma unit as wide margins had been

133

obtained and there was no evidence of perineural invasion. No other patient required

134

chemotherapy or radiotherapy as part of their treatment. For all but one other patient,

6 135

the criteria for SLNB were not met; the one patient, a heart transplant recipient with a

136

3.8mm thick melanoma, declined SLNB.

137 138

Of the 11 melanomas, eight were superficial spreading melanomas (SSM), two were

139

lentigo maligna melanomas (LMM) and 1 was a desmoplastic melanoma (Table 2).

140 141

Six invasive and five in situ melanomas developed during the observation period, a total

142

of 1280 person-years. This corresponds to a crude invasive melanoma incidence of

143

468.8 per 100,000 person-years and a crude invasive and in-situ melanoma incidence of

144

859.4 per 100,000 years. This is approximately 15-fold and 19-fold that of the general

145

population (age-standardised rates of 61.6 and 43.2 per 100,000 patient-years for men

146

and women, respectively)(14).

147 148

Nine of the eleven melanomas were <1mm Breslow thickness. Of the remainder, one

149

was a desmoplastic melanoma and 1.04mm thick; the second was a SSM and 3.8mm

150

thick. Regression was absent in seven of the 11 cases (64%) and present in four. Seven

151

of the melanomas were de novo (64%). A contiguous nevus was present in four cases of

152

which two were dysplastic.

153 154

At the end of the study period, and a mean of 7.5 years follow-up after melanoma

155

diagnosis (range 2-10 years), all melanoma patients were free of disease recurrence. All

156

melanoma patients were followed up through clinical examination. The heart transplant

157

recipient with the 3.8mm thick melanoma had further six monthly ultrasounds of his

158

lymph node basins.

159 160

Table 2: Histopathological characteristics of melanomas arising in solid organ

161

transplant recipients diagnosed in a dedicated transplant clinic.

7 162 163

Benign: Malignant Ratio

164 165

During cohort follow-up, 177 suspicious nevi were biopsied, of which 119 were benign,

166

47 were dysplastic and 11 were confirmed melanomas. Therefore the number needed to

167

excise (NNE) was 16, that is, for every melanoma diagnosed, 16 benign or dysplastic

168

pigmented nevi were biopsied.

8

Table 1: Clinical characteristics of solid organ transplant recipients diagnosed with melanoma at a dedicated transplant dermatology clinic. Patient, Organ Sex Transplanted

Subtype/Breslo w thickness (mm)/Clark Level

Age at melanoma (years)

Years post transplant

Immunosuppressiv Chemoprophy Site of e treatment at laxis melanoma melanoma diagnosis

Other biopsy proven skin lesions prior to melanoma diagnosis

Immunosuppression change at melanoma diagnosis

Follow-up period pre Follow-up melanoma diagnosis period post (months) melanoma diagnosis (months)

1M

Renal

LMM, in situ, 1

63

19

Aza, Cyclo

Acitretin

R forehead

11 BCC, 2 Bowen disease, ≥7 SCC,

Aza dose decreased, Cyclo changed to SRL

111

18

2M

Renal

SSM, in situ, 1

61

4

MMF, Pred, Tacro

Nil

Mid lower back

1 SK, 1 SCC,

Tacro changed to ERL

66

38

3M

Renal

LMM, in situ, 1

52

1

MMF, Pred, Tacro

Nil

R cheek

1 SK, 1 Bowen disease, 2 SCC Unchanged

6

97

4F

Renal

SSM, in situ, 1

35

4

MMF, Pred, SRL

Nil

R neck

1 Dysplastic naevus

Unchanged

23

104

5F

Renal

MM, in situ, 1

47

4

Cyclo, MMF, Pred

Nil

R upper arm

17 dysplastic naevi, 1 SK, 1 BCC, 1 Bowen disease,

Cyclo dose decreased

22

72

5F

Renal

Desmoplastic MM, 46 1.04, 4

3

Cyclo, MMF, Pred

Nil

R upper arm

17 dysplastic naevi, 1 SK, 1 BCC, 1 Bowen disease

Cyclo dose decreased

11

84

6M

Renal

SSM, 0.2, 2

52

10

MMF, Pred, Tacro

Acitretin

R lower leg

1 Dysplastic naevus, ≥3 BCC, 1 SCC

Unchanged

11

78

7M

Renal

SSM, 0.6, 2

68

5

MMF, Pred, SRL

Acitretin

L forehead

1 SK, ≥15 BCC, 1 Bowen disease, ≥7 SCC,

SRL dose decreased

20

72

8M

Renal

SSM, 0.8, 3

56

1

MMF, Pred, Tacro

Nil

L mid back

16

77

9M

Renal

SSM, 0.82, 3

56

7

MMF, Pred, Tacro

Nil

10M

Heart

SSM, 3.8, 4

65

11

MMF, Pred, SRL

Acitretin

3 dysplastic naevi, 1 SK ≥9 Tacro changed to SRL BCC, 1 Bowen disease, ≥6 SCC ≥8 BCC Tacro changed to SRL, pred dose decreased 1 SK, ≥10 BCC, 1 Bowen Pred and SRL dose disease, ≥10 SCC, decreased

