Distinguishing Parathyromatosis,Atypical Parathyroid Adenomas,and Parathyroid Carcinomas Utilizing Histologic and Clinical Features

Parathyromatosis is displaced parathyroid tissue in the neck and mediastinum related to prior surgery. Parathyromatosis can be difficult to distinguish from atypical adenoma and parathyroid carcinoma. The aim of this study is to evaluate clinical and morphologic features that may differentiate parathyromatosis, atypical adenoma, and parathyroid carcinoma. Cases of parathyromatosis, atypical adenoma, and parathyroid carcinoma were identified. Index cases were reviewed by consensus for histologic features, including stromal, cytologic/architectural, and invasive features. Ki67 was performed on index cases and scored using the Adsay method. Clinical information was gathered from the electronic medical record. 4 parathyromatosis, 17 atypical adenoma, and 6 parathyroid carcinoma were included. Parathyroid carcinomas were more likely to display coarse chromatin with nucleoli (P = 0.04), infiltrative invasion (P < 0.01), and metastasis (P < 0.01). Only parathyromatosis showed circumscribed invasion. Infiltrative invasion was more common in cases with progression (P = 0.046) and metastasis (P < 0.001). Necrosis and perineural invasion were only present in cases with progression and were more frequent in cases with metastasis (P = 0.079 and P = 0.19, respectively). There were no differences in presence of a fibrous capsule, capsular invasion, intralesional fibrous bands, random endocrine atypia, solid growth, Ki67 index, gland size/weight, serum PTH/calcium levels, and locoregional recurrence rates. There is overlap in the histologic features in parathyromatosis, atypical adenoma, and parathyroid carcinoma. While perineural, vascular, and infiltrative soft tissue invasion should remain diagnostic of malignancy, other atypical features such as solid growth, coarse chromatin with nucleoli, and necrosis should raise concern for recurrence and/or metastasis, and can be present in parathyroid lesions with and without recurrence.     

MRI Prediction of Fibrous Pituitary Adenomas

Summary  The transsphenoidal approach is a less invasive and safer procedure for removing pituitary adenomas. However, this procedure becomes extremely difficult when the tumour consistency is fibrous as encountered in about 10% of pituitary adenomas. In this study, we investigated predicting factors of tumour consistency in magnetic resonance images (MRIs).  MRIs of two groups, twenty-one soft and five firm (fibrous) adenomas, were retrospectively evaluated and compared in respect of tumour consistency. To compare the two groups objectively, tumour densities on MRI films and percentage of collagen content on operative specimens were expressed as numerical data using NIH-image^TM. The relationships between collagen content and T1-weighted images, T2-weighted images, grade of enhancement effect, and heterogeneity of enhancement were investigated.  Signal intensities on T1-weighted images were not correlated with tumour consistency, whereas those on T2-weighted images were significantly correlated with the percentage of collagen content. Adenomas, showing lower signal intensities on T2-weighted images, contained more collagen. On enhanced images, homogeneously enhanced adenomas tended to include more collagen, even though the grade of enhancement effect showed only weak correlation with the tumour hardness.  MRIs give us useful information on tumour consistency. Adenomas may be firm and fibrous if they show low signal intensities on T2-weighted images and homogeneous enhancement. To remove such tumours, a long sized and small-calibred ultrasonic aspirators applicable to transsphenoidal approach must be prepared and multi-staged operations may be more than likely needed.     

Imaging of Resected Nonfunctioning Pituitary Adenomas: The Cost of Surveillance

Objectives To determine the cost of annual magnetic resonance imaging (MRI) surveillance after resection of nonfunctioning pituitary adenomas (NFPAs) and its effectiveness in reducing visual compromise due to tumor recurrence.Design Retrospective case series.Setting Vanderbilt University Medical Center (2003–2011).Participants A total of 120 patients underwent primary transsphenoidal resection and surveillance of NFPAs between 2003 and 2011.Main Outcome Measures Time from initial surgery to most recent imaging or progression. Surveillance MRI costs according to Centers for Medicare and Medicaid database and visual field deficits.Results Patients received 382 surveillance scans at a total cost of $218,477.30. The median follow-up was 47 months (interquartile range [IQR]: 26–76), and the median interval between scans was 357 days (IQR: 225–434). Overall, 50 scans (13%) revealed tumor growth. The cost per scan revealing growth was $4,369.55. The cost to identify 19 patients (16%) with clinically significant growth was $11,498.80 per patient. A total of 5 of 19 patients (26%) experienced new visual deficits prior to intervention. Patients with visual decline tended to have longer scan intervals than those with preserved vision (mean: 239 versus 794 days; p = 0.0584). No patient with annual surveillance imaging experienced visual decline.Conclusions Annual MRI scans are a sensitive and cost-conscious method to identify NFPA recurrence prior to visual decline.     

