Does the morphology of cutaneous melanoma help to explain the international differences in survival? Results from 1 578 482 adults diagnosed during 2000–2014 in 59 countries (CONCORD‐3)

Abstract

Background

CONCORD‐3 highlighted wide disparities in population‐based 5‐year net survival for cutaneous melanoma during 2000–2014. Clinical evidence suggests marked international differences in the proportion of lethal acral and nodular subtypes of cutaneous melanoma.

Objectives

We aimed to assess whether the differences in morphology may explain global variation in survival.

Methods

Patients with melanoma were grouped into the following seven morphological categories: malignant melanoma, not otherwise specified (International Classification of Diseases for Oncology, third revision morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722–8723, 8726–8727, 8730, 8740–8741, 8746, 8761, 8770–8774, 8780). We estimated net survival using the nonparametric Pohar Perme estimator, correcting for background mortality by single year of age, sex and calendar year in each country or region. All‐ages survival estimates were standardized using the International Cancer Survival Standard weights. We fitted a flexible parametric model to estimate the effect of morphology on the hazard of death.

Results

Worldwide, the proportion of nodular melanoma ranged between 7% and 13%. Acral lentiginous melanoma accounted for less than 2% of all registrations but was more common in Asia (6%) and Central and South America (7%). Overall, 36% of tumours were classified as superficial spreading melanoma. During 2010–2014, age‐standardized 5‐year net survival for superficial spreading melanoma was 95% or higher in Oceania, North America and most European countries, but was only 71% in Taiwan. Survival for acral lentiginous melanoma ranged between 66% and 95%. Nodular melanoma had the poorest prognosis in all countries. The multivariable analysis of data from registries with complete information on stage and morphology found that sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes.

Conclusions

This study provides the broadest picture of distribution and population‐based survival trends for the main morphological subtypes of cutaneous melanoma in 59 countries. The poorer prognosis for nodular and acral lentiginous melanomas, more frequent in Asia and Latin America, suggests the need for health policies aimed at specific populations to improve awareness, early diagnosis and access to treatment.

What is already known about this topic?

• The histopathological features of cutaneous melanoma vary markedly worldwide.

• The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin.

What does this study add?

• We aimed to assess the extent to which these differences in morphology may explain international variation in survival when all histological subtypes are combined.

• This study provides, for the first time, international comparisons of population‐based survival at 5 years for the main histological subtypes of melanoma for over 1.5 million adults diagnosed during 2000–2014.

• This study highlights the less favourable distribution of histological subtypes in Asia and Central and South America, and the poorer prognosis for nodular and acral lentiginous melanomas.

• We found that later stage at diagnosis does not fully explain the higher excess risk of death for nodular and acral lentiginous melanoma compared with superficial spreading melanoma.

Short abstract

Linked Comment: C.M. Olsen. Br J Dermatol 2022; 187:284.

The incidence of cutaneous melanoma has been rising steadily in most white populations over the past 50 years. ¹ , ² It is now one of the 10 most common malignancies in Oceania, North America and Europe, with age‐standardized incidence rates in the range of 7.0–36.6 per 100 000 person‐years. By contrast, melanoma is rare in populations of Asian and African origin, where incidence rates are in the range of 0.4–3.0 per 100 000 person‐years. ³ The histopathological features of cutaneous melanoma vary markedly worldwide. The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin. ⁴ , ⁵

The third cycle of the CONCORD programme for the global surveillance of cancer survival (CONCORD‐3) ⁶ highlighted wide disparities in 5‐year net survival from cutaneous melanoma, which was lower in Asian populations than in the rest of the world. Age‐standardized 5‐year net survival for adults (15–99 years) diagnosed during the period 2010–2014 was 90% or higher in the USA, Australia, New Zealand and most Nordic countries, but was 60% or lower in Ecuador, China, Korea, Singapore and Taiwan.

Stage at diagnosis is recognized as the most important predictor of survival. ⁷ , ⁸ , ⁹ , ¹⁰ Age at diagnosis is also a prognostic factor, and several studies have shown much higher survival for younger patients. ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ However, the prognostic role of morphology in cutaneous melanoma is controversial. Traditionally, melanomas of the skin have been classified into the following three fairly well‐defined subgroups, characterized by different patterns of growth: superficial spreading and lentigo maligna melanoma, which is characterized by a long period of superficial growth; nodular melanoma, which is more likely to penetrate into the deeper layers of the skin if not removed; and acral lentiginous melanoma, which mostly develops on the extremities but displays similar biological behaviour to that of nodular melanoma. ¹⁶ Despite the advent of high‐resolution genomics and other proposed approaches for the classification of melanocytic tumours, the diagnosis of the different subtypes should continue to be based on the pathologist’s interpretation of the histology and how it fits into the World Health Organization (WHO) Classification of Tumours, commonly known as the WHO ‘Blue Books’. ¹⁷ However, the morphological classification has not been considered useful for prognostic purposes because of the commonly held view that the clinical development of all melanomas is similar, whatever the histological subtype, spreading horizontally within the epidermis and then extending vertically into the dermis, and that they converge in their biological behaviour once they metastasize. ¹⁸

In this study, we aimed to describe the histological distribution of cutaneous melanoma for adults diagnosed during 2000–2014 in the 59 countries that contributed data to CONCORD‐3 and to produce the first international comparison of trends in population‐based age‐standardized 5‐year net survival by morphological subtype. We also aimed to examine the role of morphological subtype in the prognosis of cutaneous melanoma.

Materials and methods

Anonymized individual tumour registrations for patients diagnosed during 2000–2014 with one of 18 cancers or groups of malignancies, including melanoma, were provided for CONCORD‐3 by 322 population‐based cancer registries in 71 countries worldwide (full details of the CONCORD Working Group are provided in Appendix S1; see Supporting Information). Patients were followed up for their vital status up to 31 December 2014. Data acquisition, ethical approval and data quality control have been described elsewhere. ⁶

We asked participating registries to submit all registrations for malignant melanoma, regardless of anatomical site. Melanoma was defined by morphology codes in the range 8720–8790 according to the International Classification of Diseases for Oncology, third revision (ICD‐O‐3). ¹⁹ We focused this analysis of survival on melanomas arising in the skin (ICD‐O‐3 topography C44.0–C44.9), including the skin of the labia majora (C51.0), vulva (C51.9), penis (C60.9) and scrotum (C63.2). Survival from melanomas arising in internal organs and in the eye will be examined in a subsequent analysis. To facilitate quality control and comparison of the intensity of early diagnostic and screening activity, we requested all melanoma registrations, regardless of behaviour, whether benign (behaviour code 0), uncertain (behaviour code 1), in situ (behaviour code 2) or invasive (behaviour code 3). However, survival analyses included only primary invasive melanomas.

Records with incomplete data, or of tumours that were benign, in situ, of uncertain behaviour, metastatic from another organ, or unknown if primary or metastatic, or for patients aged outside the range 15–99 years, were not included in survival analyses. We excluded tumours registered only on the basis of a death certificate or discovered at autopsy, as the survival is unknown in these cases. We also excluded records for which sex or vital status was unknown, and records with an invalid date or sequence of dates were also omitted.

Patients were grouped according to the following seven morphological categories using the ICD‐O‐3 classification: malignant melanoma, not otherwise specified (NOS) (morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722–8723, 8726–8727, 8730, 8740–8741, 8746, 8761, 8770–8774, 8780).

Patients were grouped according to calendar period of diagnosis, i.e. 2000–2004, 2005–2009 or 2010–2014. We examined time trends in the morphology distribution for each country. We also estimated trends in age‐standardized 5‐year net survival by country and morphology with the nonparametric Pohar Perme estimator, ²⁰ using the STATA (StataCorp, College Station, TX, USA) command stns. ²¹ The cohort approach was used for patients diagnosed during the periods 2000–2004 and 2005–2009 because these patients had all been followed up for at least 5 years. We used the period approach ²² to estimate survival for patients diagnosed during 2010–2014 because 5‐year follow‐up for vital status was not available for all patients up to 31 December 2014.

To control for wide differences in background mortality based on geographical area, sex, and over time, we constructed life tables of all‐cause mortality in the general population for each country or registry by single year of age, sex, calendar year and, where possible, by race/ethnicity (Israel, Singapore, USA, Australian Northern Territory and New Zealand).

We estimated 5‐year net survival by morphology in each of five age groups (15–44 years, 45–54 years, 55–64 years, 65–74 years and 75–99 years). We obtained age‐standardized estimates for all age groups combined using the International Cancer Survival Standard type 2 weights for the five age groups (0.28, 0.17, 0.21, 0.20 and 0.14). ²³ We did not estimate survival if fewer than 10 patients were available for analysis in a given combination of morphological subtype and calendar period. If 10–49 patients were available for a given calendar period, we only estimated survival for all ages combined. If 50 or more patients were diagnosed during the periods 2000–2004 and 2005–2009, we attempted survival estimation for each age group in each calendar period. For 2010–2014, we estimated net survival using the period approach, including in the analyses all patients diagnosed during the 5‐year period from 2010 to 2014, plus those diagnosed before 2010 who were still alive at the beginning of 2010. Therefore, for the period 2010–2014 the threshold of 50 or more patients required to attempt age‐standardization applies to the combined cohort of patients. If a single age‐specific estimate could not be obtained, we merged the data for adjacent age groups and assigned the combined estimate to both age groups before standardization for age. If two or more age‐specific estimates could not be obtained, we reported only the unstandardized estimate for all ages combined. The pooled estimates for countries with more than one registry do not include data from registries for which the estimates were less reliable. Less reliable estimates are shown with a footnote in Tables 1, 2, 3 when such estimates were the only available information from a given country or territory (see footnote in Tables 1, 2, 3 for the definition of less reliable estimates). Here, we comment only on reliable, age‐standardized survival estimates. Continental regions were defined using the United Nations Geoscheme. ²⁴

Table 1.

