Cytologic characteristics of subependymal giant cell astrocytoma in squash smears: morphometric comparisons with gemistocytic astrocytoma and giant cell glioblastoma

OBJECTIVE: To evaluate the squash smear features of subependymal giant cell astrocytoma (SEGA) in comparison with gemistocytic astrocytoma and giant cell glioblastoma. STUDY DESIGN: We compared the squash smear features of 3 cases of SEGA, 9 cases of gemistocytic astrocytoma and 3 cases of giant cell glioblastoma with the morphometric findings. RESULTS: SEGA had, on average, a 15.84 +/- 5.03-microm nucleus, 33.22 +/- 12.05-microm cytoplasm and 0.50 +/- 0.12 nuclear/cytoplasmic ratio in squash smears. In addition, SEGA showed hairlike processes distributed along the squash direction like strap cells. While the gemistocytic astrocytoma had several tumor cells showing a vertically located nucleus, the tumor cells of SEGA showed nuclei oriented mainly in parallel. CONCLUSION: These squash cytologic features of SEGA can be very helpful in the differential diagnosis by excluding mimics.     

A case of large prolactinoma supposed to be cured by bromocriptine therapy

The authors reported a patient with a large prolactinoma (PRL 1,716 ng/ml) who was treated with bromocriptine for two years and followed up for a subsequent 36 months. After the start of the therapy, the tumor size was dramatically reduced, and finally the disappearance of the tumor was confirmed by high resolution coronal CT. The serum prolactin level and pituitary function were normalized. The tumor has not regrown and the blood prolactin level has remained normal for 36 months since the discontinuation of bromocriptine administration. This is a very rare case report on the eradicative effect of bromocriptine on such a large prolactinoma. Another characteristic of this case was that the prolactin reserve was maintained not only before the therapy but also during the early stage of the therapy.     

雌激素诱发大鼠原位与移植垂体催乳素瘤中催乳素基因与TGFα和TGF …

利用本实验室建立的１７β－雌二醇诱致Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙ（ＳＤ）大鼠原位垂体和异体移植于肾囊的垂体同时形成催乳素瘤的动物模型,采用Ｎｏｒｔｈｅｍ印迹杂交方法,我们观察了Ｅ２长期作用（１２０ｄ）后诱发的原位与移植垂体ＰＲＬ瘤中ＰＲＬ基因和两种转化生长因子ＴＧＦα和ＴＧＦβ１基因表达水平的改变。结果表明：在Ｅ２长期作用后,原位垂体与异体移植于肾囊,从而远离下丘脑的垂体均可形成垂体ＰＲＬ瘤;原位     

垂体催乳素瘤的病因及发病机制的实验研究

应用在同一只雄性ＳＤ大鼠中,保留原位垂体并在肾囊内植入一异体垂体,同时背部埋植装有１７－β－雌二醇（１７－β－ｅｓｔｒａｄｉｏｌ,Ｅ２）的药泵,经Ｅ２在体作用６０￣１２０天后,其原位垂体和异体移植入肾囊的垂体同时形成２垂体催乳素（ｐｒｏｌａｃｔｉｎ,ＰＲＬ）瘤的动物模型,研究ＰＲＬ瘤的发病机制。结果表明,Ｅ２长期作用可诱发原位垂体和远离下丘脑的移植垂体同时形成ＰＲＬ瘤,并伴高ＰＲＬ血症和ＰＲＬ基因     

Intraoperative squash cytology: accuracy and impact on immediate surgical management of central nervous system tumours

