BJD

British Journal of Dermatology

E P ID EMIOL O GY AN D HE AL TH S ER VI CE S R ESEA RCH

Clinical and histological features of head and neck melanoma: a population-based study in France F. Dabouz,1 C. Barbe,2 C. Lesage,1 A. Le Clainche,2 G. Arnoult,3 E. Hibon,4 P. Bernard1 and F. Grange1 1

Service de Dermatologie, Hoˆpital Robert Debre and 2Unite d’Aide Methodologique, CHU de Reims, Reims, France Centre de Recherche et d’Investigation Clinique, Hoˆpital Maison Blanche, CHU de Reims, Reims, France 4 Laboratoire de Pathologie, Centre de Regroupement Informatique des Statistiques Anatomo-pathologiques de Champagne, Reims, France 3

Summary Correspondence Florent Grange. E-mail: [email protected]

Accepted for publication 14 October 2014

Funding sources This study was supported, in part, by grants from the Societe Francßaise de Dermatologie and Ligue Contre le Cancer.

Conflicts of interest None declared. DOI 10.1111/bjd.13489

Background Head and neck melanomas (HNMs) account for an increasing proportion of melanomas and have a poor prognosis. Objectives To compare the clinical and histological characteristics of HNMs with those of melanomas at other sites (MOS), and to identify pertinent clinicopathological subgroups of HNM. Methods A retrospective population-based study of incident in situ and invasive melanomas in the period 2004–2011 was performed. Results HNMs represented 26
7% of 1548 melanomas, corresponding to a density ratio of 3
7 between HNMs and MOS. HNMs occurred later than MOS (71
2 vs. 58
4 years; P < 0
01), included a higher proportion of in situ cases (49
6% vs. 13
5%; P < 0
01) and were mainly lentigo malignant melanomas (73
0% vs. 2
6%; P < 0
01). Invasive HNMs included a higher proportion of thick (> 2 mm) tumours [33
7% vs. 24
1% (P = 0
01); mean Breslow thickness: 2
18 vs. 1
77 mm (P = 0
03)] and nodular melanomas (20
1% vs. 12%; P < 0
01). HNMs in the peripheral area of the head and neck differed from those of central location by a younger age of onset (65
2 vs. 72
4 years; P < 0
01), male predominance (64
4% vs. 33
8%; P < 0
01), and higher proportions of invasive (67
2% vs. 42%; P < 0
01) and nodular (15
1% vs. 7
5%; P = 0
01) melanomas. Conclusions HNMs highly differ from MOS, and are clinically and histologically heterogeneous, possibly as a consequence of different patterns of sun exposure. These data could help to improve primary and secondary prevention messages for patients and doctors.

What’s already known about this topic?

• •

Head and neck melanomas (HNMs) are frequent, occur in elderly people and have a poor prognosis. Population-based data on HNMs remain limited, and few studies have included a comprehensive comparison with melanomas at other sites (MOS).

What does this study add?

• • •

© 2014 British Association of Dermatologists

In this population-based French study, HNMs differed from MOS by age of occurrence, histological type and a higher proportion of in situ cases, contrasting with a higher proportion of thick tumours. HNMs located in the peripheral and central areas of the head and neck had different clinical and histological features. Different patterns of sun exposure could explain these differences. Specific prevention messages targeting HNMs should be developed.

British Journal of Dermatology (2015) 172, pp707–715

707

708 Characteristics of head and neck melanoma in France, F. Dabouz et al.

The worldwide incidence of cutaneous melanoma has been increasing in Western populations for the last 30 years, with some estimates showing a doubling in the number of cases over the last two decades.1–4 Among all melanomas, head and neck melanomas (HNMs) deserve special consideration for several reasons. Firstly, they are more frequent than expected with regard to the surface of this anatomical area, with an estimated frequency of 12–26% of cutaneous melanomas concentrated in 9% of the whole body surface.5–12 Secondly, they occur in older people, and their incidence could increase considerably with the widespread increase in life expectancy in developed countries. Finally, several studies have demonstrated that HNMs have a worse prognosis than melanomas at other sites (MOS),5,10,13,14 and the question of whether HNMs could be a distinct entity has been debated.15–17 In any case, a better understanding of specific characteristics of HNM could help to improve their prevention and management. To date, population-based studies on HNM remain limited, and few have included a comprehensive comparison of HNMs and MOS. This prompted us to perform a population-based study including a comparison of HNM and MOS, and a comprehensive analysis of clinical and histological characteristics of HNM as a whole and according to more precise locations.

