Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene.

INTRODUCTION: Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. CASE: We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.

Hypopituitarism in the elderly: multifaceted clinical and biochemical presentation.

UNLABELLED: Hypopituitarism (HYPO) is a rare and under-investigated pathology in the elderly. AIM: to review our case records of patients > or =65 yrs with first diagnosis of anterior global hypopituitarism, in order to evaluate presentation symptoms, etiology, biochemical and hormonal pictures, pituitary morphology, and efficacy of therapy. PATIENTS: 15 patients (65-82 yrs) were studied: in 11 (73%) HYPO was secondary to pituitary macroadenoma (non-secreting in 10 and GH-secreting in 1); in 3 it was associated to empty sella, and in 1 to pituitary hypoplasia. RESULTS: major presenting symptoms were visual-field defects and asthenia (40%) but also memory and/or gait impairment and nausea (30%) and depression (20%) were significantly observed. Dyslipidemia (73%), anemia (20%) and severe hyponatremia (13%) were found. After starting substitutive therapy and clinical improvement, 10 patients with macroadenoma underwent uneventful neurosurgery, which improved visual alterations but not pituitary function. Immunohistochemistry showed positivity for FSH in one patient and for GH in one patient. Six out of the eight patients with a post-surgical tumor remnant required treatment (surgery/radiotherapy/somatostatin analogue treatment in the acromegalic patient). CONCLUSIONS: The diagnosis of HYPO is often delayed in the elderly, since symptoms may be ascribed to aging and associated comorbidities. In our series, most of the aspecific symptoms were retrospectively addressed to HYPO since their resolution/improvement with replacement therapy. The prevalent cause of HYPO remains non-functioning pituitary macroadenomas. Hyponatremia can be a life-threatening presenting symptom. Symptoms considered apparently aspecific in the elderly should be investigated in order to possibly diagnose an important treatable disorder as HYPO.

TSH-secreting adenomas: rare pituitary tumors with multifaceted clinical and biological features.

TSH-secreting pituitary adenomas (TSH-omas) are a rare cause of hyperthyroidism in clinical practice. As their diagnosis is often delayed, these tumors are mostly diagnosed as macroadenomas, preventing an effective and radical cure and leading to serious local and systemic comorbidities. In addition to neurosurgery, medical therapy with the effective and tolerable SS analogs is a fundamental tool for the treatment of TSHomas. We report 3 cases of TSH-macroadenomas which displayed different clinical presentations. All patients showed increased free-thyroid hormone levels with inappropriately normal (2 patients) or high (1 patient) TSH levels. Magnetic resonance imaging (MRI)/computed tomography (CT) evidenced a pituitary macroadenoma and octreoscan was positive in all patients. In the 2 patients who underwent neurosurgery, hormonal hypersecretion by the tumor normalized. Histology showed nuclear pleomorphism and fibrosis, whereas immunohistochemistry showed positivity for TSH and, in a lesser amount, for FSH. In one of these patient (case 1), however, the presence of a tumor remnant inside the left cavernous sinus prompted us, in accordance with the patient, to start therapy with octreotide- long-acting release. As the third patient had a cardiac comorbidity which contraindicated neurosurgery, he underwent satisfactory treatment with long-acting SS analogs alone which normalized thyroid hormone levels. In this case, previous treatment with amiodarone confused and delayed the correct diagnosis of TSH-oma. As a result of improved laboratory and morphological techniques, TSH-omas should currently be diagnosed in early stages, thus enabling most patients to be managed satisfactorily through a combined approach.

Primary leiomyosarcoma of the oral tongue: magnetic resonance and ultrasonography findings with histopathologic correlation.

