PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review

Abstract

Background

PTEN hamartoma tumour syndrome (PHTS) is a rare hereditary disorder caused by germline pathogenic mutations in the PTEN gene. This study presents a case of PHTS referred for genetic evaluation due to multiple polyps in the rectosigmoid area, and provides a literature review of PHTS case reports published between March 2010 and March 2022.

Case presentation

A 39-year-old Iranian female with a family history of gastric cancer in a first-degree relative presented with minimal bright red blood per rectum and resistant dyspepsia. Colonoscopy revealed the presence of over 20 polyps in the rectosigmoid area, while the rest of the colon appeared normal. Further upper endoscopy showed multiple small polyps in the stomach and duodenum, leading to a referral for genetic evaluation of hereditary colorectal polyposis. Whole-exome sequencing led to a PHTS diagnosis, even though the patient displayed no clinical or skin symptoms of the condition. Further screenings identified early-stage breast cancer and benign thyroid nodules through mammography and thyroid ultrasound.

Method and results of literature review

A search of PubMed using the search terms “Hamartoma syndrome, Multiple” [Mesh] AND “case report” OR “case series” yielded 43 case reports, predominantly in women with a median age of 39 years. The literature suggests that patients with PHTS often have a family history of breast, thyroid and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Gastrointestinal polyps are one of the most common signs reported in the literature, and the presence of acral keratosis, trichilemmomas and mucocutaneous papillomas are pathognomonic characteristics of PHTS.

Conclusion

When a patient presents with more than 20 rectosigmoid polyps, PHTS should be considered. In such cases, it is recommended to conduct further investigations to identify other potential manifestations and the phenotype of PHTS. Women with PHTS should undergo annual mammography and magnetic resonance testing for breast cancer screening from the age of 30, in addition to annual transvaginal ultrasounds and blind suction endometrial biopsies.

Introduction

PTEN hamartoma tumour syndrome (PHTS), commonly defined as multiple hamartoma syndrome, is a rare autosomal genodermatosis with a heterogeneous phenotype that is clinically characterized by numerous hamartomas of ectodermic, mesodermic or endodermic origin with an elevated lifetime risk of developing endometrial, breast, thyroidal, colorectal or renal carcinomas [1]. PHTS is commonly (80% of all cases) associated with pathogenic variants affecting the phosphatase and tensin homologue (PTEN) gene [2, 3]. Other disorders caused by dysfunction of this gene are Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS) [4]. BRRS tends to affect children, while CS are most commonly seen in adults. PHTS is primarily caused by pathogenic gene mutations (variants) in the PTEN tumour suppressor gene [5].

The estimated incidence of PHTS is around one in 200,000 people [1, 6], but this is likely to be an underestimation due to its phenotypic diversity and difficulty in recognition. Consequently, PHTS poses a dilemma for clinicians, who must conduct multiple medical evaluations of affected patients before the diagnosis is reached [7]. Early detection is crucial, as the best potential prognosis for patients with PHTS rests on accurate clinical observation plus ongoing surveillance of affected individuals [2]. The diagnosis is primarily clinical with genetic follow-up, and the National Comprehensive Cancer Network (NCCN®) annually reviews and develops the diagnostic criteria created by Eng et al. [8,9,10,11].

Clinical guidelines for diagnosis and surveillance are needed for PHTS due to its diversity and infrequency. Reporting cases with different characteristics can help improve national and international approaches to early diagnosis of affected patients and their family members, who are at increased risk of developing several cancers in their lifetime. Previous case reports have highlighted clinical or skin symptoms associated with PHTS, such as papillomatous skin lesions, macrocephaly, gingival hypertrophy and blood vessel problems [12,13,14,15,16,17,18,19]. CS-related hamartoma polyps in various parts of the body have been reported [6, 17], including a 16-year-old Iranian female with pathognomonic cutaneous features of CS, who was evaluated for the PTEN gene through testing by the polymerase chain reaction (PCR) [19]. However, there are no reports from Iran of breast cancer associated with PHTS.

The Iranian Hereditary Colorectal Cancer Registry (IHCCR) is a programme specifically designed to identify individuals at high risk of hereditary colorectal cancer or polyposis in Iran [20,21,22,23]. IHCCR confirms these cases through whole-exome sequencing (WES), a comprehensive genetic test that sequences all of the protein-coding gene regions [24]. A 39-year-old female with multiple rectosigmoid polyps, who underwent WES to confirm hereditary colorectal polyposis, was unexpectedly diagnosed with PHTS despite absence of any clinical symptoms of the condition. Here, we summarize the disease manifestations, treatment and management of this case. Furthermore, we conducted a literature review of case reports on PHTS, with the secondary objective to compare the clinical signs found with those reported in other relevant cases.

