. 2018 Nov 28;120(2):256–268. doi: 10.1038/s41416-018-0273-9

Table 1.

Studies reporting SIR for second primary HPV cancers after an initial HPV-associated tumour

Author^ref.	Study type	Country and data source	Study population, definition and inclusion criteria	Primary cancer diagnosis timeframe and follow-up duration	N	Second primary cancer type(s); number of cases	SIR (95% CI)	Notes
First primary cancer: Cervical/CIN
Bjorge et al.⁴³	Retrospective cohort study	Norway; Cancer Registry of Norway	Women with diagnosis of cervical carcinoma in situ; second cancer diagnosis ≥ 1 year following CIS diagnosis	1970−1992; 9.1 years (mean)	37,001	Cervix; 11 Oropharynx; 9 Vulvo-vaginal; 32	1.26 (0.6−2.3) 2.88 (2.43−3.42) 4.04 (2.76−5.70)	Incidence of second primary tongue and tonsil reported separately and pooled for this analysis
Chaturvedi (same data set)^{44, 45}	Retrospective cohort study	Denmark, Finland, Norway, Sweden, USA; data from 13 population-based cancer registries	One-year survivors of cervical cancer	1943–2001; 12.2 years (mean)	104,760	Vulvo-vaginal; 497 Anal; 817 Oropharynx; 84	4.81 (4.40−5.25) 1.84 (1.72−1.98) 1.49 (0.97−2.29)	Incidence of second primary tongue and pharynx reported separately and pooled for this analysis
Chen⁴⁶	Retrospective cohort study	Taiwan; Taiwan Cancer Registry	Women with initial diagnosis of cervical cancer and complete data available	1979−2008; 8.18 years (mean)	52972	Vulvo-vaginal; 137 Oropharynx; 37	10.48 (8.80−12.39) 1.18 (0.83−1.62)
Edgren and Sparen⁴⁷	Retrospective cohort study	Sweden; Swedish Cancer Register	Women with diagnosis of CIN Grade 3 diagnosis; second cancer diagnosis ≥ 1 year following CIN diagnosis	1968−2004; 27 years (median)	2,302,024	Vulvo-vaginal; 173 Anal; 131	3.74 (1.55−9.04) 2.81 (1.29−5.44)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Evans et al.⁴⁸	Retrospective cohort study	UK; Thames Cancer Registry	Women with a diagnosis of CIN 3 Women with a diagnosis of cervical cancer	1960−1999; 8.0 years (mean) 1960−1999; 6.7 years (mean)	59,579 21,605	Cervix; 194 Vulvo-vaginal; 61 Anal; 23 Oropharynx; 20 Cervix; 3 Vulvo-vagina; 26 Anal; 18 Oropharynx; 16	2.8 (2.4-3.2) 9.08 (2.22−37.09) 5.9 (3.7−8.8) 1.2 (0.8−1.9) 0.1 (0−0.3) 3.91 (0.96−16.01) 6.3 (3.7−10.0) 1.4 (0.8−2.2)	Study reports second cancer incidences according to whether the primary event was CIN 3 or invasive cancer. Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Fisher et al.⁴⁹	Retrospective cohort study	USA; Michigan Cancer Surveillance Records and US census data	Women living in Michigan, diagnosed and registered with cancers of the lower anogenital tract	1985–1992; 8 years (maximum)	1565	Cervical; 5 Vulvo-vaginal; 6	3.6 (1.2−8.3) 44.3 (16.2−96.5)
Gaudet et al.⁵⁰	Retrospective cohort study	Canada; British Columbia Cancer Agency cervical cancer screening programme database and British Columbia Cancer Registry	Women with pathological diagnoses of CIN 2 or 3	1985−2005; 10.1 years (median)	54,320	Vulvo-vaginal; 143 Anal; 20	4.20 (1.87−9.43) 1.75 (0.43−4.65)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Hemminki et al.⁵¹	Retrospective cohort study	Sweden; Swedish Family Cancer Database and Swedish Cancer Registry	Women with diagnoses of primary invasive cervical cancer	1958−1996; Average follow-up unknown	17,234	Cervix; 46 Genital; 67 Anal; 16 Oropharynx; 33	0.84 (0.62−1.10) 5.91 (4.58−7.41) 4.22 (2.41−6.55) 2.20 (1.51−3.01)
Hemminki et al.⁵²	Retrospective cohort study	Sweden; Swedish Family Cancer Database and Swedish Cancer Registry	Women with diagnoses of CIS	1958−1996; Average follow-up unknown	117,830	Cervix; 758 Genital; 155 Anal; 68 Oropharynx; 79	2.30 (2.14−2.47) 3.68 (3.12−4.28) 3.75 (2.91−4.69) 1.69 (1.33–2.08)
