Maria Maksymowicz

Temozolomide-Induced Shrinkage of Invasive Pituitary Adenoma in Patient with Nelson’s Syndrome: A Case Report and Review of the Literature

Introduction. Invasive tumours in Nelsons syndrome need aggressive therapy. Recent reports have documented the efficacy of temozolomide (TMZ) in the treatment of adenomas resistant to conventional management. Objective. The review of the literature concerning TMZ treatment of atypical corticotroph adenomas and a case study of 56-year-old woman who developed Nelsons syndrome. Treatment Proceeding. The patient with Cushings disease underwent transsphenoidal adenomectomy followed by a 27-month-long period of remission. Due to a regrowth of the tumor, she underwent two reoperations followed by stereotactic radiotherapy. Because of treatment failures, bilateral adrenalectomy was performed. Then she developed Nelsons syndrome. A fourth transsphenoidal adenomectomy was performed, but there was a rapid recurrence. Five months later, she underwent a right frontotemporal craniotomy. Due to a rapid regrowth of the tumour, the patient did not receive gamma-knife therapy and was treated with cabergoline and somatostatin analogue for some time. Only TMZ therapy resulted in marked clinical, biochemical, and radiological improvement. To date, this is the first case of invasive corticotroph adenoma in Nelsons syndrome treated with temozolomide in Poland. Conclusion. In our opinion, temozolomide can be an effective treatment option of invasive adenomas in Nelsons syndrome.

Gonadotroph adenoma causing ovarian hyperstimulation syndrome in a premenopausal woman

ABSTRACT Introduction: Gonadotroph adenomas occur commonly in middle-aged adults without any specific endocrinological symptoms. To date, only 30 cases of gonadotropinoma causing ovarian hyperstimulation syndrome in pre-menopausal women have been reported. Case report: A 37-year old woman with pituitary macroadenoma and hyperprolactinaemia was admitted to the Department of Endocrinology, Diabetology and Isotope Therapy. She presented with recurrent ovarian cysts, menstrual disturbances, headaches, visual impairment and galactorrhea. Her endocrine profile showed normal values of FSH, elevated concentrations of estradiol and suppressed LH levels. Transsphenoidal resection of the tumor tissue resulted in normalization of the hormone values and improvement in the clinical picture. Conclusions: Gonadotroph adenomas should be considered in the differential diagnosis in premenopausal women with OHSS. Chinese abstract 引言：促性腺激素腺瘤常见于中年人且没有任何特殊的内分泌相关症状。目前为止，也只有30例绝经前妇女促性腺激素腺瘤引起卵巢过度刺激综合征的报道。 个案报道：一名37岁妇女因垂体大腺瘤和高泌乳素血症到妇科内分泌、糖尿病及同位素门诊就诊。她叙述自己所患的卵巢囊肿已复发，同时还有月经紊乱、头痛、视力减退和溢乳的症状。其性激素检查显示FSH水平正常、雌激素浓度升高、LH水平降低。经蝶骨切除垂体腺瘤术后激素水平恢复正常，同时临床症状也得到改善。 结论：绝经前妇女发生卵巢过度刺激综合征时应考虑与促性腺激素腺瘤相鉴别。

Ganglion cell tumours in the sella turcica in close morphological connection with pituitary adenomas.

Ganglion cell tumours in the sellar region are uncommon. They are usually associated with pituitary adenomas, while isolated ganglion cell neoplasms are extremely rare. We report the clinicopathological studies of five cases diagnosed as ganglion cell tumours located in the intrasellar region: four mixed/collision tumours composed of gangliocytoma and pituitary adenoma, and one isolated ganglioglioma unrelated to adenoma. Clinically, two patients presented with acromegaly, while three others were initially diagnosed as non-functioning adenomas. In four cases, the histopathological examination of surgical specimens revealed intermixed lesions composed of pituitary adenoma and ganglion cell elements. The adenomas appeared to secrete growth hormone. Electron microscopy enabled identification of the sparsely granulated somatotroph cells. Neoplastic neuronal lesions were composed of mature ganglion cells, including binucleate or multinucleate cells. In all cases, boundaries between adenomatous and gangliocytic components were not clearly demarcated, and numerous gangliocytic cells were closely intermingled with adenomatous tissue. One case lacked endocrine symptoms, and no pituitary adenoma was identified in the surgically excised material; it was finally diagnosed as low-grade ganglioglioma. The etiopathogenesis of ganglion cell neoplasms in the sellar region is not clearly defined. Our study revealed that if ganglion cell neoplasms were combined with adenoma, both neoplastic components were closely related to each other, and numerous neuronal elements were strictly intermingled with adenoma cells. Such a tissue pattern indicates that these neoplastic changes, including their common respective etiopathogeneses, are closely related. The identification of both components in sellar regions may have some nosological implications.