N. Krishnani, N. Kumari, S. Behari, C. Rana and P. Gupta
Intraoperative squash cytology: diagnostic accuracy and its impact on immediate surgical management of central nervous system tumours Objective: To assess the diagnostic accuracy of squash cytology, reasons for deferment, disagreement and partial agreement, and assess its impact on immediate surgical management of central nervous system tumours. Study design: All cases of squash cytology received from January 2007 to July 2010 were reviewed and correlated with final histopathological diagnoses. Deferments, disagreements and partial disagreements were reviewed to look for possible reasons. The impact of disagreements and partial agreements on immediate surgical management was evaluated in consultation with neurosurgeons. Results: Overall accuracy (including complete and partial agreement) for squash smear diagnosis of 334 cases was 94.9% while complete agreement was 79.9%, excluding deferred cases. Disagreement was seen in 17 cases and 31 cases were deferred for final histopathology diagnosis. Good correlation was seen in astrocytoma, meningioma, schwannoma, medulloblastoma, pituitary adenoma and metastatic carcinoma, whereas poor correlation was seen in oligodendroglioma, ependymoma and lymphoma. Among 17 cases with disagreement and 50 cases with partial agreement, an adverse impact on immediate surgical management was found in six (35.3%) cases and one (2.0%) case, respectively. The sensitivity and specificity of squash for diagnosis of neoplastic lesions were 98.7% and 87.5%, respectively. Conclusion: Squash cytology is a rapid, reliable, simple technique for intraoperative consultation in neurosurgical practice with high overall accuracy. Causes causing an adverse impact on surgical management were rare and potential avoidable reasons for them were identified.     

Increased micronucleus,nucleoplasmic bridge,nuclear bud frequency and oxidative DNA damage associated with prolactin levels and pituitary adenoma diameters in patients with prolactinoma

Prolactinoma is the most common pituitary tumor. Most pituitary tumors are benign, but they often are clinically signi?cant. We investigated cytokinesis-block micronucleus cytome (CBMN cyt) assay parameters and oxidative DNA damage in patients with prolactinoma to assess the relations among age, prolactin level, pituitary adenoma diameter and 8-hydroxy-2’-deoxyguanosine (8-OHdG) level in patients with prolactinoma. We investigated 27 patients diagnosed with prolactinoma and 20 age- and sex-matched healthy controls. We measured CBMN cyt parameters and plasma 8-OHdG levels in peripheral blood lymphocytes of patients with prolactinoma and controls. The frequencies of micronucleus (MN), nucleoplasmic bridge, nuclear bud, apoptotic and necrotic cells, and plasma 8-OHdG levels in patients with prolactinoma were significantly greater than controls. MN frequency was correlated positively with age, prolactin levels and pituitary adenoma diameters in patients with prolactinoma. The increased chromosomal and oxidative DNA damage, and the positive correlation between MN frequency, prolactin levels and pituitary adenoma diameters may be associated with increased risk of cancer in patients with prolactinoma, because increased MN frequency is a predictor of cancer risk.     

Chordoid glioma of the third ventricle: Report of a case with cytologic features and utility during intraoperative consultation

BACKGROUND: Chordoid glioma is a rare, low grade neoplasm with a unique chordoid appearance as well as distinct clinicopathologic and immunohistochemical features. Its cytologic features have not been described. CASE: A 42-year-old woman with recent-onset amnesia and confusion underwent magnetic resonance imaging, which revealed a 5-cm mass lesion arising in the third ventricle. Intraoperative squash smears showed cellular sheets as well as nests and strands of epithelioid tumor cells with bland nuclei and polygonal to elongated cytoplasm in a mucinous background. Binucleation was commonly seen. The tumor was intimately admixed with a benign lymphoplasmacytic infiltrate and scattered Russell bodies. Histologically, the tumor cells were arranged in a syncytium with prominent lymphoplasmacytic infiltrates and scattered small foci of necrosis in a mucinous matrix. The foremost differential diagnosis was chordoid meningioma. Immunohistochemically, the tumor cells were positive for glial fibrillary acid protein (GFAP), vimentin, epithelial membrane antigen, CD34, neuron-specific enolase and CK-7 and negative for synaptophysin, S-100 protein, neurofilament, and estrogen and progesterone receptors. CONCLUSION: Intraoperative smear cytology in this case of chordoid glioma revealed distinctive cytologic features, reflecting the unique histologic pattern. Cytologic features, such as binucleation, absence of intranuclear pseudoinclusions and GFAP immunoreactivity, are particularly helpful in differentiating chordoid glioma from chordoid meningioma.     