Jakobsson et al.⁵³	Retrospective cohort study	Finland; Finnish National Hospital Discharge Register and Finnish Cancer Registry	Women receiving surgical treatment for CIN	1986−2004; 8.4 years (mean)	26,876	Cervix; 23 Vulvo-vaginal; 17: Anal; 3	1.69 (1.07–2.53) 6.84 (4.08−11.48) 3.56 (0.73−10.4)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Kalliala et al.⁵⁴	Retrospective cohort study	Finland; Finnish Population Registry and Finnish Cancer Registry	Women receiving surgical treatment for CIN at Helsinki Central University Hospital	1974−2001; 11.9 years (mean)	7564	Cervix; 22 Vulvo-vaginal; 11 Anal; 3	2.8 (1.7−4.2) 6.86 (2.40−19.65) 5.7 (1.2−17.0)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Levi et al.⁵⁵	Retrospective cohort study	Switzerland; Swiss Cancer Registry of Vaud	Women with diagnoses of CIS	1974−1993 10.1 years (average)	2190	Cervix; 10	3.4 (1.6−6.3)
Lim et al.⁵⁶	Retrospective cohort study	South Korea; Korea Central Cancer Registry	Women diagnosed with cervical cancer	1993−2010; 7.34 years (mean)	72,805	Vulvo-vaginal; 24 Anal; 11 Oropharynx; 9	4.98 (1.41−17.61) 2.42 (1.21−4.32) 1.33 (0.63–2.78)	Incidence of second primary vulva and vaginal cancers and tongue and tonsillar cancers reported separately and pooled for this analysis
Mitchell et al.⁵⁷	Retrospective cohort study	Australia; Victorian Cytology Gynaecological Service records	Women with a histologically confirmed diagnosis of CIN	1974−1976;	1281	Cervix; 6	19.8 (2.4−163.5)
Neumann et al.⁵⁸	Retrospective cohort study	France; K2 database	Men and women with potentially HPV-related primary cancer diagnoses	1989−2004; 3.1 years (median)	6049 women	Vulvo-vaginal; 8 Anal; 5	11.74 (5.23−25.99) 5.42 (1.75−12.64)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Rabkin et al.⁵⁹	Retrospective cohort study	USA; Connecticut Tumor Registry and National Cancer Institute SEER database	Women with first primary cervical cancer	1935−1988 /1973−1988; 8.5 years	9325	Vulvo-vaginal; 54 Anal; 12 Oropharynx; 47	5.6 (4.2−7.4) 4.6 (2.4−8.1) 2.2 (1.6–2.9)	Connecticut registry 1935−1988; Other US registries 1973−1988
Rose Ragin and Taioli⁶⁰	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with first primary cervical cancer	1973−2002; Average follow-up not reported	2618	Vulvo-vaginal: number of cases not reported: Anal: number of cases not reported: Oropharynx; 12	9.37 (2.96−29.79) 2.9 (1.7−4.5) 2.7 (1.4–4.7)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Saleem et al.⁶¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with a confirmed diagnosis of CIN; > 15 years old	1973–2007; 15.7 years (mean)	124075	Anal; 137	16.4 (13.7-19.2)
Saleem et al.⁶¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with a confirmed diagnosis primary cervical cancer; >15 years old	1973−2007; 11.4 years (mean)	43,669	Anal; 28	6.2 (4.1−8.7)
Sand et al.⁶²	Retrospective cohort study	Denmark; Danish civil Registration system and Danish Cancer Registry	Women born between 1918 and 1990, resident in Denmark between 1978 and 2012 with histological confirmation of CIN2 or CIN3	1978−2012; 11.5 years (mean) 1978−2012; 14.7 years (mean)	52,135 (CIN2) 104,155 (CIN3)	Vulvo-vaginal; 34 Anal; 32 Vulvo-vaginal; 168 Anal; 125	4.41 (1.39−13.94) 2.9 (2.0−4.1) 8.24 (1.99−34.22) 4.2 (3.5−4.0)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Strander et al.⁶³	Retrospective cohort study	Sweden; Swedish Cancer Registry	Women diagnosed and treated for CIN3	1958−2002 Average follow-up not reported	132,493	Cervical; 881 Vaginal; 111	2.34 (2.18−2.50) 6.82 (5.61−8.21)
Svahn et al.⁶⁴	Retrospective cohort study	Denmark; Danish Cancer Registry and danis Pathology Databank	Women born between 1918 and 1990, living in Denmark 1995−2012 and diagnosed with CIN3	1995−2012 Average follow-up not reported	101,974	Oropharyngeal; 47	2.51 (1.86−3.39)