Material and methods Population and inclusion criteria The study was approved by the institutional review board of Reims University Hospital, Reims, France. It was based on the population (1 338 500 inhabitants) of Champagne-Ardenne, a north-eastern region of France. All incident in situ and invasive cases of cutaneous melanoma diagnosed between January 2004 and December 2011 in residents of Champagne-Ardenne were eligible for the study. Cases without information on anatomical location were excluded. The regional melanoma registry (OMECHA) was used to identify cases. This registry relies on the systematic transmission of pathology reports by all private and hospital pathology laboratories in the region, as well as those in neighbouring parts of the surrounding regions that are liable to diagnose cutaneous melanoma in residents of Champagne-Ardenne, as previously reported.17 Data collection For all patients, the following data were collected: sex, date of birth, administrative departement of residence, date of histological diagnosis, invasion (in situ vs. invasive melanomas), histological type [superficial spreading melanoma (SSM), nodular melanoma (NM), lentiginous malignant melanoma (LMM), acrolentiginous melanoma and unclassifiable melanoma], Breslow thickness, ulceration and anatomical location. Anatomical location included upper limb, lower limb, trunk, hand and foot (gathered in the MOS group) and head and neck (i.e. the HNM group). For HNM, the precise sublocation was collected using (i) a review of all pathological reports; (ii) a review of medical British Journal of Dermatology (2015) 172, pp707–715

records for patients followed at the regional university hospital (i.e. Reims University Hospital); (iii) and, for other patients, questionnaires sent to referent dermatologists and/or general practitioners and surgeons. Anatomical sublocations systematically registered for HNM were scalp, forehead, temple, ear, eyelid, nose, cheek, area around the mouth/chin and neck. Finally, the head and neck location was divided into two areas as previously described:12 a peripheral area including the scalp, forehead, temples, and ears and neck, and a central area including eyelids, nose, cheeks and area around mouth/chin (Fig. 1). Melanoma densities were calculated dividing the number of melanoma cases by the corresponding surface area according to the Wallace rule (9% for head and neck and 91% for other sites). Ratios of melanoma densities were then calculated between HNM and MOS in the entire study group and according to main histological characteristics (Table 1). Statistical analysis Quantitative variables were described as mean  SD, and qualitative data as n (%). Comparisons between HNMs and MOS, on the one hand, and between HNM of the peripheral and the central area, on the other, were performed using the Student’s t-test, the Wilcoxon rank test, the v2 test or Fisher’s exact test, as appropriate. A P-value < 0
05 was considered to be statistically significant. All analyses were performed using SAS version 9.3 (SAS Inc., Cary, NC, U.S.A.).

Results Distribution of melanomas according to location Some 1557 incident melanomas were eligible for the study. Nine cases were excluded because the information on anatomical location of the tumour was missing; 1548 cases constituted the study group. Among them, 414 (26
7%) were located on the head and neck area (HNMs) and 1134 (73
3%) were located at other sites (MOS). MOS included 353 melanomas of the upper limb (31
0%), 239 of the lower limb (21
0%), 420 of the trunk (37
0%), 22 of the hand (2
0%) and 100 of the foot (9
0%). The distribution of HNM according to precise sublocations is shown in Figure 1. Overall, 254 (62
5%) were located on the central area and 152 (37
5%) were located on the peripheral area, while the precise sublocation was unknown for eight cases. Comparison of head and neck melanomas and melanomas at other sites Melanoma density was 3
7-fold higher in the head and neck area than in the rest of the body (Table 1). Compared with MOS, HNMs occurred in older patients, had different histological subtypes and included a higher proportion of in situ melanomas, but also a higher proportion of thick (> 2 mm) tumours (Tables 1 and 2). Overall, patients with HNMs were 12
8 years older than those with MOS (mean age 71
2 vs. 58
4 years; P < 0
01). © 2014 British Association of Dermatologists

Characteristics of head and neck melanoma in France, F. Dabouz et al. 709

5

4 2

7

7 8

6

1

9

3

Peripheral area: 152 (37·4%) 1 Ears: 52 (12·8%) 2 Temples: 37 (9·1%) 3 Neck: 28 (6·9%) 4 Forehead: 20 (94·9%) 5 Scalp: 15 (93·7%) Fig 1. Distribution of head and neck melanomas according to precise sublocation.