Number of patients and age‐standardized 5‐year net survival (NS, %) with 95% confidence interval (CI): adults (15–99 years) diagnosed with melanoma of the skin in North, Central and South America, by country, morphology and calendar period of diagnosis (2000–2004, 2005–2009, 2010–2014)

		Superficial spreading melanoma			Lentigo maligna melanoma			Nodular melanoma			Acral lentiginous melanoma			Desmoplastic melanoma			Malignant melanoma, NOS			Other melanoma morphologies
		N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI
America (Central and South)
Argentina	2000–2004							30	71.2	50.7–91.7							131	66.7	57.8–75.5	10	44.8	14.6–75.0
	2005–2009	31	98.5	92.3–100.0	24	100.0	85.9–100.0	76	58.1	45.8–70.4							320	62.9	57.0–68.8	44	72.6	55.6–89.5
	2010–2014	26	100.0	90.0–100.0	21	100.0	85.7–100.0	44	71.9	61.3–82.6							277	65.2	58.5–71.9	11	52.0	26.6–77.5
Brazil	2000–2004				19	100.0	100.0–100.0	75	71.7	61.8–81.7	13	65.8	36.0–95.6				359	76.0	70.1–81.9
	2005–2009	41	84.4	65.0–100.0	21	96.5	77.2–100.0	78	68.8	56.7–80.8	10	32.1	3.4–60.7				437	76.3	71.5–81.1	12	67.8	40.8–94.8
	2010–2014	43	85.0	68.9–100.0	10	95.3	72.8–100.0	43	64.8	51.5–78.1							251	69.7	64.4–75.1	13	33.7	5.6–61.8
Chile	2000–2004							12	19.0	0.0–39.7							59	57.0	42.6–71.4
	2005–2009	11	100.0	100.0–100.0	10	95.2	61.5–100.0	28	50.8	30.2–71.4	18	64.1	38.2–89.9				57	55.8	36.6–75.1
	2010–2014	16	100.0 b	100.0–100.0	20	87.9 b	48.1–100.0	36	63.5 b	39.0–88.0	25	80.5 b	46.8–100.0				154	55.6 b	43.1–68.1
Colombia	2000–2004	29	85.0 b	70.0–100.0	16	100.0 b	85.1–100.0	53	41.8 b	24.8–58.8	45	81.6 b	62.1–100.0				196	54.9 b	46.9–62.9
	2005–2009	49	84.8 b	71.0–98.5	53	99.6 b	79.6–100.0	83	63.4 b	51.3–75.4	73	75.6 b	61.4–89.7				219	64.7 b	57.1–72.4	15	42.3 b	9.0–75.6
	2010–2014				17	96.0 b	86.4–100.0	23	56.7 b	43.7–69.7	21	70.6 b	56.9–84.4				43	55.8 b	46.6–65.0	10	35.0 b	7.2–62.8
Costa Ricaa	2000–2004	47	100.0	95.8–100.0	33	100.0	100.0–100.0	34	72.6	55.2–90.1	46	75.3	59.0–91.5				104	75.6	67.0–84.2
	2005–2009	71	86.3	78.9–93.7	51	97.5	89.9–100.0	63	58.9	49.3–68.5	70	74.2	62.1–86.2				183	69.9	62.5–77.4
	2010–2014	90	83.9	74.4–93.4	103	93.6	85.3–100.0	49	58.2	44.6–71.9	65	70.5	58.8–82.2				318	75.9	69.2–82.6	23	88.2	59.1–100.0
Ecuador	2000–2004							24	69.1	46.1–92.2	12	47.5	17.8–77.2				146	56.2	47.3–65.1
	2005–2009							45	61.0	44.3–77.7	12	27.6	2.9–52.3				319	60.1	53.5–66.6	13	54.7	23.2–86.3
	2010–2014							53	67.6	52.3–82.9	17	27.1	1.4–52.8				332	57.0	50.2–63.8
Guadeloupea	2000–2004
	2005–2009
	2010–2014	16	0.1 b	0.0–0.2				11	38.5	0.0–90.8
Martiniquea	2000–2004	12	92.6 b	76.2–100.0							14	78.0 b	42.3–100.0				28	92.1b	76.0–100.0
	2005–2009	18	100.0 b	89.5–100.0							20	84.0 b	62.1–100.0
	2010–2014	18	100.0 b	90.0–100.0
Puerto Ricoa	2000–2004	12	62.4	28.2–96.6	22	100.0	92.9–100.0	25	50.9	27.4–74.5	27	56.4	33.4–79.5				296	72.4	66.4–78.4	15	68.1	34.7–100.0
	2005–2009	19	71.9	50.4–93.3				36	38.9	20.8–56.9	14	35.3	7.7–62.8				340	79.9	74.9–85.0	11	57.8	26.7–88.9
	2010–2014	20	70.8	41.0–100.0				17	62.0	31.3–92.8	10	50.5	18.2–82.8				149	76.2	68.5–83.9
America (North)
Canada	2000–2004	6720	95.1	94.1–96.1	1219	97.6	95.9–99.4	2076	72.1	69.8–74.4	297	86.1	81.6–90.5	131	79.6	69.4–89.8	8737	83.9	82.9–84.9	661	75.6	71.7–79.4
	2005–2009	8352	96.2	95.4–97.0	1492	97.8	96.4–99.3	2661	69.7	67.6–71.8	366	81.6	77.0–86.2	194	90.4	85.3–95.5	10 731	83.7	82.9–84.6	926	80.6	77.6–83.6
	2010–2014	10 737	96.8	96.0–97.5	2301	96.8	94.6–99.0	3119	72.3	70.3–74.3	391	77.9	72.8–83.0	266	91.8	87.3–96.4	11 139	84.8	84.0–85.6	762	80.9	77.7–84.2
USA	2000–2004	51 276	96.8	96.5–97.2	10 760	98.7	98.0–99.5	12 341	69.5	68.6–70.5	1771	82.2	79.9–84.6	2082	87.3	85.3–89.3	96 459	86.4	86.1–86.7	6317	84.1	82.9–85.3
	2005–2009	66 456	97.5	97.1–97.8	13 531	99.3	98.7–99.9	15 772	71.2	70.3–72.0	2229	82.6	80.6–84.6	2442	89.1	87.3–91.0	111 496	88.2	87.9–88.4	6469	85.3	84.1–86.4
	2010–2014	65 610	97.6	97.3–97.9	14 191	99.6	98.9–100.0	15 202	71.6	70.7–72.4	2317	81.6	79.6–83.7	2255	89.7	87.8–91.5	101 623	88.5	88.2–88.8	4988	84.2	83.0–85.5

NOS, not otherwise specified. ^aData with 100% coverage of the national population. ^bSurvival estimate considered less reliable, because 15% or more of patients were (i) lost to follow‐up or censored alive within 5 years of diagnosis (or if diagnosed in 2010 or later, before 31 December 2014), or (ii) registered only from a death certificate or at autopsy, or (iii) registered with incomplete dates, i.e. unknown year of birth, unknown month and/or year of diagnosis or unknown year of last vital status. Italics denote survival estimates that are not age‐standardized.

Bold values denote age‐standardized survival estimates.

Table 2.

Number of patients and age‐standardized 5‐year net survival (NS,%) with 95% confidence interval (CI): adults (15–99 years) diagnosed with melanoma of the skin in Asia and Oceania, by continent, country, morphology and calendar period of diagnosis (2000–2004, 2005–2009, 2010–2014)