Prediction of Consistency of Pituitary Adenomas by Magnetic Resonance Imaging

Objective Pituitary adenomas are typically soft. The prevalence of fibrous adenomas is ∼ 5 to 13%. Firm tumors are difficult to remove by curettage or suction. Predicting fibrous adenomas by magnetic resonance (MR) imaging is typically difficult and unreliable. We propose a new prediction method based on MR T2-sequence intensity.Methods The MRIs of 36 consecutive patients with nonsecreting macroadenomas were evaluated preoperatively by a blinded radiologist. Using an MR T2-weighted sequence, regions of interest were sampled from the adenoma and cerebellar peduncle, and the ratio was calculated. Intraoperatively, tumors were graded prospectively for their consistency by the operating surgeon.Results There were 28 soft and 6 fibrous tumors. Unpaired t test for these ratios was found to be statistically significant (p < 0.0240; 95% confidence interval, −0.8229 to −0.06207). Mean values for soft tumors were found to be 1.918 (standard error of the mean [SEM] = 0.08212); firm tumors, 1.475 (SEM = 0.1179). Soft tumors were associated with ratios > 1.5 (sensitivity 100%; specificity 66.7%); firm tumors were associated with ratios < 1.8 (sensitivity 100%; specificity 42.9%).Conclusion Fibrous adenomas are typically diagnosed intraoperatively. However, their resection can be technically challenging. Using T2 intensity ratios on routine preoperative MRI allows identification of these challenging cases. The surgeon can then be better prepared for the surgical resection.     

Molecular Pathogenesis of Pituitary Adenomas: A Review

Summary  Modern theory of tumorigenesis suggests that genetic alterations may play a role in the initiation and promotion of pituitary adenomas. Gsp and MEN-1 genes play a role in the initiation event, while p53, ras, Rb and nm23 genes play some role in the progression of the tumor. Gsp gene, that may play an important role in 40% of GH-producing tumor, activation of 10% of non-functioning tumors and 6% of corticotroph adenomas, produces cAMP, which stimulates cyclin D1 and D3 which later produce cdk2 and cdk 4 respectively, and stimulates cell progression from G1 to S phase. cAMP also induces ras gene, which inhibits binding of pRb with E2F that is necessary to prevent action of E2F in accelerating cell cycle. MEN-1 gene, although found in some sporadic tumors, is more likely associated with familial adenoma. p53, Ras, Rb, nm23 and c-myc genes play some role in the promotion of tumors especially toward their aggressive variant. p53 gene, which is found in up to 60% of ACTH producing adenomas, through action of p21 inhibits progression of cell cycle from G1 to S phase, by inhibiting the action of cyclin D3 on cdk 4. Ras oncogene, in cooperation with c-myc gene, prevents the binding of pRb with E2F, which is necessary for preventing progression cell cycle, resulting in progression of cell cycle from G1 to S phase. Nm23 gene inhibits the action of cyclin B and arrests the cell in G2 phase. Further studies will not only be helpful in understanding the genetic pathogenesis and prognosis of pituitary tumors, but also in developing a novel treatment for patients with pituitary adenomas.     

Acellular Dermal Allograft for Sellar Repair after Transsphenoidal Approach to Pituitary Adenomas

Objectives Our practice has transitioned from using fat autograft to acellular dermal matrix (AlloDerm, LifeCell Corp, Woodlands, Texas, USA). We present the largest series to our knowledge of AlloDerm for sellar floor repair after transsphenoidal approach to pituitary adenoma and compare rates of postoperative cerebrospinal fluid (CSF) leak with an earlier cohort of patients whose CSF leaks were repaired with fat autograft.Design This is a retrospective cohort study comparing sellar repair with fat autograft versus inlay Alloderm between the years 2003 and 2012. The primary end point was postoperative CSF leak.Results A total of 429 patients (368 primary; 83 revision operations) without intraoperative lumbar drainage were included. A total of 18 postoperative CSF leaks were observed (3.9%). Intraoperative CSF leak occurred in 160 cases (35.5%). Among this subset of patients with intraoperative CSF leak, 95 underwent repair with AlloDerm and 46 underwent repair with fat autograft, with postoperative CSF leak rates of 8.4% and 15.2%, respectively (p = 0.34, chi-square test); 19 patients underwent repair with other techniques or no repair at all, with postoperative leak rate of 0%.Conclusions AlloDerm is an effective alternative to fat autograft in cases of low-flow CSF leak following transsphenoidal resection of pituitary adenoma.     

