Tumor Syndrome Research Articles

Combined germline and tumor mutation signature testing identifies new families with NTHL1 tumor syndrome.

NTHL1 tumor syndrome is an autosomal recessive rare disease caused by biallelic inactivating variants in the NTHL1 gene and which presents a broad tumor spectrum. To contribute to the characterization of the phenotype of this syndrome, we studied 467 index patients by KASP assay or next-generation sequencing, including 228 patients with colorectal polyposis and 239 patients with familial/personal history of multiple tumors (excluding multiple breast/ovarian/polyposis). Three NTHL1 tumor syndrome families were identified in the group of patients with polyposis and none in patients with familial/personal history of multiple tumors. Altogether, we identified nine affected patients with polyposis (two of them diagnosed after initiating colorectal cancer surveillance) with biallelic pathogenic or likely pathogenic NTHL1 variants, as well as two index patients with one pathogenic or likely pathogenic NTHL1 variant in concomitance with a missense variant of uncertain significance. Here we identified a novel inframe deletion classified as likely pathogenic using the ACMG criteria, supported also by tumor mutational signature analysis. Our findings indicate that the NTHL1 tumor syndrome is a multi-tumor syndrome strongly associated with polyposis and not with multiple tumors without polyposis.

Role of Genetic Testing and Complex Endoscopic Examination in Differential Diagnosis of Hereditary Polyposes in Pediatric and Adolescent Patients: 10 Years Clinical Experience

Background. Hereditary polyposis syndromes (HPS) are a group of rare genetic diseases characterized by multiple epithelial lesions in the gastrointestinal tract (GIT) with high risk of malignancy and neoplasia development in other localizations. The case follow-up tactics in hereditary polyposes have significant differences, and differential diagnosis can be complicated due to the phenotype variability and the clinical manifestations similarity. Objective. The aim of the study is to determine the role of molecular genetic testing and endoscopic examination in the diagnosis and management of children with HPS. Materials and methods. The retrospective observational study included 17 patients with clinical signs of hereditary polyposes who applied to the L.A. Durnov Research Institute of Pediatric Oncology and Hematology during the period from 2013 to 2023. All patients underwent molecular genetic testing and comprehensive endoscopic examination of upper and lower GIT. Results. We have divided patients into 7 groups according to the results of genetic testing. Patients had various mutations in genes associated with hereditary tumor syndromes: STK11 (35.3%; n = 6), APC (17.6%; n = 3), PTEN (11.8%; n = 2), SMAD4 (5.9%; n = 1), BMPR1A (5.9%; n = 1), MUTYH (5.9%; n = 1), MLH1 (5.9%; n = 1). One female patient with colorectal cancer with history of adenomatous polyp had pathogenic variants in the ATM and CHEK2 genes; it could be considered as multi-locus tumor syndrome (MINAS) (5.9%, n = 1). Another female patient (5.9%) had multiple gastric body hamartoma polyps and multiple gastric gastrointestinal stromal tumors (GIST) but with no pathogenic mutations. Complex endoscopic examination was performed in 14 (82.3%) patients. Epithelial or non-epithelial lesions of the stomach and intestine were revealed in all cases. Malignant tumors of duodenum and colon were diagnosed in 3 out of 14 patients (21.4%). Morphological variants of these GIT lesions were represented by hamartoma, hyperplastic, and juvenile polyps, adenomas, serrated adenomas, adenocarcinoma, and GIST. The diagnosed epithelial lesions of the stomach, duodenum, and colon were removed via endoscopic polypectomy and endoscopic mucosal resection in 8 out of 14 patients (57.1%). Some cases required small bowel resection (14.3%, n = 2), total colectomy (14.3%, n = 2), and gastrectomy (14.3%, n = 2). Conclusion. Understanding the molecular and biological etiology of HPS, its endoscopic diagnosis, and treatment features allows us to optimize the management of such patients and to minimize the risks of developing malignant tumors in upper and lower GIT, as well as extraintestinal tumors by carrying out timely medical and preventive measures.

SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

Does a proactive procedure lead to a higher uptake of predictive testing in families with a pathogenic BRCA1/BRCA2 variant? A family cancer clinic evaluation.