		Superficial spreading melanoma			Lentigo maligna melanoma			Nodular melanoma			Acral lentiginous melanoma			Desmoplastic melanoma			Malignant melanoma, NOS			Other melanoma morphologies
		N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI
Asia
China	2000–2004																110	36.0	26.0–46.0
	2005–2009																538	44.7	39.8–49.5	15	63.2	37.1–89.4
	2010–2014																623	48.4	43.2–53.6	17	69.9	41.1–98.7
Cyprusa	2000–2004																15	84.7 b	59.6–100.0
	2005–2009	72	96.2 b	88.9–100.0				59	73.8 b	62.8–84.7							86	75.1 b	64.6–85.5	13	83.6 b	34.4–100.0
	2010–2014	101	87.3 b	78.8–95.8				94	71.4b	59.9–82.9							92	69.7 b	58.9–80.5	20	63.6 b	36.8–90.5
Israela	2000–2004	585	93.3	90.1–96.5	141	97.6	92.2–100.0	251	69.6	63.0–76.2	22	66.6	41.0–92.2				2648	84.8	83.1–86.5	58	50.7	35.4–66.1
	2005–2009	407	94.2	90.4–98.0	110	97.5	88.4–100.0	316	68.9	62.5–75.3	23	80.8	51.6–100.0				3614	89.3	87.9–90.6	42	51.1	34.3–67.9
	2010–2014	335	97.7	93.8–100.0	74	98.7	93.6–100.0	208	65.3	57.4–73.2	26	79.3	56.6–100.0	11	51.0	20.7–81.2	3314	87.8	86.3–89.3	64	64.6	52.9–76.2
Japan	2000–2004																703	68.7	64.7–72.7
	2005–2009	36	84.8	69.6–99.9	31	90.1	59.0–100.0	53	52.3	36.2–68.4	78	82.4	68.5–96.2				1605	67.2	64.3–70.1	14	35.8	7.9–63.6
	2010–2014	42	88.4	77.8–98.9	25	89.0	57.8–100.0	57	56.5	44.3–68.7	71	93.2	81.7–100.0				999	68.0	64.7–71.2	14	46.2	16.5–75.9
Koreaa	2000–2004	17	83.1	61.5–100.0				87	50.4	39.2–61.6	156	73.1	64.6–81.6				982	47.2	43.8–50.6	22	41.6	20.9–62.3
	2005–2009	27	84.0	66.5–100.0	16	94.2	72.2–100.0	113	38.0	29.5–46.6	247	80.3	74.1–86.4				1548	51.3	48.5–54.1	38	64.2	47.9–80.5
	2010–2014	39	86.3	63.0–100.0	20	100.0	85.9–100.0	192	41.5	32.1–50.9	399	79.4	73.9–84.9	16	53.7	26.2–81.3	1790	56.2	53.5–59.0	43	60.8	48.5–73.2
Singaporea	2000–2004										11	71.2	35.8–100.0				59	53.4	40.8–66.1
	2005–2009	17	66.9	41.3–92.5				15	39.8	13.2–66.3	19	62.2	34.6–89.8				71	55.5	45.2–65.9
	2010–2014	14	100.0	100.0–100.0				27	25.2	8.8–41.6	28	65.2	38.9–91.5				76	55.6	43.5–67.6
Taiwana	2000–2004	10	93.3	73.8–100.0				62	40.9	29.1–52.8	87	66.9	65.6–77.3				612	46.1	41.6–50.7	23	51.0	26.8–75.1
	2005–2009	33	81.3	66.0–96.6				81	41.8	31.4–52.2	167	68.2	59.4–77.0				667	49.6	45.2–54.0	34	33.5	15.1–51.8
	2010–2014	49	71.4	54.6–88.2				154	36.7	27.0–46.5	306	65.6	57.4–73.8				634	46.7	42.1–51.3	33	35.9	21.2–50.6
Thailand	2000–2004																103	44.9	34.4–55.4
	2005–2009																248	35.9 b	28.6–43.2
	2010–2014																151	28.0 b	21.5–34.4
Turkey	2000–2004	21	79.9 b	59.2–100.0	20	84.8 b	67.1–100.0	48	59.9 b	42.1–77.7	10	61.6 b	26.3–96.9				181	51.9 b	42.9–60.8
	2005–2009	67	77.7	66.4–88.9	58	97.3	85.8–100.0	187	52.3	44.3–60.4	67	73.8	62.3–85.3				810	52.5	48.6–56.4	36	63.2	45.2–81.3
	2010–2014	91	80.1	68.7–91.5	94	96.4	90.5–100.0	192	53.9	46.2–61.6	65	72.5	60.2–84.9				858	56.4	52.6–60.1	33	55.9	41.8–69.9
Oceania
Australiaa	2000–2004	18 244	97.4	96.8–97.9	3523	98.6	97.5–99.7	3930	79.3	77.8–80.8	230	78.1	71.5–84.6	805	84.6	81.3–87.8	19 244	88.5	87.9–89.1	2574	93.2	91.8–94.7
	2005–2009	24 151	97.5	97.0–97.9	5186	97.9	96.9–98.9	4574	79.5	78.0–81.0	274	82.3	76.6–88.0	918	84.9	81.8–88.1	17 740	87.9	87.3–88.5	2384	93.2	91.7–94.7
	2010–2014	26 279	97.5	97.1–98.0	4376	98.3	97.3–99.2	4643	80.2	78.6–81.8	288	81.2	75.6–86.8	894	84.8	81.4–88.2	13 506	87.2	86.4–87.9	2539	94.1	92.6–95.6
New Zealanda	2000–2004	3633	96.9	95.6–98.2	563	94.8	91.9–97.7	889	75.3	71.7–78.8	68	90.4	82.5–98.4	105	79.7	70.4–89.1	3617	86.3	84.8–87.8	146	84.9	77.9–91.8
	2005–2009	4998	97.2	96.3–98.2	488	95.4	92.1–98.8	1034	78.0	74.7–81.2	65	80.7	71.2–90.3	122	88.5	82.3–94.8	3891	86.6	85.2–88.0	70	81.2	67.7–94.8
	2010–2014	5786	97.9	97.0–98.9	617	90.0	79.3–100.0	1232	77.4	74.2–80.6	100	77.4	68.5–86.3	134	89.9	83.9–95.8	3523	87.0	85.6–88.5	129	81.6	73.9–89.3

NOS, not otherwise specified. ^aData with 100% coverage of the national population. ^bSurvival estimate considered less reliable, because 15% or more of patients were (i) lost to follow‐up or censored alive within 5 years of diagnosis (or if diagnosed in 2010 or later, before 31 December 2014), or (ii) registered only from a death certificate or at autopsy, or (iii) registered with incomplete dates, i.e. unknown year of birth, unknown month and/or year of diagnosis or unknown year of last vital status. Italics denote survival estimates that are not age‐standardized.

Bold values denote age‐standardized survival estimates.

Table 3.

Number of patients and age‐standardized 5‐year net survival (NS, %) with 95% confidence interval (CI): adults (15–99 years) diagnosed with melanoma of the skin in Europe, by country, morphology and calendar period of diagnosis (2000–2004, 2005–2009, 2010–2014)