Gamma-Knife Surgery for Secreting Pituitary Adenomas

Summary We report our preliminary results concerning 25 patients with secreting pituitary adenomas treated with stereotactic radiosurgery after partial transsphenoidal surgery and followed over a 6–36 month-period. Among the 15 acromegalic patients, a decrease of 65% in mean GH levels was achieved after 6 months and of 77% at 12 months after radiosurgery. Presently, only 3 patients (20%) are considered as in remission (mean GH and IGF1 level into the normal range). A decrease of 46% and 65% was observed at 6 and 12 months after radiosurgery in 4 patients with prolactinomas although no normalization of PRL levels occurred. Presently, 3/4 patients have individual PRL levels slightly above the normal range. A normalization of Urinary Free Cortisol (UFC) was noticed in 4/6 (66%) patients with Cushing's disease within 6–12 months. No pituitary deficiency was noticed in this series with the exception of 4/25 patients (16%) who received subtotal or total pituitary irradiation for postoperative remnants of secreting adenomas poorly defined on MRI. One woman, who had undergone previously a conventional irradiation and presenting with a cavernous sinus adenoma reaching the optic nerve, developed an optic neuropathy. A second woman, with a cavernous sinus remnant, presented a cranial nerve palsy (VI) after the irradiation. We can conclude that radiosurgery using the Cobalt-60 Gamma-unit is, at least, as effective as conventional radiotherapy in the control of pituitary hormone hypersecretion from postoperative adenomas remnants with less adverse effects.     

Prolactin Secreting Pituitary Adenomas: Analysis of 429 Surgically Treated Patients, Effect of Adjuvant Treatment Modalities and Review of the Literature

Summary ? Objective. We performed this retrospective analysis to determine the efficacy of surgery and radiotherapy over hormonal and volumetric control of prolactinomas, many of which had failed during dopa-agonist therapy. In the same analysis, the efficiency of topical bromocriptine application as a preliminary study was compared with standard treatment modalities.  Materials and Methods. Between 1982–1997, 429 prolactinoma patients who underwent surgery at Hacettepe University Neurosurgery Department and at Bayındır Medical Center were included in this study. All patients were classified according to Hardy's classification scheme and were further divided into `invasive' and `non-invasive' groups based on this radiological classification system. The mean follow-up time was 38.4 months. One hundred and thirty five patients had peroperative bromocriptine application into the sellar cavity¹ and these, either receiving radiotherapy (RT) or not, were analysed separately from the other 294 patients. In the early postoperative period, 104 of these patients were given conventional radiotherapy with median dose of 4500 cGy. We focused on the effects of surgery and radiotherapy over volumetric and hormonal tumour control on the basis of invasion characteristics and the early results of topical bromocriptine application in macroprolactinoma patients; and compared our results with the literature.  Results. Statistical analysis revealed that radiotherapy was not effective over hormonal and volumetric tumour control for prolactinomas. We did not observe any correlation to dural invasion of the sellar floor, recurrence, and the disease-free survival time. Topical bromocriptine application seemed to improve the volumetric control in 135 selected macroprolactinoma patients but not hormonal response compared with the standard treatment modalities.  Conclusion. Conventional radiotherapy is not as effective as expected for prolactinomas and should not be preferred considering its adverse effects. Tumoural infiltration of the sellar dura mater is not a prognostic criterion for recurrence expectation and, therefore, should not be a criterion for radiotherapy after surgery. After subtotal removal, postoperative dopa-agonist therapy should be considered even if the patient was intolerant or resistant to previous treatment since surgery seems to improve patients' drug tolerance and cooperation due probably to the lower dose requirement. The early results of topical bromocriptine application seem to improve volumetric tumour control but this should not be accepted as a judgement since we need to wait for later results and to expand the sample size for more reliable interpretation.     

