Anaplastic thyroid cancer (ATC) is a rare disease with a poor prognosis and accounts for a high proportion of thyroid cancer deaths. The present study reported on a 56-year-old male patient with ATC and examined the clinical manifestations, pathological features, differential diagnosis and genetic mutations. Immunohistochemical analysis showed positivity for vimentin, Ki-67 and cytokeratin in the tumor specimen. In addition, pathological mitotic figures of tumor cells and intra-lymph node metastasis were observed. Genetic analysis revealed the presence of a novel mutation (c.388C>T, p.R130X) in exon 5 of the phosphatase and tensin homolog (PTEN) gene, which was first detected in ATC. Gene conservation analysis showed that R130 is a highly conserved amino acid. Protein structure model predictions implied that p.R130X mutation results in a severe defect of the C2 domain and the TAD domain of PTEN, which may be a reason for the high malignancy of the tumor. The present case report highlights a novel mutation of PTEN in ATC, which expands the molecular spectrum of PTEN and further underlines the importance of PTEN.

Germline pathogenic variants found in the phosphatase and tensin homolog gene are associated with a range of rare syndromes that collectively fall under the umbrella of phosphatase and tensin homolog hamartoma tumor syndromes. Due to the wide array of possible clinical presentations and the varying degrees of symptom severity, many individuals with phosphatase and tensin homolog hamartoma tumor syndromes might remain undiagnosed for an extended period. We describe a case of a male child who received the diagnosis at the age of 12. His clinical features included macrocephaly, hypertrophy in the left arm, thyroid nodules, penile freckles, developmental delay, and an autism spectrum disorder. Whole exome sequencing revealed a de novo heterozygous variant in the phosphatase and tensin homolog. The case highlights the diverse and complex nature of phosphatase and tensin homolog hamartoma tumor syndromes, emphasizing the necessity for early diagnosis, multidisciplinary care, and surveillance protocols, offering the potential for improved prognostic outcomes and enhanced quality of life for affected individuals.

UNASSIGNED: Lhermitte-Duclos Disease (LDD), or dysplastic gangliocytoma, which is a benign hamartomatous condition involving the cerebellum, has a possible association with Cowden syndrome (CS), a rare autosomal dominant disorder due to germline mutations in the phosphatase and tensin homolog (PTEN) tumor-suppressor gene in chromosome 10. Combined CS and LDD cases are rarely reported in the literature.
UNASSIGNED: We present here a case of a young female patient presented at the emergency department with a severe headache associated with vertigo, vomiting, and cerebellar ataxia. A magnetic resonance imaging scan revealed mixed intensity posterior fossa lesion with almost preserved cerebellar cortical striations. Her facial skin had extensive trichilemmoma. Her symptoms improved after the excision of the posterior fossa lesion through suboccipital craniotomy and histopathology revealed LDD.
UNASSIGNED: In a low-resource country where genetic testing for neurosurgical condition is still inadequate, we used the validated Cleveland Clinic Adult Clinical Scoring for PTEN Testing and the patient had an 82-98% chance for a PTEN gene mutation. Finally, she along with her family was adequately counseled and was advised for regular screening and monitoring since it is a premalignant condition where early detection is imperative if any cancer arises in the near future and is now under our follow-up.

PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples.
Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome.
This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.

UNASSIGNED: Renal cell carcinoma (RCC) is the most common renal malignancy, and may metastasize to different sites in the body via hematogenous and lymphomatous routes. The pancreas is a rare metastatic site of metastatic RCC (mRCC) and isolated pancreatic metastasis of RCC (isPMRCC) is even rarer.
UNASSIGNED: The present report describes a case of isPMRCC that recurred 16 years after surgery. The patient responded well to the treatment with pancreaticoduodenectomy and systemic therapy, and no recurrence was recorded after 2 years.
UNASSIGNED: isPMRCC is a distinct subgroup of RCC with unique clinical characteristics that may be explained by its underlying molecular mechanisms. Surgery and systemic therapy confer survival benefits to patients with isPMRCCs, although the recurrence problem has to be paid attention to.

To date, the molecular mechanisms that underline aggressiveness and resistance to tyrosine kinase inhibitors in some thyroid carcinomas (TCs) are not known yet. We report the case of a young patient with a metastatic poorly differentiated (PDTC) and follicular thyroid carcinoma (FTC) refractory to conventional therapies and to Sorafenib. The patient, despite an initial partial response, died of progressive disease 21 months after diagnosis. The genetic analysis performed on the primary tumor and on lymph nodes and distant metastases allowed to identify a frameshift mutation (p.P248Tfs*5) in the PTEN gene, never described in TC. This mutation was present in the primary tumor and, with a lower allelic frequency, in metastases diagnosed after treatment with Sorafenib. Mutations in TP53 (p.C135Y and c.920-2A>G previously detected in anaplastic carcinomas and p.M133R never found in TC) were also detected in the primary tissue together with a mono-allelic expression of the p.C135Y mutant at RNA level. At metastatic sites level, we found only the TP53 splicing mutation c.920-2A>G. The presence of defects in mismatch repair (MMR) proteins and genomic instability was also evaluated. The primary tumor showed a partial expression of MMR proteins together with a strong genomic instability. In conclusion, we demonstrated that the rare combination of somatic PTEN and TP53 mutations in a patient with a metastatic FTC, together with the presence of tumor heterogeneity and genomic instability, might be associated with a high tumor aggressiveness and resistance to treatments.

