Multiple cutaneous and uterine leiomyomatosis: Reed's syndrome.

Reed's syndrome (RS) is a rare autosomal-dominant disorder characterised by multiple cutaneous and uterine leiomyomas, with a strong tendency for renal cell carcinoma (RCC) development. A woman in her 50s, who had previously undergone total abdominal hysterectomy due to multiple uterine leiomyomas, presented with painful nodules on her trunk and right arm for the past 6 years. These nodules were confirmed as leiomyomas through histopathology. Diagnosis of RS was established through clinicopathological correlation and positive family history, particularly her mother's. Early-onset uterine leiomyomas in patients with a similar family history should raise suspicion for RS, necessitating vigilant long-term follow-up. RCC detection requires mandatory renal imaging. Screening family members and providing genetic counselling are crucial.

Uterine leiomyoma with fumarate hydratase deficiency: A case report.

RATIONALE: Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant disease caused by mutations in the fumarate hydratase (FH) gene. They usually demonstrated multiple uterine myomas and preformed surgical procedures for myomectomy and/or hysterectomy 10 years earlier than sporadic myomas due to early development. This case report describes a woman with multiple uterine leiomyomas diagnosed with FH deficiency. PATIENT CONCERNS: A 37-year-old woman visited a gynecological clinic for the discovery of uterine leiomyoma for more than 1 year. The size of the largest grew from 42 × 27 × 46 to 98 × 85 × 113 mm in 1 year. She had a history of surgery for breast cancer and thyroid cancer but denied a history of uterine leiomyoma in her family. DIAGNOSIS AND INTERVENTIONS: The patient underwent successful transabdominal hysterectomy. The pathological results showed multiple uterine leiomyomas (partly cellular leiomyomas) with scattered large bizarre giant cells. Immunohistochemistry results demonstrated FH deficiency. OUTCOMES: On follow-up, the patient did not have any complications. She was finally referred to the oncologists and urologists for follow-up. LESSONS: Gynecologists should be aware that early onset uterine leiomyoma presenting as large, multiple, and symptomatic lesion, may be associated with FH deficiency.

mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.

Ultra-rare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype than deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mammalian target of rapamycin (mTOR) inhibition (adverse events, disease progression, time to colectomy and mortality) in patients with JPI. Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) and resulted in significant improvements in the serum albumin level (mean increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Early therapy with mTOR inhibitors offers effective, pathway-specific and personalized treatment for patients with JPI. Inhibition of the phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.

Precision Surgery and Kidney Cancer: Knowledge of Genetic Alterations Influences Surgical Management.

Renal cell carcinoma is a term that represents multiple different disease processes, each driven by different genetic alterations, with distinct histology, and biological potential which necessitates divergent management strategies. This review discusses the genetic alterations seen in several forms of hereditary kidney cancer and how that knowledge can dictate when and how to intervene with a focus on the surgical management of these tumors.

Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review.

Importance: Inherited variants in the tumor suppressor gene CDH1 are associated with an increased risk of gastric and breast cancers. This review aims to address the most current topics in management of the hereditary diffuse gastric cancer syndrome attributed to CDH1. Observations: Consensus management guidelines have broadened genetic testing criteria for CDH1. Prophylactic total gastrectomy is recommended for any pathogenic or likely pathogenic CDH1 variant carrier starting at the age of 20 years. Annual surveillance endoscopy is recommended to those who defer prophylactic total gastrectomy. Women with a CDH1 variant should initiate magnetic resonance imaging breast surveillance starting at age 30 years. Further research is needed to understand the pathogenesis of early-stage gastric cancers (T1a), which are pathognomonic of hereditary diffuse gastric cancer syndrome, that lead to advanced gastric cancer to develop both treatment and prevention strategies for this patient population. Conclusions and Relevance: The heritable CDH1 gene mutation is of importance to today's surgeons because it is associated with a substantial increased risk of developing both gastric and breast cancers. Management of this cancer syndrome currently uses prophylactic surgery and enhanced cancer surveillance strategies.

Impact of routine mismatch repair screening on genetic counseling and surgical management in colorectal cancer patients.

