.—Sinonasal malignancies are rare, aggressive, deadly and challenging tumors to diagnose and treat. Since 2000, age-adjusted incidence rates average less than 1 case per 100,000 per year, male and female combined, in the United States. For the entire cohort, 2000-2017, overall median age-onset was 62.6 years. Carcinoma constitutes over 90% of these upper respiratory cancers and most cases are advanced, more than 72% (regional or distant stage) when the diagnosis is made. Composite mortality at 5 years was 108 excess deaths/1000/year with a mortality ratio of 558%, and 41% of deaths occurred in this time frame. As a consequence, observed median survival was approximately 6 years with 5-year cumulative observed survival (P) and relative survival rates (SR) 53% and 60%. This mortality and survival update study follows the World Health Organization International Classification of Diseases for Oncology-3rd Edition (ICD-O-3)1 topographical identification, coding, labeling and listing of 13,404 patient-cases accessible for analysis in the United States National Cancer Institute’s Surveillance, Epidemiology and End Results program (NCI SEER Research Data, 18 Registries), 2000-2017 located in 8 primary anatomical sites: C30.0-Nasal cavity, C30.1-Middle ear, C31.0-Maxillary sinus, C31.1-Ethmoid sinus, C31.2-Frontal sinus, C31.3-Sphenoid sinus, C31.8-Overlapping lesion of accessory sinuses, C31.9-Accessory sinus, NOS.
.—1) Utilize national population-based SEER registry data for 2000-2017 to update cancer survival and mortality outcomes for 8 ICD-O-3 topographically coded sinonasal primary sites. 2) Discern similarities and contrasts in NCI-SEER case characteristics. 3) Identify current risk pattern outcomes and shifts in United States citizens, 2000-2017.
.—SEER Research Data, 18 Registries, Nov 2019 Sub (2000-2017)2,3 are used to examine the risk consequences of 13,404 patients diagnosed with sinonasal malignancies, 2000-2017, in this retrospective population-based study employing prognostic data stratified by topography, age, sex, race, stage, grade, 2 cohort entry time-periods (2000-06 & 2007-17), and disease-duration to 15 years. General methods and standard double decrement life table methodologies for displaying and converting SEER site-specific annual survival and mortality data to aggregate average annual data units in durational intervals of 0-1, 0-2, 1-2, 2-5, 0-5, 5-10, and 10-15 years are employed. The reader is referred to the “Registrar Staging Assistant (SEER*RSA)” for local-regional-distant Extent of Disease (EOD) sources used in the development of staging descriptions for the Nasal Cavity and Paranasal Sinuses (maxillary and ethmoid sinuses only) and Summary Stage 2018 Coding Manual v2.0 released September 1, 2020. Cancer staging & grading procedural explanations, statistical significance & 95% confidence levels4 are described in previous Journal of Insurance Medicine articles5,6 and other publications.7,8 Poisson confidence intervals at the 95% level based on the number of observed deaths are used in this study but not displayed here to conserve space on the mortality tables. Excluded were all death certificate only and those alive with no survival time.
.—In the SEER 18 registries, a total of 13,404 patient cases (2000-2017) were available for analysis with an incidence of less than one patient per 100,000 people. From this group, analysis for survival and mortality totaled 10,624 patients. Males comprised 59.3% of cases and females 40.7%. Whites represented 80.3% of cases and black, others & unknown patients comprised 19.7%. The most common anatomic site of malignancy was the nasal cavity (49.7%); least common was the frontal sinus (1.2%). From diagnosis, across the span of 8 primary sites, first-year mortality rates q ranged from 14.3% (C30.0-nasal cavity) to 30.2% (C31.8-overlapping sinus) with corresponding excess death rates (EDR) of 118/1000/year and 279/1000/year. For single sites, the 5-year cumulative survival ratio (SR) was highest for the nasal cavity (69.5%) and lowest for overlapping lesions of the accessory sinuses (47.2%) with EDRs of 76 and 169 per 1000 per year respectively Overall, 5-year relative survival (SR) for all sinonasal tract malignancies combined was 60.3%, excess mortality (EDR) 108 per 1000 per year and mortality ratio 558%.
.—The 8 sinonasal cancer primary sites are characterized by a low percentage of cases in the localized stage (28%). Since excess mortality is high even in the localized stage, overall prognosis is very poor for all patients. Excess mortality persists in cancer of the sinonasal tract as long as 10-15 years after diagnosis and treatment. EDR in the 15-year durational-interval, all sinonasal sites combined remained significant at 27.6 per 1000 per year with continuing decrease in cumulative survival ratio (SR) to 43.9%.
Incidence
Incidence trends are very low for cancer of the upper respiratory tract (defined in the SEER registries as nasal cavity, accessory sinuses and middle ear). Overall age-adjusted incidence rates of new cases of invasive cancer of the sinonasal region in the United States, 2000-2017, was 0.7 per 100,000 men and women per year. Chart 1 indicates that incidence rates increase with age and vary by sex and race in the US Incidence is higher in males than in females, higher in whites than in blacks, and higher with increasing age.
