Current recommendations for cancer surveillance in Gorlin syndrome: a report from the SIOPE host genome working group (SIOPE HGWG)

GS is suspected on phenotypic criteria and clinical diagnosis is established in a patient with two major diagnostic criteria and one minor diagnostic criterion or one major and three minor diagnostic criteria. (Table 1) [1, 5]. This can be molecularly confirmed by genetic analysis of the PTCH1, PTCH2 and SUFU genes. All features of GS except odontogenic keratocysts [4, 6] can be present in SUFU-related GS, but GS clinical features are less prominent in people with germline SUFU PV and many will not meet GS criteria even in later life [6]. Current testing in Manchester of patients meeting GS clinical criteria show that 134/193 (69.4%) patients have an identifiable germline PTCH1 PV, 11/193 (5.7%) have an identifiable SUFU PV and 48 (24.9%) have no identifiable PV in SUFU, PTCH1 or PTCH2. No PV of PTCH2 has been identified in this series, thus this gene is probably rarely involved in GS pathogenesis and was therefore not taken into consideration in these recommendations. The estimated birth incidence of clinical GS is 1 in 14,963 [7], suggesting that most of those with germline PTCH1 PVs (estimated frequency 1 in 3356-gnomAD; https://​gnomad.​broadinstitute.​org/​) may never reach a clinical diagnosis. As the clinical signs of GS are even less prominent in patients with germline SUFU variant, a large number of SUFU PV carriers probably remain undiagnosed.

Most patients with GS develop several benign and malignant tumors, most often at a young age. There are some differences in the clinical features and incidence of tumor occurrence depending on the gene involved (Table 2). Even though it is dominated by BCC and keratocystic odontogenic tumors, the spectrum of tumors associated with GS is large. Ovarian fibromas, meningiomas and medulloblastomas appear to be more frequent in patients with constitutional pathogenic SUFU variants than PTCH1 variants [4].

GS is characterized by multiple BCCs with a median age-at-onset of the first BCC of 33y (95% CI 28–37) [8]. In a large series from Manchester of 202 patients with Gorlin syndrome, the cumulative incidence of BCC was 13% in males and 12% in females by age 20, 76,5% in females and 80% in males by age 50 [8]. The risk of BCC seems to be lower in African Americans and in Japanese than in Caucasian patients from America or Europe [9, 10]. The risk of BCC seems to be greatly increased by irradiation [9]. There is some evidence for modifier genes especially the ‘red hair’ MC1R variant polymorphism [11] which supports some familial clustering of features beyond the PTCH1 variant.

The risk of BCC in adult patients with germline SUFU mutations has not been estimated yet. Several SUFU PV carriers identified in GS cohorts have been diagnosed with multiple BCC [12‐15], but most SUFU PVs were identified in infants treated for a medulloblastoma who were young at the time of clinical report and therefore their risk of BCC in adulthood cannot be assessed. In their relatives, the risk of BCC in adults is much lower than in classical GS related to PTCH1 PVs [6] suggesting that the risk of BCC in SUFU PV carriers is much lower than in PTCH1 PV carriers. Indeed, in a series of 22 SUFU PV carriers ascertained through a medulloblastoma, only one among 34 relatives (median age at last follow-up 51.3 years) carrying a SUFU PV had been diagnosed with a BCC [6].

Odontogenic keratocysts, are benign neoplasms of odontogenic origin. They have been described in 75–89% of patients with GS and may be the first sign of GS. These tumors seem to be restricted to PTCH1 associated GS [4] whereas patients with SUFU PV are probably spared from this risk. In most series, first odontogenic keratocysts are diagnosed during the second decade of life, but jaw cysts have been diagnosed in young children during the first years of life. Even though these tumors grow slowly, their early detection is important in order to limit the impact of surgery on the growth and development of the maxillofacial complex.

Medulloblastoma with desmoplastic or extensive nodularity histology is the main GS-associated pediatric malignant tumor. Most tumors described so far occurred before the age of 3 years. In addition, in the context of SUFU PVs, families with several children affected by medulloblastomas have been described [6, 16]. In a large series of medulloblastomas screened for germline mutations, all SUFU or PTCH1 PVs were observed exclusively in the SHH-medulloblastoma (SHH-MB) subgroup, with a frequency of 17/80 (21%) and 18/170 (11%) in infant and pediatric SHH MB, respectively [17].