		Superficial spreading melanoma			Lentigo maligna melanoma			Nodular melanoma			Acral lentiginous melanoma			Desmoplastic melanoma			Malignant melanoma, NOS			Other melanoma morphologies
		N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI	N	NS (%)	95% CI
Europe
Austriaa	2000–2004	1433	98.2	96.1–100.0	258	97.3	88.3–100.0	384	75.0	70.0–80.1	48	60.9	45.6–76.1	11	70.3	40.7–99.9	3306	77.9	76.3–79.6	89	60.2	48.7–71.7
	2005–2009	1236	95.6	93.3–97.9	245	99.6	96.7–100.0	405	67.2	61.7–72.7	55	71.3	56.4–86.3	22	100.0	85.2–100.0	4044	81.9	80.5–83.4	97	68.6	59.4–77.9
	2010–2014	1522	94.9	92.4–97.3	290	98.7	95.5–100.0	383	62.9	57.3–68.6	54	72.4	59.2–85.6	23	100.0	100.0–100.0	5180	87.1	85.8–88.4	65	70.5	59.7–81.2
Belgiuma	2000–2004	619	93.9	90.3–97.5	50	99.3	81.7–100.0	121	75.6	67.2–83.9	23	77.3	56.0–98.5				645	80.8	77.1–84.4	31	90.5	64.1–100.0
	2005–2009	3852	94.3	92.9–95.6	380	98.0	95.2–100.0	785	70.7	66.7–74.6	146	85.5	78.1–92.9	25	100.0	84.3–100.0	3181	85.1	83.5–86.7	177	82.2	75.5–88.9
	2010–2014	5590	95.4	94.1–96.7	725	98.5	96.1–100.0	940	74.9	71.3–78.5	190	87.7	81.5–94.0	43	72.4	48.7–96.1	4128	88.5	87.1–90.0	250	83.3	77.1–89.5
Bulgariaa	2000–2004	20	85.0	45.5–100.0				151	46.2	36.6–55.7							1245	51.6	48.3–54.9	180	45.4	36.7–54.0
	2005–2009	27	76.8	55.1–98.5				271	57.9	50.8–65.0							1421	57.1	54.1–60.2	186	35.0	27.2–42.8
	2010–2014	90	86.6	75.4–97.8				379	64.0	57.2–70.9							1661	61.6	58.8–64.4	210	39.9	32.0–47.8
Croatiaa	2000–2004																2174	66.3	63.8–68.7
	2005–2009	39	90.6	75.2–100.0				122	70.4	61.2–79.6							2622	74.6	72.5–76.6
	2010–2014	288	89.6	81.6–97.7				174	58.9	49.8–68.1	25	67.9	33.9–100.0				2298	77.1	75.0–79.1	57	80.8	66.6–95.0
Czech Republica	2000–2004	2214	97.0	95.1–98.9	361	97.9	93.9–100.0	2016	71.2	68.8–73.7	53	86.3	67.5–100.0	46	59.1	41.7–76.5	2546	71.3	69.2–73.4	507	77.5	72.6–82.3
	2005–2009	3142	98.1	96.7–99.6	438	97.0	93.3–100.0	2080	73.0	70.6–75.3	93	83.5	75.2–91.9	106	77.9	68.8–87.0	2964	77.2	75.4–79.1	540	80.1	75.8–84.3
	2010–2014	4082	98.2	96.9–99.6	442	99.0	96.3–100.0	2033	73.0	70.7–75.3	93	82.3	72.9–91.7	142	80.2	72.4–87.9	3335	78.9	77.2–80.7	567	81.5	77.3–85.6
Denmarka	2000–2004	2597	92.7	90.9–94.5	136	97.3	85.1–100.0	444	72.3	67.4–77.2	17	89.1	66.1–100.0				2318	83.6	81.6–85.5	27	85.5	66.8–100.0
	2005–2009	5384	95.3	94.1–96.4	218	88.6	78.8–98.4	757	72.4	68.8–76.0	66	84.3	73.9–94.7				1778	78.1	75.8–80.3	61	90.4	80.0–100.0
	2010–2014	8123	96.0	95.1–97.0	329	93.6	88.6–98.6	943	74.8	71.5–78.1	77	75.3	61.8–88.8	43	100.0	87.7–100.0	1229	77.1	74.7–79.5	69	90.9	79.9–100.0
Estoniaa	2000–2004	27	100.0	93.0–100.0	28	100.0	85.5–100.0	24	82.7	58.1–100.0							109	71.0	62.0–80.1	410	66.3	60.8–71.8
	2005–2009	32	100.0	100.0–100.0	15	95.0	71.3–100.0	14	71.6	45.3–97.8							203	70.0	63.4–76.7	500	73.7	69.2–78.1
	2010–2014	28	100.0	100.0–100.0	11	100.0	96.1–100.0	29	56.2	34.4–78.0	17	64.0	17.3–100.0				305	82.7	74.0–91.4	207	78.2	72.5–83.8
Finlanda	2000–2004																3576	84.8	83.3–86.4
	2005–2009	137	92.8	87.0–98.5	102	100.0	93.8–100.0	76	72.0	62.6–81.5	10	79.1	42.8–100.0				4452	87.0	85.7–88.3
	2010–2014	539	93.9	89.9–98.0	260	100.0	97.3–100.0	216	76.0	69.0–83.1	16	93.1	68.4–100.0				5539	88.1	86.9–89.3
France	2000–2004	2552	94.6	93.0–96.2	375	92.7	87.6–97.8	518	70.1	65.5–74.8	114	76.5	67.7–85.3	16	69.6	37.9–100.0	565	82.8	79.2–86.5	352	87.7	83.3–92.1
	2005–2009	4419	95.7	94.5–96.9	640	95.9	92.9–99.0	706	70.9	66.5–75.2	155	83.1	75.2–91.0	42	75.5	56.1–94.9	817	83.5	79.7–87.4	483	90.6	87.1–94.2
	2010–2014	1109	94.9	92.4–97.4	115	94.5	88.6–100.0	158	74.6	65.4–83.7	38	82.4	73.1–91.7				167	83.3	76.4–90.1	62	89.1	80.7–97.4
Germany	2000–2004	6566	99.2	98.2–100.0	1235	99.4	98.0–100.0	2415	74.4	72.3–76.4	319	85.4	80.4–90.4	39	91.4	77.2–100.0	3734	83.8	82.3–85.3	481	78.3	73.9–82.7
	2005–2009	11 019	98.8	98.1–99.5	2057	99.4	97.9–100.0	3394	77.7	76.0–79.5	478	83.7	79.4–88.0	56	80.9	63.6–98.3	5649	84.6	83.4–85.9	649	79.8	75.9–83.7
	2010–2014	11 676	99.0	98.4–99.7	1990	99.4	97.9–100.0	3188	77.2	75.3–79.0	450	84.7	80.5–89.0	78	91.6	82.5–100.0	6095	86.6	85.4–87.8	625	82.7	78.8–86.7
Icelanda	2000–2004	124	92.5	85.6–99.3	13	78.2	48.1–100.0	18	78.9	59.4–98.3							92	88.6	79.8–97.3
	2005–2009	132	87.4	79.7–95.2	16	82.3	55.9–100.0	17	61.6	31.3–91.9							80	87.7	78.8–96.6
	2010–2014	134	91.7	85.6–97.8				26	56.0	29.6–82.5							37	82.7	71.1–94.4
Irelanda	2000–2004	771	94.8	91.6–98.0	184	95.7	90.0–100.0	418	71.6	66.5–76.8	36	73.8	54.2–93.3	20	64.6	36.2–93.0	1007	82.0	79.0–85.1	78	78.5	68.1–89.0
	2005–2009	980	95.0	92.2–97.7	294	97.5	93.9–100.0	527	73.4	68.9–77.9	52	63.6	44.7–82.5	35	77.4	58.7–96.2	1365	84.3	81.8–86.8	124	79.3	71.0–87.7
	2010–2014	1427	96.2	93.6–98.8	359	96.0	92.3–99.8	494	76.9	72.1–81.7	69	72.5	58.5–86.5	48	80.7	67.1–94.3	1121	86.8	84.2–89.4	61	81.1	70.8–91.5
Italy	2000–2004	5044	94.4	93.2–95.6	435	98.7	96.4–100.0	1411	68.5	65.7–71.2	155	84.1	77.7–90.5	54	78.0	65.8–90.3	4548	78.9	77.6–80.3	2515	79.4	77.6–81.3
	2005–2009	8677	94.6	93.8–95.5	626	99.2	97.6–100.0	2170	68.5	66.2–70.8	250	85.4	80.3–90.6	79	77.1	62.8–91.4	5983	81.8	80.6–82.9	5130	83.0	81.8–84.2
	2010–2014	3636	95.2	94.1–96.2	202	99.3	97.0–100.0	904	66.4	63.3–69.5	96	85.0	78.0–92.0	25	78.9	64.7–93.1	1768	79.7	78.0–81.5	2554	82.8	81.3–84.3
Latviaa	2000–2004	12	100.0	76.7–100.0				36	44.5	26.3–62.7							353	60.7	54.7–66.8	291	72.7	66.2–79.1
	2005–2009							45	60.8	43.3–78.2							424	64.1	58.6–69.6	357	66.0	59.9–72.1
	2010–2014							32	76.6	63.9–89.2							410	69.8	64.3–75.3	527	73.2	67.8–78.5
Lithuaniaa	2000–2004	73	78.6	67.3–89.9	15	87.8	62.9–100.0	70	61.0	49.8–72.2							938	66.4	62.8–70.0
	2005–2009	336	85.2	80.1–90.3	39	100.0	85.8–100.0	273	66.7	60.0–73.4	13	93.7	68.4–100.0				573	59.5	54.8–64.2	12	83.5	56.5–100.0
	2010–2014	331	88.3	82.6–94.0	41	100.0	100.0– 100.0	226	65.5	57.4–73.6	13	77.8	45.1– 100.0				339	63.3	57.0–69.7
Maltaa	2000–2004	59	100.0	92.5–100.0				29	73.0	54.0–91.9							54	83.8	73.8–93.8
	2005–2009	85	87.6	81.1–94.1				15	61.2	35.8–86.6							72	76.5	68.0–85.1
	2010–2014	88	90.1	81.7–98.5	11	100.0	100.0–100.0	25	61.0	37.1–84.9							71	72.4	62.6–82.2
The Netherlandsa	2000–2004	8326	93.9	92.7–95.0	509	97.2	93.4–100.0	2046	76.3	74.1–78.6	132	79.8	71.9–87.8	34	86.4	68.3–100.0	2630	82.5	80.5–84.5	499	79.4	75.2–83.5
	2005–2009	12 494	94.7	93.9–95.5	663	97.9	95.4–100.0	2473	73.0	71.0–75.0	138	80.3	72.5–88.1	60	76.8	60.4–93.2	2781	83.6	81.9–85.4	517	88.0	84.3–91.8
	2010–2014	18 354	95.1	94.4–95.8	1,317	98.0	95.0–100.0	2931	74.2	72.2–76.1	229	87.5	80.9–94.2	115	83.6	76.4–90.7	2385	84.3	82.6–86.1	455	85.8	81.9–89.8
Norwaya	2000–2004	2780	93.7	92.2–95.3	158	100.0	87.0–100.0	1103	74.1	71.0–77.2	40	93.6	76.3–100.0	33	71.9	49.8–94.1	967	78.3	75.2–81.4	29	85.1	56.3–100.0
	2005–2009	3143	93.7	92.3–95.1	197	97.1	85.4–100.0	1304	74.0	71.2–76.9	32	84.4	68.6–100.0	44	100.0	85.2–100.0	1428	83.4	81.0–85.8	34	64.2	45.2–83.3
	2010–2014	4853	94.5	93.2–95.8	266	97.4	93.6–100.0	1642	77.2	74.5–79.9	38	85.5	77.3–93.6	46	75.9	61.8–89.9	1798	87.0	84.9–89.0	59	76.5	63.9–89.1
Polanda	2000–2004	509	84.2	79.4–88.9	205	98.4	94.4–100.0	566	63.2	58.5–67.9	37	84.3	70.4–98.2				7413	60.5	59.2–61.8	687	62.6	58.4–66.8
	2005–2009	847	88.9	85.6–92.2	259	99.0	95.4–100.0	956	59.0	55.4–62.6	48	90.1	77.4–100.0				9291	64.9	63.7–66.0	545	67.0	62.5–71.6
	2010–2014	1380	88.6	85.7–91.6	193	98.7	94.6–100.0	1216	58.3	54.8–61.9	60	84.0	73.5–94.5	19	53.0	21.4–84.7	10 938	68.1	67.1–69.1	655	66.5	62.1–70.9
Portugala	2000–2004	323	92.6	88.2–97.0	81	100.0	100.0–100.0	233	59.2	52.1–66.3	80	85.9	74.5–97.3				1766	76.2	73.8–78.5	45	72.1	56.5–87.6
	2005–2009	748	91.7	88.4–94.9	157	97.9	88.4–100.0	355	63.0	57.2–68.9	136	82.4	74.2–90.6	12	69.2	29.1–100.0	2283	79.8	77.9–81.8	66	82.8	71.5–94.1
	2010–2014	1214	88.0	80.3–95.7	151	97.7	90.9–100.0	425	75.8	65.3–86.2	107	69.8	58.6–81.0	15	45.5	3.4–87.6	1064	81.8	77.7–85.9	92	74.4	62.3–86.4
Romania (Cluj)	2000–2004
	2005–2009	17	75.5	52.7–98.3				33	61.2	40.3–82.1							137	64.6	56.1 – 73.0	27	89.5	73.5–100.0
	2010–2014	58	90.0	80.6–99.3				53	61.7	42.4–81.0							85	63.3	51.9 – 74.7	19	84.0	57.1–100.0
Russia	2000–2004							21	87.9	64.2–100.0							943	62.1	58.3–65.9	377	70.2	63.4–77.0
	2005–2009	16	85.4	56.2–100.0				41	56.7	39.2–74.2							1316	61.5	58.3–64.8	210	69.9	61.7–78.1
	2010–2014	16	86.0	58.9–100.0				115	58.8	47.0–70.6							1623	66.4	63.3–69.5	216	66.6	58.6–74.6
Slovakiaa	2000–2004	1141	88.3	85.1–91.5	130	86.4	77.5–95.3	553	59.5	54.6–64.4	38	81.3	64.1–98.6				542	63.0	58.1–67.8	115	61.9	51.8–72.0
	2005–2009	1494	91.0	88.4–93.5	138	93.5	86.0–100.0	689	69.3	64.7–74.0	31	67.4	46.3–88.5	11	100.0	37.5–100.0	720	63.5	58.8–68.2	77	48.8	36.1–61.5
	2010–2014	363	89.5	83.5–95.4	22	98.9	90.9–100.0	164	69.2	60.2–78.2							137	54.3	44.3–64.4
Sloveniaa	2000–2004	492	90.5	86.5–94.6	60	90.2	75.0–100.0	277	65.6	59.4–71.8	19	72.5	43.8–100.0				525	74.9	70.3–79.4	109	71.3	61.8–80.8
	2005–2009	882	95.1	92.3–97.9	74	89.6	76.0–100.0	284	71.8	65.8–77.8	18	78.8	54.0–100.0				724	78.5	75.0–82.1	114	71.5	62.2–80.7
	2010–2014	899	95.0	92.1–97.9	48	89.0	77.0–100.0	224	73.1	66.6–79.5	21	65.2	51.1–79.3				783	79.7	76.0–83.3	34	68.9	57.1–80.8
Spain	2000–2004	1465	92.9	90.3–95.6	268	95.4	90.8–100.0	501	68.9	64.3–73.5	144	71.9	63.0–80.8	20	58.6	33.7–83.4	1049	81.1	78.3–84.0	274	81.0	75.2–86.8
	2005–2009	1996	95.3	93.5–97.0	364	97.8	94.7–100.0	652	67.3	63.3–71.3	164	79.0	71.9–86.1	35	65.5	46.1–84.9	1167	82.8	80.3–85.4	300	85.6	80.6–90.7
	2010–2014	1198	96.8	94.3–99.3	188	97.8	93.5–100.0	411	60.4	54.0–66.8	83	82.8	74.0–91.5	28	39.2	10.1–68.3	659	84.6	80.5–88.6	130	80.6	72.3–88.9
Swedena	2000–2004	4549	93.7	92.6–94.9	496	99.2	96.7–100.0	1509	71.9	69.0–74.8	103	84.0	76.5–91.5	32	59.6	36.4–82.9	2477	87.5	85.8–89.2	45	87.5	66.8–100.0
	2005–2009	6319	95.7	94.8–96.6	732	99.3	97.4–100.0	2077	71.4	68.8–74.0	125	81.1	74.3–88.0	67	76.7	61.0–92.4	2566	88.9	87.3–90.5	50	75.6	57.6–93.6
	2010–2014	9437	95.9	95.1–96.7	1041	96.3	92.6–99.9	2375	74.2	71.8–76.6	155	84.6	78.4–90.7	90	86.1	75.1–97.0	2620	90.8	89.4–92.3	56	83.0	71.5–94.5
Switzerland	2000–2004	1022	96.9	94.6–99.3	157	91.8	75.5–100.0	213	70.8	62.8–78.7	48	86.9	61.5–100.0				259	80.4	74.6–86.2	41	62.2	45.7–78.7
	2005–2009	2134	97.6	96.1–99.2	369	98.6	96.0–100.0	442	69.8	64.6–74.9	132	90.1	84.3–96.0	23	78.8	57.5 – 100.0	852	90.2	87.5–93.0	107	81.8	74.0–89.7
	2010–2014	1725	98.1	96.6–99.5	268	100.0	97.8–100.0	256	72.6	66.7–78.5	122	91.1	85.6–96.5				542	88.7	85.7–91.6	84	83.6	75.6–91.7
UKa	2000–2004	15 962	97.5	95.5–99.5	2142	98.0	94.7–100.0	5,109	73.1	68.6–77.6	519	81.7	73.8–89.5	155	36.5	1.9–71.1	15 485	79.2	76.1–82.2	951	70.3	61.1–79.5
	2005–2009	25 047	97.4	96.8–97.9	3254	98.0	96.1–99.8	6,925	74.5	73.2–75.8	714	79.7	75.9–83.5	225	83.3	76.8–89.8	17 094	82.1	81.4–82.8	1189	84.4	81.8–87.1
	2010–2014	37 002	97.5	97.1–98.0	4940	97.4	95.6–99.3	8,735	74.9	73.7–76.2	1,033	78.5	74.8–82.1	373	82.3	75.3–89.3	15 586	84.3	83.6–85.1	895	85.0	82.1–87.9