Precise sublocation was unknown in eight cases (0·1%)

This difference increased to 17
0 years in the group of in situ melanomas (72
0 vs. 55 years; P < 0
01). HNMs were divided equally between in situ (49
6%) and invasive cases (50
3%), whereas MOS were mostly invasive cases (86
5%) (P < 0
01). The density of in situ melanomas was 13
5-fold higher for HNMs than for MOS (Table 1). In situ HNMs were mostly of the LMM type (97
0%), while 82
3% of in situ MOS were SSMs. Invasive HNMs were characterized by a high frequency of LMMs (49
3% vs. 1
7% in the MOS group; P < 0
01), a low frequency of SSMs (25
4% vs. 76
2% in the MOS group; P < 0
01) and a high frequency of NMs (20
1% vs. 12
0%; P = 0
01). The density of NM was 3
6-fold higher in the head and neck area than at other sites © 2014 British Association of Dermatologists

Central area: 254 (62·5%) 6 Cheeks: 185 (45·6%) 7 Eyelids: 33 (98·1%) 8 Nose: 24 (5·9%) 9 Area around mouth/chin: 12 (3·0%)

(Table 1). Finally, HNMs were thicker than MOS (mean and median Breslow thickness 2
18 and 1
3 mm vs. 1
77 and 0
9 mm, respectively; P = 0
03). Thick (> 2 mm) tumours represented 33
7% of HNMs vs. 24
1% of MOS (P = 0
01). The density of thick tumours was 2
9-fold higher in the head and neck area than in other sites, while the density ratio was only 1
6 for thin (≤ 2 mm) tumours (Table 1). Comparison of central and peripheral head and neck melanomas Significant differences were observed between HNMs of the central area and those of the peripheral area (Table 3). British Journal of Dermatology (2015) 172, pp707–715

710 Characteristics of head and neck melanoma in France, F. Dabouz et al. Table 1 Comparison, according to histological characteristics, of the density of head and neck melanomas (HNMs) with melanomas at other sites (MOS)

HNMs

MOS

Density ratio (head and neck/ other sites)

All casesa 414 (46
0) 1134 (12
4) 3
7 In situ 205 (22
7) 153 (1
6) 13
5 SSM 6 (0
6) 126 (1
3) 0
5 LMM 199 (22
1) 13 (0
1) 157
0 Unclassifiable 0 (0) 7 (0
1) 0 Invasive 209 (23
2) 980 (10
7) 2
16 SSM 53 (5
8) 746 (8
1) 0
7 LMM 103 (11
4) 17 (0
2) 57
0 NM 42 (4
6) 116 (1
2) 3
6 ALM 0 (0) 45 (0
5) 0 Unclassifiable 11 (1
2) 55 (0
6) 2
1 Breslow thickness (mm) ≤2 138 (15
3) 844 (9
2) 1
6 >2 70 (7
7) 236 (2
6) 2
9 Values are given as n (density) unless otherwise specified. SSM, superficial spreading melanoma; LMM, lentiginous malignant melanoma; NM, nodular melanoma; ALM, acrolentiginous melanoma. aData regarding invasion (in situ vs. invasive) were missing for one case of MOS.

Patients with a peripheral HNM were 7
2 years younger than those with a central HNM (mean age 65
2 vs. 72
4 years; P < 0
01). This difference increased to 11
0 years for invasive cases (63
2 vs. 74
2; P < 0
01) but was not observed for in situ cases. Some 64
4% of patients with a peripheral HNM were men, while 66
1% of those with a central melanoma were women (P < 0
01). Consistently, 53
3% of HNM diagnosed in men were located in the peripheral area, while 75
7% of cases in women occurred in the central area (P < 0
01). In situ HNMs were more frequent in the central than in the peripheral area (58
0% vs. 32
8%; P < 0
01). Some 147 of the 197 in situ cases (74
6%) were located in the central area, while the distribution of invasive cases was balanced between the two areas. Finally, different histological subtypes were observed in both areas, with a higher proportion of LMMs in the central area (82
7% vs. 55
3% in the peripheral area; P < 0
01), and a higher proportion of SSMs and NMs in the peripheral area [27
0% vs. 7
0% (P < 0
01) and 15
1% vs. 7
5% (P = 0
01), respectively]. Some 210 of 294 LMMs (71
4%) occurred in the central area. No difference was observed between central and peripheral HNMs with regard to Breslow thickness and ulceration.