Leiomyosarcoma is a malignant smooth muscle tumor that frequently occurs in the gastrointestinal tract and female genital tract. It is aggressive and tends to recur and metastasize. Clinical behavior is unpredictable, mostly influenced by a proper surgical approach. Oral leiomyosarcoma, in particular of the tongue, is extremely rare and poorly documented in the radiology literature. Diagnostic assessment of oral leiomyosarcoma is often challenging, mostly founded on its peculiar immunohistological features. However, imaging evaluation is essential in staging and for preoperative planning. We illustrate the case of a 52-year-old woman with 2-months history of a painless growing mass on the left hemitongue, with magnetic resonance and ultrasonographic features correlated to histopathologic examination.

Molecular mechanisms involved in the pathogenesis of gastric carcinoma: interactions between genetic alterations, cellular phenotype and cancer histotype.

Gastric cancer develops through the accumulation of multiple genetic lesions that involve oncogenes, tumor suppressor genes and DNA mismatch repair genes. Lauren's classification of gastric carcinoma does not correlate with cellular phenotypes expressed by neoplastic cells and gastric and intestinal cell differentiation markers are widely expressed in both types (intestinal and diffuse) of gastric carcinoma. In contrast, the study of the correlation between morphologic events and genetic alterations, which come about in the cancerogenetic process, seems to indicate the existence of distinct cancerogenetic pathways for the intestinal (or glandular) and diffuse type carcinoma, both originating from a HP-positive gastritis. In particular there seem to be three different profiles of cancerogenesis: 1) p53 mutations which accompany the onset of dysplasia and intestinal-type carcinoma; 2) DNA repair mechanism alterations conditioning microsatellite instability, seem mutually exclusive with regards to p53 mutations. Microsatellite instability correlates with antrally located intestinal-type carcinoma, with little metastatic tendency and a better prognosis; microsatellite instability frequently involves the TGF beta RII, IGF II R genes or the BAX proapoptotic gene, in as much as these contain microsatellite sequences; 3) alterations of E-cadherin, both with regards to mutations and abnormal expression. These lead to junctional and cell polarity loss and are primarily associated with diffuse type carcinoma, which is characterized by poorly cohesive neoplastic cells. Some tumors, initially arising as intestinal-type (glandular structure), acquire a mixed histotype during neoplastic progression, in which both the typical alterations of the intestinal cancerogenesis (p53, microsatellite instability) and those of the diffuse carcinoma (E-cadherin) coexist. The identification of a mixed histotype could have importance both in epidemiologic, pathogenetic and prognostic terms.

Laparoscopic inguinal hernia repair: optimal technical variations and results in 1700 cases.

A follow-up series of 1700 laparoscopic inguinofemoral herniorrhaphies by a single surgical team is presented (1381 patients). Two standard techniques were used: transabdominal preperitoneal (1452 cases) and totally extraperitoneal (248 cases). Mean follow-up was 5.3 years. There were 348 patients with bilateral hernias, 121 with recurrent hernias, and 27 with incarcerated hernias. Numerous technical variations were used as the study progressed. A SurgiPro mesh (USSC, Norwalk, CT) with staple/tack fixation was used in all patients. Average operating time was 41 minutes for unilateral repairs, and 97.3 per cent of the procedures were outpatient procedures. Five recurrences were reported. The postoperative permanent neuropathy rate was found to be negligible, but a 5.1 per cent rate of uncomplicated ipsilateral postoperative seromas is reported. All patients were instructed to return to unrestricted physical activities on postoperative day one. Ninety per cent of the patients were able to do so within 5 days versus 93 per cent in 7 days. Ninety-six per cent of all patients felt minimal pain and discomfort after 72 hours. There was no significant difference in recovery or morbidity between the transabdominal preperitoneal and totally extraperitoneal repairs. To date laparoscopic inguinal herniorrhaphy continues to be a difficult procedure with a significant learning curve. The reported surgical performance data and the described optimal technical variations make this procedure a viable and competitive repair in the surgical management of inguinofemoral hernia.

Transabdominal preperitoneal laparoscopic inguinal herniorrhaphy: results of 509 repairs.

