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Advances in dermatology and venereology Acta Dermato-Venereologica
Nodular Melanoma : A Histopathologic Entity ?
Adele C . GREEN 1 , 2 , Amaya VIROS 1 , Maria Celia B . HUGHES 2 , Caroline GAUDY-MARQUESTE 1 , Victoria AKHRAS 3 , Martin G . COOK 4 and Richard MARAIS 1
1
Molecular Oncology Group , CRUK Manchester Institute , University of Manchester , Wilmslow Road , Manchester , UK , 2 QIMR Berghofer Medical Research Institute , Cancer and Population Studies , Brisbane , QLD , Australia , 3 St George ’ s Hospital , London , and 4 Histopathology , Royal Surrey County Hospital , Egerton Road , Guildford and Division of Clinical Medicine , University of Surrey , Guildford , Surrey , UK . E-mail : Adele . Green @ qimrberghofer . edu . au Accepted Nov 24 , 2017 ; Epub ahead of print Nov 28 , 2017
Cutaneous melanoma is a heterogeneous cancer that varies in its clinical characteristics and genetic alterations . While general features like size can give clues to likely prognosis , histopathologic appearance remains the gold standard for assessing cutaneous melanoma . Numerous histopathologic subtypes have been described , but the most common are superficial spreading melanoma ( SSM ) ( 60 – 80 %), nodular melanoma ( NM ) ( around 15 %) and lentigo maligna melanoma ( LMM ) ( 5 – 15 %) ( 1 , 2 ). Of these , NM has the poorest outcome .
There has long been debate over whether NM ’ s poor prognosis signifies a distinct , inherently ‘ aggressive ’ entity ( 3 ) or if it simply reflects higher median thickness at diagnosis than other subtypes ( 4 , 5 ). While current international classification ( 6 ) favors the latter , there remains compelling evidence that NM is unique in its clustering of high-risk features such as high mitosis rates ( 7 ) and ulceration ( 8 ), and in its lethality ( 9 ). We undertook a detailed evaluation of NM as a possible histopathologic entity in a collaborative study between England and Australia . We hypothesised that if they were a distinctly aggressive subtype , then from the outset when relatively thin , primary NMs would be more mitotic than other subtypes of equal thickness . We further tested this hypothesis by estimating disease-free survival ( DFS ) rates according to histological subtype in subgroups of equal thickness among the Australian study patients .
METHODS
Patients aged 16 – 89 years , newly diagnosed with invasive , clinical stage IB or II cutaneous melanomas ( 6 ) in 2010 – 2014 were eligible for inclusion . In England , patients were ascertained at St George ’ s Hospital , London , with pathology review . In Australia , patients were diagnosed in primary care , regional or tertiary hospitals in Queensland ( 10 ). The study was approved by institutional ethics committees .
Subtype , site , thickness ( mm ), mitotic rate ( per mm 2 or per 10 hpf ) and ulceration ( present vs absent ) were obtained from histopathology reports . We classified tumor thickness as > 0 to 2 mm ( no stage IA and too few stage IB tumors ≤ 1 mm for meaningful analysis ), > 2 to 4 , and > 4 mm , and mitotic rates per mm 2 as < 1 , 1 –< 2 , 2 to 6 , > 6 to give adequate numbers per category ( n = 147 ( 10 %) had 0 mitoses ). Outcomes for English patients were not available , but were obtained for all Australian patients to August 31 , 2017 via patient self-report , supplemented by systematic follow-up for melanoma recurrence or death in patients ’ clinical records and the Queensland Cancer Registry . Differences in age , sex and histopathologic characteristics between melanoma patients diagnosed in England and Australia were assessed using chi-squared tests of homogeneity . Mean log-transformed mitotic rates of NMs adjusted for age , sex , thickness , ulceration , and country were compared with corresponding rates of SSM , LMM and ‘ other ’ ( comprising unknown 55 %, desmoplastic 14 %, acral lentiginous 10 %, naevoid 9 %, other 11 %) subtypes within categories of thickness . Differences between the adjusted least-squares means of log-transformed mitotic rates and between DFS rates were tested and analyses were performed in SAS 9.4 .
RESULTS
There were 709 eligible patients with 724 melanomas diagnosed 2010 – 2014 in the English series ( mean age 60 years , 51 % male ) and 789 patients from Australia ( mean age 62 years , 57 % male ). More melanomas occurred on the lower limb in England and head and neck in Australia ( p < 0.003 ) and melanomas were thicker at diagnosis in England ( 3.15 ± 3.57 mm ) than Australia ( 1.99 ± 1.67 mm ) ( p < 0.0001 ). SSM comprised 57 % and 43 % of the English and Australian series , respectively , nodular 24 % and 22 %, LMM 3 % in both , and other subtypes , 14 % and 26 % respectively ( p < 0.0001 ). The two series were combined since the same factors were associated with NM in both ( Table SI 1 ), namely older age , male sex and head and neck location versus SSM , and thicknesses > 1 mm in relation to all subtypes ( Table I ). Ulcerated and highly mitotic (> 6 per mm 2 ) melanomas were more likely to be nodular than another subtype .
On average , the English melanoma patients had thicker lesions at diagnosis than the Australian patients ( Table SII 1 ) and this was also true for each sex ( median 2.2 mm vs 1.7 mm in males ; 1.7 mm vs 1.3 mm in females ). When mitosis rate was examined in relation to categories of thickness , thinner ( ≤ 2 mm ) nodular subtypes had higher rates than all other subtypes ≤ 2 mm and except for LMM , differences were significant ( Table II , Table SII 1 ). However for melanomas > 2 mm thick , there were no significant differences in mitosis rates between nodular , SSM or LMM subtypes ; only remaining other subtypes had lower mitosis rates than NMs ( Table II ).
Australian patients were followed-up after diagnosis for 2.9 to 6.9 years . Among those with known melanoma subtype whose melanomas were thinner ( ≤ 2 mm ), DFS was 82 % for NM , substantially worse than 91 % for
1 https :// www . medicaljournals . se / acta / content / abstract / 10.2340 / 00015555-2855 doi : 10.2340 / 00015555-2855 Acta Derm Venereol 2018 ; 98 : 460 – 462
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica .