The Burden of Rare Cancers in North America

Abstract

Background:

Rare cancers are difficult to study owing to their infrequent diagnosis. Using aggregate incidence data from population-based cancer registries in Europe, the Surveillance of Rare Cancers in Europe project compiled a list of clinically relevant, topography and morphology defined rare cancers operationally defined as having a crude annual incidence rate of <6 per 100,000 persons. In 2020, this list of rare cancers was updated. The objective of this study was to assess the utility of a rare cancer recode variable for use in the Cancer in North America (CiNA) dataset and to provide a first look at the burden of rare cancers in Canada and the United States.

Methods:

Data were obtained from 62 registries in Canada and the United States that met North American Association of Central Cancer Registries (NAACCR) high-quality data standards. The list of rare cancers was programmed as a Rare Cancer Classification variable within SEER*Stat. SEER*Stat was used to estimate case counts and crude and age-specific incidence rates per 100,000 for cancers diagnosed 2015–2019 by age at diagnosis, country, and country-specific geographic regions in Canada and the United States, and by race/ethnicity in the United States.

Results:

In Canada and the United States, 21% and 22% of all invasive cancers were classified as rare, respectively. The percentage of rare cancers ranged between 18% to 21% across geographic regions in Canada and the United States. Children (aged 0–14 years) had the highest percentage and lowest incidence rates of rare cancers. The percentage of rare cancers decreased, and incidence increased with increasing age. In the United States, Hispanics had the highest percentage (27%) and non-Hispanic Whites and non-Hispanic Blacks the lowest percentage (21%) of rare cancers.

Conclusions:

While individual rare cancers are infrequently diagnosed, in aggregate, they account for a substantial percentage of all cancers diagnosed in the population and pose a substantial public health burden. We report variations in percentage of rare cancers by age, and race/ethnicity (United States only). Such variations in the burden of these cancers may suggest possible areas for public health research.

Introduction

Rare cancers comprise a group of heterogenous cancers defined as having a low frequency of diagnosis in the general population. However, these cancers, in aggregate, comprise a substantial percentage of all cancers.^1-5

To standardize the definition of rare cancers, the Surveillance of Rare Cancers in Europe (RARECARE) project, in consultation with pathologists, hematologists, clinicians, and epidemiologists, used aggregate incidence data from population-based cancer registries in Europe to compile a list of clinically relevant topography- and morphology-defined rare cancers. An operational definition was proposed for rare cancers as those having an annual crude incidence rate of less than 6 cases per 100,000.² In 2020, the Joint Action on Rare Cancers (JARC), consisting of partners from health ministries, universities, public health agencies, oncological institutes, cancer registries, and patient organizations, reviewed and slightly revised the list of rare cancers and reaffirmed the operational definition of rare cancers based on a crude annual incidence rate of less than 6 cases per 100,000 population.⁶

Experts from RARECARE and JARC released a list of rare cancers grouped into 3 tiers.^2,6 The bottom tier (tier 3) comprised individual cancer entities and their corresponding ICD-O-3 topography and morphology codes.⁷ These cancer entities were then rolled up into an additional 2 tiers that grouped cancers related to medical decision-making and management. Tier 2 contained clinically distinct categories of cancers having similar diagnostic and treatment approaches that could be used as eligibility criteria for a clinical trial. Tier 2 cancers were further grouped into 68 tier 1 major cancer categories of organizational importance (eg, patient referral).² For example, the more general tier 1 category, epithelial tumors of breast, includes tier 2 category mammary Paget's disease of breast (ICD-O topography C50 and ICD-O morphology codes 8540–8541, 8543) and tier 2 category salivary gland type tumor of breast (ICD-O topography C50 and ICD-O morphology codes 8200, 8430, 8550, and 8982). This standardized definition of rare cancers that are diagnostic and clinically related for decision-making allows for consistent categorization and comparisons of rare cancers across jurisdictions such as was recently reported between the United States and the European Union.⁸

In North America, population-based cancer registries operate in all 50 states, Puerto Rico, the District of Columbia, and select regional and metropolitan areas in the United States, as well as in all 13 provinces and territories in Canada. These registries collect information on all invasive cancers diagnosed in their jurisdiction. Invasive cancers collected by the registries includes in situ bladder cancers, which are considered invasive for the purpose of incidence reporting, and excludes basal and squamous cell skin cancers. All Canadian and US registries are members of the North American Association of Central Cancer Registries (NAACCR). Each year, NAACCR compiles incidence data from member registries whose data meet high quality data standards for inclusion in the Cancer Incidence in North America (CiNA) database.⁹ CiNA data provide a unique opportunity to describe the burden of rare cancers in North America using high quality incidence data and the Rare Cancer Classification variable.

Methods

Data Source

CiNA incidence data for patients diagnosed with an invasive cancer between 2015 and 2019 were obtained from 51 registries covering 99% of the US population and 11 registries covering 74% of the Canadian population.⁹ Topography and morphology information were coded according to the third edition of the International Classification of Diseases for Oncology (ICD-O-3).⁶

Using the 2020 updated list of rare cancers, the Surveillance, Epidemiology, and End Results (SEER) Program introduced a Rare Cancer Classification variable into SEER*Stat¹⁰ that includes tier 1 and tier 2 cancer groups (https://seer.cancer.gov/siterecode/index.html). It should be noted that the Rare Cancer Classification variable includes recodes for all invasive cancers including rare, common, and other and not otherwise specified (NOS), including other morphology classifications not sufficient in number to warrant their own category or to be meaningfully grouped in separate clinically relevant categories. These classifications were applied to microscopically confirmed cases.

Statistical Analysis

CiNA data, available in SEER*Stat (version 8.4.2)¹⁰, was used to generate case counts and crude and age-specific incidence rates per 100,000 for cancers diagnosed in Canada and the United States between 2015 and 2019. Rare cancer groups (tier 1 or tier 2) were further combined into an all-rare-cancers combined group.

Incidence rates were based on corresponding country- and age-specific population estimates. The US population estimates are curated by the National Cancer Institute for the purpose of cancer surveillance and made available in SEER*Stat (https://seer.cancer.gov/data-software/uspopulations.html). Population estimates for Canada were obtained directly from Statistics Canada. For sex-specific rare cancers, incidence rates were also based on corresponding sex-specific population estimates. The percentage of rare cancers were estimated by age, geographic region within country, and, in the United States only (because Canadian registries do not collect race information), by race and ethnicity, including Hispanic, non-Hispanic White (NHW), non-Hispanic Black (NHB), non-Hispanic Asian and Pacific Islander (NHAPI), and non-Hispanic American Indian/Alaskan Native (NHAIAN). NHAIAN estimates were restricted to residents of geographic areas within which Indian Health Service care is made available to members of an identified Indian community that resides in the area.⁹ The percentage of rare cancers were expressed as the total number of microscopically confirmed rare cancers among all invasive cancers.

Results

Between 2015 and 2019, a total of 8,716,138 invasive cancer cases were diagnosed in the United States and 770,340 in Canada (Table 1). Of these cases, 8,123,869 (93.2%) were microscopically confirmed in the United States and 699,120 (90.8%) were microscopically confirmed in Canada. The majority of invasive cancer cases were identified as common (64.5% in the United States and 63.1% in Canada), followed by rare (21.5% in the United States and 20.6% in Canada), and other and NOS (5.8% in the United States and 6.0% in Canada). An additional 1.4% of cases in the United States and 1.1% of cases in Canada could not be classified as tier 1 or tier 2 cancers.

Table 1.

Number and Percent of Invasive Cancer Cases in the United States and Canada by Rare Cancer Classification, 2015–2019

	United States		Canada
	n	%	n	%
Total invasive cases	8,716,138		770,340
Microscopically confirmed	8,123,869	93.2%	699,120	90.8%
Common	5,622,673	64.5%	485,911	63.1%
Rare	1,877,726	21.5%	158,567	20.6%
Other and not otherwise specified	503,297	5.8%	46,191	6.0%
Not classified	120,173	1.4%	8,451	1.1%

Source of data: SEER*Stat Database: NAACCR Incidence Data—CiNA Research Data, 1995–2019, for Expanded Races, Standard File, Hofer—Rare cancer in North America (which includes data from CDC's National Program of Cancer Registries (NPCR), CCR's Provincial and Territorial Registries, and the NCI's Surveillance, Epidemiology and End Results (SEER) Registries), certified by the North American Association of Central Cancer Registries (NAACCR) as meeting high-quality incidence data standards for the specified time periods, submitted December 2021. United States: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, District of Columbia, Florida, Georgia, Hawaii, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Mississippi, Minnesota, Missouri, Montana, Nebraska, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia, Wisconsin, Wyoming. Canada: Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territory, Nunavut, Ontario, Prince Edward Island, Saskatchewan, Yukon. Note: These registries cover 99% and 74% of the United States and Canadian population, respectively.

Approximately 375,545 and 31,713 rare cancers were diagnosed annually in the United States and Canada, respectively. Cases of rare cancers were distributed among 68 tier 1 and 234 tier 2 groups in both Canada and the United States (Table 2). Similar results were observed in both countries with one exception. Among these groups, two tier 2 groups were either rare in the United States or Canada but not in both countries based on crude annual incidence rates: squamous cell carcinoma with variants of oropharynx (6.3 and 5.1 per 100,000, respectively) and adenocarcinoma with variants of stomach (5.6 and 7.7 per 100,000, respectively).

Table 2.

Average Annual Cancer Cases and Crude Incidence Rates Classified According to Rare Cancer Site Recode Variable, Canada and the United States, 2015–2019

Rare Cancer Site Recode	United States			Canada
	Averaged annual		Class.*	Averaged annual		Class.
	Rate	No.		Rate	No.
1 EPITHELIAL TUMORS OF NASAL CAVITY AND SINUSES
1.1 Squamous cell carcinoma with variants of nasal cavity and sinuses	0.396	6,436	R	0.421	575	R
1.2 Lymphoepithelial carcinoma of nasal cavity and sinuses	0.001	19	R	0.001	1	R
1.3 Undifferentiated carcinoma of nasal cavity and sinuses	0.027	440	R	0.031	42	R
1.4 Intestinal type adenocarcinoma of nasal cavity and sinuses	0.006	104	R	0.015	20	R
1.5 Other epithelial tumors of nasal cavity and sinuses	0.032	513	O	0.041	56	O
2 EPITHELIAL TUMORS OF NASOPHARYNX
2.1 Squamous cell carcinoma with variants of nasopharynx	0.450	7,304	R	0.636	869	R
2.2 Papillary adenocarcinoma of nasopharynx	0.001	24	R	0.001	1	R
2.3 Other epithelial tumors of nasopharynx	0.081	1,312	O	0.122	167	O
3 EPITHELIAL TUMORS OF MAJOR SALIVARY GLANDS AND SALIVARY-GLAND TYPE TUMORS
3.1 Epithelial tumor of major salivary glands	1.400	22,744	R	1.434	1,960	R
3.2 Salivary gland type tumor of head and neck	0.450	7,310	R	0.471	643	R
4 EPITHELIAL TUMORS OF HYPOPHARYNX AND LARYNX
4.1 Squamous cell carcinoma with variants of hypopharynx	0.674	10,953	R	0.536	732	R
4.2 Squamous cell carcinoma with variants of larynx	3.625	58,868	R	2.500	3,416	R
4.3 Other epithelial tumors of hypopharynx and larynx	0.053	867	O	0.040	54	O
5 EPITHELIAL TUMORS OF OROPHARYNX
5.1 Squamous cell carcinoma with variants of oropharynx	6.276	101,932	C	5.119	6,996	R
5.2 Other epithelial tumors of oropharynx	0.056	911	O	0.054	74	O
6 EPITHELIAL TUMORS OF ORAL CAVITY AND LIP
6.1 Squamous cell carcinoma with variants of oral cavity	3.888	63,148	R	4.235	5,787	R
6.2 Squamous cell carcinoma with variants of lip	0.551	8,950	R	0.858	1,173	R
6.3 Other epithelial tumors of oral cavity and lip	0.046	742	O	0.070	96	O
7 EPITHELIAL TUMORS OF ESOPHAGUS
7.1 Squamous cell carcinoma with variants of esophagus	1.499	24,342	R	1.767	2,415	R
7.2 Adenocarcinoma with variants of esophagus	3.592	58,340	R	3.677	5,025	R
7.3 Salivary gland type tumor of esophagus	0.001	18	R	0.000	0	R
7.4 Undifferentiated carcinoma of esophagus	0.005	78	R	0.016	22	R
7.5 Other epithelial tumors of esophagus	0.154	2,508	O	0.169	231	O
8 EPITHELIAL TUMORS OF STOMACH
8.1 Adenocarcinoma with variants of stomach	5.608	91,076	R	7.697	10,518	C
8.2 Squamous cell carcinoma with variants of stomach	0.079	1,283	R	0.128	175	R
8.3 Salivary gland-type tumor of stomach	0.000	4	R	0.000	0	R
8.4 Undifferentiated carcinoma of stomach	0.005	76	R	0.020	28	R
8.5 Other epithelial tumors of stomach	0.179	2,901	O	0.283	387	O
9 EPITHELIAL TUMORS OF SMALL INTESTINE
9.1 Adenocarcinoma with variants of small intestine	0.855	13,892	R	1.086	1,484	R
9.2 Squamous cell carcinoma with variants of small intestine	0.006	97	R	0.017	23	R
9.3 Other epithelial tumors of small intestine	0.038	617	O	0.085	116	O
10 EPITHELIAL TUMORS OF COLON (including appendix)
10.1 Adenocarcinoma with variants of colon	30.313	492,333	C	40.299	55,071	C
10.2 Squamous cell carcinoma with variants of colon	0.023	372	R	0.018	25	R
10.3 Fibromixoma and low grade mucinous adenocarcinoma of the appendix	0.344	5,593	R	0.345	471	R
10.4 Other epithelial tumors of colon (including appendix)	0.469	7,621	O	0.431	589	O
11 EPITHELIAL TUMORS OF RECTUM
11.1 Adenocarcinoma with variants of rectum	8.284	134,538	C	13.886	18,976	C
11.2 Squamous cell carcinoma with variants of rectum	0.295	4,792	R	0.138	188	R
11.3 Other epithelial tumors of rectum	0.132	2,144	O	0.162	222	O
12 EPITHELIAL TUMORS OF ANAL CANAL
12.1 Squamous cell carcinoma with variants of anal canal	2.046	33,232	R	1.766	2,413	R
12.2 Adenocarcinoma with variants of anal canal	0.214	3,477	R	0.263	359	R
12.3 Pagets disease of anal canal	0.006	102	R	0.020	27	R
12.4 Other epithelial tumors of anal canal	0.027	446	O	0.022	30	O
13 EPITHELIAL TUMORS OF PANCREAS
13.1 Adenocarcinoma with variants of pancreas	11.865	192,699	C	8.975	12,265	C
13.2 Squamous cell carcinoma with variants of pancreas	0.036	591	R	0.029	40	R
13.3 Acinar cell carcinoma of pancreas	0.044	720	R	0.031	42	R
13.4 Mucinous cystadenocarcinoma of pancreas (invasive)	0.008	128	R	0.006	8	R
13.5 Intraductal papillary mucinous carcinoma invasive of pancreas	0.047	759	R	0.070	96	R
13.6 Solid pseudopapillary carcinoma of pancreas	0.053	867	R	0.027	37	R
13.7 Serous cystadenocarcinoma of pancreas	0.000	8	R	0.000	0	R
13.8 Carcinoma with osteoclast-like giant cells of pancreas	0.008	123	R	0.007	9	R
13.9 Other epithelial tumors of pancreas	0.221	3,589	O	0.164	224	O
14 EPITHELIAL TUMORS OF LIVER AND INTRAHEPATIC BILE TRACT (IBT)
14.1 Hepatocellular carcinoma of Liver and IBT	4.241	68,874	R	3.117	4,259	R
14.2 Hepatocellular carcinoma, fibrolamellar	0.019	307	R	0.013	18	R
14.3 Cholangiocarcinoma of IBT	1.546	25,115	R	1.290	1,763	R
14.4 Adenocarcinoma with variants of liver and IBT	0.336	5,460	R	0.411	562	R
14.5 Undifferentiated carcinoma of liver and IBT	0.002	26	R	0.004	6	R
14.6 Squamous cell carcinoma with variants of liver and IBT	0.007	110	R	0.007	10	R
14.7 Bile duct cystadenocarcinoma of IBT	0.001	18	R	0.001	1	R
14.8 Other epithelial tumors of liver and intrahepatic bile tract (IBT)	0.114	1,844	O	0.083	114	O
15 EPITHELIAL TUMORS OF GALLBLADDER AND EXTRAHEPATIC BILIARY TRACT (EBT)
15.1 Adenocarcinoma with variants of gallbladder	1.085	17,623	R	1.024	1,399	R
15.2 Adenocarcinoma with variants of EBT	1.761	28,607	R	2.645	3,615	R
15.3 Squamous cell carcinoma of gallbladder and EBT	0.025	412	R	0.019	26	R
15.4 Oth epithelial tumors of gallbladder and extrahepatic biliary tract (EBT)	0.099	1,600	O	0.207	283	O
16 EPITHELIAL TUMORS OF TRACHEA
16.1 Squamous cell carcinoma with variants of trachea	0.036	580	R	0.047	64	R
16.2 Adenocarcinoma with variants of trachea	0.002	39	R	0.013	18	R
16.3 Salivary gland type tumor of trachea	0.010	165	R	0.014	19	R
16.4 Other epithelial tumors of trachea	0.002	35	O	0.013	18	O
17 EPITHELIAL TUMORS OF LUNG
17.1 Squamous cell carcinoma with variants of lung	14.625	237,529	C	11.668	15,945	C
17.2 Adenocarcinoma with variants of lung	29.404	477,557	C	31.231	42,680	C
17.3 Adenosquamous carcinoma of lung	0.679	11,035	R	0.421	576	R
17.4 Large cell carcinoma of lung	0.239	3,879	R	0.239	327	R
17.5 Poorly differentiated endocrine carcinoma of lung	9.496	154,225	C	7.999	10,931	C
17.6 Salivary gland type tumor of lung	0.053	868	R	0.043	59	R
17.7 Sarcomatoid carcinoma of lung	0.413	6,710	R	0.327	447	R
17.8 Other epithelial tumors of lung	4.482	72,792	O	5.354	7,317	O
18 EPITHELIAL TUMORS OF THYMUS
18.1 Malignant thymoma	0.301	4,892	R	0.334	457	R
18.2 Squamous cell carcinoma of thymus	0.044	720	R	0.060	82	R
18.3 Adenocarcinoma with variants of thymus	0.007	113	R	0.012	17	R
18.4 Other epithelial tumors of thymus	0.013	205	O	0.011	15	O
19 EPITHELIAL TUMORS OF BREAST
19.1 Inv carcinoma of no special type-NST (obs Invasive ductal carc of breast)	65.047	1,056,462	C	63.746	87,114	C
19.2 Invasive lobular carcinoma of breast	8.053	130,798	C	6.929	9,469	C
19.3 Mammary Pagets disease of breast	0.177	2,876	R	0.376	514	R
19.4 Special types of adenocarcinoma of breast	2.536	41,183	R	2.661	3,637	R
19.5 Metaplastic carcinoma of breast	0.448	7,283	R	0.544	743	R
19.6 Salivary gland type tumor of breast	0.076	1,229	R	0.053	73	R
19.7 Other epithelial tumors of breast	1.703	27,658	O	1.603	2,191	O
20 EPITHELIAL TUMORS OF CORPUS UTERI (female cases)
20.1 Adenocarcinoma with variants of corpus uteri	27.419	226,143	C	30.333	20,889	C
20.2 Squamous cell carcinoma with variants of corpus uteri	0.081	672	R	0.049	34	R
20.3 Adenoid cystic carcinoma of corpus uteri	0.000	0	R	0.000	0	R
20.4 Clear cell adenocarcinoma, NOS	0.483	3,986	R	0.508	350	R
20.5 Serous (papillary) carcinoma	2.755	22,721	R	2.814	1,938	R
20.6 Mullerian mixed tumor	1.642	13,544	R	1.342	924	R
20.7 Other epithelial tumors of corpus uteri	0.396	3,267	O	0.556	383	O
21 EPITHELIAL TUMORS OF CERVIX UTERI (female cases)
21.1 Squamous cell carcinoma with variants of cervix uteri	5.096	42,027	R	5.564	3,832	R
21.2 Adenocarcinoma with variants of cervix uteri	1.967	16,226	R	2.139	1,473	R
21.3 Undifferentiated carcinoma of cervix uteri	0.008	67	R	0.003	2	R
21.4 Mullerian mixed tumor of cervix uteri	0.048	392	R	0.023	16	R
21.5 Other epithelial tumors of cervix uteri	0.452	3,725	O	0.369	254	O
22 EPITHELIAL TUMORS OF OVARY AND FALLOPPIAN TUBE (female cases)
22.1 Adenocarcinoma with variants of ovary	8.425	69,488	C	10.085	6,945	C
22.2 Mucinous adenocarcinoma of ovary	0.654	5,390	R	0.754	519	R
22.3 Clear cell adenocarcinoma of ovary	0.683	5,629	R	1.000	689	R
22.4 Primary peritoneal serous/papillary carcinoma	0.679	5,604	R	0.378	260	R
22.5 Mullerian mixed tumor of ovary and falloppian tube	0.466	3,846	R	0.392	270	R
22.6 Adenocarcinoma with variants of fallopian tube	1.489	12,283	R	1.208	832	R
22.7 Other epithelial tumors of ovary and falloppian tube	0.756	6,239	O	0.575	396	O
23 NON EPITHELIAL TUMORS OF OVARY (female cases)
23.1 Sex cord tumor of ovary	0.303	2,499	R	0.177	122	R
23.2 Malignant/Immature teratoma of ovary	0.115	947	R	0.154	106	R
23.3 Germ cell tumor of ovary	0.188	1,552	R	0.163	112	R
23.4 Other non epithelial tumors of ovary	0.000	1	O	0.000	0	O