NOS, not otherwise specified. ^aData with 100% coverage of the national population. ^bSurvival estimate considered less reliable, because 15% or more of patients were (i) lost to follow‐up or censored alive within 5 years of diagnosis (or if diagnosed in 2010 or later, before 31 December 2014), or (ii) registered only from a death certificate or at autopsy, or (ii) registered with incomplete dates, i.e. unknown year of birth, unknown month and/or year of diagnosis or unknown year of last vital status. Italics denote survival estimates that are not age‐standardized.

Bold values denote age‐standardized survival estimates.

To estimate the effect of morphology on the hazard of death owing to melanoma, we fitted a flexible parametric model on the log cumulative hazard scale, using stpm2 ²⁵ in STATA. We restricted this analysis to registries where at least 65% of registrations had a specific morphology code, i.e. not malignant melanoma, NOS. Among these registries, we further selected those for which data on stage were available for at least 75% of registrations using one of the following classifications: Union for International Control Tumour–Node–Metastasis staging system, 7th edition, ²⁶ Condensed TNM ²⁷ or Surveillance Epidemiology and End Results Summary Stage 2000. ²⁸ Using this constraint, we were able to include data from one regional cancer registry in Germany (Lower Saxony), two registries in Spain (Basque Country and Granada) and the Norwegian national cancer registry.

For each country, we first fitted a model with only morphology as a covariable (model 1). We then included, as additional covariables, sex, a restricted cubic spline for the effect of age at diagnosis (four degrees of freedom) and stage at diagnosis (metastatic vs. nonmetastatic) (model 2). We excluded patients for whom stage at diagnosis was unknown (complete case analysis).

Results

We obtained data from 284 registries in 59 countries for 2 303 095 adults who were diagnosed with melanoma during 2000–2014 (Table 4). Of these patients, 49% were diagnosed in North America, 37% in Europe, 12% in Oceania, and only 2% in Asia and less than 1% in both Africa and in Central and South America.

Table 4.