Case presentation

A 39-year-old Iranian woman presented with minimal bright red blood per rectum at Emam Reza Hospital in Mashhad, the referral university hospital in north-eastern Iran. The patient was married, unemployed, had nine siblings and denied any history of alcohol, tobacco or medication. The patient presented with multiple skin tags on her neck, which were determined to be non-PHTS-related. An intraoral examination revealed no significant findings. However, early-stage breast cancer had been detected during mammography screening.

Notably, the patient had a significant family history of cancer. At the age of 52, her father was diagnosed with cancer of the stomach, which subsequently metastasized to the liver and ultimately led to his death, and a cousin had been diagnosed with breast cancer. There was no reported history of radiation exposure or goitre in her family. The patient’s family tree (Fig. 1) represents all close relatives, both affected and unaffected by disease.

Fig. 1

Family tree of the patient, with squares representing men and circles women. Arrow indicates the patient

Diagnostic investigation

Upper endoscopy and colonoscopy were recommended due to resistant dyspepsia, rectal bleeding, family history of stomach cancer and mild anaemia. Oesophago-gastro-duodenoscopy (EGD) revealed 20–50 small sessile polyps in the stomach and duodenum. Microscopic examination of a biopsy from the gastric mucosa showed non-dysplastic, polypoid tissue. Notably, colonoscopy revealed over 50 diminutive sessile polyps in the rectosigmoid area, while other parts of the colon were normal. Subsequent histological examination confirmed these polyps as hyperplastic, hamartomatous polyps.

Since the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) [25] recommend genetic testing for patients with more than 20 colon polyps, the patient was enrolled in the IHCCR programme for genetic consultation. Its charge is to identify individuals at high risk of hereditary colorectal cancer or polyposis in Iran confirming their findings by WES.

Whole exome sequencing

DNA was extracted from whole blood using standard procedures. Human whole exome enrichment was performed using ‘Agilent SureSelect V6 Target Enrichment Kit’ (www.agilent.com) according to the manufacturer’s protocol. Briefly, genomic DNA was captured using biotinylated RNA probes, which target all exonic regions and 10 flanking base-pairs (bp). After amplification and sequencing using the Illumina HiSeq4000 platform (Illumina, Inc.), the data were analysed using standard bioinformatics tools. Variant calling was performed using the genome analysis toolkit (GATK) software (https://gatk.broading.org) [26] that detects variations, such as single point mutations and small Indels (within 20 bp). The DNA sequence was mapped and analyzed in comparison with the published human genome build (UCSC hg19 reference sequence). Variants with a minor allele frequency (MAF) ≥ 0.1% (heterozygous variants) or ≥ 1% (homozygous variants) were excluded using 1000 Genomes (Asian), Iranom and the Genome Aggregation Database (gnomAD) [27]. Sorting intolerant from tolerant (SIFT) [27], Polymorphism Phenotyping, version 2 (PolyPhen2) combined with HumVar, a dataset that provides pre-computed predictions of the functional impact of human non-synonymous (change of amino acids) variants [28] and combined annotation-dependent depletion (CADD) with Phred score ≥ 20 [29] were used for prediction of missense variants. The raw data used in the genetic evaluation of this case are provided as a supplementary file [30].

The WES analysis of the patient’s DNA revealed a heterozygous pathogenic variant on the PTEN gene, specifically a pathogenic non-sense variant (c.697C > T, p.Arg233Ter) with a CADD score of 37 and a Deep Neural Network (DANN) [31] score of 0.997 (Table 1). The PTEN gene is associated with autosomal dominant PHTS [32], but in this case, the patient did not exhibit any skin or clinical symptoms of the condition. According to guidelines of the National Comprehensive Cancer Network (NCCN) and the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), PHTS-suspected cases should undergo gene panel testing [9, 33].

Table 1 Details on the methods and results of whole exome sequencing in the study

Clinical presentation

The International Cowden Syndrome Consortium (ICSC) [9, 10] recommends surveillance for additional manifestations of PHTS and potentially related malignancies, as outlined in Table 2. Patients suspected of having PHTS are at increased risk of cancers of the breast, thyroid, colon and rectum necessitating further investigation [34]. Furthermore, the American Gastroenterology Association recommends annual comprehensive physical examination, thyroid ultrasound screening beginning at the time of diagnosis, endometrial suction biopsy starting at the age 30–35 and colonoscopy screening beginning at 35 years of age or 5–10 years before the initial documented case of colon cancer in the family [35].

Table 2 Diagnostic criteria proposed by the International Cowden Syndrome Consortium [9, 10]

The patient in question presented with a solid mass measuring 22 × 17 mm in the lower outer quadrant of the right breast, which was detected by mammography. Ultrasonography confirmed the presence of dense, oval nodules with well-defined margins measuring approximately 20 × 15 mm located at the 6 o’clock position of the right breast, 5 cm from the nipple. Based on the Breast Imaging Reporting and Data System (BIRADS), these nodules were categorized as BIRADS IV, indicating a suspicious abnormality that necessitates further workup to ascertain whether or not likelihood of malignancy.