First primary cancer: Vulvo-vaginal/VIN
Hemminki et al.⁵¹	Retrospective cohort study	Sweden; Swedish Family Cancer Database and Swedish Cancer Registry	Women with diagnoses of primary invasive genital cancer	1958−1996; Average follow-up unknown	2528	Cervical; 7 Genital ; 15 Anal; 6 Oropharynx; 9	1.88 (0.75−3.54) 8.81 (4.92−13.84) 13.97 (5.03−27.39) 4.65 (2.11−8.19)
Neumann et al.⁵⁸	Retrospective cohort study	France; K2 database	Men and women with potentially HPV-related primary cancer diagnoses	1989−2004; 3.1 years (median)	6049 women	Vaginal primary: Cervical; 2 Vulvar primary: Cervical; 3 Vaginal; 1 Anal; 1	13.70 (1.54–49.45) 12.10 (2.43−35.36) 25.84 (0.34−143.95) 11.77 (0.15−65.51)	Reported separately for primary vulvar and vaginal cancers
Saleem et al.⁶¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with a confirmed diagnosis of VIN; >15 years old	1973−2007; 8.9 years (mean)	6792	Anal; 55	22.2 (16.7−28.4)
Saleem et al.⁶¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with a confirmed diagnosis of invasive vulvar cancer; >15 years old	1973–2007; 7.1 years (mean)	9950	Anal; 28	17.4 (11.5−24.4)
Saleem et al.⁶¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with a confirmed diagnosis of Vaginal in situ; >15 years old	1973−2007; 11 years (mean)	1463	Anal; 5	7.6 (2.4−15.6)
Saleem et al.⁶¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Women with a confirmed diagnosis of invasive vaginal cancer; >15 years old	1973−2007; 4.5 years (mean)	3257	Anal; 25	1.8 (0.2−5.3)
First primary cancer: Anal/AIN
Frisch et al.⁶⁵	Matched case-control study using	Denmark; Danish Cancer Registry (cases) and Central population register (controls)	Patients with diagnoses of primary invasive epidermoid anal cancer	1943−1989; Average follow-up (men): 5.1 years Average follow-up (women); 5.6 years	955	Cervical; 2 Vulvo-vaginal; 5 Penile; 7	1.6 (0.1−4.5) 12.3 (4.0−28.7) 1.8 (0.7−3.7)
Hemminki et al.⁵¹	Retrospective cohort study	Sweden; Swedish Family Cancer Database and Swedish Cancer Registry	Men and women with diagnoses of primary invasive anal cancer;	1958−1996; Average follow-up unknown	334 men 744 women	Genital; 2 Oropharyngeal; 2 Cervical; 1 Genital; 2 Anal; 1 Oropharyngeal; 3	60.24 (5.68–172.66) 6.78 (0.64–19.42) 1.12 (0.00–4.39) 4.73 (0.45−13.55) 7.07 (0.00−27.71) 6.01 (1.13−14.75)
Neumann et al.⁵⁸	Retrospective cohort study	France; K2 database	Men and women with potentially HPV-related primary cancer diagnoses	1989−2004; 3.1 years (median)	6049 women	Cervical; 2 Oropharyngeal; 2	2.95 (0.3–10.66) 19.28 (2.17−69.60)
Rabkin et al.⁵⁹	Retrospective cohort study	USA; Connecticut Tumor Registry and National Cancer Institute SEER database	Men and women with first primary anal cancer	1935−1988/1973−1988; 5.12 years	530	Cervical; 2 Vulvo-vaginal; 2 Oropharynx; 4	11.3 (0.2−4.5) 2.5 (0.3−9.4) 1.0 (0.3–2.6)	Connecticut registry 1935−1988; Other US registries 1973−1988
Shah and Budhathoki⁶⁶	Retrospective cohort study	USA; National Cancer Institute SEER database	Patients with a primary diagnosis of anal carcinoma	1992−2013; 87 months (median)	7661 (Men: 3196; Women: 4465)	Vulvo-vaginal; 24 Anal; 56 Penile; 1	10.154 (6.61−15.60) 30.87 (23.32−40.09) 2.93 (0.07−16.33)	Incidence of second primary vulva and vaginal cancers reported separately and pooled for this analysis
Sikora et al.⁶⁷	Retrospective cohort study	USA; National Cancer Institute SEER database	Men with primary anal cancer diagnoses; aged 20 years or greater	1973−2004 5.3 years median	2080	Oropharyngeal; 10	5.99 (2.98–12.05)	Incidence of second primary tongue and tonsil reported separately and pooled for this analysis
First primary cancer: Penile/PIN