Trends in SEER incidence rates age-adjusted to the 2000 US Standard Population by sex & race indicate that the average annual percent change (AAPC) from 1975-2017 was −0.3 per 100,000 per year in all races & both sexes; the percent change (PC) in this time-period was −8.5.
Nose, Nasal Cavity, Middle Ear, Sinuses, SEER 21 Registries, 2000-2017: SEER Age-Adjusted Incidence Rates, 2000-20173
SEER CASE STATISTICS
The 13,404 cases of cancer of the nasal cavity, middle ear and sinuses present in the SEER 18 Registries, 2000-2017, were distributed for the sinonasal group composite by age, sex, race, stage, and grade shown in Chart 2. Data for individual topographical primary sites are presented in Chart 3. The SEER historic stage A selection code is used for staging (local, regional or distant). Overall, there were 8996 staged cases and 2,722 (23.2%) unstaged. Local cases 27.8%, regional 51.5%, distant 20.7%; regional-distant staging 72.2%. A total of 6899 cases were graded and 4247 (38.1%) were of unknown grade. After exclusion of cases with no follow-up data, 10,624 patients remained for survival and mortality analysis. Mean ages for males and females were 61.6 years and 64.2 years, respectively. Ethnic mean ages were whites 63.7, blacks 56.7, other 57.9, and unknown 60.8 years. As shown in the Figure, one-third of female cases were diagnosed at ages 75 and higher. There was a 1.5-to-1 male-to-female ratio by diagnostic frequency with males accounting for 59.3% of cases and females 40.7%. The ethnic distribution of patients with sinonasal region cancer in the SEER frequency database was white 80.3%, black 9.0%, other 9.8%, and unknown 0.9%.
Comparative male and female sinonasal topography group-composite diagnostic frequency with advancing age is illustrated in the Figure. The zenith of male diagnostic frequency (12.4%) occurs at quinquennial ages 60-64; male mean age at diagnosis, 61.6-years. Female diagnostic frequency crests at ages 85+ (12.1%), with approximately one-third of cases diagnosed from age 75 to 85+ years. Female mean age at diagnosis was 64.2 years.
CANCER CASES STUDIED
Overall demographic data are given above for 13,404 patients with cancer of the nasal cavity, sinuses and middle ear in the 2000-2017 database. After the exclusion of patients with no follow-up data, 10,624 patients remained for analysis of mortality and survival. Of these remaining patients, 8404 were white (79%), 2220 were black, and other and unknown patients made up 20.9%. Nasal cavity contained most patient cases (6604), all sinuses combined contained 6473 cases, and least cases (163) were contained in the frontal sinus. The mean age at diagnosis for males and females, all sites combined, was 62.6 years.
FOLLOW-UP
Standard procedures were used by the 18 SEER registries in the follow-up (FU) of patients and in the confirmation of death data. Losses to FU were very low, less than 0.5% of all entrants at 5 years. Losses were higher in Hispanics than in black and white patients.
RESULTS
Because of the small number of cases, results have been confined to 4 tables. Table 1 presents data for the entire sinonasal cancer group composite, with an age division restricted to those age <65 and those age 65 and up. There is no separation by cohort in Table 1, and data by sex are given only for all ages and stages combined. Annual EDR values (excess death rate) in the first duration interval ranged from 16 per 1000 in localized stage patients under 65, to 394 per 1000 in distant stage patients 65 and up. Excess mortality decreased with duration after diagnosis but was still significantly present from 10 to 15 years afterward. EDRs were also significantly higher in older patients and in males compared with females. Mortality ratios (MRs) were high in patients under 65, but relatively low in the older patients despite the high EDR values. Five-year survival ratios were correspondingly reduced from 88% in the localized stage (patients under <65) to 37% in the distant stage (patients 65 and up).
Table 2 summarizes overall results, all ages, male and female combined, for durations 0-5 and 5-10 years in 2 cohorts of patient-entrants, 2000-06 and 2007-17. Excess mortality increased by stage, and survival ratios decreased as they did in Table 1. When tumor grading is known as in local and regional stages, results by cohort show a consistent improvement from the 2000-06 cohort to the 2007-17 cohort. At duration 0-5 years EDR in patients with local cancer, grades 1&2 (more differentiated, less malignant) were 25 per 1000 per year in the 2000-06 cohort; with higher malignancy, grades 3&4, the EDR was 68 per 1000 per year. The corresponding EDR values in the 2007-2017 cohort were 15 and 65 per 1000, respectively. Cell grading for differentiation/malignancy is relatively less effective in the regional than in the local stage. Grade 1&2 cases predominate in the localized stage, and grades 3&4 in the regional stage. No grading data have been shown for cases in the distant stage. Approximately 38% of the cases had no grading reported (Chart 2). In these cases, the EDR and MR values were intermediate. Data are also shown for the total cases staged and for the unstaged cases. Excess death rates were modestly but consistently improved in the latter cohort (2007-17) in both local and regional disease and for both grading groups in the 0-5-year duration but not so in the 5-10-year duration.