Giant invasive pituitary adenoma extending into the sphenoid sinus and nasopharynx: report of a case with intraoperative cytologic diagnosis

BACKGROUND: Invasive pituitary adenomas involving the skull base are difficult to distinguish from other, more aggressive tumors. Intraoperaive diagnoses are crucial for deciding the course of treatment. CASE: A large mass extending from the sella turcica to the sphenoid sinus and nasopharynx was identified in a 42-year-old male. Because of the lack of endocrine abnormalities and lack of an apparent rise in pituitary hormones, preoperative diagnoses included chordoma, chondrosarcoma, meningioma and pituitary adenoma. Tumor fragments were easily squeezed into a thin layer of cells for cytologic specimens. Uniform, round tumor cells were arranged in minimally cohesive cell sheets and possessed regular, ovoid nuclei with a fine chromatin pattern and granular cytoplasm with prominent Golgi areas. The cytologic features indicated a probable diagnosis of pituitary adenoma and excluded other possibilities. Immunohistochemical demonstration of prolactin and ultrastructural features established the final diagnosis of prolactinoma. With the administration of bromocriptine, a large reduction in tumor size occurred. As compared to frozen sections, cytologic preparations are more effective for the intraoperative diagnosis of pituitary adenomas. Such neoplasms should always be included in the differential diagnosis of tumors involving the skull base.     

垂体瘤微环境免疫细胞浸润与肿瘤侵袭性的相关性研究

目的:探讨垂体瘤免疫微环境中免疫细胞浸润情况及其与垂体瘤侵袭性的相关性。方法:选取35例垂体瘤病理组织切片,通过免疫组化染色分析巨噬细胞、T细胞以及中性粒细胞的特异性标记蛋白CD68、CD4、CD8和MPO的表达情况。结合临床和影像学数据分析,分析生长激素腺瘤、泌乳素腺瘤和无功能腺瘤的侵袭性与免疫细胞浸润数量的相关性。结果:在15例生长激素腺瘤,10例泌乳素腺瘤和10例无功能性腺瘤患者中,侵袭性垂体瘤中有更多的巨噬细胞浸润(P分别为0.014,0.032和0.032)。侵袭性促生长激素腺瘤、泌乳素腺瘤和无功能性腺瘤巨噬细胞浸润数量均明显多于非侵袭性促生长激素腺瘤、泌乳素腺瘤和无功能性腺瘤(P0.05)。结论:在垂体腺瘤中,巨噬细胞是肿瘤免疫微环境的主体。巨噬细胞浸润可能促进垂体瘤的进展。     

Pituitary prolactin-secreting tumor formation: recent developments

Prolactinoma is the most common type of primary pituitary tumors. It occurs more frequently in women than in men. Dopaminergic agonists are effective in the shrinkage of prolactin-secreting pituitary tumor and are preferred in some patients. However, pituitary radiotherapy may enable the long-term removal of prolactin-secreting tumor cells. Recent evidence suggests that prolactinoma is a heterogeneous disorder with complicated and multifactorial etiology and pathogenesis. Apparently, a thorough understanding of prolactinoma tumorigenesis would be important. To facilitate investigations on tumorigenesis of prolactinoma, animal models for prolactinomas have been developed. These models have expedited our progress in the recent years. Many researchers consider the F(344) rat to be the most sensitive strain of rats to estrogen (E(2))-induced prolactinoma formation. Nonetheless, E(2) treatment for 60 days also induces the formation of pituitary prolactin-secreting adenoma in male Sprague-Dawley (SD) rats. Evidently, the SD rat is also a good animal for prolactinoma investigations. Following E(2) implantation, prolactinomas developed in the eutopic adenohypophysis in situ and/or ectopic pituitary grafted under the renal capsule in SD rats. These observations favor the hypothesis that prolactinoma growth is the result of pathological changes in the adenohypophysis and/or hypothalamus. In the latter case, abnormal release of hypothalamic dopamine, GABA, or brain-gut peptides (such as cholecystokinin, vasoactive intestinal polypeptide, galanin, angiotensin, opioid peptide, gastrin, gastrin-releasing peptide, pancreatic polypeptide, and adrenocorticotropic hormone) results in some of the pathological changes that may lead to hyperprolactinemia and/or prolactinoma development. Dysregulation of prolactin synthesis and secretion may be the result of prolactin gene modulation. In E(2)-induced rat prolactinomas, prolactin mRNA contents and the expression of some proto-oncogenes, e.g. c-myc and c-ras, TGFalpha and TGFbeta1 mRNA were significantly changed. The above findings are consistent with results in human prolactinoma development. In addition, in rats abnormal expression of the prolactin gene was correlated with hypomethylated status of CpG sites in exons 1, 2 and 4 of the prolactin gene, as well as the increase in hypersensitive sites to DNase 1 in the encoding region of the prolactin gene. In E(2)-treated rats, a point mutation with a base substitution from cytidine (C) to adenine (A) was found at the -36-bp site of the proximal promoter of the prolactin gene in eutopic pituitary prolactinomas, but no change was observed in the same sequence of the prolactin gene in ectopic prolactinoma. The association of a base substitution with the hyperexpression of the prolactin gene in eutopic prolactinomas suggests that different mechanisms may mediate the formation of eutopic and ectopic prolactin-secreting tumors. Melatonin decreases the expression of the prolactin gene in vitro suggesting that this pineal hormone may be a potential anticarcinogen in vivo. It has also been shown that MT(2) (Mel(1b)) melatonin receptors are expressed in anterior pituitary cells. The use of melatonin as a preventive or therapeutic drug for prolactinomas should be further investigated. In summary, improved knowledge on tumorigenesis of prolactinomas, especially in the rat model, was noted. These E(2)-induced rat prolactinoma models would facilitate future investigations, and expected results shall be fruitful and exciting for the development of future drug designs for the prevention and/or treatment of prolactin-secreting pituitary tumors.     