The uptake of genetic counseling and predictive genetic testing by family members at risk for hereditary tumor syndromes is generally below 50%. To address this issue, a new guideline was introduced in the Netherlands in 2019 that aims to improve the sharing of information within families. In addition to cascade screening supported by follow-up telephone calls with the proband, municipal records were accessed to allow the geneticist to contact at-risk family members directly. We evaluated this procedure in 32 families with a (likely) pathogenic germline BRCA1/BRCA2 variant diagnosed at our hospital between May 1, 2020, and July 31, 2021, comparing current uptake with outcomes achieved for 33 families diagnosed in 2014. Fifteen months after diagnostic testing of the proband, the uptake was 43% (120/277), comparable to the 44% (87/200) registered previously. Among a subgroup of women at 50% risk aged 25-75 years, 71% (47/66) were tested, comparable to an earlier uptake of 69% (59/86). Of the 34 at-risk relatives we contacted directly, 17 (50%) underwent predictive testing. In conclusion, we found no evidence that the new procedure leads to a substantially increased uptake. Future research should be primarily aimed at understanding intrafamilial communication barriers.

Prognostic Significance of the Number of Copy Numbervariations by Mlpa Technique in Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is a hematological malignancy with a higher frequency in children than in adults. Adult ALL is associates with increased morbidity and mortality and a significantly lower survival rate compared to its pediatric counterpart with an average survival of 40% at 5 years. The prognosis of patients with ALL is determined by multiple factors, such as age, tumor syndrome, white blood cell counts, cytogenetic abnormalities, and therapeutic response. The Multiplex Ligation dependent Probe Amplification technique (MLPA) is used to determine the copy number variations (CNV) of several key genes involved in disease progression and resistance, such as IKAROS family zinc finger 1 (IKZF1), PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A/2B, CRLF2. In this study, we sought to investigate the relationship between these genetic markers and standard prognostic factors in a small cohort of adult ALL patients with the aim of improving our risk stratification strategies. Materials and Methods: We investigated a group of 29 patients diagnosed with B- ALL at the Hematology Clinic of the Iasi Regional Oncology Institute between 2017 and 2021. DNA extraction and MLPA analysis were performed according to the standard technical protocol. Results: MLPA analysis reported deletions in 61% of cases and duplications in 39% of the investigated cases. The most frequent deletion identified was IKZF1 (31 %), followed by CDKN2A/2B (24.1 %), PAX5 (17.2 %), RB1 (17.2 %), ETV6 (10.3%) and, lastly, JAK2 (6.9 %). Conclusions: Our study demonstrated similar CNV profiles as in the literature data, which proves that these mutations could potentially play a role in a more sensitive risk stratification score.

Application of the PGT-M strategy using single sperm and/or affected embryos as probands for linkage analysis in males with hereditary tumor syndromes without family history.

Hereditary tumor syndromes have garnered substantial attention due to their adverse effects on both the physical and psychological health of patients, as well as the elevated risk of transmission to subsequent generations. This has prompted a growing interest in exploring preimplantation genetic testing (PGT) as a treatment option to mitigate and eliminate these impacts. Several studies have demonstrated that de novo variants have become a great cause of many hereditary tumor syndromes, which introduce certain difficulties to PGT. In the absence of adequate genetic linkage information (parents and offspring), haplotype construction seems unrealizable. In the study, researchers used single sperm or affected embryos as proband to perform single-nucleotide polymorphism linkage analysis for cases with de novo variants. For complicated variants, the strategy that sperm combined with embryo detection will increase accuracy while avoiding the limitations and potential failures of using a single detection material. The study recruited 11 couples with male de novo carriers, including 3 tumor types and 4 genes. To date, 4 couples have been clinically confirmed as pregnant and three healthy babies have been born. The results of amniocentesis or umbilical cord blood verification were consistent with the results of PGT-M. The study aims to introduce the application of the PGT-M strategy in hereditary tumor syndromes.