Discussion In this study, HNMs represented 26
7% of all incident melanomas, confirming the importance of this location in terms of public health. This rate was even higher than those previously reported: 22
3% in a population-based study in another British Journal of Dermatology (2015) 172, pp707–715

French region;11 15
0–24
0% of all cutaneous melanomas and 12
0–20
0% of invasive cases in other European populations;5–9,18 and 18
0% of invasive melanomas in the U.S.A., according to the Surveillance, Epidemiology and End Results programme.10 The high rate of HNMs in our study could be explained by the demographic characteristics of the Champagne-Ardenne region, which is, to a large extent, a rural region that is home to a large number of elderly people.19 Interestingly, the rate of HNM in our study is close to that reported in Dorset (24
4%), a similarly rural region in England,18 a rate much higher than that observed in the more urban county of Buckinghamshire, England (15
0%).20 Consistent with the high frequency of HNMs in our study, the density ratio of HNMs was 3
7-fold higher than that of MOS; this ratio increased to 13
5 for in situ melanomas. Similar results were found in a population-based Swedish study, with 3
4fold more melanomas on the face than at other locations, and a density ratio reaching 9
6 for in situ cases.7 In a German registry-based study including 5702 patients, Hoersch et al.15 found a density ratio of 2
6, this lower value possibly being explained by the exclusion of in situ cases. Patients with HNMs were nearly 13 years older than those with MOS (mean age 71
2 vs. 58
4 years), this difference reaching 17 years for in situ cases. This result is in accordance with many population-based studies, which found HNMs to be much more frequent in the elderly than in younger people, whatever the population and the latitude.5,8,10,15,21–24 HNMs included more in situ cases than MOS (49
6% vs. 13
5%). As nearly all in situ HNM (97
0%) were of the LMM type, this high frequency of in situ melanoma in this location must be interpreted in light of the high frequency of LMMs among HNMs. The high rate of LMMs was also observed among invasive cases (49
0%). These results are consistent with numerous previous studies that found LMM to be the prevailing type of melanoma in the head and neck area.7,15,16 In addition, NM was also more frequent among invasive HNMs than among invasive MOS (20
1% vs. 12%; P = 0
01), with a density ratio between HNM and MOS reaching 3
6. These differences in histological types between HNM and MOS could, in large part, result from differences in sun exposure according to anatomical location. It has been suggested that the development of melanoma may follow different causal pathways according to different patterns of exposure to ultraviolet (UV) radiation.25,26 The first causal pathway is related to chronic and cumulative sun exposure, and is associated with the occurrence of melanomas on chronically exposed sites, mainly LMM of the head and neck in the elderly. In this pathway, a mechanism of photoadaptation could progressively take place and have a protective effect for a while, explaining the delayed occurrence of melanomas in chronically exposed sites.27,28 This hypothesis has been reinforced by a comparative study of two genetically similar populations living under different conditions of sun exposure, one in Queensland, Australia, and the other in Scotland. HNMs occurred at a younger age in Queensland, suggesting that a cumulative dose of chronic UV exposure, able to overcome the photoadaptation © 2014 British Association of Dermatologists

Characteristics of head and neck melanoma in France, F. Dabouz et al. 711 Table 2 Comparison of head and neck melanomas (HNMs) with melanomas at other sites (MOS)

All cases Age (years) Mean (range) Median Histological typea SSM NM ALM LMM Unclassifiable Invasionb In situ Invasive In situ cases Age (years) Mean (range) Median Sex Male Female Histological type SSM ALM LMM Unclassifiable Invasive cases Age (years) Mean (range) Median Sexc Male Female Histological typed SSM NM ALM LMM Unclassifiable Breslow thickness (mm)e Mean (range) Median 2 Ulcerationf

P-value

HNMs

MOS

414 (100)

1134 (100)

71
2 (17
0–99
0) 73
4

58
4 (17
0–106
0) 58
6

59 42 0 302 11

872 116 52 30 62

< 0
01

(14
2) (10
1) (0) (73
0) (2
7)