Alternative splicing of iodothyronine deiodinases in pituitary adenomas. Regulation by oncoprotein SF2/ASF.

Pituitary tumors belong to the group of most common neoplasms of the sellar region. Iodothyronine deiodinase types 1 (DIO1) and 2 (DIO2) are enzymes contributing to the levels of locally synthesized T3, a hormone regulating key physiological processes in the pituitary, including its development, cellular proliferation, and hormone secretion. Previous studies revealed that the expression of deiodinases in pituitary tumors is variable and, moreover, there is no correlation between mRNA and protein products of the particular gene, suggesting the potential role of posttranscriptional regulatory mechanisms. In this work we hypothesized that one of such mechanisms could be the alternative splicing. Therefore, we analyzed expression and sequences of DIO1 and DIO2 splicing variants in 30 pituitary adenomas and 9 non-tumorous pituitary samples. DIO2 mRNA was expressed as only two mRNA isoforms. In contrast, nine splice variants of DIO1 were identified. Among them, five were devoid of exon 3. In silico sequence analysis of DIO1 revealed multiple putative binding sites for splicing factor SF2/ASF, of which the top-ranked sites were located in exon 3. Silencing of SF2/ASF in pituitary tumor GH3 cells resulted in change of ratio between DIO1 isoforms with or without exon 3, favoring the expression of variants without exon 3. The expression of SF2/ASF mRNA in pituitary tumors was increased when compared with non-neoplastic control samples. In conclusion, we provide a new mechanism of posttranscriptional regulation of DIO1 and show deregulation of DIO1 expression in pituitary adenoma, possibly resulting from disturbed expression of SF2/ASF.

Clinicopathological predictive factors in the early remission of corticotroph pituitary macroadenomas in a tertiary referral centre.

Objective Corticotroph macroadenomas are a rare cause of Cushings disease (CD), but their properties are not well-recognised. The aim of this study was to evaluate the clinical and pathological aspects of corticotroph macroadenomas with particular emphasis on proliferation markers and their associations with the efficacy of surgical treatment. Design A prospective cohort study was conducted in a tertiary referral centre in Poland. Methods In total, 59 patients with CD (20 macroadenomas and 39 microadenomas) were included in this study. Hormonal and imaging parameters, histopathological and ultrastructural features of the corticotroph tumours and the early surgical outcomes were evaluated. Results ACTH and ACTH/cortisol ratios were higher in macroadenomas (P<0.001 and P=0.002 respectively). Greater tumour volumes were associated with higher Ki-67 and p53 expression (Ptrend=0.009 and Ptrend=0.024 respectively) and the rates of sparsely granulated adenomas (Ptrend=0.036). Immediate postoperative remission and early biochemical remission rates were lower in macroadenomas compared to microadenomas (P<0.001). A logistic regression model showed that the immediate postoperative remission or early biochemical remission depended on tumour volume (P=0.005 and P=0.006 respectively) and invasiveness based on Knosp grades 3 and 4 for macroadenomas and a lack of surgical pseudocapsule for microadenomas (P=0.004 and P=0.007 respectively). Conclusion Corticotroph macroadenomas differ from the more common microadenomas not only in terms of hormonal and imaging characteristics but also in terms of immunohistochemical and ultrastructural features and proliferation markers. The early effectiveness of surgery depends primarily on tumour volume and invasiveness.