Data quality indicators, patients diagnosed with melanoma of the skin during 2000–2014, by continent and country

			Ineligible (%)				Exclusions (%)			Data quality indicators (%)
	Calendar period	Patients submitted	Incomplete dates	In situ	Othera	Eligible patients	DCO	Otherb	Available for analysis	MV	Nonspecific morphology	Lost to follow–up	Censored
Africa		498	9.6	0.0	9.2	404	0.0	8.9	368	91.3	45.9	3.0	54.1
Algerian registries	2000–2014	331	13.3	0.0	0.9	284	0.0	12.7	248	99.2	25.0	0.0	47.6
Mauritiusc	2010–2012	5	0.0	0.0	20.0	4	0.0	0.0	4	100.0	100.0	0.0	0.0
Nigeria (Ibadan)	2005–2014	87	4.6	0.0	16.1	69	0.0	0.0	69	72.4	92.8	0.0	87.0
South Africa (Eastern Cape)	2000–2014	75	0.0	0.0	37.3	47	0.0	0.0	47	76.6	83.0	23.4	44.7
America (Central and South)		10 610	3.2	10.7	5.1	8599	1.4	0.3	8452	99.0	62.4	0.5	6.8
Argentinian registries	2000–2013	1196	4.7	0.8	3.3	1092	0.7	0.0	1084	99.6	67.7	0.0	0.0
Brazilian registries	2000–2014	2169	0.7	12.7	5.6	1758	4.8	0.0	1674	99.2	73.1	0.0	2.0
Chilean registries	2000–2012	569	0.0	0.0	2.5	555	0.2	0.0	554	99.5	60.1	0.0	19.3
Colombian registries	2000–2014	1698	3.8	5.2	10.0	1376	0.2	0.0	1373	98.8	49.4	0.0	25.0
Costa Ricac	2002–2014	1448	0.0	0.0	0.8	1436	0.0	0.3	1432	98.3	44.7	0.0	0.0
Ecuadorian registries	2000–2013	1483	11.2	8.4	6.5	1096	0.4	1.1	1080	98.8	78.0	0.2	5.3
Guadeloupe (France)c	2008–2013	60	0.0	13.3	0.0	52	0.0	0.0	52	100.0	0.0	0.0	71.2
Martinique (France)c	2000–2012	177	0.0	0.0	2.8	172	0.0	4.7	164	100.0	23.2	25.0	0.0
Puerto Ricoc	2000–2011	1810	2.2	34.6	4.5	1062	2.2	0.0	1039	99.3	75.6	0.0	0.0
America (North)		1 134 825	0.6	35.2	2.7	706 357	0.5	0.0	703 094	99.2	51.1	3.8	0.1
Canadian registries	2000–2014	94 011	0.1	17.2	4.5	73 496	0.3	0.0	73 278	95.6	41.8	0.0	0.0
US registries	2000–2014	1 040 814	0.6	36.0	2.6	632 861	0.5	0.0	629 816	100.0	52.0	2.6	0.1
Asia		41 718	0.5	14.9	8.4	31 768	1.1	0.3	31 337	98.2	76.4	0.4	2.0
Chinese registries	2003–2013	1733	0.2	0.0	16.1	1450	0.1	0.0	1449	99.0	95.4	4.8	0.2
Cyprusc	2004–2014	687	3.6	3.1	6.1	599	1.7	0.0	589	99.7	32.8	0.0	53.7
Indian registries	2000–2014	61	0.0	0.0	8.2	56	0.0	7.1	52	98.1	94.2	3.8	5.8
Israelc	2000–2013	18 303	0.0	28.3	4.2	12 348	0.7	0.0	12 265	98.0	78.1	0.0	0.0
Japanese registries	2000–2014	6462	1.3	10.4	22.3	4263	5.7	0.0	4018	95.3	88.1	0.0	2.4
Jordanc	2000–2014	306	0.3	1.0	27.8	217	0.0	1.4	214	99.5	84.1	14.0	0.0
Koreac	2000–2014	5824	0.9	0.0	0.0	5771	0.0	0.0	5771	98.6	74.9	0.0	0.0
Kuwaitc	2000–2013	21	0.0	0.0	14.3	18	0.0	0.0	18	100.0	72.2	0.0	0.0
Qatarc	2000–2014	61	0.0	1.6	8.2	55	0.0	0.0	55	98.2	87.3	0.0	70.9
Singaporec	2000–2014	521	0.0	9.0	20.3	368	0.3	0.0	367	100.0	56.1	0.0	0.0
Taiwanc	2000–2014	3123	0.3	3.4	0.6	2988	0.0	0.0	2988	100.0	64.0	0.0	0.0
Thai registries	2000–2014	817	0.0	0.0	5.9	769	0.0	9.6	695	99.7	95.0	0.3	3.9
Turkish registries	2000–2013	3799	1.4	4.8	18.4	2866	0.3	0.0	2856	99.3	64.8	0.2	4.8
Europe		842 368	0.1	16.8	5.3	651 577	0.5	0.1	647 719	99.3	34.1	1.7	3.9
Austriac	2000–2014	28 233	0.0	24.2	5.9	19 742	2.9	0.1	19 150	97.5	65.4	0.0	0.0
Belgiumc	2004–2014	29 278	0.0	22.8	2.4	21 905	0.0	0.0	21 905	99.9	36.3	1.9	0.0
Bulgariac	2000–2014	6057	0.0	0.0	0.0	6056	3.0	0.0	5875	100.0	73.7	0.0	0.0
Croatiac	2000–2014	8602	0.0	2.0	3.5	8126	3.4	0.0	7848	99.9	90.4	0.0	0.0
Czech Republicc	2000–2014	33 285	0.0	16.0	0.5	27 802	0.0	0.0	27 800	100.0	31.8	0.0	0.0
Denmarkc	2000–2014	24 683	0.0	0.0	0.2	24 630	0.0	0.0	24 630	99.7	21.6	0.6	0.0
Estoniac	2000–2012	2556	0.0	11.8	9.9	2002	0.9	0.0	1983	98.4	31.1	1.2	0.0
Finlandc	2000–2014	15 873	0.4	0.0	5.3	14 968	0.1	0.0	14 949	100.0	90.8	0.3	0.0
French registries	2000–2010	14 962	0.3	0.0	6.0	14 017	0.0	2.4	13 677	100.0	11.4	3.4	0.0
German registries	2000–2014	99 363	0.3	16.2	2.6	80 338	2.0	0.0	78 713	99.4	28.4	0.6	28.7
Gibraltarc	2000–2010	39	0.0	12.8	7.7	31	0.0	0.0	31	100.0	19.4	0.0	51.6
Icelandc	2000–2014	715	0.0	0.0	0.3	713	0.0	0.0	713	99.9	29.3	0.0	0.0
Irelandc	2000–2013	14 683	0.0	35.3	0.1	9475	0.1	0.0	9470	99.8	36.9	0.0	0.0
Italian registries	2000–2014	53 776	0.0	7.8	5.4	46 634	0.1	0.0	46 607	98.2	26.5	1.2	1.5
Latviac	2000–2014	2507	0.0	0.0	0.2	2503	0.1	0.0	2501	99.8	47.5	0.0	0.0
Lithuaniac	2000–2012	4129	0.0	6.3	13.4	3317	0.0	0.0	3317	100.0	55.8	0.0	0.9
Maltac	2000–2013	725	0.0	14.2	10.9	543	0.4	0.0	541	99.6	36.4	0.0	0.0
The Netherlandsc	2000–2014	80 641	0.0	20.0	6.6	59 141	0.0	0.1	59 088	100.0	13.2	1.1	0.0
Norwayc	2000–2014	31 469	0.0	8.6	27.9	19 997	0.0	0.0	19 994	99.9	21.0	0.3	0.0
Polandc	2000–2014	38 834	0.0	0.2	7.3	35 932	0.0	0.3	35 834	100.0	77.1	0.0	0.0
Portugalc	2000–2014	10 897	0.3	11.3	2.5	9358	0.0	0.0	9358	99.3	54.6	2.1	0.1
Romania (Cluj)	2006–2012	515	0.0	3.9	11.5	436	0.0	0.0	436	98.9	50.9	0.0	0.0
Russian registries	2000–2014	5081	0.0	0.1	2.9	4927	0.1	0.2	4914	99.5	79.0	2.5	0.7
Slovakiac	2000–2010	7933	0.0	11.1	7.3	6478	1.4	0.0	6389	100.0	21.9	0.0	0.0
Sloveniac	2000–2013	7442	0.0	18.8	5.9	5605	0.0	0.0	5603	100.0	36.3	0.1	0.0
Spanish registries	2000–2013	14 567	0.5	18.8	3.2	11 292	0.3	0.1	11 242	99.7	25.8	0.6	0.1
Swedenc	2000–2014	58 528	0.0	30.2	6.7	36 925	0.0	0.0	36 921	100.0	20.8	0.3	0.1
Swiss registries	2000–2014	19 030	0.0	19.4	2.1	14 923	0.1	0.1	14 893	99.9	20.0	7.2	7.9
UKc	2000–2014	227 965	0.1	22.9	4.8	163 761	0.2	0.0	163 337	98.5	30.8	4.3	0.0
Oceania		273 076	0.2	29.6	1.5	187 846	0.2	0.0	187 512	99.0	32.8	0.0	0.0
Australiac	2000–2014	241 133	0.2	33.5	1.4	156 531	0.1	0.0	156 302	98.9	32.3	0.0	0.0
New Zealandc	2000–2014	31 943	0.0	0.0	2.0	31 315	0.3	0.0	31 210	99.7	35.3	0.0	0.0
Total		2 303 095	0.4	27.7	3.5	1 586 551	0.5	0.0	1 578 482	99.2	43.2	2.5	1.6

DCO, death certificate only; MV, microscopically verified. ^aOther, records with incomplete data or for tumours that are benign (behaviour code 0), of uncertain behaviour (behaviour code 1), metastatic from another organ (behaviour code 6), or unknown if primary or metastatic (behaviour code 9); or for patients aged outside the range 15–99 years (adults); or with a topography code that is not in the range for skin (C440–C449), or the skin of the labia majora (C510), vulva (C519), penis (C609) or scrotum (C632). ^bOther, tumour coded with unknown vital status; or for patients for whom the sex is unknown. ^cData with 100% coverage of the national population.