BACKGROUND: Mismatch repair (MMR) deficiency in colorectal cancer (CRC) should prompt consideration of genetic counseling (GC) as a Lynch syndrome (LS) diagnosis may have several implications for the patient and family. The study aims were to examine how routine MMR testing influences the rate of GC and surgical resection extent. METHODS: A single-institution retrospective review was performed on CRC specimens (including colonoscopic biopsies) routinely screened for MMR deficiency from 2012 to 2018. MLH1-deficient cancers with mutated BRAF or MLH1-promoter hypermethylation were excluded. RESULTS: MMR deficiency was identified in 295 of 1139 CRC specimens. After exclusions, 57 patients remained. Forty-two patients (74%) were identified preoperatively, and 35 (83%) were referred to GC: 16 were seen preoperatively, 9 postoperatively. Eight patients were diagnosed with Lynch syndrome (LS) preoperatively: 2 had no resection, 2 underwent segmental resection and 4 underwent extended resection. CONCLUSIONS: Most MMR-deficient patients were identified and referred to GC preoperatively, though not all were seen. Of the preoperatively diagnosed LS patients, half underwent extended resection. Barriers to GC and decision-making around resection extent bears further study.

Clinical characteristics and treatments of hereditary leiomyomatosis renal cell carcinoma: two case reports and literature review.

BACKGROUND: The objective of this study is to discuss clinical characteristics and treatments of hereditary leiomyomatosis renal cell carcinoma on the basis of 2 cases and to review recent literature, in order to present medical advances. METHODS: A 29-year old male patient came to our hospital because of a huge tumour on the right kidney. Enhanced CT showed that the tumour was about 15.5*10.5 cm, and was considered to be malignant. Another case was a 38-year old female patient. She complained was found to have a right kidney tumour in a routine physical examination. Enhanced CT showed an early-stage tumour of about 4.3*3.7 cm on the lower pole of the right kidney. The male patient underwent open radical nephrectomy and the female patient underwent laparoscopic radical nephrectomy and extensive retroperitoneal lymph node dissection. The two patients underwent genetic testing and were diagnosed as having hereditary leiomyomatosis with renal cell carcinoma. RESULTS: The postoperative pathology in both patients revealed type 2 papillary renal cell carcinoma but with different prognosis. The male patient suffered multiple metastasis 10 months post-operation. The metastatic tumour of the abdominal wall was resected to confirm recurrence and hereditary leiomyomatosis renal cell carcinoma was diagnosed by the genetic test. While the female patient had a specific family history and uterine leiomyomas, the genetic test helped us to identify hereditary leiomyomatosis renal cell carcinoma pre-operation. Because of the early diagnosis and timely treatment, the female patient was considered to have a good prognosis. CONCLUSION: Hereditary leiomyomatosis renal cell carcinoma is a rare hereditary disease resulting from FH gene mutation. There are currently no effective treatments.Our cases demonstrate that hereditary leiomyomatosis renal cell carcinoma is a very aggressive disease. Early screening and surveillance are recommended for patients with a family history or who are at risk of hereditary leiomyomatosis renal cell carcinoma. Surgical and palliative therapy still play an important role in clinical treatment.

SDH-deficient renal cell carcinoma: a clinicopathological analysis highlighting the role of genetic counselling.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) accounts for 0.05-2% of all RCCs. The majority of patients have germline mutations, most frequently in the SDHB gene. People with these mutations are predisposed to developing paragangliomas, phaeochromocytomas and gastrointestinal stromal tumours. Patients should be referred to genetic services for further workup and close surveillance imaging due to the risk of development of further tumours. We present a woman with SDH-deficient RCC and review the literature associated with this uncommon entity.

Surgical Treatment of Brooke-Spiegler Syndrome.

ABSTRACT: Brooke-Spiegler Syndrome (BSS) is a very rare autosomal dominant hereditary disease which arises from heterozygous mutations in the CYLD gene. Patients with BSS are predisposed to multiple skin appendage tumors such as cylindromas, which are benign tumors occurring mainly on the scalp. The tumors mostly appear around puberty and usually show slow growth throughout life. Malignant cylindroma formation in BSS patients has been reported. Apart from the skin, major and minor salivary glands have rarely been involved.We here report a case of a 46-year-old female patient with BSS presenting with multiple aesthetically and functionally unpleasing cylindromas covering almost her entire hair-bearing scalp with further tumors on her face. Interestingly, her parotid glands were enlarged and showed multiple lesions with a diameter up to 18 to 20 mm. She was successfully treated by total subgaleal scalp excision and coverage through a dermal substitute and split thickness skin graft. Constant follow-up imaging was initiated to prevent unhindered tumor growth of salivary glands.

A Novel Approach in the Surgical Management of Nasal Tip Hemangiomas: A 26-Year Experience.