Paradoxical prolactin response to growth hormone-releasing hormone in a patient with hyperprolactinemia and empty sella.

In a 30-year-old woman with amenorrhea due to hyperprolactinemia, serum PRL increased to twice the basal amount in response to growth hormone-releasing hormone (GHRH). Roentgenological studies revealed no pituitary adenoma but empty sella. Bromocriptine therapy normalized serum PRL and made the paradoxical response to GHRH disappear. The paradoxical response did not occur in any of eight other patients with hyperprolactinemia due to prolactinoma. Although this case is rare, GHRH stimulates PRL as well as GH release remarkably in some cases with hyperprolactinemia without a GH-producing tumor.     

褪黑素通过减弱催乳素基因增强子的突变抑制大鼠垂体催乳素瘤的增生

本工作旨在探讨褪黑素(melatonin,MLT)抑制17-β-雌二醇(17-β-estradiol,E2)诱发的Sprague-Dawley大鼠垂体催乳素(prolactin,PRL)瘤增生的分子机制。结果表明,每只大鼠每日定时皮下注射一定剂量的MLT(0.25、0.50mg)能显著抑制E2诱发的大鼠垂体PRL瘤的增生;偏低(0.05mg)或过高剂量(1.00、2.00mg)的MLT也抑制PRL瘤的增生,但无统计学意义。采用PCR和DNA直接测序显示,与正常垂体对照组比较,PRL瘤中PRL基因增强子出现五处突变,-1885bp位点由C突变为G,-1857~-1855由ACA替换为G,-1792~-1791插入G,-1383~-1382插入GGTGTGTG片段,-1265~-1250缺失GTGTGTGTGTGTGTGT片段。0.25mg/dMLT处理组,PRL瘤中的PRL基因增强子上述个别突变部位仍然存在(-1885由C突变为G),突变消失(-1792~-1791无插入G),大部分表现为突变减弱(-1856~-1855缺失AC,-1385~-1384缺失TG,-1250~-1253缺失GTGT)。采用荧光素酶报告基因检测PRL基因增强子活性显示,正常垂体、PRL瘤和0.25mg/dMLT处理的PRL瘤三组中,PRL基因增强子的活性分别为(13448.17±3012.74)、(161831.67±60996.01)和(10212.17±2634.71)OD单位。PRL瘤组增强子活性较正常垂体升高11倍(P<0.001),MLT处理组增强子活性较PRL瘤组降低93.69%(P<0.001)。上述三组PRL基因增强子空间结构的分析表明,PRL基因增强子DNA的曲折程度为PRL瘤组>MLT处理组>正常垂体。以上结果证实,MLT抑制大鼠垂体PRL瘤增生的重要分子机制之一可能是减弱PRL基因增强子的突变,也提示MLT可减弱PRL基因增强子的突变,从而下调PRL基因的高表达,可能与降低DNA的曲折程度有关。     