(77
0) (10
4) (4
6) (2
6) (6
4)

205 (49
6) 209 (50
3) 205 (100)

153 (13
5) 980 (86
5) 153 (100)

72
0 (38
0–94
0) 73
0

44
0 (18
0–106
0) 56
4

< 0
01 < 0
01 0
60 – < 0
01 – < 0
01

< 0
01

0
26 87 (42
5) 118 (57
5) 6 0 199 0 209

(3
0) (0) (97
0) (0) (100)

56 (36
6) 97 (63
4) 126 7 13 7 980

(82
3) (4
6) (8
5) (4
6) (100)

70
3 (17
0–99
0) 73
5

58
9 (17
0–97
0) 59
0

98 (46
8) 111 (53
2)

446 (45
5) 533 (54
5)

53 42 0 103 11

(25
4) (20
1) (0) (49
3) (5
2)

746 116 45 17 55

(76
2) (12
0) (4
6) (1
7) (5
5)

2
18 1
3 97 41 70 42

(0
15–15
0)

1
77 0
9 555 189 236 193

(0
1–35
0)

< < – < –
2 mm) tumours (33
7% vs. 24
1%). This result is British Journal of Dermatology (2015) 172, pp707–715

712 Characteristics of head and neck melanoma in France, F. Dabouz et al. Table 3 Comparison of head and neck melanomas in peripheral and central areas

a

All cases Age (years) Mean (range) Median Sex Male Female Histological type SSM LMM NM Unclassifiable Invasion In situ Invasive In situ cases Age (years) Mean (range) Median Sex Male Female Histological type SSM LMM Invasive cases Age (years) Mean (range) Median Sex Male Female Histological type SSM LMM NM Unclassifiable Ulcerationb Yes No Breslow thickness (mm)b Mean (range) Median 2

Peripheral area

Central area

152 (100)

254 (100)

65
2 (17
0–99
0) 70
0

72
4 (23
0–97
0) 75
0

P-value < 0
01

< 0
01 98 (64
4) 54 (35
6)

86 (33
8) 168 (66
1)

41 84 23 4

18 210 19 7

(27
0) (55
3) (15
1) (2
6)

(7
0) (82
7) (7
5) (2
8)

50 (32
8) 102 (67
2) 50 (100
0)

147 (58
0) 107 (42
0) 147 (100
0)

69
3 (44
0–90
0) 71
0

71
1 (38
0–94
0) 74
0

< 0
01 < 0
01 < 0
01 0
01 – < 0
01

0
44

< 0
01 33 (66
0) 17 (34
0)

52 (35
3) 95 (64
7)

4 (8
0) 46 (92
0) 102 (100
0)

2 (1
3) 145 (98
7) 107 (100
0)

63
2 (17
0–99
0) 68
0

74
2 (23
0–97
0) 79
0

0
04 0
01 0
01

< 0
01 < 0
01

65 (63
7) 37 (36
3)

34 (32
0) 73 (68
0)

37 38 23 4

16 65 19 7

(36
3) (37
2) (22
5) (4
0)

28 (27
7) 73 (72
3)

(15
0) (60
7) (17
8) (6
5)

< 0
01 < 0
01 < 0
01 0
44 – 0
19

21 (20
0) 84 (80
0) 0
74

2
15 1
30 46 22 34

(0
15–15
0) (45
0) (21
6) (33
4)

2
29 1
16 52 18 37

(0
02–15
0) (48
6) (16
9) (34
5)

0
67 0
67 0
67

Values are given as n (%) unless otherwise specified. SSM, superficial spreading melanoma; LMM, lentiginous malignant melanoma; NM, nodular melanoma. aPrecise sublocations were unknown in eight cases. bData were unknown in three cases.

paradoxical as the head and neck region is easily visible by patients themselves, their close relations and their doctors, while other sites like the trunk may be less easily accessible for direct examination. A second paradox is the contrast between the high frequency of thick tumours among HNMs, on the one hand, and the high proportion of LLMs (i.e. a slow-growing type of melanoma) and of in situ cases on the other. Indeed, the results of the present study support the idea that HNMs are British Journal of Dermatology (2015) 172, pp707–715

clinically and histologically heterogeneous, including a high proportion of slow-growing LMMs and rapidly growing melanomas, mainly of the nodular type.30–32 Obstacles to early recognition and excision of both types of tumours, particularly in elderly people, could contribute to the high frequency of thick/life-threatening tumours in this location. This high proportion has been reported in many previous studies,33,34 and is probably the main factor contributing to the poor prognosis of © 2014 British Association of Dermatologists