Infantile hemangiomas are common benign tumors of infancy with a predilection for the face. Nasal-tip hemangiomas, termed the "Cyrano deformity," can have especially devastating psychological effects. The ideal surgical approach and timing for these patients is unclear, as numerous designs have been reported in the literature. The authors present a novel approach to nasal tip reconstruction involving an algorithmic approach to incision selection and leaving a thin rim of hemangioma tissue under the dermis after debulking to minimize skin envelope atrophy. Nineteen cases were treated with the senior author's preferred method, with a mean age of 3.3 years and follow-up of 2.5 years. At follow-up, 10 patients were deemed by the senior author to have a very good aesthetic result, and the remaining nine patients were deemed to have an excellent one. The results of this study suggest that surgical intervention as early as 3 to 4 years of age is safe and provides good aesthetic outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, IV.

Repeat ablative therapy in hereditary or multifocal renal cancer: Functional and oncological outcomes.

OBJECTIVES: To report managing renal tumors in patients at greater risk of repeated interventions (genetic predisposition, multifocal tumors) with thermoablative treatments (AT). A known significant challenge in these patients is the balance between nephron preservation and oncologic outcome. MATERIAL AND METHODS: This retrospective, single-center study was based on data from patients treated with one or more AT for hereditary or multifocal renal tumors between 2007 and 2017. All medical records were systematically reviewed, and 10 patients meeting inclusion criteria were selected. Six patients had confirmed von Hippel-Lindau disease, 1 Bird-Hogg-Dubé syndrome, 1 chromosome 3 translocation, and 2 had a presumed genetic predisposition. RESULTS: Median age at cancer diagnosis was 39.5 years (±8.9). Fifty-seven tumors, including 41 de novo tumors that appeared during follow-up, were treated with 32 AT sessions (cryotherapy or radiofrequency) with an average tumor size of 13.5 mm (±9) and a median RENAL score of 6 [5; 7]. One patient underwent concomitant partial nephrectomy for a 55 mm lesion which was close to the bowel. Treatment was unsuccessful in 2 cases, subsequently managed successfully by retreatment with AT. Median delay of appearance of de novo tumor after the first AT was 18 months [6 ; 24]. One patient had metastatic progression. Overall and cancer specific survival was 90% and 100%, respectively, with a mean follow-up of 7.5 years (±4.9). The mean decrease in Chronic Kidney Disease - Epidemiological Collaboration equation-estimated glomerular filtration rate at the end of follow-up was 5.5 ml/min/1.73 m2 (±24). CONCLUSION: This study suggests that AT allows to meet the oncological objectives whilst preserving renal function in patients with renal cancer at greater risk of repeated treatments.

Histopathologic Analysis of Signet-ring Cell Carcinoma In Situ in Patients With Hereditary Diffuse Gastric Cancer.

Hereditary diffuse gastric cancer (HDGC) is a rare autosomal dominant syndrome associated with an increased risk of developing Laurén's diffuse-type gastric carcinoma and lobular breast carcinoma. Although signet-ring cell carcinoma (SRCC) in situ (SRCC-pTis) has been reported as a characteristic lesion in HDGC cases with CDH1 germline mutations (CDH1 pathogenic variant), and a precursor of conventional intramucosal SRCC (SRCC-pT1a), its histopathologic features and specificity have not been sufficiently clarified. Here, we examined gastrectomy samples from 6 Japanese HDGC patients with CDH1 germline mutation, belonging to 4 families, and analyzed SRCC lesions histologically and immunohistochemically. Of the 274 foci found in the 6 samples, SRCC-pT1a accounted for 225 lesions (range: 8 to 107, mean 45.7 lesions per patient), while 46 foci were of SRCC-pTis (range: 1 to 15, mean 7.67 foci per patient). All SRCC-pTis foci were observed in the fundic gland area and on the superficial side of the mucosa. Histologically, tumor cells of SRCC-pTis were found between normal foveolar epithelial cells and the basement membrane, following a typical pagetoid spread pattern. Immunohistochemically, E-cadherin expression was lost in SRCC-pTis (27/28, 96.4%) more frequently than in SRCC-pT1a (95/197, 48.2%; P<0.001). To elucidate the specificity of SRCC-pTis for HDGC, 60 samples (range: 0.12 to 1.49 m, total 28.8 m of mucosal length) from gastric cancer cases were analyzed as controls, in which no SRCC-pTis were identified. Our results indicate that SRCC-pTis is a distinct histologic feature with high specificity for HDGC cases with CDH1 germline mutations.

Two independent families with strongly suspected hereditary diffuse gastric cancer based on the probands' endoscopic findings.