24 EPITHELIAL TUMORS OF VULVA AND VAGINA (female cases)
24.1 Squamous cell carcinoma with variants of vulva and vagina	3.321	27,394	R	4.213	2,901	R
24.2 Adenocarcinoma with variants of vulva and vagina	0.183	1,507	R	0.331	228	R
24.3 Pagets disease of vulva and vagina	0.167	1,376	R	0.274	189	R
24.4 Undifferentiated carcinoma of vulva and vagina	0.001	9	R	0.001	1	R
24.5 Mullerian mixed tumor of vulva and vagina	0.012	99	R	0.015	10	R
24.6 Other epithelial tumors of vulva and vagina	0.078	644	O	0.102	70	O
25 TROPHOBLASTIC TUMORS OF PLACENTA (female cases)
25.1 Choriocarcinoma of placenta	0.045	372	R	0.036	25	R
25.2 Other trophoblastic tumors of placenta	0.011	89	O	0.006	4	O
26 EPITHELIAL TUMORS OF PROSTATE (male cases)
26.1 Adenocarcinoma with variants of prostate	127.317	1,017,764	C	117.777	79,843	C
26.2 Squamous cell carcinoma with variants of prostate	0.014	113	R	0.022	15	R
26.3 Infiltrating duct carcinoma of prostate	0.258	2,060	R	0.353	239	R
26.4 Transitional cell carcinoma of prostate	0.017	139	R	0.022	15	R
26.5 Basal cell adenocarcinoma of prostate	0.004	34	R	0.004	3	R
26.6 Other epithelial tumors of prostate	1.380	11,032	O	0.850	576	O
27 TESTICULAR AND PARATESTICULAR CANCERS (male cases)
27.1 Paratesticular adenocarcinoma with variants	0.001	9	R	0.004	3	R
27.2 Non seminomatous testicular cancer	2.385	19,063	R	2.548	1,727	R
27.3 Seminomatous testicular cancer	2.877	22,995	R	3.543	2,402	R
27.4 Spermatocytic seminoma	0.021	247	R	0.066	45	R
27.5 Teratoma with malignant transformation	0.003	23	R	0.009	6	R
27.6 Testicular sex cord cancer	0.042	332	R	0.038	26	R
27.7 Other testicular and paratesticular cancers	0.129	1,035	O	0.068	46	O
28 EPITHELIAL TUMORS OF PENIS (male case)
28.1 Squamous cell carcinoma with variants of penis	0.890	7,115	R	1.242	842	R
28.2 Adenocarcinoma with variants of penis	0.008	63	R	0.024	16	R
28.3 Other epithelial tumors of penis	0.014	110	O	0.024	16	O
29 EPITHELIAL TUMORS OF KIDNEY
29.1 Renal cell carcinoma with variants	16.895	274,398	C	14.882	20,338	C
29.2 Squamous cell carcinoma spindle cell type of kidney	0.005	81	R	0.010	14	R
29.3 Squamous cell carcinoma with variants of kidney	0.012	192	R	0.024	33	R
29.4 Other epithelial tumors of the kidney	0.145	2,355	O	0.244	334	O
30 EPITHELIAL TUMORS OF PELVIS AND URETER
30.1 Transitional cell carcinoma of pelvis and ureter	1.666	27,062	R	1.455	1,989	R
30.2 Squamous cell carcinoma with variants of pelvis and ureter	0.022	354	R	0.017	23	R
30.3 Adenocarcinoma with variants of pelvis and ureter	0.018	289	R	0.032	44	R
30.4 Other epithelial tumors of pelvis and ureter	0.028	455	O	0.044	60	O
31 EPITHELIAL TUMORS OF URETHRA				0.138
31.1 Transitional cell carcinoma of urethra	0.084	1,365	R	0.072	98	R
31.2 Squamous cell carcinoma with variants of urethra	0.045	724	R	0.039	53	R
31.3 Adenocarcinoma with variants of urethra	0.033	532	R	0.016	22	R
31.4 Other epithelial tumors of urethra	0.008	124	O	0.011	15	O
32 EPITHELIAL TUMORS OF BLADDER
32.1 Transitional cell carcinoma of bladder	21.720	352,767	C	26.809	36,637	C
32.2 Squamous cell carcinoma with variants of bladder	0.296	4,807	R	0.234	320	R
32.3 Adenocarcinoma with variants of bladder	0.196	3,183	R	0.217	296	R
32.4 Salivary gland type tumor of bladder	0.000	0	R	0.000	0	R
32.5 Other epithelial tumors of bladder	0.344	5,584	O	0.263	359	O
33 EPITHELIAL TUMORS OF EYE AND ADNEXA
33.1 Squamous cell carcinoma with variants of eye and adnexa	0.087	1,418	R	0.111	152	R
33.2 Adenocarcinoma with variants of eye and adnexa	0.021	339	R	0.029	39	R
33.3 Other epithelial tumors of eye and adnexa	0.013	204	O	0.013	18	O
34 EPITHELIAL TUMORS OF MIDDLE EAR
34.1 Squamous cell carcinoma with variants middle ear	0.008	134	R	0.010	14	R
34.2 Adenocarcinoma with variants of middle ear	0.003	56	R	0.000	0	R
34.3 Other Adenocarcinoma with variants of middle ear	0.001	11	O	0.000	0	O
35 MALIGNANT MESOTHELIOMA
35.1 Mesothelioma of pleura and pericardium	0.724	11,760	R	1.220	1,667	R
35.2 Mesothelioma of peritoneum and tunica vaginalis	0.112	1,822	R	0.152	208	R
35.3 Other malignant mesothelioma	0.052	846	O	0.020	28	O
36 MALIGNANT SKIN MELANOMA
36.1 Superficial spreading melanoma	9.489	154,123	C	8.397	11,475	C
36.2 Nodular melanoma	2.007	32,599	R	2.705	3,697	R
36.3 Lentigo maligna melanoma	1.975	32,083	R	1.768	2,416	R
36.4 Acral lentiginous melanoma malignant	0.274	4,451	R	0.310	424	R
36.5 Other malignant skin melanoma	12.508	203,145	O	11.587	15,834	O
37 MALIGNANT MELANOMA OF MUCOSA AND EXTRACUTANEOUS	0.200	3,251	R	0.258	353	R
38 MALIGNANT MELANOMA OF EYE
38.1 Malignant melanoma of conjunctiva	0.037	599	R	0.050	68	R