Long-term complete remission of Crooke’s corticotropinoma after temozolomide treatment

INTRODUCTION Crookes corticotropinomas are the unique cause of Cushings disease. The majority of them are aggressive macroadenomas, refractory to conventional therapy, with a high recurrence rate. The aim of the study was the presentation, in relation to data from the literature, of a case of a patient with ACTH-dependent Cushings syndrome caused by recurrent Crookes cells corticotropinoma, who achieved 33-month complete remission after treatment with temozolomide (TMZ). CASE REPORT A 54-year-old man was diagnosed with Cushings disease five years earlier on the basis of a typical clinical picture and hormonal tests. MRI revealed 32 × 29 × 24 mm macroadenoma. The patient underwent three subtotal selective transsphenoidal adenomectomies without retirement of hypercortisolaemia. A postoperative pathologic exploration revealed a densely granulated corticotroph Crookes cells adenoma with MIB-1 index < 1%. Because of the large size of the tumour with its expansion to both cavernous sinuses and suprasellar region together with a compression of the optic chiasm, the patient was disqualified for gamma-knife. Due to an exhaustion of all conventional therapeutic options the patient was qualified to TMZ therapy. The standard dose of TMZ (150 g/m²) for five days every 28 days was implemented. After three courses of TMZ pronounced regression of tumour size with a marked hormonal and clinical improvement was certified. After six courses, consecutive tumour regression was observed. Nine courses resulted in a total radiological tumour shrinkage and hormonal normalisation. Despite the cassation of TMZ treatment the complete remission of the disease maintained for 33 months. CONCLUSION Temozolomide can be an effective treatment option in invasive Crookes cell corticotropinoma. (Endokrynol Pol 2016; 67 (5): 526-533).

DNA methylation profiling in nonfunctioning pituitary adenomas

Nonfunctioning pituitary adenomas (NFPAs) are among the most frequent intracranial tumors but their molecular background, including changes in epigenetic regulation, remains poorly understood. We performed genome-wide DNA methylation profiling of 34 NFPAs and normal pituitary samples. Methylation status of the selected genomic regions and expression level of corresponding genes were assessed in a group of 75 patients. NFPAs exhibited distinct global methylation profile as compared to normal pituitary. Aberrant DNA methylation appears to contribute to deregulation of the cancer-related pathways as shown by preliminary functional analysis. Promoter hypermethylation and decreased expression level of SFN, STAT5A, DUSP1, PTPRE and FGFR2 was confirmed in the enlarged group of NFPAs. Difference in the methylation profiles between invasive and non-invasive NFPAs is very slight. Nevertheless, invasiveness-related aberrant epigenetic deregulation of the particular genes was found including upregulation of ITPKB and downregulation CNKSR1 in invasive tumors.

A 39-Year-Old Woman with Progressive Vision Impairment: Correspondence

A 39-year old otherwise healthy woman was referred to our center in June 2002 due to progressive deterioration of vision in her left eye and visual field restriction of about two months’ duration. Ever since she gave birth in 2000, she had been amenorrheic but still lactating. Neurological examination revealed bitemporal hemianopsia. Her endocrine function was normal. MRI scan revealed a heterogenous intrasellar mass measuring 28 3 21 3 19 mm with suprasellar expansion and marked compression of the optic chiasm, hyperintense on T1-weighed images (Figure 1A,B) and isointense on T2-weighed images. The tumor penetrated into the left cavernous sinus narrowing the left internal carotid artery and extending into the middle cranial fossa. Gadolinum contrast enhancement of the dura lining the medial part of the middle cranial fossa and the clivus was noted. The patient underwent transsphenoidal surgery. The sella contained abundant brownish masses of atypical consistency resembling a clotted hematoma. The pituitary gland of normal appearance was identified on the right side of the sella. A subtotal excision of this lesion was carried out with some of its mass left in the left cavernous sinus. The postoperative course was uneventful and the patient reported a significant improvement in vision. Owing to the presentation of the tissue found in the sella and substantial intraoperative bleeding, a four-vessel cerebral angiography was additionally performed revealing no vascular malformations in the circle of Willis. MICROSCOPIC PATHOLOGY

Interesting coincidence of atypical TSH-secreting pituitary adenoma and chronic lymphocytic leukemia

Thyrotropin-secreting adenomas (TSH-oma) are very rare pituitary tumours. They are macroadenomas usually presenting with signs and symptoms of hyperthyroidism, and mass effects. They can co-secrete other hormones such as growth hormone or prolactin. Different malignancies, including haematological ones, are reported in patients with pituitary diseases. Chronic lymphocytic leukemia (CLL) occurs mostly in older patients, more often in males. CLL is associated with increased risk of second malignancies such as other blood neoplasms, skin and solid tumours. We present a successful neurosurgical outcome in a patient with an interesting coincidence of atypical TSH-oma and asymptomatic CLL.