In addition, thyroid ultrasonography revealed multiple, well-defined, isoechoic and hyperechoic nodules in both thyroid lobes. Further evaluation through fine-needle aspiration (FNA) biopsy showed a follicular lesion with undetermined significance classified as BETHESDA III. This category denotes that the specimen obtained is non-diagnostically relevant but does not exclude the possibility of malignancy, with and clinical correlation, repeat FNA and/or surgical excision recommended.

The patient underwent further evaluation as recommended but a biopsy of the endometrium revealed no abnormalities. Biochemical assessments of renal, liver and thyroid function were within the normal range, and the patient did not exhibit macrocephaly, which is a common PHTS feature.

Histology and immunohistochemistry

Multiple foci of intraductal hyperplasia with mild to moderate nuclear grade and an area of invasive pattern suspicious for cribriform carcinoma were observed in the breast core needle biopsy (Fig. 2). Immunohistochemistry (IHC) staining according to the 2013 ASCO/CAP HER2 guidelines [36] was performed and revealed positivity for p63 and actin, indicating a solid nest of ductal carcinoma in situ (DCIS). The tumour cells also tested positive for estrogen and progesterone receptors in 90% of the cells. The HER2 status of the tumour was initially equivocal (2 +), with weak membranous staining in 30% of tumoural cells. To clarify the result, fluorescence in situ hybridization (FISH) testing was performed and it revealed a negative HER2/neu gene status in the tumoural cells. As a result, the final HER2 status of the tumour was negative. A Ki-67 index was found in 5% of the tumour cells, indicating a low proliferation rate. Following partial mastectomy, a 2.2 cm invasive cribriform carcinoma with a Bloom-Richardson grade [37] of 1(2 + 1 + 1) was observed. Notably, there was no evidence of vascular or perineural invasion and the surgical margins were free of tumour involvement.

Fig. 2

Haematoxylin and eosin staining of breast tissue from the patient (magnification: 100 x); the slides show invasive neoplastic proliferation of atypical epithelial cells with cribriform pattern and desmoplastic stroma consistent with the characteristic features of breast cancer in patients with the PTEN hamartoma tumour syndrome

Literature review

A literature review was conducted using the PubMed database to identify cases of PHTS reported between March 2010 and March 2022. The search strategy used the terms “Hamartoma Syndrome, Multiple” [Mesh] AND “case report” OR “case series”. A comprehensive reference list search of related literature was performed, with the review limited to articles in the English language, excluding letters to the editor and review articles.

We identified 43 cases of PHTS, the characteristics of whom are summarised in Table 3. The median age of the cases was 39 years (IQR: 31–52; min–max: 14–75) and we noted that the disease predominantly affected women. Of the 43 cases, 23 had a family history of PHTS with complications, such as breast, thyroidal and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Pathognomonic characteristics of PHTS, including acral keratosis, trichilemmomas, and mucocutaneous papillomas were reported in about 70% of the cases. Figure 3 depicts the clinical criteria used to diagnose PHTS patients and their medical history, as reported in the literature review. Gastrointestinal polyps were frequently reported as clinical manifestations. Figure 4 visualizes the mutated sites of the PTEN pathogenic variants indicating that pathogenic variants in exon 5 were frequent.

Table 3 Results of the literature review

Fig. 3

a Clinical criteria considered for diagnosing PHTS patients; and b Medical observations reported for these cases according to the literature review

Fig. 4

PTEN pathogenic variants found in tumours and PHTSs in the case reports reviewed; mutated sites of the pathogenic variants are shown in the exons and introns of the PTEN gene

Discussion

In this report, we described the features of PHTS in an Iranian female patient. Our initial examination revealed the presence of 50–100 rectosigmoid polyps, which prompted us to apply WES to confirm hereditary colorectal polyposis. Intriguingly, despite the patient’s lack of skin or clinical symptoms of the condition, the WES results revealed a heterozygous c.697C > T (p.Arg233Ter) pathogenic variant of the PTEN gene that is linked with autosomal dominant PHTS. However, the patient’s family history was found to be significant. Previous studies indicate that PHTS have a family history in one-third of patients [70, 71]. The father and a cousin of our patient had cancer, while our literature review revealed a family history of cancer for 42% of patients with PHTS. Therefore, it is important to screen family members and obtain a thorough family history to identify additional cases of PHTS as early as possible.

Acral keratosis, trichilemmomas, and mucocutaneous papillomata are pathognomonic features of PHTS [72]. Literature reports reveal that cutaneous lesions manifest as trichilemmomas and acral keratosis, with pits on the palms, lips and soles in around 70% of PHTS patients. However, our case lacked these lesions.