Pituitary apoplexy. Report of 25 patients

A series of 25 patients with a clinical diagnosis of pituitary apoplexy (PA) is reviewed. It included 14 men and 11 women aged between 20 to 79 years (mean age: 54 years). Twenty-two patients did not know that they had a pituitary tumor when the apoplexy occurred. A precipitating event was found in 3 cases. Symptoms and signs ranged from isolated ocular paresis to a deep coma. Seventeen patients experienced a decrease in their visual acuity. CTscan and MRI showed a pituitary adenoma in all cases, a hemorrhage was also present in 10 out of the 24 CTscans, and in all the 8 MRI performed. Twenty patients underwent surgery; 18 of them by a transsphenoidal approach. A complete recovery of visual acuity was observed in 75% of patients operated within the week following the onset of symptoms, and in 56% of patients operated later on. There was no case of complete visual recovery among the blind patients. Pituitary apoplexy is a clinical concept. It applies only to symptomatic cases. It is generally a complication of a pituitary adenoma which is in most cases unknown. There are different degrees of severity; PA can even be life-threatening. The principal aim of surgery in the acute phase is the improvement of visual prognosis. In our series, blind patients or those with a history of visual loss for more than a week or with a blindness had a poorer prognosis.     

垂体腺瘤性男性不育

垂体腺瘤是男性不育的重要病因。现代内分泌和影像学检查能够早期诊断垂体腺瘤引起的男性不育症。针对垂体腺瘤的病因治疗是治疗此类不育症的最佳选择。     

替莫唑胺治疗难治性垂体腺瘤

目的 探讨替莫唑胺在难治性垂体腺瘤中的疗效。方法 回顾性分析近年收治的3例难治性垂体腺瘤患者,包括1例侵袭性无功能腺瘤,1例肢端肥大症,1例库欣病,总结其临床过程及应用替莫唑胺治疗后的效果并结合文献进行分析。结果 侵袭性无功能腺瘤患者经12个月替莫唑胺治疗,肿瘤明显缩小,随访1年,未见肿瘤进展;肢端肥大症患者经过6个月治疗,随访3月,肿瘤有所缩小,激素水平无明显下降;库欣病患者经过4个月治疗,肿瘤无明显变化,激素水平无下降。结论 替莫唑胺在控制难治性垂体腺瘤大小可能有一定作用,但短疗程的治疗对肢端肥大症和库欣病患者的激素水平控制效果不理想,日后仍需继续研究。     

改良翼点入路显微手术切除垂体巨腺瘤及术中垂体柄保护

目的 探讨巨大型垂体腺瘤显微手术切除及垂体柄保护方法。方法 采用改良翼点入路对48例巨大垂体腺瘤（直径〉40mm）行显微手术切除，术中注意保护垂体柄。结果 肿瘤伞切除36例，近全切除8例，大部切除4例，其中全切除患者垂体柄保留30例（83．3％）。所有病例无一例死亡。术后发生尿崩症31例（64．6％），其中21例在1～2周内恢复正常，7例在3个月内恢复，3例尿崩症状持续2年左右？随访2～3年，无复发病例，无其他并发症。结论 采用改良翼点入路治疗巨大垂体瘤效果确切，术中垂体柄保留是降低术后尿崩症发生率、提高手术疗效的关键措施。     

显微镜下经单鼻孔蝶窦入路切除垂体腺瘤

目的评价显微镜下经单鼻孔蝶窦入路切除垂体腺瘤的疗效. 方法采用经单鼻孔蝶窦入路行垂体腺瘤切除术20例,其中微腺瘤8例(<10 mm),小腺瘤8例(10～20 mm),中腺瘤3例(20～30 mm),大腺瘤1例(>30 mm);PRL腺瘤9例,GH腺瘤6例,ACTH腺瘤5例. 结果本组20例无并发症,平均随访5(2～10)个月,患者临床症状较术前均有不同程度改善,手术效果良好. 结论经单鼻孔蝶窦入路垂体瘤切除术效果好,术中损伤小,患者痛苦少,术后康复快,没有或较少出现并发症.     

Long-term Outcomes of Hypofractionated Stereotactic Radiotherapy for the Treatment of Perioptic Nonfunctioning Pituitary Adenomas