Giant cell carcinoma of the lung with hypertrophic pulmonary osteoarthropathy as a paraneoplastic syndrome: a case report

BackgroundHypertrophic pulmonary osteoarthropathy is a rare syndrome characterized by a triad that includes periostitis, digital clubbing, and painful arthropathy of the large joints, especially large joints in the lower limbs with lung cancer. Herein we describe a case of a giant cell carcinoma of the lung with hypertrophic pulmonary osteoarthropathy as a paraneoplastic syndrome. The tumor was successfully resected, and complete remission of the syndrome was achieved after surgery.Case presentationA 48-year-old man with right fingers and bilateral ankle arthralgias was referred to our hospital. These arthropathies were painful and refractory to the oral administration of several non-steroidal anti-inflammatory drugs; thus, oxycodone hydrochloride hydrate was prescribed. Additionally, the fingers and toes had a clubbed appearance and the tubular bones were shown as double lines on radiographs of both arms and legs, indicating periosteal thickening. A 45-mm mass-like shadow was present on the right upper-to-middle lung field on the chest x-ray, which was confirmed to be a mass in the upper lobe of the right lung on the chest CT scan. An abnormal uptake was observed in the area of the mass on the FDG-PET scan; the standardized uptake value maximum was 11.8. The histologic diagnosis of a bronchoscopic biopsy was an undifferentiated carcinoma, and the clinical diagnosis was non-small cell lung cancer. The clinical stage was c-T2bN0M0 with paraneoplastic syndrome as a hypertrophic pulmonary osteoarthropathy. A right upper lobectomy with an S6 partial resection adjacent to the upper lobe of the right lung and an ND2a-2 lymph node dissection was performed. The postoperative course was uneventful. The pathologic diagnosis was a giant cell lung carcinoma, which was classified as p-T3 (52 mm in diameter) N0M0, stageIIB. A gradual decrease in arthritic pain was observed from the first operative day. No anodyne, including oxycodone, was required approximately 2 months after surgery. No tumor or paraneoplastic syndrome recurrence was observed 2 years postoperatively.ConclusionsHypertrophic pulmonary osteoarthritis may occur as a secondary manifestation of lung malignancies. Thus, the paraneoplastic syndrome should be considered in such cases.

Preliminary Study of Whole-Genome Bisulfite Sequencing and Transcriptome Sequencing in VHL Disease-Associated ccRCC.

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumor syndrome with an incidence of approximately 1/36,000. VHL disease-associated clear cell renal cell carcinoma (ccRCC) is the most common congenital RCC. Although recent advances in treating RCC have improved the long-term prognosis of patients with VHL disease, kidney cancer is still the leading cause of death in these patients. Therefore, finding new targets for diagnosing and treating VHL disease-associated ccRCC is still essential. In this study, we collected matched tumor tissues and normal samples from 25 patients with VHL disease-associated ccRCC, diagnosed and surgically treated in the Department of Urology, Peking University First Hospital. After screening, we performed whole genome bisulfite sequencing (WGBS) on 23 pairs of tissues and RNA-seq on 6 pairs of tissues. And we also compared the VHL disease-associated ccRCC transcriptome data with the sporadic ccRCC transcriptome data from the The Cancer Genome Atlas (TCGA) public database RESULTS: We found that the methylation level of VHL disease-associated ccRCC tumor tissues was significantly lower than that of normal tissues. The tumor tissues showed a difference in the copy number of 3p loss and 5q and 7q gain compared with normal tissues. We integrated RNA-seq and WGBS data to reveal methylation candidate genes associated with VHL disease-associated ccRCC; our results showed 124 hypermethylated and downregulated genes, and 245 hypomethylated and upregulated genes. By comparing the VHL disease-associated ccRCC transcriptome data with the sporadic ccRCC transcriptome data from the TCGA public database, we found that the major pathways of differential gene enrichment differed between them. Our study mapped the multiomics of copy number variation, methylation and mRNA level changes in tumor and normal tissues of clear cell renal cell carcinoma with VHL syndrome, which provides a solid foundation for the mechanistic study, biomarker screening, and therapeutic target discovery of clear cell renal cell carcinoma.

Metastasis Associated in Colorectal Cancer 1 (MACC1) mRNA Expression Is Enhanced in Sporadic Vestibular Schwannoma and Correlates to Deafness.