A total of 637 957 patients (28%) who were diagnosed with an in situ tumour were excluded from survival analysis, which ranged from 11% in Central and South America to 35% in North America. The proportion of in situ melanoma was 20% or higher in 10 countries (Table 4), which suggests that the approach to early diagnosis in these countries was highly effective. We excluded a further 78 587 patients for other reasons (see footnote in Table 4). The proportion of melanomas of benign or uncertain behaviour was particularly high in Norway (22%), highlighting the intensive monitoring activity for atypical naevi and premalignant lesions in this country.

Of the 1 586 551 eligible patients, we further excluded 7139 patients (0.5%) who were diagnosed only on the basis of a death certificate or where melanoma was discovered at autopsy, and 930 patients (less than 0.1%) were excluded for other reasons. Finally, 1 578 482 patients diagnosed with a primary invasive melanoma of the skin were available for survival analysis (99.5% of those eligible). More than 99% of these tumours were microscopically confirmed, either cytologically or histologically.

About 42% of the tumours were registered as malignant melanoma, NOS. The proportion of such tumours was generally high in countries in Asia (76%), Central and South America (63%), North America (51%) and Africa (46%) and much lower in Oceania (33%). In Europe, the proportion of melanomas with a nonspecific morphology was higher in Eastern European countries (57%) than in Southern (37%), Northern (32%) and Western European countries (27%). The proportion of melanomas diagnosed with a nonspecific morphology fell substantially in Australia (from 40% in 2000–2004 to 26% in 2010–2014), Denmark (from 42% to 11%), Iceland (from 36% to 18%), Italy (from 32% to 19%), Lithuania (from 85% to 35%), Portugal (from 70% to 35%) and the UK (from 39% to 23%) (Table S1; see Supporting Information).

Overall, superficial spreading melanoma was the second most common histological subtype (36% of all cases). It accounted for more than half of the patients in Denmark, France, Iceland, the Netherlands, Norway, Sweden and Switzerland (Figure 1). Nodular melanoma accounted for 7% of all cases in North America and Asia, 9% in Oceania and 13% in Central and South America. In Europe, 12% of the cases were registered as nodular melanoma, with higher proportions in the Czech Republic, Ireland, Norway, Romania, Slovakia and Sweden. About 6% of adults were diagnosed with lentigo maligna melanoma, ranging from 2% in Asia to 8% in Oceania. Acral lentiginous melanoma was very rare in North America, Europe and Oceania (less than 2% of all cases) but the proportion was higher in Central and South America (more than 10% in Colombia, Costa Rica, Guadeloupe and Martinique) and Asia (more than 10% in Korea, Singapore and Taiwan). Less than 1% of the patients were diagnosed with desmoplastic melanoma. The proportion of patients diagnosed with other morphological subtypes was higher than 20% in Estonia, Italy and Latvia.

Fig 1.

Morphology distribution by continent and country, all periods combined.

NOS, not otherwise specified. [Colour figure can be viewed at wileyonlinelibrary.com]

Malignant melanoma, not otherwise specified

Age‐standardized 5‐year net survival varied widely between world regions (Tables 1, 2, 3). It was in the range of 85–89% in Oceania and North America during 2010–2014. It was higher than 80% in all Western European countries and ranged from 54% to 79% in Eastern Europe. In Central and South America, age‐standardized 5‐year net survival ranged from 57% in Ecuador to 76% in Costa Rica and Puerto Rico. The 5‐year survival was lower than 70% in all countries in the Asia region except Israel (88%), and was as low as 47% in Taiwan.

The 5‐year survival increased between 2000–2004 and 2010–2014 by 10% or more in China (from 36% to 48%), Bulgaria (from 52% to 62%), Croatia (from 66% to 77%) and Estonia (from 71% to 83%).

Superficial spreading melanoma

Age‐standardized 5‐year net survival for patients diagnosed during 2010–2014 was 90% or higher in North America, Oceania and almost all European countries; survival was lower than 90% in only Slovakia, Poland, Lithuania, Portugal and Bulgaria. In the Asia region, survival ranged from 71% in Taiwan to 98% in Israel (Figure 2).

Figure 2.

Age‐standardized 5‐year net survival for patients diagnosed with cutaneous melanoma during 2010–2014 by continent, country and morphology group [Colour figure can be viewed at wileyonlinelibrary.com]

Lentigo maligna melanoma

The lentigo maligna melanoma subtype had the most favourable prognosis; age‐standardized 5‐year net survival was close to 100% in North America, Australia and most European countries. Estimates were not available for most countries in Central and South America and Asia because of the small numbers of patients diagnosed with this specific subtype.

Nodular melanoma

The prognosis for nodular melanoma was the poorest in all continents. Age‐standardized 5‐year net survival for patients diagnosed during 2010–2014 reached 72% in Canada and the USA, 77% in New Zealand and 80% in Australia. In Central and South America, it ranged from 58% in Costa Rica to 72% in Argentina, and in Europe, it ranged from 58% in Poland to 80% in Ireland. Survival improved dramatically in Bulgaria (from 46% in 2000–2004 to 64% in 2010–2014) and in Portugal (from 59% to 76%).

Acral lentiginous melanoma

The 5‐year net survival for adults diagnosed during 2010–2014 was in the range of 77–82% in North America and Oceania and 70–95% in Europe. Most of the estimates for countries in Asia and Central and South America were not age‐standardized because of the small numbers of patients available for survival analysis.

The 5‐year net survival for adults diagnosed with desmoplastic melanoma during 2010–2014 ranged between 76% and 91%. Estimates were not available for Central and South America or for most countries in Asia because of the small numbers of patients available for analysis.

With the excess hazard of death for patients with superficial spreading melanoma taken as the reference category, the excess hazard ratio for patients diagnosed with nodular melanoma was 21.8 [95% confidence interval (CI) 14.7–32.3] in Germany, 12.1 (95% CI 8.1–18.1) in Spain and 6.7 (95% CI 5.7–7.9) in Norway (Table 5). The excess hazard ratios were lower after controlling for sex, age and stage at diagnosis, but the excess hazard of death for patients with nodular melanoma was still 13.5 (95% CI 9.6–18.9) times higher in Germany, 6.7 (95% CI 4.8–9.3) times higher in Spain and 4.1 (95% CI 3.6–4.8) times higher in Norway, than for patients in the same country diagnosed with superficial spreading melanoma.

Table 5.

Excess hazard ratio (EHR) of death in patients with malignant melanoma of the skin, by morphological type (reference category superficial spreading melanoma) in Germany, Spain and Norway

	Germany (Lower Saxony)			Spanish registriesa			Norwayb
	n (%)	Model 1, EHR (95% CI)	Model 2, EHR (95% CI)	n (%)	Model 1, EHR (95% CI)	Model 2, HR (95% CI)	n (%)	Model 1, EHR (95% CI)	Model 2, EHR (95% CI)
Superficial spreading	9326 (58.9)	1.0	1.0	1642 (39.8)	1.0	1.0	8624 (54.0)	1.0	1.0
Lentigo maligna	1305 (8.2)	0.2 (0.0–35.1)	0.1 (0.0–26.9)	232 (5.6)	0.4 (0.0–17.2)	0.4 (0.1–2.1)	478 (3.0)	0.3 (0.1–6.4)	0.5 (0.2–1.4)
Nodular	1514 (9.6)	21.8 (14.7–32.3)	13.5 (9.6–18.9)	627 (15.2)	12.1 (8.1–18.1)	6.7 (4.8–9.3)	3234 (20.3)	6.7 (5.7–7.9)	4.1 (3.6–4.8)
Acral lentiginous	341 (2.2)	15.2 (9.0–25.5)	10.8 (6.8–17.1)	138 (3.4)	9.0 (5.2–15.5)	5.0 (3.1–8.1)	91 (0.6)	1.7 (0.5–5.1)	2.2 (1.0–4.9)
Malignant melanoma, NOS	2953 (18.7)	6.5 (4.3–9.9)	5.4 (3.8–7.6)	1178 (28.6)	4.2 (2.8–6.4)	2.9 (2.0–4.0)	3338 (20.9)	3.9 (3.3–4.7)	2.8 (2.4–3.3)
Other morphologies	385 (2.4)	8.6 (4.7–15.6)	6.5 (3.8–11.0)	307 (7.4)	5.6 (3.4–9.2)	3.7 (2.4–5.6)	201 (1.2)	4.5 (2.9–6.9)	2.4 (1.6–3.7)

NOS, not otherwise specified. EHR, excess hazard ratio. ^aGranada and Basque Country. ^bNational coverage. Model 1 included only morphology. Model 2 included morphology, sex, age and stage at diagnosis.

The excess hazard ratio for patients diagnosed with acral lentiginous melanoma vs. superficial spreading melanoma was 15.2 (95% CI 9.0–25.5), 9.0 (95% CI 5.2–15.5) and 1.7 (95% CI 0.5–5.1) in Germany, Spain and Norway, respectively. After controlling for sex, age and stage at diagnosis, the excess hazard of death for patients with acral lentiginous melanoma was still 10.8‐fold (95% CI 6.8–17.1) higher in Germany, fivefold (95% CI 3.1–8.1) higher in Spain and 2.2‐fold (95% CI 1.0–4.9) higher in Norway, than for patients diagnosed with superficial spreading melanoma.

Discussion

This study of over 1.5 million adults diagnosed with cutaneous melanoma worldwide during 2000–2014 highlights wide international differences in the distribution of histological subtypes and differences in survival by subtype. For all countries investigated, the prognosis is poorest for nodular and acral lentiginous melanoma.