Hereditary diffuse gastric cancer (HDGC) is the most famous of hereditary gastric cancer syndromes with an autosomal dominant inheritance pattern, and its diagnosis can be made by identifying a pathogenic germline variant in CDH1. We report two independent families that were strongly suspected of having HDGC based on endoscopic findings (multiple tiny, pale areas) obtained in the probands; the probands were pathologically diagnosed as having signet ring cell carcinoma (SRCC) and were genetically confirmed to have a pathogenic CDH1 germline variant. Although the updated International Gastric Cancer Linkage Consortium (IGCLC)'s clinical guidelines for HDGC (2015) state that screening/surveillance endoscopy should be performed (Cambridge protocol), the endoscopic findings obtained in the two presently reported families suggest that pale areas should be suspected as indicating the presence of SRCCs, and biopsies should be performed in addition to obtaining a precise family history in cases suspected of having HDGC.

Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family.

BACKGROUND: Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. CASE PRESENTATION: A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. CONCLUSION: Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.

Successful Treatment of Juvenile Polyposis of Infancy With Sirolimus.

Juvenile polyposis syndrome is a rare autosomal dominant condition characterized by multiple hamartomatous polyps throughout the gastrointestinal tract. Juvenile polyposis of infancy is a generalized severe form of juvenile polyposis syndrome associated with a poor prognosis. A 47-month-old female infant presented initially with gastrointestinal bleeding and protein-losing enteropathy at 4 months of age. At the age of 12 months, the condition worsened, requiring albumin infusions every 24 to 48 hours and red blood cell transfusions every 15 days. Upper gastrointestinal endoscopy, colonoscopy, and small-bowel enteroscopy revealed diffuse polyposis that was treated with multiple endoscopic polypectomies. Despite subtotal colectomy with ileorectal anastomosis, protein-losing enteropathy and bleeding persisted, requiring continued blood transfusions and albumin infusions. A chromosomal microarray revealed a single allele deletion in chromosome 10q23, involving both the PTEN and BMPR1A genes. Loss of PTEN function is associated with an increased activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway involved in cell proliferation. Treatment with sirolimus, an mTOR inhibitor, was initiated with the aim of inhibiting polyp growth. Soon after initiation of treatment with sirolimus, blood and albumin infusions were no longer needed and resulted in improved patient growth and quality of life. This case represents the first detailed report of successful drug therapy for life-threatening juvenile polyposis of infancy.

Screening and surgical prophylaxis for hereditary cancer syndromes with high risk of endometrial and ovarian cancer.

In the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Two of these conditions, which carry an increased risk of female cancers including endometrial, ovarian, breast, are hereditary breast and ovarian cancer syndrome and Lynch syndrome. Risk-reducing surgery, such as mastectomy, salpingo-oophorectomy, and hysterectomy may decrease cancer risk for mutation carriers. Background, indications, techniques, and consequences of these surgical procedures are reviewed.

A systematic review of risk-reducing cancer surgery outcomes for hereditary cancer syndromes.

Cancer predisposition genes are rare mutations that confer a high risk of cancer. For many hereditary cancer syndromes, risk reducing surgery is the single most effective strategy for preventing cancer, but it is irreversible. It has recently attracted significant media attention, following celebrity endorsement, which has led to a perceived lack of ill-effect and guaranteed successful outcome by the general public. Given these high expectations for risk-reducing surgery, a systematic review was performed to evaluate the reported complications for patients undergoing risk-reducing surgery. A systematic review of MEDLINE, EMBASE, CINAHL, AMED and PubMed work was conducted using PRISMA for risk-reducing surgery in adults for cancer predisposition genes in breast, ovary, stomach, thyroid and colorectal. The main outcomes were 30-day morbidity and mortality associated with these procedures. Twenty-five studies (2366 patients) reporting on outcomes following risk-reducing surgery were analysed, 5 related to breast and/or ovary, 3 for stomach, 2 for thyroid and the remaining 15 were colorectal. Risk-reducing surgery was uniformly associated with 30-day morbidity, particularly for breast (variable rates), colorectal (311/1400 patients (22%)) and stomach (35/75 patients (47%)) surgery. The 30-day morbidity for ovarian risk-reducing surgery was relatively low (11/244 patients (5%)). There was also a small mortality risk associated with colorectal (1/1400 patients) and stomach (1/75 patients). This study provides an important and necessary summary of the current data, enabling clinicians to better inform patients of the associated short and long-term outcomes in risk-reducing surgery for cancer predisposition genes.