Vestibular schwannoma (VS) are benign cranial nerve sheath tumors of the vestibulocochlear nerve. Their incidence is mostly sporadic, but they can also be associated with NF2-related schwannomatosis (NF2), a hereditary tumor syndrome. Metastasis associated in colon cancer 1 (MACC1) is known to contribute to angiogenesis, cell growth, invasiveness, cell motility and metastasis of solid malignant cancers. In addition, MACC1 may be associated with nonsyndromic hearing impairment. Therefore, we evaluated whether MACC1 may be involved in the pathogenesis of VS. Sporadic VS, recurrent sporadic VS, NF2-associated VS, recurrent NF2-associated VS and healthy vestibular nerves were analyzed for MACC1 mRNA and protein expression by quantitative polymerase chain reaction and immunohistochemistry. MACC1 expression levels were correlated with the patients' clinical course and symptoms. MACC1 mRNA expression was significantly higher in sporadic VS compared to NF2-associated VS (p < 0.001). The latter expressed similar MACC1 concentrations as healthy vestibular nerves. Recurrent tumors resembled the MACC1 expression of the primary tumors. MACC1 mRNA expression was significantly correlated with deafness in sporadic VS patients (p = 0.034). Therefore, MACC1 might be a new molecular marker involved in VS pathogenesis.

Novel anti-PTEN C2 domain monoclonal antibodies to analyse the expression and function of PTEN isoform variants.

PTEN is a major tumor suppressor gene frequently mutated in human tumors, and germline PTEN gene mutations are the molecular diagnostic of PTEN Hamartoma Tumor Syndrome (PHTS), a heterogeneous disorder that manifests with multiple hamartomas, cancer predisposition, and neurodevelopmental alterations. A diversity of translational and splicing PTEN isoforms exist, as well as PTEN C-terminal truncated variants generated by disease-associated nonsense mutations. However, most of the available anti-PTEN monoclonal antibodies (mAb) recognize epitopes at the PTEN C-terminal tail, which may introduce a bias in the analysis of the expression of PTEN isoforms and variants. We here describe the generation and precise characterization of anti-PTEN mAb recognizing the PTEN C2-domain, and their use to monitor the expression and function of PTEN isoforms and PTEN missense and nonsense mutations associated to disease. These anti-PTEN C2 domain mAb are suitable to study the pathogenicity of PTEN C-terminal truncations that retain stability and function but have lost the PTEN C-terminal epitopes. The use of well-defined anti-PTEN mAb recognizing distinct PTEN regions, as the ones here described, will help to understand the deleterious effects of specific PTEN mutations in human disease.

Detection and yield of thyroid cancer surveillance in adults with PTEN Hamartoma Tumour Syndrome.

Thyroid cancer surveillance (TCS) with ultrasound (US) is advised for PTEN Hamartoma Tumour Syndrome (PHTS) patients due to increased thyroid cancer (TC) risk. However, data supporting TCS guidelines are scarce. We aimed to assess the detection and yield of annual TCS with US in adult PHTS patients without a TC history, and to evaluate the impact of a reduced US interval on the TCS yield. A retrospective cohort study including adult PHTS patients and medical record data between 2005-2021. The yield from annual TCS was compared with hypothetical biennial and triennial TCS after two initial US with annual interval by counting delayed detection of nodular growth, thyroid adenoma and TC. During 279 follow-up years, 84 patients (median age 40 years) underwent 349 US. Thyroidectomy was performed in 6/84 (7%) patients, revealing a minimally invasive follicular TC in one patient aged 22 and a thyroid adenoma in two patients aged 21 and 53. Multiple thyroid nodules were diagnosed in 73/84 (87%) patients (median age 36 years). Nodular growth was detected in 9/56 (16%) patients, and its detection would have been delayed in 4-7% US rounds with biennial TCS, and in 2-6% US rounds with triennial US. US-based thyroiditis and indeterminate non-malignant lymph nodes were found in 8/74 (11%) and 7/72 (10%) patients, respectively. Following our findings combined with literature, we propose starting TCS before age 18, and reducing the follow-up frequency after the initial two US from annual to biennial if no suspicious findings are detected.

68Ga-DOTANOC PET/CT for Screening and Surveillance of Von Hippel-Lindau (VHL) disease.