R posterior shoulder L upper thigh

17

72

42

48

Aza (Azathioprine), MMF (Mycophenolate mofetil), Pred (Prednisolone), Tacro (Tacrolimus), Cyclo (Cyclosporine), Sirolimus (SRL), Everolimus (ERL), BCC (basal cell carcinoma), SCC (squamous cell carcinoma), Bowen disease = Squamous cell carcinoma in situ, SK (solar keratosis), SSM (superficial spreading melanoma), LMM (lentigo maligna melanoma), MM (malignant melanoma)

9

Table 2: Histopathological characteristics of melanomas arising in solid organ transplant recipients diagnosed in a dedicated transplant dermatology clinic. Patient

Type

1

LMM

In situ or invasive In situ

Thickness (mm) na

2

SSM

In situ

na

3

LMM

In situ

4

SSM

In situ

5

Desmoplastic MM

Invasive

5

MM

6

Clark level

Regression

Nevus or de novo

Ulceration

De novo

Tumour-infiltrating lymphocyte (TIL) na

Absent

Mitotic rate (per mm) na

1

No

1

No

Nevus (intradermal)

Absent

Absent

na

na

1

No

De novo

Absent

Absent

na

na

1

Yes

Nevus (dysplastic)

na

Absent

na

1.04

4

No

Nevus (dysplastic)

Absent

Absent

0

In situ

na

1

No

De novo

na

Absent

0

SSMM

Invasive

0.2

2

Yes

De novo

Absent

Absent

0

7

SSMM

Invasive

0.6

2

No

De novo

Absent

Absent

1

8

SSM

Invasive

0.8

3

Yes

Absent

Absent

0

9

SSM

Invasive

0.82

3

No

Nevus (compound melanocytic) De novo

Absent

Absent

1

10

SSM

Invasive

3.8

4

Yes

De novo

Small numbers present

Absent

6

10 169

Discussion

170 171

Over a ten year period, we diagnosed five in-situ and six invasive melanomas in a cohort

172

of OTR referred to a dedicated Transplant Dermatology Clinic. Of the invasive

173

melanomas, only two had a Breslow thickness greater than 1 mm. After an average 7.5

174

years of follow up from melanoma diagnosis, all patients remained recurrence-free and

175

alive.

176 177

The outcome from our patient group appears more favourable than published data for

178

population-based cohorts of transplant recipients. It has been reported that de novo

179

melanomas that occur post-transplant are associated with greater Breslow thicknesses

180

and worse survival outcomes (2, 15, 16). A population-based study of melanomas in

181

Australian renal transplant recipients found that the mortality rate of de-novo

182

melanomas was 76% over a median of 6.6 years follow-up (8). In our cohort, only two

183

patients had melanoma > 1mm thick.

184 185

We suspect that our diagnosis of thin de-novo post-transplant melanomas and

186

subsequent good prognosis was due to increased vigilance and screening in this cohort.

187

Patients were referred to our service as part of routine skin surveillance, not just when

188

there was a suspicious lesion. Patients were therefore being monitored prior to

189

melanoma diagnosis. Education on skin surveillance and photo protection commences

190

on first visit to our service, which may improve patient self-detection of suspicious

191

changes. On subsequent visits to the Transplant Dermatology Clinic, patients reported

192

improved sun protection compliance as well as performing regular self-skin

193

examinations due to the education provided at the SCF Clinic.

194

A study performed on Victorian renal transplant recipients, which included some

195

patients who attended our clinic, showed that the sun-associated risk behaviour of these

11 196

patients is significantly better than the general population, especially with regard to the

197

use of sunscreens and clothing (17).

198 199

In our cohort the melanomas were more likely to originate on sun exposed anatomical

200

sites (64% on the head and neck, face or upper limbs) unlike other studies that found

201

melanomas occurred most frequently on the trunk of transplant recipients (2, 7, 17).

