Diagnosis and treatment of primary seminoma of the prostate: A case report and review of literature.

BACKGROUND: Primary seminoma of the prostate (PSP) is a rare type of extragonadal germ cell tumour that is easily misdiagnosed, owing to the lack of specific clinical features. It is therefore necessary for clinicians to work toward improving the accuracy of PSP diagnosis. CASE SUMMARY: A 59-year-old male patient presenting with acute urinary retention was admitted to a local hospital. A misdiagnosis of benign prostatic hyperplasia led to an improper prostatectomy. Histopathology revealed PSP invading the bladder neck and bilateral seminal vesicles. Further radiotherapy treatment for the local lesion was performed, and the patient had a disease-free survival period of 96 mo. This case was analysed along with 13 other cases of PSP identified from the literature. Only four of the cases (28.6%) were initially confirmed by prostate biopsy. In these cases, imaging examinations showed an enlarged prostate (range 6-11 cm) involving the bladder neck (13/14). Of the 14 total cases, 11 (78.6%) presented typical pure seminoma cell features, staining strongly positive for placental alkaline phosphatase, CD117, and OCT4. The median age at diagnosis was 51 (range 27-59) years, and patients had a median progression-free survival time of 48 (range 6-156) mo after treatment by cisplatin-based chemotherapy combined with surgery or radiotherapy. The remaining three were cases of mixed embryonal tumours with focal seminoma, which had clinical features similar to those of pure PSP, in addition that they also had elevated serum alpha-fetoprotein, beta-human chorionic gonadotropin, and lactose dehydrogenase. CONCLUSION: PSP should be considered in patients younger than 60 years with an enlarged prostate invading the bladder neck. Further prostate biopsies may aid in proper PSP diagnosis. Cisplatin-based chemotherapy is still the main primary therapy for PSP.

[Clinical and genetic analysis of seven Chinese pedigrees affected with multiple endocrine neoplasia type 2A with cutaneous lichen amyloidosis].

OBJECTIVE: To explore the pathological characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A) with cutaneous lichen amyloidosis (CLA). METHODS: Clinical data of 51 members from 7 unrelated pedigrees of MEN2A-CLA were collected. Systemic clinical investigations including biochemical testing, imaging examination, germline RET variant screening and histopathological examination were carried out. RESULTS: RET gene variants were detected in 28 patients with MEN2A (C634G/F/R/S/W and C611Y) including 12 males and 16 females, with the mean age of diagnosis being (41.1 ± 18.3) years old, which were consistent with their clinical manifestations. The incidence of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), hyperparathyroidism (HPTH) and CLA among 28 MEN2A patients were 89.3%, 28.6%, 7.1% and 28.6%, respectively. Comparison of the incidence of MTC/PHEO/HPTH and CLA between C611Y and C634G/F/R/S/W, only PHEO and CLA in C611Y were lower than those in C634G/F/R/S/W (P < 0.05; P < 0.05). Among 8 patients with CLA, the male to female ratio was 2 : 6. The clinical features included pruritus in the interscapular region and presence of dry, thickened, scaly, brown pigment, clustered or desquamate-like plaques. The mean onset age of CLA [(18.4 ± 4.6) years] versus the mean age at diagnosis of CLA or MEN2A were significantly different (P < 0.001; P < 0.001). CONCLUSION: MEN2A-CLA may be the early clinical manifestation of MEN2A and most frequently occurred along with RET-C634 variant. To facilitate the recognition of MEN2A-CLA, to combine family investigation and screening of RET variant are helpful for early diagnosis and standardized treatment, which can improve the long-term outcome of MEN2A-specific tumors.

Simultaneous bilateral laparoscopic cortical-sparing adrenalectomy for bilateral pheochromocytomas in multiple endocrine neoplasia type 2.

Purpose: This study aimed to assess the feasibility of synchronous bilateral laparoscopic or open cortical-sparing adrenalectomy (SB-LCSA or SB-OCSA) for bilateral pheochromocytomas (bPHEOs) in multiple endocrine neoplasia type 2 (MEN2). Methods: Altogether, 31 patients (54.8% were women) were diagnosed with MEN2-related bPHEOs, and 29 of them underwent varying specific adrenalectomies. We systematically analyzed and evaluated their clinical profiles, mutation types, tumor histopathological features, and follow-up records. Results: All 31 patients with bPHEOs presented with RET-C634 (90.3%) and RET-M918T (9.7%) mutations, and the median age at initial presentation was 38 years (range, 23-78). bPHEOs were synchronous in 27 patients and metachronous in 4 (12.9%) patients. In total, 29 patients underwent initial cortical-sparing adrenalectomy (CSA) including 23 (79.3%) undergoing synchronous bilateral CSA (18 SB-LCSA and 5 SB-OCSA) and 6 (20.7%) undergoing metachronous CSA. SB-LCSA and synchronous surgery were associated with less bleeding volume and shorter length of hospital stay than SB-OCSA and metachronous surgery (all P's < 0.05). Corticosteroid replacement treatment was necessary for 14 patients (45.2%) after bilateral CSA. During a median follow-up period of 7 years (range, 1.8-23), three of these patients (10.3%) had a recurrent disease that required reoperation. Conclusion: SB-LCSA is feasible for treating synchronous bPHEOs and should be recommended as a prioritized surgical approach.

[Multiple endocrine neoplasia type 2A caused by a p.C618R RET proto-oncogene mutation in a Chinese pedigree].

OBJECTIVE: To explore the clinical characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A). METHODS: Comprehensive medical history was obtained for 5 members from a 3-generation family from southern China. Clinical investigations have included biochemical testing, imaging, and screening of germline RET proto-oncogene mutations. RESULTS: Genetic screening has revealed a missense mutation at codon 618(TGC>CGC) of exon 10 in 3 patients(p.C618R), which was consistent with their clinical manifestations. For the 3 individuals, the age at diagnosis was 21, 26 and 36 yr, and the maximum diameter of medullary thyroid carcinoma was 22, 25 and 39 cm, respectively. The 36-year-old female patient initially underwent right total thyroidectomy plus right neck lymph node dissection. Four years later, she again underwent left adrenal tumorectomy and left total thyroidectomy plus left neck lymph node dissection. The 21-year-old male patient underwent right total thyroidectomy plus right modified neck dissection. The follow-up was respectively 146 and 26 months following the initial operation. Two patients still presented elevated calcitonin and had bilateral neck lymph node masses and/or left thyroid masses on imaging examination. The 26-year-old female patient, who presented bilateral thyroid masses and elevated calcitonin, has refused thyroidectomy. CONCLUSION: Combined family survey and RET gene screening can facilitate early diagnosis and surgical treatment to improve the prognosis.

The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma.

We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T greater than G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A greater than G (p.A45A), IVS4 + 48A greater than G, c. 1296A greater than G (p.A432A), c. 2071G greater than A (p.G691S), c. 2307T greater than G (p.L769L) and a variant c. 833C greater than A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.

[The clinical patterns and RET proto-oncogene identification of pheochromocytoma in 13 multiple endocrine neoplasia type 2A pedigrees].

OBJECTIVE: To explore the clinical patterns and clinical significance for RET screening in adrenal pheochromocytoma (PHEO) associated with multiple endocrine neoplasia type 2A (MEN2A). METHODS: The clinical data of 32 PHEO patients with MEN2A from 13 unrelated MEN2A pedigrees from August 1989 to January 2013 were analyzed. The comprehensive medical data included systemic examinations and germline RET gene screening. RESULTS: Among 68 patients belonging to 13 MEN2A families, 32 (47.1%) presented with PHEO. There were 19 males and 13 females with a mean age of (41 ± 12) years. And the mean maximum diameter of PHEO was (4.6 ± 2.2) cm. The diagnosis of PHEO was made after medullary thyroid carcinoma (n = 12, 37.5%), simultaneously (n = 12, 37.5%), initially (n = 7, 21.9%) and death during appendectomy for PHEO-induced hypertensive crisis (n = 1, 3.1%). The diagnosis of PHEO was made before (n = 22) or after (n = 10) clinical screening. The former had 12 symptomatic cases while the latter only 1 case (12/22 vs 1/10, P = 0.024).Except for 5 asymtomatic fatal cases during non-PHEO operations, bilateral PHEO was found in 17 cases including 3 unilaterally treated cases developing another PHEO in contralateral adrenal with a lag period of 5, 10 and 17 years. There were 7 symptomatic patients in bilateral cases versus 6 in unilateral cases (7/17 vs 6/10, P = 0.440). Twenty-five patients underwent PHEO surgery: laparascopic approach in 14 cases (8 with bilateral simultaneous adrenalectomy) and open approach in 11 (2 with bilateral simultaneous adrenalectomy). And 10 patients undergoing bilateral adrenal-sparing operations or adrenalectomy required hormonal replacement therapy. During a mean observation period of 72 (1-282) months, no local recurrence, distant metastasis or Addisonian crisis were noted in 25 cases (contralateral relapse in 3 cases). Among them, 2 cases developed adrenocortical insufficiency unresponsive to an adjustment of hormonal doses.RET screening showed 4 recurrent missense substitutions in 32 MEN2A-PHEO patients: p. C634Y exon 11 (n = 27, 84.4%), p. C634R exon 11 (n = 3, 9.4%), p. C634F exon 11 (n = 1, 3.1%) and p. C618R exon 10 (n = 1, 3.1%). CONCLUSIONS: The mutations of RET proto-oncognene of PHEO in MEN2A are frequently located at codon 634. A combination of pedigree examination and RET gene screening may facilitate an early diagnosis and early treatment of asymptomatic PHEO patients in MEN2A.Laparoscopic cortical-sparing adrenalectomy for preserving adrenocortical function is a preferred surgical approach.

p.N78S and p.R161Q germline mutations of the VHL gene are present in von Hippel-Lindau syndrome in two pedigrees.

Von Hippel-Lindau (VHL) disease is an autosomal dominant familial cancer syndrome. VHL is characterized by the development of renal cell carcinoma (RCC), hemangioblastomas of the central nervous system or retina and pheochromocytoma (PCC). RCC and PCC are known to be caused by germline mutations of six and ten genes, respectively. In the present study, 30 individuals from two unrelated pedigrees with type 2A and 2C VHL syndrome were investigated. The patients were clinically examined and treated by radical nephrectomy [or nephron­sparing surgery (NSS)] and cortical-sparing adrenalectomy (CSA), and all members of the two families underwent genetic screening. Two members from the first family were diagnosed with PCC and RCC, and three individuals from the second family who had only hypertension were diagnosed with PCC. Heterozygous variants of the VHL gene, c.A233G (p.N78S) within exon 1 and c.G482A (p.R161Q) within exon 3, were verified, respectively. Surgery was performed on all the patients, with the exception of an asymptomatic 5-year-old p.N78S male in family 1, in addition to genetic testing and genetic counseling. Further patient follow-up was warranted with regard to blood pressure and health, although normal blood pressure and no local recurrence and distant metastasis of VHL were observed previously. The present study suggests that molecular genetic testing may aid the diagnosis and clinical management of VHL syndrome.

[Clinical diagnosis and treatment of familial medullary thyroid carcinoma caused by a p.C618Y RET proto-oncogene mutation in a Chinese pedigree].