PHTS is associated with a high prevalence of breast, thyroid, and endometrial neoplasias, which are the primary complications of the disease [34, 73]. The lifetime risk of developing breast cancer in women with PHTS ranges from 54.3 to 75.8% [34]. Hence, women with PHTS are recommended to self-examine their breasts and undergo regular mammography [13]. In the present case, mammography facilitated the early detection of breast cancer. Preventative measures such as bilateral mastectomy are advised for PHTS patients with extensive fibrocystic breast disease or breast cancer [74].

Compared to previously reported rates [2, 9, 34, 73, 75,76,77], recent literature suggests that PHTS patients may have an even higher risk of developing breast cancer (up to 80%) and endometrial cancer (up to 28%). In addition, these patients may develop a significant number of benign thyroid lesions (up to 60%) and thyroid cancer (over 10%) [34, 78]. Genetic and molecular studies of PHTS have revealed the presence of pathogenic variants in the PTEN/MMAC1 gene, located on chromosome 10 at position q 22–23, which is implicated in breast and thyroid cancer [73, 79,80,81,82]. While the clinical and laboratory diagnostic criteria serve as the foundation for diagnosis [9], molecular genetic testing can be used to identify these pathogenic variants [55, 83]. However, recent prospective studies suggest that the prevalence of germline pathogenic variants in PTEN can be estimated at only 25% of patients with this condition, which is lower than previously thought [2, 84]. We applied both approaches and obtained positive results for our patient, who was diagnosed with breast cancer, multiple thyroid nodules, and more than the 50–100 range of rectosigmoid polyps in addition to a significant family cancer history.

Patients with PHTS may also develop tumours in various parts of the body, including the gastrointestinal or genitourinary tract, or the brain [85, 86]. Gastrointestinal polyposis is a common symptom that affects any part of the digestive system [20, 87, 88]. It is essential to recommend earlier endoscopic screening due to the high frequency of colon polyps in PHTS, estimated to be between 65.6 and 93% [38]. However, the risks and benefits of early intervention should be carefully weighed against the financial expenses and health risks associated with increased endoscopic surveillance [38].

Innella et al. [69] reported two cases of PHTS referred for genetic testing due to endoscopic findings of multiple colorectal polyps, which was similar to our case. While our literature review showed gastrointestinal polyps to be common in PHTS patients, mucocutaneous lesions are the most common diagnostic criteria. Therefore, all the various manifestations of PHTS among these patients should be carefully considered. Colorectal screening, starting at age 35–40 years [85, 89], is recommended for those with PTEN pathogenic variants.

Table 3 demonstrates that both the upper and lower gastrointestinal tracts are frequently involved in PHTS patients, including our case which revealed numerous small rectosigmoid, gastric and duodenal polyps. These findings suggest that colon polyposis is an under-reported characteristic in PHTS guidelines. Furthermore, evidence supports the elevated risk of colorectal cancer in PHTS patients [34, 76, 85, 89, 90]. However, the association between PHTS and gastrointestinal malignancies is still a controversial subject [40, 78, 91,92,93,94,95].

The dysplastic, cerebral ganglion cell tumour LDD is a significant pathological diagnostic criterion for PHTS [40, 74, 96]. To rule out its potential presence, it is recommended that patients presenting with headaches undergo MRI of the brain, as has been stated in multiple sources [61, 65, 67]. While ovarian tumours are a rare occurrence in PHTS, this possibility should not be overlooked as an ovarian dysgerminoma has been documented in a patient with PHTS [13].

To the best of our knowledge, this is the first reported case of PHTS detected through WES during a hereditary polyposis evaluation of rectosigmoid polyps in an Iranian patient. Although our review was not a systematic one, we found 43 case reports on PHTS. It is therefore probable that this affliction than though so far. Indeed, our search was limited to PubMed and we may well have missed additional cases reported in other databases. Although a language bias may exist with regard to our review, the English tongue is widely perceived as the universal language of science, and studies in medical sciences have not shown any systematic bias resulting from this restriction [97, 98].

Conclusion

The detection of rectosigmoid polyps should prompt practitioners to consider genetic evaluation for hereditary colorectal polyposis and to also consider the possibility of PHTS and thus look for other associated manifestations of this syndrome. Importantly, the finding of pathogenic variants in the PTEN gene led to early screening for breast cancer with a positive outcome. The presence of > 50 polyps in the rectosigmoid, coupled with the absence of typical familial adenomatous polyposis or other forms of colon polyposis, warrants further studies to identify the PHTS phenotype. Early cancer detection through regular surveillance is critical for the management of PHTS and has been shown to improve overall survival. Thus, all PHTS patients should receive annual thyroid ultrasound scans and dermatologic evaluations, while women should receive annual mammograms and breast MRIs from age 30, along with annual transvaginal ultrasound investigations and blind suction endometrial biopsies.