38.2 Malignant melanoma of uvea	0.330	5,353	R	0.251	343	R
38.3 Other malignant melanoma of eye	0.025	400	O	0.023	31	O
39 EPITHELIAL TUMORS OF SKIN
39.1 Basal cell carcinoma of skin	0.011	178	R	0.021	29	R
39.2 Squamous cell carcinoma with variants of skin	0.035	566	R	0.031	43	R
39.3 Other epithelial tumors of skin	0.006	104	O	0.009	12	O
40 ADNEXAL CARCINOMAS OF SKIN
40.1 Nodular hidradenoma, malignant	0.023	370	R	0.020	27	R
40.2 Sebaceous adenocarcinoma	0.244	3,970	R	0.279	381	R
40.3 Adenoid cystic carcinoma	0.018	293	R	0.053	73	R
40.4 Pagets disease extramammary	0.058	946	R	0.107	146	R
40.5 Apocrine adenocarcinoma	0.013	211	R	0.026	35	R
40.6 Mucinous adenocarcinoma	0.035	561	R	0.031	43	R
40.7 Pilomatrix carcinoma	0.000	0	R	0.000	0	R
40.8 Eccrine poroma, malignant	0.061	986	R	0.106	145	R
40.9 Mixed tumor malignant, NOS	0.003	56	R	0.006	8	R
40.10 Sclerosing sweat duct carcinoma	0.034	550	R	0.081	111	R
40.11 Malignant eccrine spiradenoma	0.006	97	R	0.013	18	R
40.12 Tubular adenocarcinoma	0.000	0	R	0.000	0	R
40.13 Eccrine papillary adenocarcinoma	0.014	229	R	0.023	31	R
40.14 Other adnexal carcinomas of skin	0.141	2,295	O	0.247	338	O
41 NEUROBLASTOMA AND GANGLIONEUROBLASTOMA	0.205	3,323	R	0.173	236	R
42 NEPHROBLASTOMA	0.147	2,383	R	0.120	164	R
43 EMBRYONAL TUMORS OF EYE
43.1 Retinoblastoma	0.046	742	R	0.020	28	R
43.2 Medulloepithelioma	0.000	4	R	0.000	0	R
44 HEPATOBLASTOMA	0.049	798	R	0.036	49	R
45 PLEUROPULMONARY BLASTOMA	0.007	113	R	0.005	7	R
46 PANCREATOBLASTOMA	0.002	36	R	0.002	3	R
47 OLFACTORY NEUROBLASTOMA	0.054	869	R	0.048	65	R
48 ODONTOGENIC MALIGNANT TUMORS
48.1 Odontogenic tumor, malignant	0.008	130	R	0.009	12	R
48.2 Clear cell odontogenic carcinoma	0.001	12	R	0.002	3	R
48.3 Ghost cell odontogenic carcinoma	0.000	5	R	0.000	0	R
48.4 Other odontogenic malignant tumors	0.015	238	O	0.010	13	O
49 EXTRAGONADAL GERM CELL TUMORS
49.1 Non seminomatous germ cell tumor	0.092	1,494	R	0.088	120	R
49.2 Seminomatous germ cell tumor	0.018	285	R	0.016	22	R
49.3 Germ cell tumor of Central Nervous System (CNS)	0.061	985	R	0.069	94	R
49.4 Other extragonadal germ cell tumors	0.018	288	O	0.015	20	O
50 SOFT TISSUE SARCOMA
50.1 Soft tissue sarcoma of head and neck	0.328	5,332	R	0.327	447	R
50.2 Soft tissue sarcoma of limbs	1.607	26,095	R	1.698	2,321	R
50.3 Soft tissue sarcoma of superficial trunk	0.785	12,743	R	0.757	1,035	R
50.4 Soft tissue sarcoma of mediastinum	0.031	498	R	0.031	42	R
50.5 Soft tissue sarcoma of heart	0.025	414	R	0.020	28	R
50.6 Soft tissue sarcoma of breast	0.208	3,375	R	0.279	381	R
50.7 Soft tissue sarcoma of uterus	0.678	11,018	R	0.658	899	R
50.8 Soft tissue sarcoma of paratestis	0.047	763	R	0.073	100	R
50.9 Soft tissue sarcomas of other genitourinary tract	0.165	2,677	R	0.196	268	R
50.10 Soft tissue sarcoma of viscera	0.259	4,212	R	0.222	304	R
50.11 Soft tissue sarcoma of retroperitoneum and peritoneum	0.409	6,646	R	0.501	684	R
50.12 Soft tissue sarcoma of pelvis	0.338	5,497	R	0.351	480	R
50.13 Soft tissue sarcoma of skin	0.544	8,830	R	0.914	1,249	R
50.14 Soft tissue sarcoma of paraorbit	0.007	114	R	0.008	11	R
50.15 Soft tissue sarcoma of brain and other parts of the nervous system	0.123	2,001	R	0.121	166	R
50.16 Embryonal rhabdomyosarcoma of soft tissue	0.076	1,231	R	0.072	98	R
50.17 Alveolar rhabdomyosarcoma of soft tissue	0.048	773	R	0.051	70	R
50.18 Ewings sarcoma of soft tissue	0.086	1,397	R	0.093	127	R
50.19 Other soft tissue sarcoma	0.249	4,045	O	0.165	225	O
51 BONE SARCOMA
51.1 Osteogenic sarcoma	0.290	4,707	R	0.276	377	R
51.2 Chondrogenic sarcoma	0.281	4,562	R	0.330	451	R
51.3 Notochordal sarcoma, chordoma	0.112	1,812	R	0.124	170	R
51.4 Vascular sarcoma	0.015	245	R	0.019	26	R
51.5 Ewings sarcoma	0.133	2,160	R	0.112	153	R
51.6 Other high grade sarcomas (fibrosarcoma, malignant fibrous histiocytoma)	0.010	162	R	0.004	6	R
51.7 Other bone sarcoma	0.102	1,649	O	0.074	101	O
52 GASTROINTESTINAL STROMAL SARCOMA	1.215	19,733	R	0.895	1,223	R
53 KAPOSIS SARCOMA	0.318	5,159	R	0.252	344	R
54 NET GEP
54.1 Well diff not functioning endocrine carc of pancreas and digestive tract	5.406	87,809	R	4.813	6,578	R
54.2 Well diff functioning endocrine carc of pancreas and digestive tract	0.013	219	R	0.029	40	R
54.3 Poorly differentiated endocrine carcinoma of pancreas and digestive tract	1.419	23,048	R	1.630	2,228	R
54.4 Malignant mixed pancreatic endocrine and exocrine tumor	0.011	173	R	0.005	7	R
54.5 Other NET GEP	0.000	0	O	0.000	0	O
55 NET LUNG/TYPICAL AND ATYPICAL CARCINOID OF THE LUNG	1.290	20,949	R	1.191	1,627	R
56 NET OTHER SITES
56.1 Pheochromocytoma, malignant	0.034	548	R	0.032	44	R