Hereditary tumor syndrome Von Hippel-Lindau (VHL) disease is characterized by various benign and malignant tumors that are known to express somatostatin receptors (SSTR). We evaluated the role of 68Ga-DOTANOC PET/CT scan in patients with positive germline mutation of the VHL gene, presented initially or on follow-up, for the detection of recurrent or synchronous/metachronous lesions. Fourteen patients (8 males; 6 females) with mean age 30 ± 9.86years were retrospectively analyzed, were tested positive for VHL on gene dosage analysis, and underwent 68Ga-DOTANOC PET/CT scan for disease evaluation. The number and site of lesions were determined. The tracer uptake was analyzed semi-quantitatively by calculating the maximum standardized uptake values (SUVmax) of lesion. Four of the 14 patients underwent scan for initial diagnosis as baseline, 6 patients for post-therapy disease status, and 4 patients for initial diagnosis as well as follow-up evaluation of the disease. A total of 67 lesions were detected in 14 patients. The sites of lesions were cerebellar/vertebral/spinal (17; mean SUVmax = 7.85); pancreatic neuroendocrine tumor (NET) (11; mean SUVmax = 20.64); retina (3; mean SUVmax = 10.46); pheochromocytoma (10; mean SUVmax = 16.32); paragangliomas (3; mean SUVmax = 10.65); pancreatic cyst (9; mean SUVmax = 2.54); and renal cyst (8; mean SUVmax = 1.56) and miscellaneous lesions constituted 6 lesions. Our results show that 68Ga-DOTANOC PET/CT may be a useful modality for screening and follow-up of associated tumors in patients with germline gene mutation for VHL. It can be used as a one-stop imaging modality for VHL patients and may substitute for separate radiological investigations, making it more convenient for patients in terms of time and cost.

Integrating somatic CNV and gene expression in breast cancers from women with PTEN hamartoma tumor syndrome

Women with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS) have up to 85% lifetime risk of female breast cancer (BC). We previously showed that PHTS-derived BCs are distinct from sporadic BCs both at the clinical and genomic levels. In this study, we examined somatic copy number variations (CNV) and transcriptome data to further characterize the somatic landscape of PHTS-derived BCs. We analyzed exome sequencing data from 44 BCs from women with PHTS for CNV. The control group comprised of 558 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. Here, we found that PHTS-derived BCs have several distinct CNV peaks compared to TCGA. Furthermore, RNA sequencing data revealed that PHTS-derived BCs have a distinct immunologic cell type signature, which points toward cancer immune evasion. Transcriptomic data also revealed PHTS-derived BCs with pathogenic germline PTEN variants appear to have vitamin E degradation as a key pathway associated with tumorigenesis. In conclusion, our study revealed distinct CNV x transcript features in PHTS-derived BCs, which further facilitate understanding of BC biology arising in the setting of germline PTEN mutations.

The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome.

Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p= 9.2×10-3 in all samples; p= 4.2×10-3 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p= 4.6×10-2); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p=3.3×10-2). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS.

Prospects for diagnostics and treatment of neurofibromatosis type 1 in Russia

Purpose of the study. Analysis of available data on modern methods of diagnosis and treatment of neurofibromatosis type 1 (NF1) and their application in the Russian Federation. Material and Methods. The search for relevant sources was carried out in the Scopus, Web of Science, PubMed, Elibrary systems, including publications from February 1992 to December 2022. Of the 1873 scientific articles found, 48 were used to write a systematic review. Results. Neurofibromatosis type 1 (NF1) is caused by germline heterozygous mutations in the NF1 gene, which encodes the neurofibromin protein, which suppresses mitogen-activated signaling pathways necessary for cell proliferation. Clinical manifestations of NF1 are similar to Peutz–Jeghers, Laugier–Hunziker, Rusalkab–Muret–Smith, Bannayan–Zonnana, LEOPARD syndromes, neurofibromatosis type 2 and lipomatosis; therefore, to confirm the diagnosis, the most important criterion is the detection of a gene mutation by sequencing, since there are no mutagenesis hotspots in the NF1 gene. To detect 17q11.2 locus microdeletions, MLPA method is used. In Russia, such methods of molecular genetic identification of NF1 were carried out in Moscow and in the Republic of Bashkortostan. Surgical interventions using a neodymium laser and therapy with mitogen-activated protein kinase inhibitors are the most effective for the treatment of tumor syndrome. Scientific results of the use of a surgical laser in the treatment of plexiform neurofibromas and extramedullary tumors of the spinal cord have been published in Russia. Treatment of NF1 with selumetinib in Russia was announced by the interregional public organization for assistance to patients with neurofibromatosis “22/17”, which provides the drug to children with inoperable neurofibromas free of charge. Conclusion. In modern medicine, it is necessary to widely use methods for identifying mutations in the NF1 gene by creating universal panels of targeted sequencing. This will allow not only the differential diagnosis of NF1, but also the identification of the cause of chemoresistance of sporadic malignant neoplasms for the introduction of mitogen-activated protein kinase inhibitors in their treatment. Combination of this method with surgical excision of neurofibromas using a neodymium laser is optimal.