Characteristics of head and neck melanoma in France, F. Dabouz et al. 713

HNM compared with MOS.5,10,13,14 In addition, the head and neck location has been demonstrated to be an adverse prognostic factor independent of Breslow thickness,10,13,35,36 suggesting that other factors may also play a deleterious role. Older age was found to have an independent effect in several studies,37–39 and may be associated with more rapidly growing and/or invasive tumours, possibly related to declining immune function. The rich and complex vascular drainage pattern in the head and neck may facilitate the spreading of melanoma cells, explaining the high rate of regional and cerebral dissemination in HNM.40,41 Clinical practice may differ between (older) patients with HNMs and those with MOS. It has recently been demonstrated in French population-based studies that delayed treatment and insufficient surgical margins were more frequent in elderly patients and/or those with HNMs.21,42,43 The head and neck location was found to be an independent factor associated with the absence of sentinel lymph node analysis in a prospective study of patients’ choices. Furthermore, this procedure is able to guide further management, and surveillance may be particularly difficult in this site.44 Taken together, these factors probably contribute to making HNM a severe and challenging disease in Western and increasingly aged populations. We found important differences between HNM in the central and peripheral areas of the head and neck. HNMs in the peripheral area occurred in younger patients, predominated in men, were mostly invasive cases, and included a high proportion of SSMs and NMs, while HNMs in the central area occurred in older people, most often women, included a majority of in situ cases and were mostly of the LMM type. These data confirm and extend previous results,12 and further underline the role of hair protection, leading to differential patterns of sun exposure between men and women, and between the peripheral and the central area of the head and neck. The central area is a chronic, lifelong sun exposure area in both sexes, leading to frequent melanomas of the LMM type in elderly patients. The peripheral area is very well protected by hair – in young women in particular, but also in most middle-aged and even elderly women – explaining the low rate of melanomas at this site in women. In contrast, the peripheral area in men is often exposed in the later part of life after having been protected earlier on, which may prevent photoadaptation mechanisms. In addition, exposure of the peripheral area may be more intermittent than that of the central part, the neck being mostly covered in winter but exposed in warm seasons, the scalp and forehead being intermittently covered or exposed, and the lateral parts of the face being lengthily exposed in specific circumstances such as travelling by car.12,45 These facts could explain, in large part, the frequency, early occurrence and characteristics of peripheral HNMs in men. In contrast with the much lower frequency of in situ melanomas in the peripheral area compared with the central one, we did not observe any difference in Breslow thickness between these two areas. However, it should be noted that previous studies found thicker tumours on the scalp and the neck than at other head locations.8,10 © 2014 British Association of Dermatologists

This study has some limitations. Firstly, it did not include survival analyses allowing further evaluation of the prognostic value of specific characteristics of HNM. Secondly, personal patient histories of sun exposure, occupation, hairstyle, and alopecia and photoprotection habits were not available. Finally, clinical and histological characteristics of melanomas according to location could not be correlated with specific genotypes, while differences in BRAF, NRAS and KIT mutations according to the body site and pattern of sun exposure have been previously demonstrated.46–49 In conclusion, the head and neck are prone to frequent and severe melanomas, making HNM an important public health problem. Owing to the increasing proportion of elderly (with an expected rate of one in three persons aged over 60 years in 2030 compared with one in five in 2005 in our study region),50 HNM could, in the near future, represent one-third to half of all melanoma cases in many developed countries. Primary prevention messages should alert to the risk associated with cumulative sun exposure on the face, and intermittent sun exposure and sunburns on the lateral part of the head and neck, and emphasize the usefulness of protective hairstyles and wearing hats and caps covering the ears. Secondary prevention messages should target tumours that do not initially look like naevi, i.e. LMMs (any slow-growing pigmented spot) and more rapidly growing melanoma subtypes, including nodular, frequently achromic tumours. Examination of the peripheral area should not be neglected, especially in men, during routine examination by general practitioners. More attention should be paid to the elderly. In view of their specific characteristics and clinical and histological heterogeneity, further studies of HMNs are required, including molecular and genetic analyses.

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