The efficacy of stereotactic radiotherapy (SRT) has been well established for postoperative residual and recurrent nonfunctioning pituitary adenomas (NFPAs). However, the risk of visual impairment due to SRT for lesions adjacent to the optic pathways remains a topic of debate. Herein, we evaluated the long-term clinical outcomes of hypofractionated stereotactic radiotherapy (HFSRT) for perioptic NFPAs. From December 2002 to November 2015, 32 patients (18 males and 14 females; median age 63 years; range, 36–83 years) with residual or recurrent NFPAs abutting or displacing the optic nerve and/or chiasm (ONC) were treated with HFSRT. The median marginal dose was 31.3 Gy (range, 17.2–39.6) in 8 fractions (range, 6–15). Magnetic resonance imaging (MRI) and visual and hormonal examinations were performed before and after HFSRT. The median follow-up period was 99.5 months (range, 9–191). According to MRI findings at the last follow-up, the tumor size had decreased in 28 (88%) of 32 patients, was unchanged in 3 (9%), and had increased in 1 (3%). The successful tumor size control rate was 97%. Visual functions remained unchanged in 19 (60%) out of 32 patients, improved in 11 (34%), and deteriorated in 2 (6%). Two patients had deteriorated visual functions; no complications occurred because of the HFSRT. One patient developed hypopituitarism that required hormone replacement therapy. The result of this long-term follow-up study suggests that HFSRT is safe and effective for the treatment of NFPAs occurring adjacent to the ONC.     

Pituitary adenomas: Trans‐sphenoidal experience of 300 cases

Objective: The main aim of the present study was to examine the effectiveness and complication rate of the 1 cm right‐sided unilateral sublabial trans‐sphenoidal surgery for patients with pituitary adenoma equal to or greater than 5 mm in diameter. Method: A total of 350 patients were surgically treated for pituitary adenomas between December 1999 and December 2003 in an academic neurosurgical unit in China. Three hundred patients (86%) were treated with the 1‐cm right‐sided unilateral sublabial trans‐sphenoidal approach. The mean age of patients was 43 years (range 10–78 years) and female patients accounted for 59% of the total. One hundred and ninety‐six (64%) patients had functioning endocrine tumours and 104 (36%) patients had non‐functioning tumours or macroadenomas. Tumours which were outside this simple and basic classification were excluded from the study. Results: There were no operative mortalities. One patient developed hypopituitarism and 16 (5%) developed transient diabetes insipidus that required pituitrin treatment. The remission rate for macroadenoma was 85% and that for microadenoma was 98.5% during a medium term follow‐up of 1–5 years. One hundred and fifteen patients had prolactin secreting tumours and 90.4% achieved endocrine remission. Fifty‐six patients had growth hormone secreting tumours and 75.4% achieved endocrine remission. Preoperatively, one hundred and fifty‐one patients presented with visual impairment and 148 (98%) achieved a documented improvement in visual acuity. The mean duration of hospital stay was 4 days (range 3–7 days). Conclusion: This minimally invasive trans‐sphenoidal surgery for pituitary adenomas could be used as the primary treatment for small pituitary tumours. The effectiveness of the tumour removal and low morbidity rate compare favourably with the conventional sublabial approach as well as the more recently developed endoscopic endonasal approaches.     

Pilot Study on Early Postoperative Discharge in Pituitary Adenoma Patients: Effect of Socioeconomic Factors and Benefit of Specialized Pituitary Centers

Introduction Pituitary neoplasms are benign entities that require distinct diagnostic and treatment considerations. Recent advances in endoscopic transsphenoidal surgery have resulted in shorter lengths of stay (LOS). We implemented a postoperative day (POD) 1 discharge paradigm involving a multidisciplinary approach and detailed preoperative evaluation and review of both medical and socioeconomic factors.Methods The experience of a single neurosurgeon/ears, nose, throat (ENT) team was reviewed, generating a preliminary retrospective database of the first 30 patients who underwent resection of pituitary lesions under the POD 1 discharge paradigm. We assessed multiple axes from their preoperative, in-house, and postoperative care.Results There were 14 men and 16 women with an average age of 53.8 years (range: 27–76 years). There were 22 nonsecretory and 8 secretory tumors with average size of 2.80 cm (range: 1.3–5.0 cm). All 30 patients underwent preoperative ENT evaluation. Average LOS was 1.5 ± 0.7 days. A total of 18 of 30 patients were discharged on POD 1. The insurance status included 15 with public insurance such as emergency Medicaid and 15 with private insurance. Four patients had transient diabetes insipidus (DI); none had permanent DI. Overall, 28 of 30 patients received postoperative steroids. Factors that contributed to LOS > 1 day included public insurance status, two or more medical comorbidities, diabetes mellitus, transient panhypopituitarism, and DI.Conclusion The implementation of a POD 1 discharge plan for pituitary tumors is feasible and safe for elective patients. This implementation requires the establishment of a dedicated Pituitary Center model with experienced team members. The consistent limitation to early discharge was socioeconomic status. Efforts that incorporate the analysis of social disposition parameters with proper management of clinical sequelae are crucial to the maintenance of ideal LOS and optimal patient outcomes.