UNASSIGNED: Cowden syndrome is a rare autosomal dominant genetic disease associated with PTEN mutation and is mainly shown as systemic multisystem lesions. The incidence of adenocarcinoma of the duodenum with Cowden syndrome in Asian males is rare. We hereby describe the diagnosis, treatment, and prognosis of a patient with duodenal carcinoma and Cowden syndrome.
UNASSIGNED: A 40-year-old Chinese man was hospitalized because of gastrointestinal hemorrhage and anemia due to infiltrating adenocarcinoma of the descending part of the duodenum. He also had typical signs of Cowden syndrome, such as multiple polyps of the gastrointestinal tract, macrocephaly, papilloma of the tongue, soles hyperkeratosis, and melanosis spots. After the pancreaticoduodenectomy (classic Whipple), the lesions revealed the presence of hamartomatoid polyps, and some of them mutated into non-mucinous adenocarcinoma (80%) and mucinous adenocarcinoma (20%). Further investigation showed a lack of PTEN protein expression in the duodenal neoplasm, and genetic analysis showed the mutation of p.E242fs in PTEN. The patient was followed up for 1 year. There was no appearance of recurrence or distant metastasis.
UNASSIGNED: It is suggested that we should pay more attention to the differential diagnosis of duodenal carcinoma combined with gastrointestinal polyps. If multiple gastrointestinal polyps with gastrointestinal bleeding are encountered, Cowden syndrome should be considered, and timely diagnosis and treatment should be implemented.

OBJECTIVE: EEG anomalies and epilepsy are a not so rare clinical manifestation in patients with Phosphatase and tensin homolog (PTEN) variants. The main aim of this study is to analyze the characteristics of EEG traces, neuroimaging findings and epilepsy to better define the neurological aspects in a set of patients with PTEN variants collected in four Italian Centres. As a secondary aim, we describe the neurodevelopmental profile and the psychiatric comorbidities of this cohort.
METHODS: Patients with PTEN variants, identified by Sanger sequencing or target resequencing, were enrolled. For each subjects, clinical data were retrospectively extracted from medical charts, with a focus on epilepsy and neuroimaging data.
RESULTS: 54 patients with PTEN variants were enrolled, with a mean age of 18.8 years. 72.2% have at least one psychiatric diagnosis, being Autism Spectrum Disorder and Intellectual Disability the most frequent diagnosis (29 and 25 cases, respectively). 22 subjects show an abnormal EEG and 8 received a diagnosis of epilepsy, mainly focal epilepsy (7/8), with a mean age at seizure onset of 3.8 years. 3/8 subjects have a drug resistant epilepsy, independently from the underlying neuroimaging pattern. The finding of a Focal cortical dysplasia is significantly associated with both an abnormal EEG (p = 0.02) and the occurrence of seizures (p = 0.002).
CONCLUSIONS: EEG should be taken into consideration in the first-line diagnostic flowchart of subjects with PTEN variants. The onset of a focal epilepsy, independently from its response to antiepileptic drugs, highly recommends to carry out a neuroimaging exam.

Prostate cancer (PC) is mainly known to metastasize to bone, lung and liver, but isolated metastases of prostate cancer, including ductal carcinoma, in the urinary tract are very rare. We describe two patients with nodular masses in the urinary tract (the anterior urethra or the urinary bladder) that were found on cystoscopy during treatment of castration-resistant prostate cancer.
In both cases, the pathological diagnosis from transurethral tumor resection showed that they were androgen indifferent prostate cancer (AIPC), including aggressive variant prostate cancer (AVPC) in Case 1 and treatment-induced neuroendocrine differentiation prostate cancer (NEPC) in Case 2. In Case 1, Loss of genetic heterozygosity (LOH) of BRCA2 and gene amplification of KRAS was identified from the urethra polyps. In Case 2, homozygous deletion was observed in PTEN, and LOH without mutation was observed in RB1.
These are the first reports of two cases of urinary tract metastasis of AIPC.

BACKGROUND: Invasive breast carcinoma with a choriocarcinomatous pattern (IBC-CP) is extremely rare, and its molecular basis is yet unclear. The choriocarcinomatous pattern is characterized by the biphasic arrangement of multinucleated syncytiotrophoblast-like cells around clusters of monotypic tumor cells in a hemorrhagic background, along with β-human chorionic gonadotropin (β-hCG) expression. The differentiation of IBC-CP from metastatic choriocarcinoma of the breast (MC-B) is difficult due to the histologic similarity.
METHODS: Based on a literature review and our own case, the clinicopathologic differences between IBC-CP patients (n = 17) and MC-B patients (n = 8) were analyzed. Moreover, in our case of IBC-CP, next-generation sequencing (NGS) comparative analysis was conducted for both choriocarcinomatous and invasive breast carcinoma (IBC) components.
RESULTS: Compared to the MC-B patients, the IBC-CP patients were older (p < 0.001) and less frequently had past histories of gestational trophoblastic disease/pregnancy/abortion (p = 0.001) and distant metastases (p = 0.005). Our case, a 49-year-old female patient, presented with masses in the right breast and axilla. Following neoadjuvant chemotherapy, a radical mastectomy found an 8.5-cm-sized tumor. Microscopically, multinucleated syncytiotrophoblast-like cells were observed around mononuclear tumor cells with hemorrhage and necrosis. Some tumor cells showed β-hCG immunopositivity, which was compatible with IBC-CP. NGS results showed a missense mutation in exon 5 of the TP53 gene in both the choriocarcinomatous and IBC components. Meanwhile, copy number loss in the PTEN gene was only identified in the choriocarcinomatous components.
CONCLUSIONS: The present IBC-CP case is triple-negative breast cancer with TP53 mutation. The PTEN gene may be associated with choriocarcinomatous differentiation. Obtaining a medical history is mandatory to exclude metastatic lesions.