There are currently no direct estimates of the incidence of SUFU and PTCH1 PV carriers in the general population and no unbiased estimates of the risk of childhood medulloblastoma for each condition. The great majority of testing of SUFU is for childhood medulloblastoma and only limited testing has been carried out to identify healthy carriers in those families [17‐19]. In the largest study thus far, Waszak et al. in 2018 [17], found a germline SUFU or PTCH1 PV in 20/1022 (2%) patients with medulloblastoma (9 PTCH1, 11 SUFU). However, just over 200 of the Waszak series were over 18 years of age (Table 3), thus 11/800 (1.4%) of childhood medulloblastoma had a SUFU PV and 9/800 (1.1%) had a PTCH1 PV. Brugieres et al. in 2012 found a much higher incidence of SUFU PVs, 8/131 (6.1%), [18] whereas Wang et al. found only one PV each for SUFU and PTCH1 in their series of 129 medulloblastomas (0.8%) [19]. These differences may be related to the distribution of age-at-diagnosis and histological subtypes in the different series. Taking combined data from the three series 20/1060 (1.9%) had a SUFU PV and 10/929 (1.1%) had a PTCH1 PV.

A direct estimate of medulloblastoma risk in childhood can be derived from a population-based study in the Manchester region of NW England from 1954 to 1989. In 36 years of assessment, 173 childhood medulloblastomas were registered in the Manchester Childhood tumors registry [20]. This gives an annual incidence of 4.8 in an average childhood population of 800,000 or 0.6/100,000 in the Manchester region of NW England. The childhood risk of medulloblastoma would therefore be 16 (16 years of childhood risk) × 0.6 per 100,000 = 9.6 per 100,000 or 1 in 10,400. Three patients of that series of 173 (1.73%) have subsequently been found to have a germline SUFU PV with two probable PTCH1 PVs (1.15%) [13, 21]. As such, the likelihood of a childhood SUFU related medulloblastoma is 9.6 × 0.0173 = 0.166 per 100,000 or 1 in 601,400. The population frequency of SUFU PVs can be estimated from gnomAD (https://​gnomad.​broadinstitute.​org/​). Only three clearly pathogenic variants (excluding truncating variants in the last exon) were found in an average population sample of 124,185 people (1 in 41,395), although one was African and the other Finnish. Therefore the population estimate for European (non-Finnish) was 1 in 55,400. Taking these two estimates together, this would mean an estimated penetrance for medulloblastoma associated with a SUFU variant of 7–9.2%. Likewise, the estimate for medulloblastoma associated with PTCH1 from gnomAD was 1 in 3356, giving an estimated penetrance of 0.37%. These estimates are about 1/3rd of those from estimated risks in Gorlin syndrome families [13]. An alternative indirect estimate based on an aggregate of around 2% for SUFU PVs in childhood medulloblastoma and 1% for PTCH1 PVs from Table 3 is shown in Table 4. This generates almost identical estimates for each gene.

Considering the high incidence of PTCH1 and SUFU PVs in medulloblastomas, and in particular SHH-MBs in young children, experts recommend a germline PTCH1 and SUFU PVs screening for all children with SHH-MB, especially those diagnosed before the age of 5. The identification of a predisposition syndrome for medulloblastoma caused by a germline PV in SUFU or PTCH1 gene is fundamental, because the presence of an underlying genetic anomaly can have an impact on the therapeutic management, due to the different behavior of SUFU or PTCH1-related medulloblastomas, including differences in their responses to SHH inhibitors [22]. The best therapeutic strategy for this group of patients still has to be assessed. In addition, identifying SUFU PVs in these young patients may have a major impact on familial genetic counseling and surveillance of young relatives carrying the PV, especially siblings [16].

