Atypical pituitary adenoma with neurocytic transformation.

Here, we report an example of an atypical prolactin-producing pituitary adenoma showing clear morphologic and immunohistochemical evidence of neurocytic transformation. Its features support the concept that neoplastic neuroendocrine cells, in this case adenohypophyseal cells, are capable of neuronal differentiation and broaden the morphologic spectrum of such rare tumors. Our findings have implications with respect to the nosology of neuronal tumors of the adenohypophysis.

Microvessel density and VEGF expression in pituitaries of pregnant women.

OBJECTIVE: In pregnant women, the pituitary is enlarged and the prolactin (PRL) secreting cells increase in size and number. This PRL cell hyperplasia is associated with hyperprolactinemia. The aim of the present work was to investigate adenohypophysial vascularization and immunoexpression of vascular endothelial growth factor (VEGF) in pituitaries of pregnant and post-partum women and compare the results with age-matched adenohypophyses of nonpregnant women who had no endocrine diseases. DESIGN: Pituitaries (n=18) obtained by autopsy from female patients of reproductive age who had died during pregnancy, after abortion or during post-partum were immunostained for CD-34 and VEGF using the streptavidinbiotin- peroxidase complex method. RESULTS: The results showed that microvessel densities and VEGF immunoexpression in the adenohypophyses of pregnant and post-partum women were similar to those found in the control pituitaries. CONCLUSION: It can be concluded that pituitary enlargement and PRL cell hyperplasia in pregnant women may occur without neovascularization and increased VEGF immunoexpression.

Pituicytoma with gelsolin amyloid deposition.

Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition.

On pseudo-onion bulb intraneural proliferations of the non-major nerves of the oral mucosa.

Perineurial cells (PCs) participate in reactive and neoplastic processes, of the latter pure perineurial being intraneural (IP) and soft tissue perineuriomas with oral examples being reported in both. In our review of over 500 peripheral nerve sheath tumors including granular cell tumor, we identified a single ostensible case of IP occurring on the tongue of a 45-year-old African-American male that was characterized by classic perineurial pseudo-onion bulbs (PsOb), proliferating PCs among these PsOb, sclerosis apparently due to long term duration and a plexiform pattern. We have also encountered 37 examples of apparently reactive, hyperplastic or traumatic, PsOb intraneural pseudoperineuriomatous proliferation (IPP) simulating microscopically some of the properties of IP. The majority of the lesions occurred in women and close to 80 % affected the tongue. Three microscopic patterns were appreciated. Type I lesions were those where IPP was seen only focally, type II where it was seen in roughly half of the lesion, and type III where the majority of the lesional tissue or the lesion itself was characterized by IPP. Immunohistochemically, IPP featured PsOb with generally a single layer of PCs decorated by epithelial membrane antigen, glut-1 or claudin-1, and decreased numbers of S-100 positive Schwann cells. The number of axons was not apparently altered. A prominent collagenous intraneural component was occasionally evident among PsOb and the affected nerve featured discontinuous or absent perineurial envelop. While type I and II IPP can be distinguished from IP, the distinction from type III lesions can be problematic. However, the discontinuity of the perineurium of the affected nerve, the spacing and collagenization among PsOb, the limited perineurial cell layer defining the pseudo-onion bulbs, the absence of proliferating PCs between PsObs and the decreasing number of Schwann cells may be of help in the distinction from IP.

Pituitary stalk lesions: the Mayo Clinic experience.

CONTEXT: Pituitary stalk lesions have various etiologies, often not clinically apparent. Pathological samples from these lesions are rarely obtained, because of the critical location and function of the hypophyseal stalk. OBJECTIVES: The purpose of this study was to characterize the etiological spectrum of pituitary stalk lesions seen at Mayo Clinic Rochester over 20 years and to determine whether specific magnetic resonance imaging (MRI) characteristics could provide clinician guidance with regard to the etiology of infundibular lesions. DESIGN: A retrospective review of patients with pituitary stalk lesions seen at Mayo Clinic Rochester between 1987 and 2006 was conducted. Demographic, clinical presentation, imaging, laboratory, operative, and pathology data were reviewed and are reported using descriptive statistics. RESULTS: Of the 152 pituitary stalk lesions included, 49 (32%) were neoplastic, 30 (20%) were inflammatory, 13 (9%) were congenital anomalies, and 60 (39%) were of unclear etiology. Diabetes insipidus was diagnosed in 43 (28%) of the 152 patients, and 49 (32%) patients had at least one anterior pituitary hormone deficit. Secondary hypogonadism was the most common endocrine deficiency. Eleven of 13 congenital lesions were round in appearance and 5 of 7 patients with neurosarcoidosis confirmed by pathology had a uniformly thickened pituitary stalk on MRI. There were no statistically significant correlations between hypopituitarism and the pattern of enhancement or size of the lesion. CONCLUSIONS: Findings on MRI remain key in guiding the diagnosis of pituitary stalk lesions, particularly when used in conjunction with other clinical clues. There are no good imaging predictors for hypopituitarism, making clinical evaluation of all patients with pituitary stalk lesions crucial.