OBJECTIVE: To explore the clinical characteristics, therapeutic and clinical significance for RET proto-oncogene screening in a pedigree with familial medullary thyroid carcinoma. METHODS: Comprehensive medical history was obtained from 19 members in a 4-generate southern Chinese family. Systemic clinical investigations including biochemical testing, imaging examinations and germline RET screening. RESULTS: RET screening showed heterozygous missense mutations of TGC to TAC at codon 618 on exon 10 in 8 cases (p.C618Y) completely consistent with the clinical manifestations. The clinical data of 7 patients with medullary thyroid carcinoma (MTC) and 2 carriers of asymptomatic RET mutation from were analyzed. Single/bilateral multi-centric MTC with lymph node metastases was confirmed in 6 cases by histopathology and 1 case by clinical examination. There were 1 male and 6 females with an initial mean diagnostic age was 49.6 years (range: 24 - 78). All had palpable neck masses. And the mean maximum diameter of MTC was 2.6 cm (range 1.4 - 4.4). Seven patients underwent thyroidectomy except a 78-year-old female patient: right total and left subtotal thyroidectomy (n = 1), right total thyroidectomy (previous left total thyroidectomy for benign mass) (n = 1) and total thyroidectomy (n = 4) were performed. All procedures were accompanied by at least bilateral level VI lymph node dissection and/or with modified single/bilateral neck dissection. After the first operation, 6 patients still presented a high value of calcitonin: 1 patient died of metastasis 64 months postoperatively; 3 patients underwent reoperation at 6 months after initial operation, the calcitonin levels dropped to normal in 2/3 cases and stayed higher in 1 case; another two cases presented bilateral thyroid gland residua, local lymph node enlargement on imaging examination and elevated levels of calcitonin at 214 and 60 months postoperation respectively. However, 1/2 asymptomatic with elevated pre-operative calcitonin subjects underwent total thyroidectomy and histopathological examination showed bilateral C cell hyperplasia. The other carriers, without surgery, with normal neck images, close monitoring and a 10-month follow-up, still presented undetectable calcitonin. CONCLUSIONS: Based on family survey, integrated RET screening and serum levels of calcitonin facilitate an early diagnosis and normalize surgery to improve the prognosis. For asymptomatic RET mutation carriers, their levels of calcitonin shall guide the individualized regimen of prophylactic thyroidectomy or strict monitoring and follow-ups.

Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations.

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, and duplication sequences of PKD1. Recently, targeted resequencing by pooling long-range polymerase chain reaction (LR-PCR) amplicons has been used in the identification of mutations in ADPKD. Despite its high sensitivity, specificity and accuracy, LR-PCR is still complicated. We performed whole-exome sequencing on two unrelated typical Chinese ADPKD probands and evaluated the effectiveness of this approach compared with Sanger sequencing. Meanwhile, we performed targeted gene and next-generation sequencing (targeted DNA-HiSeq) on 8 individuals (1 patient from one family, 5 patients and 2 normal individuals from another family). Both whole-exome sequencing and targeted DNA-HiSeq confirmed c.11364delC (p.H3788QfsX37) within the unduplicated region of PKD1 in one proband; in the other family, targeted DNA-HiSeq identified a small insertion, c.401_402insG (p.V134VfsX79), in PKD2. These methods do not overcome the screening complexity of homology. However, the true positives of variants confirmed by targeted gene and next-generation sequencing were 69.4%, 50% and 100% without a false positive in the whole coding region and the duplicated and unduplicated regions, which indicated that the screening accuracy of PKD1 and PKD2 can be largely improved by using a greater sequencing depth and elaborate design of the capture probe.

RET proto-oncogene genetic screening of families with multiple endocrine neoplasia type 2 optimizes diagnostic and clinical management in China.