The prognostic role of the morphology of cutaneous melanomas is controversial. Clinical guidelines indicate that stage at diagnosis is the most important prognostic factor. The prevalent idea is that melanomas of different morphologies converge in their biological behaviour once they metastasize, ²⁹ so the recommended treatment options do not differ between morphological subtypes at a given stage at diagnosis. Furthermore, clinical guidelines indicate that the histological subtype is only an optional item for inclusion in pathology reports. ³⁰ This probably explains why the primary histological subtypes of melanoma are often poorly specified, if at all, in pathology reports. ¹¹ , ¹⁴ This in turn determines the high proportion of melanomas that are coded as ‘malignant melanoma, not otherwise specified (NOS)’ in cancer registry data. ¹³ In this global study, 43% of melanomas were registered as malignant melanoma, NOS. The proportion varied widely, and was higher in Asia, Central and South America, and Eastern Europe, as has been shown elsewhere. ¹³ , ³¹ However, our study demonstrates that the proportion of melanomas with poorly specified morphology has fallen in most countries over the last 15 years, which suggests that there have been improvements in pathological practice. ³²

Overall, superficial spreading melanoma was the most frequent of the specific morphologies, and the proportion of this morphological subtype has been increasing over time. This subtype is generally associated with an excellent prognosis in Europe, North America and Oceania, as has been shown in previous studies. ¹³ , ¹⁴ , ²⁹ , ³³ Several international studies have shown an increasing incidence of thinner melanomas (1 mm or less) ¹⁵ , ³⁴ , ³⁵ , ³⁶ , ³⁷ , ³⁸ , ³⁹ , ⁴⁰ as a result of raised public awareness and earlier detection, especially for superficial spreading melanomas. The result is an increasing number of people with melanoma who are less likely to die as a result of their tumours. This phenomenon may help to explain the improvement in the already high 5‐year net survival for superficial spreading melanoma.

Acral lentiginous melanoma accounted for less than 1% of the patients in Europe, North America and Oceania, but almost 6% of the patients in Asia and 7% in Central and South America. Very few studies have focused on survival from cutaneous melanoma in Asia and Central and South America, perhaps because the overall incidence is much lower than in fairer‐skinned populations. In Singapore, acral lentiginous melanoma accounted for 16% of all cases diagnosed during 2008–2017. ⁴¹ In a study of 915 patients diagnosed with melanoma during 1997–2011 in Brazil, the acral subtype accounted for 7% of all cases and the 5‐year cause‐specific survival for this subtype was much lower (51%) than for superficial spreading melanoma (82%). ⁴² A study of 142 patients in China confirmed the poor prognosis for patients with acral lentiginous melanoma; the 5‐year cause‐specific survival was 53%. ⁴³ By contrast, an analysis of 252 patients diagnosed in a single institution in Japan during 2001–2014 showed no difference between 5‐year survival for acral and nonacral lentiginous subtypes (59% vs. 62% in men and 71% vs. 85% in women); ⁴⁴ however, the numbers of patients were too small to derive definitive conclusions.

Our study found that age‐standardized 5‐year net survival for acral lentiginous melanoma was generally lower than for other morphological subtypes, with the only exception of nodular melanoma, and was in the range of 66–95% globally. The poorer prognosis for acral lentiginous melanoma, which usually develops on the palms, the sole of the foot or underneath the nails, is commonly ascribed to delayed diagnosis because these areas are not routinely examined by patients or primary care physicians. ⁴⁵ Moreover, the proportion of the acral subtype is higher in black patients than in white patients; ⁴⁶ but because the risk of melanoma in black populations is perceived to be low, the lack of secondary prevention is also considered a major cause of late diagnosis. ⁴⁷ , ⁴⁸

Nodular melanoma had the poorest prognosis in all countries, as has been reported elsewhere. ⁴⁹ , ⁵⁰ , ⁵¹ In a study published over 40 years ago, a multivariable analysis of 339 patients diagnosed in a single institution in the USA during 1960–1977 found that the increased risk associated with nodular histology was confounded by an increase in thickness and ulceration; in other words, the higher risk of death was due to more advanced stage at diagnosis, and was not intrinsic to the morphological subtype. ⁵² On the basis of this conclusion from a small study, the American Joint Committee on Cancer did not include histological subtype in the cutaneous melanoma staging system because it was not considered to be a significant prognostic factor. ⁵³ However, 30 years later, a very large population‐based study of 118 508 patients diagnosed in the USA with superficial spreading or nodular melanoma during 1973–2012 showed that morphology is in fact an independent predictor of survival. ²⁹ After controlling for thickness, ulceration, mitotic index and stage at diagnosis, nodular subtype remained an independent risk factor for death from melanoma (hazard ratio 1.55, 95% CI 1.41–1.70). Another population‐based study of 82 901 patients diagnosed in Germany during 1997–2013 showed that differences in 5‐year survival by histological subtype were “only” partially explained by tumour size. ⁵⁴

Our population‐based study confirms these findings. The multivariable analysis of data from four population‐based registries with complete information on stage and morphology highlights a much higher excess risk of death for nodular or acral lentiginous melanoma than for superficial spreading melanoma, after controlling for major confounders. Sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes. The different magnitude of the excess hazard ratios in Germany, Spain and Norway may be due to the low baseline hazard for superficial spreading melanoma in Germany, where national skin cancer screening for people aged 35 years or more who have health insurance was introduced in 2008. This may have improved early detection of the generally slow‐growing, less aggressive superficial spreading melanomas. ⁵⁴

Our study has also shown that while 5‐year survival from cutaneous melanoma in Eastern Europe has been increasing in recent years, survival continues to lag behind the rest of Europe for each morphological subtype of melanoma. A study of seven common malignancies diagnosed in Europe during 2000–2007 found that late stage at diagnosis alone did not explain the lower survival for melanoma of the skin in Eastern Europe. ⁵⁵ In the current study, data on stage at diagnosis in Eastern European countries were available only for Russia and Slovakia, where the proportion of metastatic disease (6% and 7%) was higher than in Norway (2%) and Denmark (3%) (data not shown). More detailed information on morphology would have helped in the investigation of the reasons for the persistent gap in survival.

The major limitation of our study was the high proportion of melanomas registered with poorly specified morphology, as this meant that the interpretation of net survival estimates for melanomas with specific morphological subtypes in all countries was limited. Information on stage at diagnosis was also limited; complete data could have contributed to the disentangling of the prognostic role of morphology at an international level. Additionally, we were not able to control for surgical margins, which are a relevant prognostic factor, as these data were not available.

Our study is the largest analysis to date of survival from cutaneous melanoma. It provides, for the first time, international comparisons of population‐based survival for the main histological subtypes of melanoma from more than 50 countries. The higher frequency and poorer survival of nodular and acral lentiginous melanomas in Asia and in Central and South America suggest the need for health policies in these populations that are designed to improve public awareness, and especially to facilitate earlier diagnosis and prompt access to optimal treatment.

Funding sources

This project was supported by the American Cancer Society, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research Foundation, Swiss Cancer League, Institut National du Cancer, La Ligue Contre le Cancer, Rossy Family Foundation, The National Cancer Institute and the Susan G. Komen Foundation.

Conflicts of interest

The authors declare they have no conflicts of interest.

Data availability

These data are provided by more than 300 cancer registries worldwide. We hold the data in trust from each of the participating registries in order to perform the analyses agreed in the protocol. The protocol prohibits us from performing other analyses and from sharing the raw data with other parties, without express approval from the participating cancer registries.

Ethics statement

This study contains the results of secondary analysis of sensitive personal data, carried out with statutory approval from the Health Research Authority and ethical approval from the National Health Service Research Ethics Service.

Author contributions

Veronica Di Carlo: Conceptualization (lead); formal analysis (lead); methodology (lead); validation (lead); visualization (lead); writing – original draft (lead). Charles Stiller: Writing – review and editing (supporting). Nora Eisemann: Writing – review and editing (supporting). Andrea Bordoni: Writing – review and editing (supporting). Melissa Matz: Writing – review and editing (supporting). Maria Paula Curado: Writing – review and editing (supporting). Laetitia Daubisse‐Marliac: Writing – review and editing (supporting). Mikhail Valkov: Writing – review and editing (supporting). Jean‐Luc Bulliard: Writing – review and editing (supporting). David Morrison: Writing – review and editing (supporting). Chris Johnson: Writing – review and editing (supporting). Fabio Girardi: Writing – review and editing (supporting). Rafael Marcos‐Gragera: Writing – review and editing (supporting). Mario Šekerija: Writing – review and editing (supporting). Siri Larønningen: Writing – review and editing (supporting). Eunice Sirri: Writing – review and editing (supporting). Michel P Coleman: Formal analysis (supporting); funding acquisition (lead); supervision (equal); validation (supporting); writing – original draft (supporting); writing – review and editing (supporting). Claudia Allemani: Conceptualization (supporting); funding acquisition (lead); investigation (supporting); methodology (supporting); validation (supporting); visualization (supporting); writing – original draft (supporting); writing – review and editing (supporting).

Supporting information

Appendix S1 CONCORD Working Group.

Table S1 Malignant melanoma of the skin: distribution by morphology group, country and calendar period of diagnosis.