Numbers of cases are much reduced at durations 5-10 years because of the attrition due to the high mortality and poor survival. Although comparative mortality showed considerably lower EDR and MR values than in the first 5 years of FU, substantial excess mortality persisted. Ten-year survival ratios ranged from 85% to 31%.
Overall differences by race are shown at the bottom of Table 2. Nonwhite EDR values were higher at duration 0-5 years, 128 vs 109 extra deaths per 1000 per year, but the difference was much smaller at duration 5-10 years.
Tables 3 & 4 present aggregate average annual mortality and survival prognostic data, 2000-2017, for each sinonasal cancer primary site location. In Chart 4, prognostic results are summarized for each site at the terminal 10-15-year follow-up duration. With cumulative excess death rates (EDR), observed cumulative survival rate (P), and cumulative survival ratio (SR) weighted by exposure as the appropriate indices for primary site differences in excess mortality and survival, maxillary sinus carried the worst long-term prognosis. Maxillary sinus had the highest excess death rate of 37.5 per 1000 persons exposed to the risk of death per year at the end of follow up and the lowest 15-year cumulative observed survival rate (P) of 22.3%. Corresponding expected cumulative survival (P’) was 68.3% with consequently reduced cumulative survival ratio of 32.7% (SR=100P/P’). For all sinuses combined, the EDR was 26.3 per 1000 per year, observed cumulative survival rate (P) of 25.7%, SR 36.9%, and median survival time, approximately 3.7 years. With 4775.5 person-years of exposure (E) and 268 deaths (d), the observed mortality rate for the entire sinonasal tract (100d/NER) for the last interval was 5.6%, EDR 27.6 per 1000, observed cumulative survival (P) 30%, and cumulative survival ratio (SR) 43.9%.
COMMENT
Upper respiratory tract sinonasal malignancies are rare cancers with poor prognosis regardless of anatomic primary site. The tables in this section provide a comprehensive medical-actuarial population-based retrospective analysis of comparative mortality and survival in 8 sinonasal cancers contained in the National Cancer Institute’s SEER Research Data, 18 Registries, 2000-2017. Age-adjusted incidence rates are very low, averaging less than 1 case per 100,000 per year, male and female combined. Remarkably, as noted in Tables 3 and 4, diminished numbers of entrants exposed to the risk (E) in some primary sites amounting to 500 person-years or less in the 1st durational interval (C30.1, C31.2-3, C31.8-9), nevertheless, due to extremely high 1st year observed mortality rates (q=100d/E) are linked to very high excess death rates and mortality ratios. For example, C31.8-Overlapping lesion of accessory sinus has 218.5 person-years exposure and 66 deaths in the 1st (0-1 year) interval corresponding to a 30.2% observed interval mortality rate with consequent EDR of 276/1000/year and MR of 1162%, and diminishing to 7.2% in the 3rd (2-5 year) interval with much reduced EDR of 50/1000/year and MR 331%.
Most of the cases, nearly 75%, are advanced (regional or distant) at the time of diagnosis. As a consequence, overall EDR for all sinonasal primary sites combined, 2000-2017, duration 0-5 years, averages 108/1000/year, and the cumulative relative survival rate (survival ratio-SR) is only 60%. Grading of cellular differentiation for malignancy does have a predictive effect on prognosis in local and regional cases. For example, in the 2007-2017 cohort, EDR in regional stage-grade 1&2 cases is 117/1000/year per at duration 0-5 years, but with advanced grades 3&4 differentiation, increases to 160/1000/year.
Excess mortality increases with age, and is higher in males than in females, and in nonwhites than in whites. Although excess mortality decreases with duration, significant excess mortality persists even to duration 10-15 years in all sinonasal sites. Excess death rates were modestly but consistently improved in the latter cohort (2007-17) in both local and regional disease and for both grading groups in the 0–5-year duration but not so in the 5-10-year duration.
Lifetime follow-up is essential, and monitoring of patients must be frequent and meticulous because more than 41% of the deaths, all primary sites combined, occurred within 5 years of diagnosis and most treatment failures occur within this period. Additionally, nearly 33% of patients will develop second primary cancers in the upper aerodigestive tract.
For information on aspects and treatment of cancer of the nasal cavity, middle ear and sinuses the reader is referred to the website of the National Cancer Institute, www.cancer.gov, and to monographs such as editions of Clinical Oncology, issued by the American Cancer Society.
In Memoriam: Richard Bunker Singer, M.D., March 22, 1914–February 19, 2010.
Consummate gentleman, dear friend, scholar, colleague, and ‘Man for All Seasons.’