56.2 Paraganglioma	0.031	509	R	0.026	36	R
56.3 Endocrine carcinoma of thyroid gland	0.282	4,578	R	0.250	341	R
56.4 Neuroendocrine carcinoma of skin	0.839	13,629	R	0.833	1,139	R
56.5 Neuroendocrine carcinoma of other sites	1.559	25,325	R	1.013	1,385	R
57 CARCINOMAS OF PITUITARY GLAND
57.1 Pituitary carcinoma	0.004	58	R	0.004	5	R
57.2 Other carcinomas of pituitary gland	0.002	30	O	0.004	5	O
58 CARCINOMAS OF THYROID GLAND
58.1 Papillary adenocarcinoma, NOS	8.753	142,164	C	8.571	11,713	C
58.2 Follicular carcinoma, NOS	0.495	8,045	R	0.254	347	R
58.3 Undifferentiated/anaplastic carcinoma	0.141	2,285	R	0.135	185	R
58.4 Mucoepidermoid carcinoma	0.002	36	R	0.001	2	R
58.5 Mucinous carcinoma	0.000	1	R	0.000	0	R
58.6 Spindle cell tumor with thymus-like differentiation (SETTLE)	0.000	6	R	0.001	2	R
58.7 Carcinoma showing thymus-like differentiation (CASTLE)	0.000	3	R	0.001	1	R
58.8 Other carcinomas of thyroid gland	4.967	80,671	O	7.245	9,901	O
59 CARCINOMAS OF PARATHYROID GLAND	0.027	445	R	0.032	44	R
60 CARCINOMAS OF ADRENAL CORTEX
60.1 Adrenal cortical carcinoma	0.120	1,943	R	0.147	201	R
60.2 Other carcinomas of adrenal cortex	0.021	341	O	0.045	62	O
61 TUMORS OF CENTRAL NERVOUS SYSTEM (CNS)
61.1 Astrocytic tumors of CNS	4.803	78,015	R	5.002	6,835	R
61.2 Oligodendroglial tumors of CNS	0.335	5,442	R	0.448	612	R
61.3 Ependymal tumors of CNS	0.216	3,514	R	0.192	263	R
61.4 Neuronal and mixed neuronal-glial tumors	0.009	145	R	0.016	22	R
61.5 Choroid plexus carcinoma of CNS	0.007	118	R	0.003	4	R
61.6 Malignant meningiomas	0.078	1,262	R	0.080	110	R
61.7 Tumors of the pineal gland	0.027	440	R	0.026	36	R
61.8 Other tumors of central nervous system (CNS)	0.031	509	O	0.023	31	O
62 EMBRYONAL TUMORS OF CNS
62.1 Medulloblastoma	0.090	1,456	R	0.088	120	R
62.2 Desmoplastic nodular medulloblastoma	0.027	431	R	0.024	33	R
62.3 Medulloblastoma, large cell/anaplastic	0.010	169	R	0.010	13	R
62.4 Medulloblastoma, WNT-activated	0.002	30	R	0.003	4	R
62.5 Medulloblastoma, SHH-activated and TP53-mutant	0.001	15	R	0.000	0	R
62.6 Medulloblastoma, non-WNT/non-SHH	0.008	138	R	0.004	6	R
62.7 CNS Embryonal tumor, NOS	0.014	235	R	0.014	19	R
62.8 CNS ganglioneuroblastoma	0.002	34	R	0.004	5	R
62.9 CNS neuroblastoma	0.009	152	R	0.010	13	R
62.10 CNS embryonal tumor with rhabdoid features	0.024	393	R	0.021	29	R
62.11 Medulloepithelioma, NOS	0.001	10	R	0.000	0	R
62.12 Embryonal tumor with multilayered rosettes, C19MC-related/NOS	0.002	29	R	0.001	2	R
62.13 Other embryonal tumors of CNS	0.003	56	O	0.001	1	O
63 LYMPHOID DISEASES
63.1 Hodgkin lymphoma, classical	2.581	41,922	R	2.537	3,467	R
63.2 Hodgkin lymphoma nodular lymphocyte predominance	0.231	3,753	R	0.259	354	R
63.3 Precursor B/T lymphoblastic leukemia/lymphoblastic lymphoma (and Burkitt)	2.126	34,537	R	1.645	2,248	R
63.4 T cutaneous lymphoma (Sezary syn, Mycosis fung)	0.858	13,936	R	0.979	1,338	R
63.5 Other T cell lymphomas and NK cell neoplasms	1.297	21,061	R	1.464	2,000	R
63.6 Diffuse B lymphoma	8.108	131,678	C	8.849	12,093	C
63.7 Follicular B lymphoma	4.012	65,162	R	5.109	6,982	R
63.8 Hairy cell leukemia	0.302	4,901	R	0.350	478	R
63.9 Plasmacytoma/Multiple Myeloma (and Heavy chain diseases)	7.691	124,906	C	6.759	9,237	C
63.10 Other non Hodgkin, Mature B cell lymphoma	9.308	151,169	C	10.078	13,772	C
63.11 Mantle cell lymphoma	1.033	16,777	R	1.016	1,389	R
63.12 Prolymphocytic leukemia, B cell	0.032	513	R	0.024	33	R
63.13 Other lymphoid diseases	2.120	34,431	O	2.072	2,832	O
64 ACUTE MYELOID LEUKEMIA AND RELATED PRECURSOR NEOPLASMS
64.1 Acute promyelocytic leukemia (AML with t(15;17) with variants	0.345	5,603	R	0.242	331	R
64.2 AML	4.767	77,422	R	4.491	6,137	R
65 MYELOID AND LYMPHOID NEOPLASMS	0.133	2,168	R	0.091	125	R
66 MYELOPROLIFERATIVE NEOPLASMS
66.1 Chronic myeloid leukemia	1.447	23,499	R	1.182	1,615	R
66.2 Other myeloproliferative neoplasms	2.856	46,382	R	2.847	3,891	R
66.3 Mast cell tumor	0.063	1,025	R	0.134	183	R
67 MYELODYSPLASTIC SYNDROME AND MYELODYSPLASTIC/MYELOPROLIFERATIVE DISEASES
67.1 Myelodysplastic syndrome with 5q syndrome	0.191	3,098	R	0.083	113	R
67.2 Other myelodysplastic syndrome	3.786	61,497	R	3.419	4,672	R
67.3 Chronic Myelomonocytic leukemia	0.554	8,995	R	0.727	993	R
67.4 Atypical chronic myeloid leukemia BCR/ABL negative	0.028	448	R	0.025	34	R
67.5 Other myelodysplastic syn and myelodysplastic/myeloproliferative diseases	0.682	11,069	O	1.494	2,042	O
68 HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS
68.1 Histiocytic malignancies	0.200	3,241	R	0.147	201	R
68.2 Lymph node accessory cell tumors	0.038	618	R	0.039	53	R
69 Not Classified	7.399	120,173		6.184	8,451