202

This anatomical distribution is similar to that observed for melanomas occurring in the

203

Australian (Queensland) general population (19).

204 205

Previous papers have reported melanomas in transplant recipients arising in most cases

206

in precursor dysplastic nevi (14, 18). In contrast, in our cohort, only four out of eleven

207

patients (36%) developed melanomas from precursor lesions, similar to that reported

208

by Le Mire et al. (33%) (3).

209 210

In terms of risks, we found that 10 of 11 (90.1%) patients who developed melanoma had

211

a prior diagnosis of keratinocyte cancer. In addition, five patients (45%) had also had

212

prior dysplastic naevi histologically diagnosed.

213 214

Hence, we recommend that all OTRs are evaluated and followed-up according to their

215

individual risk factors. Patients with dysplastic nevi should be followed up at least

216

annually (14) particularly looking out for new nevi. Serial dermoscopy can improve the

217

preoperative diagnostic accuracy of cutaneous melanoma and has a role in the

218

monitoring of some naevi (18). In addition to improved sensitivity, serial dermoscopy is

219

shown to reduce unnecessary excisions of benign nevi. The comparison of dermascopic

220

images helps detect subtle changes that may indicate cutaneous melanoma (19). When

221

available, reflectance confocal microscopy (RCM) could also play a role in detecting

222

melanomas in this patient cohort as it can detect malignant features in clinically and

12 223

dermoscopically subtle questionable lesions and can improve the benign:malignant

224

biopsy ratio. (20). However, such microscopes are not widely available so there may be

225

access issues for some patients. Patients should be educated on signs of melanoma,

226

especially new nevi and taught how to perform self-checks with the help of family

227

members.

228 229

In our cohort of transplant patients, for every one melanoma diagnosed, 16 pigmented

230

nevi were biopsied. There is no prior data on the NNE for pigmented lesions in a

231

transplant cohort. The NNE of pigmented lesions in the immunocompetent dermatology

232

population is about 5:1. In our clinical experience some of the melanomas appearing in

233

transplant recipients are clinical and dermoscopically bland. Given that this is a high –

234

risk group, we opted for excision of any concerning pigmented lesion ahead of short-

235

term follow up with serial photography. This explains our elevated benign to malignant

236

ratio. However, this approach may be justified due to the poorer prognosis of de-novo

237

transplant melanomas in Australia (3, 7, 8, 11).

238 239

Where a primary invasive melanoma has been detected in an OTR, reduction of

240

immunosuppression and / or switching from calcineurin inhibitor to mTOR inhibitor is

241

thought to be a reasonable and effective adjuvant treatment strategy to surgical excision

242

according to expert consensus (21). All but one of our patients with invasive melanoma

243

had their immunosuppression reduced or calcineurin inhibitor replaced with mTOR

244

inhibitors. In the case of multidrug regimens, the agent discontinued was tacrolimus in

245

three out of ten patients.

246 247

There is currently a scarcity of reliable data to guide the clinical management of

248

melanomas in transplant recipients.

249

13 250

A strength of this study is that all skin cancers were histopathologically proven. In

251

addition, the patients’ full medical records were available; therefore we had complete

252

capture of clinical and histopathological information. Study limitations include crude

253

incidence rates, which are not age standardised, unlike the comparison rates of

254

melanoma in the general population. The cohort is small, but representative of a high-

255

risk subset.

256

Conclusion

257 258

Our data indicate that increased surveillance and expert dermatological management of

259

OTR in a dedicated Transplant Dermatology Clinic may result in earlier diagnosis of

260

melanomas and reduce the proportion of OTRs presenting with thick melanomas. It may

261

also improve patient outcomes, although we acknowledge our cohort is small and a good

262

survival profile is anticipated for the 5 patients with in-situ melanomas.

263 264

Due to the increased risk of multiple types of skin cancers in transplant recipients,

265

suspicious pigmented lesions should be excised promptly and unnecessary ultraviolet

266

radiation exposure minimised. Close monitoring following transplantation is warranted,

267

particularly for patients with risk factors for melanoma. In addition, primary prevention

268

through adopting sun-protective behaviour and regular medical surveillance for all

269

patients undergoing organ transplantation is paramount.

270 271 272 273 274 275 276

14 277 278

15 References:

279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324

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Capsule Summary: • •

Improved prognosis of post-transplant melanomas may be due to early diagnosis due to screening of organ transplant recipients in a dedicated transplant dermatology clinic. The benign to malignant ratio of pigmented lesions in our cohort was 16:1.