DS20 Longevity of patients following Mohs micrographic surgery for the treatment of basal cell carcinomas

Abstract Basal cell carcinomas (BCCs) are slow-growing, nonaggressive skin cancers (metastatic rate &amp;lt; 0.1%). They are common, especially in the elderly population (Sreekantaswamy S, Endo J, Chen A et al. Aging and the treatment of basal cell carcinoma. Clin Dermatol 2019; 37:373–8). Basal cell carcinoma guidelines recommend Mohs micrographic surgery (MMS) for primary high-risk BCCs and high-risk recurrent BCCs suitable for surgery (Mosterd K, Krekels GA, Nieman FH et al. Surgical excision vs. Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up. Lancet Oncol 2008; 9:1149–56). Mohs micrographic surgery allows for the removal of the tumour in stages with rapid processing of specimens using frozen section analysis. Complete surgical margins are analysed in near real time. It has, compared with other treatments, lower recurrence rates (&amp;lt; 1%) and often better cosmetic outcomes, but it has higher costs and longer operating times (Sreekantaswamy et al.; Mosterd et al.). Factors that need to be considered when deciding on treatment options are comorbidities, performance status and the risk of causing harm if left untreated. The term ‘lag time to benefit’ entails not only looking at how effective a specific treatment is, but also when a treatment will become beneficial in relation to the patient’s life expectancy (Sreekantaswamy et al.). In patients with a limited life expectancy, nonsurgical treatment can be an appropriate and possibly even the preferred choice (Sreekantaswamy et al.). A retrospective single-centre review of all available BCC MMS patient data from January 2011 to December 2017 was performed. Patients from out of area or with tumour syndromes were excluded. Survival rates following MMS were recorded. Of the 2518 patients reviewed, 1905 met the inclusion criteria. In total, 357 (18.7%) were aged ≥ 80 years; at 5 years post-MMS, 24% and 30.7% of the 80–89-year-old females and males had died, respectively, suggesting they had a higher life expectancy than the same general demographic. It would be interesting to compare these results with survival rates following other treatments, such as conventional excision or curettage and cautery. Limitations include missing documentation (n = 258) and not all internal logs being tracked appropriately (19.6% were not tracked, n = 615/3133). We propose a patient-centred, tailored approach to the treatment of BCCs. Based on the fundamental ethical principles, informed and effective shared decision-making is vital; patient values, preferences and experiences should also be considered.

Renal Neoplasia Occurring in Patients With PTEN Hamartoma Tumor Syndrome : Clinicopathologic Study of 12 Renal Cell Carcinomas From 9 Patients and Association With Intrarenal "Lipomas".