BACKGROUND: Genetic screening for germline mutations in the RET proto-oncogene has been extensively exploited worldwide to optimize the diagnostic and clinical management of multiple endocrine neoplasia type 2 (MEN2) patients and their relatives. However, a distinct lag period exists not only in the recognition but also in the medical treatment of patients with MEN2. Here we present a comprehensive genetic and clinical analysis of MEN2 among Chinese families followed from 1975 to 2011. Our series comprises 36 index cases and 134 relatives from 11 independent families. METHODS: Genetic diagnosis was performed in all participants by direct sequencing all relevant RET exons. Thyroidectomy was performed in 50 patients with varying cervical neck dissection procedures. Patients with pheochromocytoma (PHEO) underwent specific surgery. Demographic, clinical profiles, mutation types, tumor histopathologic features, and follow-up records were systematically analyzed. RESULTS: The RET mutations p.C634Y (n=34), p.C634R (n=6), p.C618S (n=13), p.V292M/R67H/R982C (n=7), p.L790F (n=2), and p.C634Y/V292M/R67H/R982C (n=1) were confirmed in 31 index cases and then identified in 32 at-risk relatives (mutation carriers), with MEN2A as the most common clinical subtype. The overall penetrance of PHEO in patients with MEN2A was 46.7%. A total of 50 patients underwent thyroidectomy, and there was a significant lowering of their mean age at thyroidectomy and the tumor diameter of the mutation carriers that were detected and operated on compared with the index cases (age at first surgery: 29.3 vs. 39.3 years, p<0.05; maximum size: 1.1 vs. 3.3 cm, p<0.001). There was also a decrease in the TNM staging and the proportion of patients who underwent inappropriate initial thyroid surgery (pN1: 31.6% vs. 100%, p<0.001; inappropriate surgery: 0% vs. 29%). Meanwhile, disease-free survival (DFS) increased (DFS: 100% vs. 58.1%, p<0.05). Both medullary thyroid carcinoma-specific (n=1) and PHEO-specific (n=5) deaths were reported during the study period. CONCLUSIONS: Our results further substantiate that gene scanning of all relevant RET exons is a powerful tool in the management of MEN2 patients, especially in asymptomatic carriers, and has led to earlier diagnosis and more complete initial treatment of patients with MEN2 in China.

RET germline mutations identified by exome sequencing in a Chinese multiple endocrine neoplasia type 2A/familial medullary thyroid carcinoma family.

BACKGROUND: Whole exome sequencing provides a labor-saving and direct means of genetic diagnosis of hereditary disorders in which the pathogenic gene harbors a large cohort of exons. We set out to demonstrate a suitable example of genetic diagnosis of MEN 2A/FMTC (multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma) using this approach. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced the whole exome of six individuals from a large Chinese MEN2A/FMTC pedigree to identify the variants of the RET (REarranged during Transfection) protooncogene and followed this by validation. Then prophylactic or surgical thyroidectomy with modified or level VI lymph node dissection and adrenalectomy were performed for the carriers. The cases were closely followed up. Massively parallel sequencing revealed four missense mutations of RET. We unexpectedly discovered that the proband's daughter with MEN 2A-related MTC presented a novel p.C634Y/V292M/R67H/R982C compound mutation, due to the involvement of p.C634Y in the proband with MEN 2A and p.V292M/R67H/R982C in the proband's husband with FMTC. In the maternal origin, p.C634Y caused bilateral MTC in all 5 cases and bilateral pheochromocytoma in 2 of the 5; the earliest onset age was 28 years. In the paternal origin, one of the six p.V292M/R67H/R982C carriers presented bilateral MTC (70 years old), one only had bilateral C-cell hyperplasia (44 years), two had bilateral multi-nodules (46 and 48 years) and two showed no abnormality (22 and 19 years). CONCLUSIONS/SIGNIFICANCE: The results confirmed the successful clinical utility of whole exome sequencing, and our data suggested that the p.C634Y/V292M/R67H/R982C mutation of RET exhibited a more aggressive clinical phenotype than p.C634Y or p.V292M/R67H/R982C, while p.V292M/R67H/R982C presented a relatively milder pathogenicity of MTC and likely predisposed to FMTC.