Hemminki et al.⁵¹	Retrospective cohort study	Sweden; Swedish Family Cancer Database and Swedish Cancer Registry	Men with diagnoses of primary invasive genital cancer	1958−1996; Average follow-up unknown	1127	Genital; 3 Oropharyngeal; 2	12.71 (2.40–31.15) 2.57 (0.81–5.32)
Sikora et al.⁶⁷	Retrospective cohort study	USA; National Cancer Institute SEER database	Men with primary penile cancer diagnoses;	1973−2004; 6.7 years median	2217	Oropharyngeal; 12	4.74 (2.54–8.85)	Incidence of second primary tongue and tonsil reported separately and pooled for this analysis
First primary cancer: Head and neck (oropharynx)
Bhattacharyya⁶⁸	Retrospective cohort study	USA; National Cancer Institute SEER database	Cases from the SEER programme with primary head and neck cancer	1988−1999; Follow-up: 42.2 months (mean) Minimum follow-up at least 3 m	4122	Oropharyngeal: Number of cases not reported	5.951 (3.611−9.808)	Number of cases of second primary cancer not reported
Bosetti⁶⁹ Chuang⁷⁰ (same data set)	Retrospective cohort study	Australia, Canada, Denmark, Finland, Norway, Scotland, Singapore, Slovenia, Sweden, Spain; data from 13 population-based cancer registries	Cases with primary head and neck cancer diagnoses	1943−2000; 4.9 years (mean)	99,257	Oropharyngeal; 760	13.67 (10.06−18.58)	Incidence of second primary tongue and pharynx reported separately and pooled for this analysis
†Hemminki et al.⁵¹	Retrospective cohort study	Sweden; Swedish Family Cancer Database and Swedish Cancer Registry	Men and women with diagnoses of primary invasive oral cancers	1958−1996; Average follow-up unknown	10,780 (men) 3366 (women)	Anal; 2 Genital; 7 Oropharyngeal; 194 Cervical; 8 Vulvo-vaginal; 7 Anal; 1 Oropharyngeal; 71	2.68 (0.25−7.69) 3.7 (1.47−6.96) 10.16 (8.78–11.64) 1.73 (0.74–3.13) 3.74 (1.48−7.02) 1.88 (0.00−7.38) 29.43 (22.98−36.68)
Jain et al.⁷¹	Retrospective cohort study	USA; National Cancer Institute SEER database	Men and women with diagnoses of primary invasive squamous cell carcinoma of the head and neck	1979−2008 Average follow-up not reported	16,877	Oropharyngeal; number of cases not reported	136.7 (107.1−171.8)
Levi et al.⁷²	Retrospective cohort study	Switzerland; Vaud and Neuchatel Cancer Registries	Men and women with diagnoses of primary oropharynx cancers	1974−2003; 3.9 years (average)	3092	Oropharyngeal; 233	31.7 (27.7−36.0)
Morris et al.⁷³	Retrospective cohort study	USA; National Cancer Institute SEER database	Men and women with primary diagnoses of oropharynx cancers	1975−2006 69.1 months (median)	8440	Cervix; 7 Oropharynx; 38	2.80 (1.28−5.32) 40.16 (28.42−55.12)	Total cohort has all H&N primary cancers (N = 75,087), Number of specificallyoropharynx primaries are a subset of the total and not reported separately in this article but assumed the same number as reported in ref. ⁴⁸
Neumann et al.⁵⁸	Retrospective cohort study	France; K2 database	Men and women with potentially HPV-related primary cancer diagnoses	1989−2004; 3.1 years (median)	6049 women 4078 men	Oropharyngeal; 3 Anal; 1 Oropharyngeal; 45	56.26 (11.31−164.38) 4.49 (0.06−24.97) 26.65 (19.44–35.66)	Incidence of second primary tongue and tonsil reported separately and pooled for this analysis
Sikora et al.⁶⁷	Retrospective cohort study	USA; National Cancer Institute SEER database	Men with primary cancer diagnoses in the tongue or tonsil;	1973−2004 4.0 years median 1973−2004 4.3 years median	5912 10,752	Tonsil primary: Anal; 2 Tongue primary: Anal; 3 Penile; 1	3.1 (0.4–11.1) 2.3 (0.5−6.7) 0.9 (0.0–4.7)	Reported separately for primary tonsil and tongue cancers
Soderholm et al.⁷⁴	Retrospective cohort study	Finland; Finnish Cancer Registry	Patients with primary diagnoses of cancer in the lip or oropharynx	1953−1989 Average follow-up not reported (minimum = 6 months)	3459	Oropharyngeal; 11	5.8 (2.8−10.0)