Immunohistochemical expression of PTTG in brain tumors.

BACKGROUND: Pituitary tumor-transforming gene (PTTG1) has been implicated in several oncogenic processes. The aim of this study was to determine PTTG expression in brain tumors. MATERIALS AND METHODS: We investigated 88 benign and malignant brain tumors. PTTG immunoexpression was evaluated using a scale of 0 to 3. PTTG immunoexpression was nuclear and cytoplasmic in most tumors, except for medulloblastomas and hemangiopericytomas. Expression was highest in medulloblastomas. Higher grade gliomas including glioblastoma multiforme (GBM) IV and astrocytoma III had the highest level of PTTG expression, whereas low-grade gliomas had the lowest levels of PTTG expression. Hemangiopericytomas had the lowest levels of PTTG immunoreactivity, with meningiomas and schwannomas exhibiting similarly low PTTG levels. Nuclear PTTG immunoreactivity was higher than cytoplasmic in higher-grade tumors. CONCLUSION: Our results indicate that PTTG immunoexpression is higher in aggressive brain tumors including medulloblastomas, GBM IV, and astrocytoma III, whereas in more benign tumors, PTTG immunoexpression is lower.

Sellar meningiomas: an endocrinologic perspective.

To review the clinical manifestations and outcomes of those with sellar meningiomas treated surgically at Mayo Clinic between 1975 and 2003. This is a retrospective chart and pathology review of 17 patients with a diagnosis of purely or largely intrasellar meningiomas treated surgically at our institution. Data in regards to presentation, endocrine hormonal status, surgical approach, pathology findings, outcome and adjunctive treatment were abstracted from the medical records. The majority of patients present with visual disturbances. All 17 tumors were WHO grade I. Surgical cure was achieved in 53 % after initial surgery. Postsurgical hypopituitarism occurred with high frequency. A substantial proportion of patients required subsequent surgical intervention or adjunctive treatment with external beam radiation. Sellar meningiomas are technically challenging and carry a high risk for visual disturbance and pituitary hormonal abnormalities. Many patients experience persistent disease requiring further intervention. These patients require long-term follow-up for evaluation of recurrence or development of new pituitary hormonal insufficiencies.

Melanoma of the sellar region mimicking pituitary adenoma.

We report here the case of an 82-year-old woman who presented with visual disturbance. MRI demonstrated a sellar mass. The diagnosis of pituitary adenoma was made. She underwent transnasal surgery. Histologic, immunohistochemical and ultrastructural studies indicated that the tumor was a melanoma. Despite an exhaustive search for a primary lesion elsewhere, none was found. The sellar tumor was considered a primary lesion, although extrasellar primary tumor imaging cannot be excluded with 100% certainty. Reported examples of melanoma affecting the sellar region are few. They exhibit morphologic features identical to those of melanomas arising elsewhere. Although very rare, primary melanomas enter into the differential diagnosis of sellar lesions.

Hemangioblastoma of spinal nerve: a report of six cases.

AIMS: Hemangioblastomas may arise sporadically or in the setting of Von Hippel-Lindau (VHL) disease. In either instance, it rarely occurs outside the central nervous system. By analysis of a large case series, we sought to further characterize the clinical, radiologic and pathologic features of hemangioblastomas involving nerve root. MATERIALS AND METHODS: The clinical resentations of 6 proximal nerve root hemangioblastomas (1 an aggressive tumor) were analyzed with emphasis on the neuroimaging, operative, and pathologic findings. The literature is fully reviewed and updated. RESULTS: Nerve hemangioblastoma usually affects proximal spinal roots. Peripheral nerve is rarely involved. Both clinically and radiologically, the diagnosis is usually not suspected before surgery. Profuse bleeding at resection may be the first indication of the nature of the lesion. These tumors may arise both sporadically and in association with VHL disease. CONCLUSION: Given their rarity, nerve root hemangioblastomas are not generally considered in the preoperative differential diagnosis of proximal nerve root lesions. Given their propensity to bleed profusely at surgery and the potential association with VHL disease, knowledge of this entity is important.

