Symptomatic Intraspinal Oncocytic Adrenocortical Adenoma

Most intraspinal neoplasms of epithelial origin are metastases from primary carcinomas. Benign epithelial tumors are rarely found at this site. We here present the case of a 44-year-old woman with a lesion in the cauda equina that fulfilled the radiologic criteria of schwannoma and caused clinical symptoms for 3 years. The excised tumor was composed of nests of large polygonal cells with eosinophilic partial granular cytoplasm. Significant atypia, necrosis, and mitosis were absent from this lesion. The tumor showed diffuse positivity for melan-A, synaptophysin, and alpha-inhibin. Steroidogenic factor 1 and cytokeratins 8 and 18 were focally seen in the absence of S-100 and chromogranin. This immunoprofile indicated adrenocortical origin. Ultrastructural examination showed abundant mitochondria, suggesting an oncocytic tumor. The diagnosis of an oncocytic adrenal cortical adenoma was made. These extraadrenal tumors are thought to arise from heterotopic adrenocortical tissue in the spinal cavity. Oncocytic tumors are rare neoplasms and they comprise non-functioning variants of adrenal cortical adenomas. To date, only five such intraspinal tumors have been observed. Immunohistochemistry excluded oncocytic paraganglioma, oncocytic meningioma, renal cell carcinoma, alveolar soft part sarcoma, and granular cell tumor. A view of the literature of these rare but probably underdiagnosed intraspinal tumors is given.     

Pituitary adenomas and granular cell tumors. Incidence, cell type, and location of tumor in 100 pituitary glands at autopsy.

Incidentally detected pituitary adenomas were investigated in 100 pituitary glands at autopsy to determine the number, cell type, and location of tumors, and the presence of coexisting granular cell tumors in the neurohypophysis. Pituitary glands were sagittally sectioned at 1.5-mm intervals in toto and embedded in 1 cassette to orient location of each tumor. Twenty-four pituitary glands harbored adenomas, most smaller than 3 mm and the largest 6 x 5 x 4 mm. Two pituitary glands contained double adenomas of immunocytochemically different cell types. Of the 26 adenomas, 10 had lactotrophs, 2 had mixed lactotrophs-somatotrophs, 1 had mixed lactotrophs-luteinizing hormone cells, and 12 were nonfunctioning. One adenoma with adenocorticotropic hormone cells was also detected. Thus 25 of 26 (96%) adenomas were either lactotrophic or nonfunctioning; this percentage is much higher than that of surgically resected tumors. Twenty-two tumors were contiguous with or adjacent to the capsule from which the adenomas originated. Nine granular cell tumors were noted in the neurohypophysis; 3 coexisted with pituitary adenomas. Fourteen additional cases revealed small granular cell nests. Thus the incidental finding of nonfunctioning pituitary adenomas is relatively common in adults (24% of cases in this study), and the coexistence of pituitary adenomas and granular cell tumors may suggest a possible histogenic connection between anterior and posterior pituitary tumorigenesis.     

P53 expression in choroid plexus neoplasms: an immunohistochemical study

OBJECTIVE: To evaluate choroid plexus neoplasms for p53 expression. CASE MATERIAL: We studied 10 choroid plexus tumors (four papillomas and six carcinomas) by immunohistochemistry using the DO7 anti-p53 monoclonal antibody. RESULTS: Three of four choroid plexus papillomas demonstrated no staining. Scattered nuclear and rare cytoplasmic positivity was present in one papilloma, which showed foci of increased mitotic activity (labeling index 2.5%). Six of six carcinomas were immunoreactive for p53, and three cases had labeling indexes of over 70%. All immunopositive choroid plexus tumors (7/7) exhibited nuclear staining. Punctate cytoplasmic positivity was identified in 5 of 7 cases. CONCLUSION: Our study suggests that altered p53 expression is detectable by immunohistochemistry in choroid plexus neoplasms and is consistently present in choroid plexus carcinomas.     

Transthyretin immunoreactivity in choroid plexus neoplasms and brain metastases.

Although choroid plexus papillomas (CPP) and primary choroid plexus carcinomas (CPC) are rare neoplasms of the central nervous system, they have been the subject of a number of immunohistochemical studies. To date, no unique or specific marker for these neoplasms has been found, however. Normal choroid plexus is a major site of transthyretin (TTR) synthesis, and recently this protein has been proposed as a possible specific marker of choroid plexus differentiation in tumors. In this study, we performed immunohistochemistry for TTR on 13 choroid plexus tumors (six CPP and seven CPC) and on 23 carcinomas metastatic to the brain, four of which had a papillary architecture. We also included four ovarian teratomas that contained choroid plexus elements. Two of the CPP had diffuse staining for TTR, while the four others stained only focally. Five of the CPC stained only focally and less intensely than the control, while one case was negative. Only one CPC stained as strongly and diffusely as normal choroid plexus. Two of the papillary and six of the nonpapillary metastases had focal staining similar to that seen in the five focally positive CPC. The choroid plexus elements of the ovarian teratomas stained as strongly as the positive control. These findings indicate that TTR immunoreactivity is not restricted to primary choroid plexus tumors. Furthermore, most choroid plexus carcinomas stain only weakly or not at all. This limits the usefulness of TTR immunohistochemistry in the diagnosis of primary choroid plexus neoplasms and in the distinction of CPC from metastatic carcinoma.     

Renal cell carcinoma with extensive oncocytic features

Oncocytic features are a hallmark of renal oncocytoma, but can be seen in other renal tumors such as clear cell renal cell carcinoma with granular cells and eosinophilic variant of chromophobe cell tumors. Up to 5% of renal neoplasms are ultimately diagnosed as unclassified renal cell carcinoma with oncocytic features accounting for a significant number of these tumors. Also a recent morphological variant of mucinous tubular and spindle cell carcinoma with oncocytic changes has been described, adding another challenge. Here we report an unusual case of unclassified renal cell carcinoma with extensive oncocytic changes and we discuss the differential diagnosis.     