Rates are per 100,000.

^*C, common;

R, rare; O, other and not otherwise specified.

In North America, children under the age of 5 years had the highest percentage of rare cancers (Figure 1). For each increasing 5-year age group, the percentage of rare cancers decreased until it stabilized at approximately 20% at age ≥55 years. Age-specific incidence of rare cancers increased with age for both all invasive cancers and all rare cancers, although the incidence of all invasive cancers was nearly 5-fold higher than that for rare cancers in the older age groups.

Figure 1.

Percent of All Rare Cancers Among All Invasive Cancers and Age-Specific Incidence Rates of Rare Cancers by Age Group, North America, 2015–2019

The percentage of rare cancers among all invasive cancers ranged from 18.4% in the Atlantic region of Canada to 20.9% in the western region of the United States (Figure 2).

Figure 2.

Percent of Rare Cancers Among All Invasive Cancers by Geographic Region, North America, 2015–2019

In the United States, Hispanics of any race had the highest percentage of rare cancers (26.9%), followed by NHAPI (24.9%), NHAIAN (23.4%), NHB (21.1%), and NHW (20.9%) (Figure 3).

Figure 3.

Percent of Rare Cancers Among All Invasive Cancers by Race/Ethnicity, United States, 2015–2019

Discussion

While individual rare cancers are infrequently diagnosed, in aggregate, rare cancers account for a substantial percentage of all cancers diagnosed. These cancers pose a substantial public health burden in the United States and Canada. Patients are often diagnosed at a later stage of disease and have worse outcomes than patients diagnosed with many of the more common cancers.^2,3,5 This is likely due to delays in accurate diagnosis, inadequate treatments, and fewer opportunities for patients to participate in clinical trials.^11,12 And the burden of rare cancers will likely increase as more molecular subsets of common cancers are identified and differentiated clinically.¹³

Using the operational definition and list of rare cancers proposed by RARECARE and updated by JARC as a standard definition, the percentage of rare cancers among all invasive cases in Canada and the United States was 21% and 22%, respectively, and comparable to that previously reported in the United States^1,3, Europe ², and Australia.⁵ The consistency of the percentages of rare cancers in different populations worldwide, including geographic areas within Canada and the United States, and the relatively low overall incidence of these cancers across all age groups does not support a strong role for exogenous factors in elevating a patient's risk for developing a rare cancer. The fact that rare cancers disproportionately impact younger ages may indicate more of a genetic component that would benefit from clinically relevant genomic assessments.¹³

Differences seen in the percentage of rare cancers by race and ethnicity in the United States is consistent with that reported by DeSantis.³ However, caution is advised when interpreting population-based proportional differences. A higher percentage of rare cancers may result when there is a higher incidence of these cancers or when there is a lower incidence of common cancers. For instance, the incidence of common cancers of the colon, breast, prostate, lung, and bladder increases with increasing age and varies by race and ethnicity in the United States.⁹ Variation in the incidence of common cancers may contribute to the disproportionate percentage of rare cancer observed in different racial and ethnic populations.

CiNA data is a comprehensive source of high-quality cancer incidence data covering 99% of the US population and 74% of the Canadian population. Incidence data from NAACCR member registries is comparable because all registries use standardized procedures for the collection and reporting of incidence data.¹⁴ Each year, incidence data from member registries are evaluated to assess the quality, accuracy, and completeness of their data. Unusual topography and morphology combinations are flagged for manual review and verified by registry staff prior to data submission. Only data meeting high quality standards are pooled for inclusion in the CiNA research file. The low percentage of death-certificate only cases (1.8% in the United States and 1.0% in Canada, data not shown), the high level of microscopically confirmed cases (93% in the United States and 90% in Canada), and low percentage of cases not able to be classified (Table 1 and Table 2) attest to the quality and completeness of CiNA data.

However, our case counts likely reflect undercounts of the true burden of rare cancers in the population. The identification of rare cancers requires accurate and specific morphology information. The other and NOS group within the tier 1 cancer groups included nonspecific morphology codes (ie, ICD-O-3 8000-8001) that resulted in the cancer case not being assigned to a common or rare cancer group. The absence of specific morphology information may be due to a lack of such information being available or collected in the clinical setting, or because this information was not transmitted to the cancer registry. The inclusion of even a small number of additional cases could result in some tier 2 rare cancer groups being reassigned as common cancers. The threshold of less than 6 per 100,000 for defining rare cancers is arbitrary as demonstrated: two tier 2 groups were rare in either Canada or the United States, but not in both countries. However, the incidence of these cancers was similar in both countries. The cancer registry community should continue efforts to obtain detailed pathology information as available and to limit the use of nonspecific codes as much as possible

Furthermore, this study only included microscopically confirmed invasive cancer cases. Additional assessment is needed to describe the burden of rare cancers in non–microscopically confirmed cases as well as nonmalignant cancers. About 3% of all malignant cancers were excluded from this analysis as they were radiologically confirmed without microscopic confirmation (data not shown). Cancer registries collect some nonmalignant cancers, which include most in situ cancers and, beginning in 2004, benign, border-line, and in situ brain cancers. Radiologic confirmation is an important diagnosis tool for brain cancers, accounting for about 10% of all malignant and nearly 60% of all nonmalignant brain cancers in the CiNA dataset during this time period. Further evaluation for all cancers is needed for a more comprehensive understanding of the burden of rare cancers in North America. Also, future research in North America aimed at examining differences in stage distributions and survival among patients with rare cancer compared to common cancers is needed to understand their cumulative burden due to these unique challenges.

Cancer registries will continue to play a critical role in describing and monitoring the burden of rare cancers in the population and can serve as an important resource in the conduct of public health research. For example, cohort studies of rare cancers require complete and accurate diagnosis and follow-up information which is often not available through self-reported data and active follow-up.¹⁵ The Virtual Pooled Registry Cancer Linkage System (VPR-CLS), which is coordinated through NAACCR (https://www.naaccr.org/about-vpr-cls/), could be leveraged to help provide this information. The VPR-CLS could also be used to link cancer outcomes data to tissue repositories to support genomic research.

Many factors have been linked to poorer outcomes in rare cancers, including accuracy and timeliness of diagnosis, lack of standard of care guidelines, or delayed and limited treatment options, including clinical trials.^{2,3,5,11,16,17} Recent advances in precision medicine have allowed for novel approaches in clinical trials to accelerate progress in development of treatment and timeliness of updated standard of care guidelines for rare tumors.¹⁷

Next Steps

The Rare Cancer Classification variable will be available to approved researchers with the 1995–2021 CiNA research datasets in Spring of 2024 (https://www.naaccr.org/cina-data-products-overview/). We encourage additional evaluation of the variable and wider assessment of the burden of rare cancers using the CiNA dataset. NAACCR will develop resources to assist researchers in applying the rare cancer variable in their studies.