ACTH-secreting Crooke cell carcinoma of the pituitary.

PURPOSE: While pituitary adenomas are common, pituitary carcinomas are rare. It is unclear whether pituitary carcinomas arise de novo or evolve from adenomas. METHODS: We studied the clinical characteristics and tissue samples from eight pituitary surgeries and the autopsy from a patient with pituitary carcinoma. A 16-year-old female patient was diagnosed with an aggressive Crooke cell macroadenoma. Following transsphenoidal surgery, clinical signs of Cushing disease quickly reappeared. During the 14-year course of the illness, eight pituitary surgeries, three courses of extracranial irradiation and two (90) Yttrium-DOTATOC treatments were undertaken. A bilateral adrenalectomy was performed. The patient died of metastatic disease and uncontrolled hypercortisolism due to an adrenal remnant. A systematic morphologic study (histologic staining, electron microscopy) of all available surgical and autopsy specimens was undertaken. RESULTS: Brisk mitotic activity, high Ki-67 and p53 immunolabelling were present in the pituitary samples from the onset. High proportion of tumour cells showed irregular nuclei and large nucleoli, and gradual increase in MGMT staining was observed. The tumour remained of Crooke cell type throughout the course. Autopsy disclosed a postirradiation sarcoma in the pituitary area. CONCLUSIONS: The question whether pituitary carcinomas arise de novo or transform from an adenoma cannot be answered at present with certainty.

Biomarkers of pituitary neoplasms.

In a wide spectrum of tumors, cell proliferation, vascularity, apoptosis, cell adhesion, and cell-cycle progression may indicate tumor progression. In this review article, the literature regarding apoptotic markers and p53, as well as cyclooxygenase-2, galectin-3, and pituitary tumor-transforming factor, proliferative markers, angiogenesis, including vascular endothelial growth factor and its receptor, pituitary tumor-transforming gene, microarrays, stem cells, and microenvironment and tumor heterogeneity are presented. Only a particular group of selected biomarkers show promise in differentiating pituitary tumors which will behave in an aggressive manner. Therefore, the most common and promising biomarkers and terms were analyzed, proposing the need for uniform design and application of methods and standardized criteria for the interpretation of results. The new spectrum of biomarkers may shed light upon the pathogenetic mechanisms and also may serve as standardized diagnostic tool for daily pathologic practice.

Malignant peripheral nerve sheath tumor: the utility of fascicular biopsy and teased fiber studies.

We present the case of a 67-year-old man with a malignant peripheral nerve sheath tumor (MPNST) affecting the brachial plexus. He presented with progressive right upper extremity paresthesias, numbness, weakness, and severe pain. Nerve conduction studies/electromyography demonstrated a right lower and middle trunk predominant brachial plexopathy. Three-tesla magnetic resonance imaging of the brachial plexus showed a soft tissue mass with central necrosis and cystic changes and irregular contrast enhancement. Positron emission tomography showed increased fluorodeoxyglucose uptake within the mass. Targeted fascicular nerve biopsy revealed hypercellular tumor, featuring atypical cells with mitotic figures and limited immunoreactivity for S-100 protein. The findings were those of an MPNST. The effects on the variably involved fascicles were also seen in teased fiber preparations, paraffin sections, and through immunohistochemistry. This case illustrates the presentation of this rare type of tumor, and characteristic neuroimaging and pathologic features of MPNSTs.

Meningiomas in pregnancy: a clinicopathologic study of 17 cases.