A follow-up series of 509 transabdominal preperitoneal (TAPP) laparoscopic inguinal hernia repairs is presented. The technique used was an original TAPP approach using a SurgiPro Mesh with two technical variations. Age restrictions were removed after the first few cases; thereafter, all patients cleared for general anesthesia were entered into this study without restrictions. Our average operating time was 48 minutes for unilateral hernia repairs. All procedures were outpatient procedures with the exception of 11 overnight admissions for urinary retention. The procedure was well tolerated. Ninety-three per cent of all patients reported minimal pain or discomfort within 72 hours. All patients were instructed to resume unrestricted physical activities within 24 to 48 hours after the procedure; 89 per cent were able to resume activities within 5 days, 94 per cent within 7 days, and 97 per cent within 10 days. No significant morbidity nor mortality were reported, with the exception of two postoperative neuropathies. Nineteen patients developed postoperative seromas that were successfully aspirated. One recurrence has been reported to date. Due to the lack of long term follow-up, these results remain inadequate to establish an accurate recurrence rate. This procedure remains technically difficult and is subject to a learning curve, but the rate of recovery for these patients is significantly improved. In conclusion, the superiority of this procedure in comparison to its open counterpart cannot be proven until long term follow-up becomes available.

Laparoscopic inguinal hernia repair results: 131 cases.

Since its introduction, laparoscopic inguinal hernia has been plagued with multiple technical problems. A series of 131 laparoscopic inguino-femoral hernia repairs is presented. The technique used was an original transabdominal pre-peritoneal approach using a SurgiPro mesh with two technical variations. In the beginning, this procedure was only offered to patients less than 50 years of age. These guidelines were eliminated as the study progressed. For our first 10 cases, our average operating time was 1 hour and 39 minutes. For the last 40 cases, it averaged 63 minutes. All but four patients were discharged the same day. Ninety-six per cent of all patients felt minimal pain or discomfort within 72 hours. Four per cent felt pain or discomfort until the tenth post-operative day. All patients were ambulatory the day of surgery, and 94 per cent of all patients resumed regular activities before the tenth postoperative day. No significant morbidity and no mortality were identified with the exception of five postoperative inguinal seromas, which were successfully aspirated. No recurrence was demonstrated, but this series is clearly insufficient to establish a rate of recurrence. The cost of these procedures appeared to be higher than for a conventional repair; however, it has recently been reduced. The procedures remain difficult, but the rate of recovery for these patients is shown to be significantly improved. The superiority of this procedure over its open counterpart has not yet been proven.

The use of dura mater allograft in the surgical repair of large defects of the abdominal wall.

The dura mater allograft is being used as an abdominal fascia substitute and major advantages are documented. It was used successfully in four patients at this institution, with a ten month follow-up period. Its strength, durability, tissue tolerance, flexibility, ease of handling, nonallergenic property, availability and stability in the presence of infection make it a good graft to be used in the repair of large abdominal hernias. We are quite convinced that long term follow-up results will verify the results of the animal experiments done by others and affirm the durability of the graft. In one patient, this graft has been shown to be adequate for placement in an infected bed and to have a definite resistance to infection. The results of incidental operative biopsy in another patient, have shown an excellent incorporation of the dura graft into the surrounding tissues. In our hands, the experience with the dura graft using monofilament sutures has been quite positive.

Embolization and vessel wall perforation in argon laser recanalization.

The primary concerns in the development of a laser catheter for intravascular use are the potential hazards of vessel wall perforation and distal embolization. We present evidence, using technetium 99-labeled thrombi in two rabbit aortas and one human cadaver coronary artery, that distal embolization does not occur after argon laser recanalization. Also, no vessel wall perforation was observed during recanalization of 15 thrombosed rabbit aortas and 1 inferior vena cava, used because of their extremely thin walls. Laser recanalization of three peripheral arteries with atherosclerotic plaque obstruction, in amputated human legs, showed no evidence of vessel wall perforation. The incidence of vessel wall perforation can be minimized by preferential use of the argon laser, strict maintainance of a coaxial relationship between the laser catheter and the vessel, and exercising care during the actual lasing process. Distal embolization does not appear to be an important consideration.