Caveolin-1 sensitizes rat pituitary adenoma GH3 cells to bromocriptine induced apoptosis

Background  

Prolactinoma is the most frequent pituitary tumor in humans. The dopamine D₂ receptor agonist bromocriptine has been widely used clinically to treat human breast tumor and prolactinoma through inhibition of hyperprolactinemia and induction of tumor cell apoptosis, respectively, but the molecular mechanism of bromocriptine induction of pituitary tumor apoptosis remains unclear. Caveolin-1 is a membrane-anchored protein enriched on caveolae, inverted flask-shaped invaginations on plasma membranes where signal transduction molecules are concentrated. Currently, caveolin-1 is thought to be a negative regulator of cellular proliferation and an enhancer of apoptosis by blocking signal transduction between cell surface membrane receptors and intracellular signaling protein cascades. Rat pituitary adenoma GH3 cells, which express endogenous caveolin-1, exhibit increased apoptosis and shrinkage after exposure to bromocriptine. Hence, the GH3 cell line is an ideal model for studying the molecular action of bromocriptine on prolactinoma.     

转录因子E2F-1与垂体肿瘤转化基因（PTTG）在大鼠PRL瘤中的表达

目的通过检测垂体肿瘤转化基因（PTTG）与腺病毒E2启动子结合因子1（E2F-1）在大鼠催乳素（PRL）瘤中的表达来探讨两者在PRL瘤发生发展过程中的作用。方法 40只大鼠随机分为两组：实验组（E组,n=20）：皮下植入17β-雌二醇的方法诱发大鼠PRL瘤;对照组（C组,n=20）：皮下植入空白硅胶管。雌激素诱导10周后处死大鼠,心脏穿刺取血,4%多聚甲醛体内灌流取出脑垂体,称重,ELISA方法检测两组大鼠血清PRL水平,垂体组织行病理组织学观察,免疫组化SP方法检测两组大鼠垂体组织中PTTG蛋白质、E2F-1蛋白质的表达。结果雌二醇作用10周后,据垂体重量、垂体组织学变化和血清PRL水平证实PRL瘤诱导成功。PRL瘤组中,PTTG蛋白质、E2F-1蛋白质均明显高于对照组,差异具有统计学意义（P〈0.01）;且PTTG蛋白质和E2F-1蛋白质的表达呈明显正相关（γ=0.764,P〈0.01）。结论 PTTG与E2F-1在大鼠PRL瘤中共同过度表达,参与了大鼠PRL瘤的发生发展。     

Use of DES-treated rats as an animal model for assessment of pituitary adenoma imaging agents

Prolactin (PRL) secreting pituitary adenomas are the most common type of pituitary tumors. An imaging agent which specifically localized in prolactinomas would be of considerable clinical value for both initial detection and also for monitoring the effects of dopamine agonist therapy. Tritiated spiroperidol (³HSp) was selected for initial evaluation as a possible imaging agent based on: (1) demonstrated localization in the pituitary and (2) demonstrated binding to human PRL-secreting tumor tissue. DES was implanted in Fischer F344 rats and induced prolactinoma formation was evidenced by increased pituitary weight, elevated serum PRL levels and by an increase in the proportion of PRL-secreting cells in the pituitary. ³HSp concentrations in pituitary and other tissues of DES-treated rats were assessed in female rats and correlation studies showed that a 5-fold increase in serum PRL was associated with a 6-fold increase in both pituitary weight and % dose/organ accumulation of ³HSp. The number of pituitary D₂ receptors per mg of protein in tissue homogenates was similar in both normal and DES-treated females. A blocking study with (+)-butaclamol demonstrated a D₂ receptor-mediated component to ³HSp localization. In summary, an animal model for prolactinoma was characterized. An assessment of ³HSp accumulation indicates that radiolabelled spiroperidol shows excellent potential for detecting PRL-secreting tumors of the pituitary.     