BACKGROUND: Dramatic growth of meningiomas is occasionally encountered during pregnancy. While cell proliferation is often assumed, hemodynamic changes have also been touted as a cause. OBJECTIVE: We identified 17 meningiomas resected during pregnancy or within 3 weeks post-partum and characterized them to determine the cause of occasional rapid growth in pregnancy. METHODS: Seventeen tumors were identified from searches at 4 university centers. All available clinical records, radiology images, and tissue specimens were reviewed, with immunohistochemical studies performed as needed. RESULTS: Sixteen patients underwent tumor resection and 1 died of complications prior to surgery. Average patient age was 32 years. Nine experienced onset of symptoms in the third trimester or within 8 days post-partum. Principle physical findings included visual complaints (59%) and cranial nerve palsies (29%). Ten tumors (59%) were located in the skull base region. The Ki-67 labeling index was low (0.5-3.6%) in 11 of 13 benign (grade I) tumors and elevated (11-23.2%) in 3 of 4 atypical (grade II) meningiomas. Eight (50%) tumors featured hypervascularity with at least focal CD34-positive hemangioma-like microvasculature. Fourteen (82%) showed evidence of intra- and/or extracellular edema, 1 so extensive that its meningothelial nature was not apparent. Five tumors (29%) exhibited intratumoral hemorrhage and/or necrosis. CONCLUSION: Our series suggests that pregnancy-associated meningiomas located in the skull base are likely to require surgical intervention for visual complaints and cranial nerve palsies. The rapid tumor growth is more often due to potentially reversible hemodynamic changes rather than hormone-induced cellular proliferation.

Malignant perineurioma (malignant peripheral nerve sheath tumor with perineural differentiation).

The great majority of malignant peripheral nerve sheath tumors (MPNST) exhibit Schwannian differentiation. In recent years, a subset of perineurial MPNST (malignant perineurioma) has been identified based on their histologic, immunohistochemical and ultrastructural features. Immunopositivity for epithelial membrane antigen (EMA), glut-1 and claudin-1, is characteristic. Such tumors must be distinguished from benign perineurioma and a variety of atypical or malignant soft tissue tumors featuring EMA positivity. Herein, we report a perineurial MPNST involving the buttock of a 42-year-old woman. Nerve involvement was noted. The clinicopathologic features of reported examples are ummarized and key differential diagnoses are discussed.

Transdifferentiation of pituitary thyrotrophs to lactothyrotrophs in primary hypothyroidism: case report.

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.

Temozolomide in aggressive pituitary adenomas and carcinomas.

Temozolomide is an alkylating agent used in the treatment of gliomas and, more recently, aggressive pituitary adenomas and carcinomas. Temozolomide methylates DNA and, thereby, has antitumor effects. O6-methylguanine-DNA methyltransferase, a DNA repair enzyme, removes the alkylating adducts that are induced by temozolomide, thereby counteracting its effects. A Medline search for all of the available publications regarding the use of temozolomide for the treatment of pituitary tumors was performed. To date, 46 cases of adenohypophysial tumors that were treated with temozolomide, including 30 adenomas and 16 carcinomas, have been reported. Eighteen of the 30 (60%) adenomas and 11 of the 16 (69%) carcinomas responded favorably to treatment. One patient with multiple endocrine neoplasia type 1 and an aggressive prolactin-producing adenoma was also treated and demonstrated a good response. No significant complications have been attributed to temozolomide therapy. Thus, temozolomide is an effective treatment for the majority of aggressive adenomas and carcinomas. Evidence indicates that there is an inverse correlation between levels of O6-methylguanine-DNA methyltransferase immunoexpression and therapeutic response. Alternatively, high-level O6-methylguanine-DNA methyltransferase immunoexpression correlates with an unfavorable response. Here, we review the use of temozolomide for treating pituitary neoplasms.

Pituitary tumors in patients with MEN1 syndrome.

We briefly review the characteristics of pituitary tumors associated with multiple endocrine neoplasia type 1. Multiple endocrine neoplasia type 1 is an autosomal-dominant disorder most commonly characterized by tumors of the pituitary, parathyroid, endocrine-gastrointestinal tract, and pancreas. A MEDLINE search for all available publications regarding multiple endocrine neoplasia type 1 and pituitary adenomas was undertaken. The prevalence of pituitary tumors in multiple endocrine neoplasia type 1 may vary from 10% to 60% depending on the studied series, and such tumors may occur as the first clinical manifestation of multiple endocrine neoplasia type 1 in 25% of sporadic and 10% of familial cases. Patients were younger and the time between initial and subsequent multiple endocrine neoplasia type 1 endocrine lesions was significantly longer when pituitary disease was the initial manifestation of multiple endocrine neoplasia type 1. Tumors were larger and more invasive and clinical manifestations related to the size of the pituitary adenoma were significantly more frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Normalization of pituitary hypersecretion was much less frequent in patients with multiple endocrine neoplasia type 1 than in subjects with non-multiple endocrine neoplasia type 1. Pituitary tumors in patients with multiple endocrine neoplasia type 1 syndrome tend to be larger, invasive and more symptomatic, and they tend to occur in younger patients when they are the initial presentation of multiple endocrine neoplasia type 1.