The aim of this study was to assess the histopathologic spectrum of renal tumors in patients with PTEN hamartoma tumor syndrome (PHTS), with a specific focus on potential features predictive of the underlying syndrome. A multi-institutional study was conducted to obtain clinical and pathologic data on renal tumors arising in patients with PHTS, either diagnosed by germline mutational analysis or clinical criteria for Cowden syndrome. Histologic sections of the renal tumors were re-reviewed for classification. Twelve renal epithelial tumors from 9 patients were identified (4 males and 5 females, with a mean age of 41.8y), 7 of whom carried germline PTEN mutations. All 12 renal epithelial tumors were renal cell carcinomas (RCCs): 5 were chromophobe RCCs, 4 papillary RCCs, and 3 RCC not otherwise specified. Pathologic stage distribution was: 7 (59%) pT1a, 2 (17%) pT1b, 1 (8%) pT2a, 1 (8%) pT2b, and 1 (8%) pT3a. World Health Organization/International Society of Urological Pathology (WHO/ISUP) histologic grade was applicable in 7 (54%) nonchromophobe tumors: 4 (57%) G2, 2 (29%) G3, and 1 (14%) G4. An unexpected histologic finding was the presence of 2 patients with incidental microscopic collections of intrarenal adipocytes that had no features of angiomyolipoma (and were negative with 2 sensitive PEComa markers: cathepsin-K and GPNMB); both were classified as lipoma/"lipomatous hamartomas." The average follow-up interval was 67.8 months (13 to 172mo): 5 patients had no evidence of disease, 2 were lost to follow-up, 1 died of other (non-PHTS) causes (ie, prostate cancer), and 1 was alive with metastatic RCC to the lung (RCC not otherwise specified with rhabdoid differentiation). All tumors showed loss of nuclear PTEN staining by immunohistochemistry. Fumarate hydratase was retained and 2SC was negative in all papillary RCCs. CK7 was moderate-strong/diffuse positive in 4 of 5 chromophobe RCCs and in 3 of 4 papillary RCCs. Renal epithelial tumors associated with PHTS represent a heterogeneous group of RCCs, but classic chromophobe and papillary RCC are most common. The majority have a favorable clinical behavior as would be predicted by subtype. In contrast to other hereditary renal neoplasia syndromes, morphologic features of the RCCs do not allow identification of PHTS-associated neoplasia with any degree of specificity in the absence of clinical setting and/or prior history, but the presence of microscopic "lipomas" within the kidney may provide a clue in rare cases. Therefore, clinical suspicion and genetic counseling with germline testing remain necessary for identifying PHTS-associated RCC.

P18 A novel presentation of glycogenic acanthosis of the lip

Abstract Glycogenic acanthosis (GAc) is a benign epithelial disorder, commonly observed in the oesophagus during endoscopy as multiple raised nodules affecting otherwise normal oesophageal mucosae (Tsai SJ, Lin CC, Chang CW et al. Benign esophageal lesions: endoscopic and pathologic features. World J Gastroenterol 2015; 21:1091). Despite its indolent disease course, oesophageal GAc is a minor diagnostic criterion for Cowden syndrome (CS). Glycogenic acanthosis affecting tissues other than the oesophagus is extremely rare. There have only been six cases of oral GAc reported to date, with no confirmed reports of GAc affecting the lip. We present the case of a 65-year-old White man with a 6-month history of asymptomatic white papules on the left lower lip. He was a lifelong nonsmoker. His past medical history was notable for colorectal cancer, which was in remission posthemicolectomy. He had also undergone ablative treatment for nasal polyps. He had no history of gastro-oesophageal reflux disease, or of thyroid disease, benign or malignant. Prominent facial actinic damage was present, and a biopsy was performed to rule out dysplasia. Histology demonstrated thickened hyperplastic epidermis and cytoplasmic clearing in the superficial epidermis. Keratinocytes with enlarged cytoplasm were positive on periodic acid–Schiff staining, supporting a diagnosis of GAc. On review, 3 months later, a single residual white papule was observed on the left lower lip. There were no other cutaneous features suggestive of CS. CS is caused by mutations in PTEN and is part of a spectrum of disorders known as PTEN hamartoma tumour syndrome (PHTS). It is associated with increased risk of solid-organ malignancies. Of the prior six reported cases of oral GAc, only one (Nishizawa A, Satoh T, Watanabe R et al. Cowden syndrome: a novel mutation and overlooked glycogenic acanthosis in gingiva. Br J Dermatol 2009; 160:1116–18) had a confirmed association with CS. Our patient remains under endoscopic surveillance but does not currently meet the criteria for either diagnosis or further genetic evaluation of CS. Oral glycogenic acanthosis may be an under-recognized entity due to its subtle clinical presentation. Biopsy and full-skin examination are warranted in suspected cases, to identify any association with an underlying genodermatosis.

Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia

BackgroundInactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. MethodsRetrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. ResultsNeuroimaging analysis revealed four main cerebral phenotypes—hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed “macrocephaly with complicated gyral pattern” (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. ConclusionsA spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. NCT04969926.