Meningiomas have been reported in 0.8–5% of people in large series’ of GS [4, 9, 23, 24]. Meningiomas are probably more frequent in SUFU related GS than in PTCH1 related GS. Indeed, in the Manchester cohort, the incidence of meningiomas was much higher in SUFU PV carriers (4/9) than in patients with a PTCH1 PV (2/126). Meningiomas have also been described, mostly as case reports, in patients with SUFU variants, either as the first brain tumor [12, 14, 25] or, more frequently, after irradiation for a medulloblastoma [6, 13, 26, 27]. Most de novo meningiomas described so far occurred after the age of 40, whereas they occurred earlier in patients previously treated for a medulloblastoma. In addition, two multigenerational families with meningiomas as the major feature in multiple affected family members have been associated with an inherited germline SUFU variant [12, 25].

Ovarian fibromas or fibrothecomas are benign sex-cord stromal tumors which have been described in 6–43% of female patients with GS. They are usually revealed by abdominal discomfort due to compression of adjacent organs when they become large or by acute pain due to adnexal torsion. Their incidence is probably underestimated, since most tumors are asymptomatic. With systematic screening by pelvic ultrasound, they have been detected in 9/52 (17%) females with de GS in the NIH cohort [9] and 10% in the Manchester cohort [4]. The main characteristics of GS-associated ovarian fibroma are their bilaterality and the presence of calcification. Most sporadic tumors are diagnosed in adults, but ovarian fibroma has been described in prepubertal girls in GS [28, 29]. Data from the Manchester cohort suggest that ovarian fibroma could be more frequent in SUFU PV female carriers (3/7) than in PTCH1 related GS (4/68) or in patients in whom no PV was identified (4/27). Early diagnosis is important to allow detection of small tumors, resectable by minimal-access surgery.

Cardiac fibroma is another hallmark tumor of GS. These tumors have been described in 1–3% of patients in large GS series [1, 10]. Most patients are diagnosed in utero or during the first years of life, but diagnoses later in life up to 60 years have been reported [30].

A wide spectrum of other tumors has been reported, such as sarcomas, including rhabdomyosarcomas [6, 31‐33] and thyroid carcinomas [6, 10, 34]. Due to their extreme rarity, the relative risk of these tumors in patients with GS has not been established. In addition, multiple tumor types, including sarcomas and Wilms tumors, have been described in patients with GS due to 9q22.3 microdeletion encompassing the PTCH1 locus [35, 36].

Even though the risk of BCC is probably lower in SUFU-related GS than in PTCH1-related GS, a yearly skin examination by an experienced dermatologist should be offered in both groups of patients. The age of starting should be 10 years for PTCH1-PV carriers and 20 years for patients with SUFU PVs. In both groups of patients, dermatological examination should begin earlier in people who have had previous radiotherapy in the first years after treatment completion. The interval between dermatological examinations should be shortened after the occurrence of the first BCC. In addition, recommendations for sun protection should be given in all patients.

After treatment of medulloblastoma, follow-up should be prolonged and adapted to the risk of secondary tumors, such as meningioma, but also BCC and thyroid carcinomas if the patient has been treated with radiotherapy.

The benefit and harms of screening for asymptomatic meningioma is still a matter of debate especially since there are uncertainties about the most appropriate care for those tumors detected through systematic screening [40].

Due to the low incidence of meningioma in PTCH1 PV carriers, specific screening procedures for this tumor are not required. In SUFU PV carriers in whom the incidence is much higher, brain MRI every 3–5 years could be proposed, beginning at age 30 years for patients with no previous medulloblastoma. For those previously treated with craniospinal irradiation, MRI of brain (+ / − spine) should be performed every 3–5 years starting after completion of medulloblastoma imaging follow-up.

Although these tumors are benign, an early detection is important to facilitate conservative surgery which may be complicated due to the high incidence of bilateral and multifocal tumors. Patients and parents should be informed of the symptoms and especially of risk of torsion so that in case of abdominal pain, imaging evaluation can be performed urgently. For females with GS associated with a PTCH1 PV in whom the risk is probably around 5%, we recommend at least one pelvic ultrasound performed at the end of adolescence (18y). In patients with a SUFU PV, a first pelvic ultrasound is recommended at 10 years of age and subsequent follow-up depends on the findings. Pelvic ultrasound every 3 years is recommended if the first was normal. Monitoring should be more frequent in case of detection of a suspicious lesion. In patients in whom ovarian evaluation by ultrasound is not feasible, pelvic MRI should be discussed.

A baseline cardiac ultrasound should be performed at the time of diagnosis of GS, ideally within the first 6 months of life.