Malacoplakia of the Uterine Cervix and Endometrium

A rare case of malacoplakia involving the female genital tract is presented. The characteristic granular histiocytes with intracytoplasmic Michaelis-Gutmann bodies were identified in a cervical smear. The cytological preparation also showed prominent capillary vessels and differed from biopsy material in that cytoplasmic bacteria were easily identified.     

Increased MIB-1/Ki-67 labeling index as a predictor of an aggressive course in a case of prolactinoma

Secondary resistance to dopamine agonists is a rare phenomenon in patients with a prolactinoma. We describe a 55-year-old male with a macroprolactinoma initially responding favorably to bromocriptine treatment with normalization of prolactin levels and tumor shrinkage. Two years later, he developed resistance to bromocriptine treatment and subsequently to cabergoline. The aggressive course of the disease necessitated three surgical interventions. Staining of the pituitary tissue revealed a very high MIB/Ki-67 labeling index that increased further in specimens derived from repeated surgery. This case demonstrates that high and increasing levels of the MIB/Ki-67 labeling index may indicate an aggressive course associated with secondary dopamine resistance.     

Pituitary Adenoma: A Clinician’S Perspective

ObjectiveTo review the underlying causes of pituitary lesions, a rational approach to their diagnosis, and therapeutic options.MethodsThe types of pituitary lesions and their clinical manifestations are reviewed, and treatment strategies and long-term follow-up are discussed.ResultsA pituitary adenoma is quite common and poses a challenge to the clinician to determine the clinical significance, the appropriate diagnosis, the need for treatment, and the appropriate therapy or therapies. The treatment of a pituitary adenoma depends on the type of tumor; a prolactinoma is treated medically with a dopamine agonist drug, and other lesions are usually treated by transsphenoidal surgical removal. Replacement of a deficient hormone or hormones is necessary for optimal functioning. Some patients require more than one treatment, including surgical intervention, replacement of a hormone or hormones, medications to lower hormone hypersecretion to normal (for prolactinoma, acromegaly, or Cushing disease), pituitary radiation therapy (optimally with focused irradiation such as the Gamma Knife or LINEAC), and, in the situation of persistent Cushing disease, bilateral adrenalectomy as a last resort. Lifelong monitoring is necessary for all these patients.ConclusionThe goal is to decrease the mass effect of the adenoma, to restore normal pituitary function, and to suppress hormone hypersecretion. Achievement of this goal necessitates the cooperation and interdisciplinary efforts of several medical specialties. (Endocr Pract. 2008;14:757-763)     

Exfoliative cytology of a lymphoepithelioma-like carcinoma in a cervical smear. A case report

BACKGROUND: Lymphoepithelioma-like carcinoma of the cervix (LELC) is cytologically identical to its counterparts at other sites, such as the nasopharynx. LELC can be suspected on a cervical cytologic smear. The differential diagnosis includes nonkeratinizing squamous cell carcinoma with prominent stromal inflammation, carcinoma with intense stromal eosinophilia, glassy cell carcinoma, malignant lymphoma (especially lymphoepitheloid-Lennerts lymphoma) and metastatic Schmincke-Regaud tumor. CASE: A 55-year-old female presented with an ulcerated endophytic tumor in the cervix. Exfoliative cytology showed uniform, large tumor cells, often associated with inflammatory cells, with round or oval nuclei and one or more prominent nucleoli. The cytoplasm was finely granular to flocculent, and the nuclei were uniformly vesicular. The chromatin was peripherally marginated. The cell borders were indistinct. There was no evidence of dyskeratotic or keratinized cells, koilocytes or glandlike formations. These findings were highly suspicious for LELC and were confirmed by biopsy. Flow cytometry showed DNA aneuploidy, with a DNA index of 1.08. In situ hybridization was negative for human papillomavirus 16 and 18. CONCLUSION: LELC of the uterine cervix has cytologic features that are sufficiently characteristic for a specific cytologic diagnosis. The diagnosis, nevertheless, has to be proven by histology.