Absence of expression of SMARCB1/INI1 in malignant rhabdoid tumors of the central nervous system, kidneys and soft tissue: an immunohistochemical study with implications for diagnosis.

Malignant rhabdoid tumors are high-grade neoplasms of the central nervous system (CNS), kidneys and soft tissue that usually occur in children. The histologic diagnosis of malignant rhabdoid tumor depends on identification of characteristic rhabdoid cells-large cells with eccentrically located nuclei and abundant, eosinophilic cytoplasm-and immunohistochemistry with antibodies to vimentin, keratin and epithelial membrane antigen. In most malignant rhabdoid tumors, the SMARCB1/INI1 gene, located in chromosome band 22q11.2, is inactivated by deletions and/or mutations, so genetic diagnosis is often possible. However, tissue may not be available for genetic analysis or studies not confirmatory. We assessed SMARCB1/INI1 expression in 17 rhabdoid tumors and 57 other tumors of the CNS, kidney or soft tissue using immunohistochemistry. In total, 12 brain, three renal and two soft tissue rhabdoid tumors were examined along with four glioblastomas, four pilocytic astrocytomas, four oligodendrogliomas, two ependymomas, two choroid plexus papillomas, five pituitary adenomas, four germinomas, four renal carcinomas with Xp11.2 translocations, two clear cell sarcomas, two Wilms' tumors, one renal medullary carcinoma, two desmoplastic small round cell tumors, two alveolar rhabdomyosarcomas, two embryonal rhabdomyosarcomas, one low-grade chondrosarcoma, two extraskeletal myxoid chondrosarcomas, one mesenchymal chondrosarcoma, four malignant peripheral nerve sheath tumors, five metastatic carcinomas and four epithelioid sarcomas, two primary and two metastatic. The neoplastic cells of all rhabdoid tumors, the four epithelioid sarcomas and the renal medullary carcinoma did not express SMARCB1/INI1 by immunohistochemistry; neoplastic cells of all other tumors expressed SMARCB1/INI1. Immunohistochemistry to assess expression of SMARCB1/INI1 may be useful in the diagnosis of rhabdoid tumors of the CNS, kidneys and soft tissue.     

Oncocytic meningioma: a case report

Oncocytic meningioma is a recently described rare variant of meningothelial neoplasms that typically occurs as a large cell tumor with granular cytoplasm. The distinct histological features of numerous cells with granular cytoplasm and the ultrastructural evidence of numerous mitochondria in the cytoplasm differentiate this tumor from other neoplasms with granular appearance. We report an additional case of oncocytic meningioma investigated by ultrastructural and immunohistochemical methods.     

Askenazi (Hurtle) cell tumors of the thyroid

Oncocytic adenomas have primarily follicular structure; trabeculas, solid areas, necrosis are rare. They may possess malignant potential as their malignant transformation occurs in 35% cases against 5% in adenomas of follicular cells. Oncocytic follicular carcinomas can be hardly distinguished from oncocytic adenomas. Tumors larger than 4-5 cm in diameter are considered to be malignant. Main difference with adenomas is invasion into the capsule surrounding thyroid or into the vessels. They can be well or poorly differentiated or anaplastic. Oncocytic papillary carcinoma and oncocytic medullary carcinoma are rare. The clinical course of oncocytic tumors is more aggressive than that of tumors from follicular cells. Of key importance in differential diagnosis is electron microscopy (EM) and immunohistochemistry with antimitochondrial antibodies. EM may be also useful in determination of the degree of oncocytic tumors maturation.     

Chromosome abnormalities in low-grade central nervous system tumors.

Ependymomas, oligodendrogliomas, and low-grade astrocytomas are slow-growing central nervous system (CNS) tumors that occur in both adults and children, whereas craniopharyngiomas and choroid plexus papillomas occur predominantly in children. We examined karyotypes of 32 of these low-grade tumors, including ten oligodendrogliomas, six ependymomas, 11 low-grade astrocytomas, four craniopharyngiomas, and one choroid plexus papilloma. Only normal karyotypes were obtained from 6 oligodendrogliomas. The rest had normal stemlines; three tumors had 45,X,-Y sidelines and one tumor had a sideline of monosomy 22. The most frequent abnormalities in the ependymomas were +7 (three tumors), -21 (two tumors), -22 (two tumors), and del(9)(p22) (two tumors). Gains of chromosome 7 and deletions of 9p were found more often in high-grade gliomas. Seven low-grade astrocytomas had normal stemlines, two had chromosome 7 abnormalities, a pilocystic astrocytoma had +der(15), and one tumor had a -Y sideline. The four craniopharyngiomas and one choroid plexus tumor were all apparently normal. The cytogenetics of low-grade CNS tumors differ from higher grade gliomas in that most low-grade tumors show little deviation from the normal karyotype.     

The determination of glial fibrillary acidic protein for the diagnosis and histogenetic study of central nervous system tumors: a study of 152 cases

Glial fibrillary acidic protein (GFAP) was purified from human spinal cord and cerebral white matter. GFAP was localized by an immuno-peroxidase method in normal adult and fetal human brains, rat brains, and 152 central nervous system (CNS) tumors. GFAP was found in reactive and normal astrocytes, immature cells of fetal brain at the 18th to 21st gestational weeks, and normal rat astrocytes. This GFAP staining was quite specific for glial tumors, including astrocytomas, glioblastomas, astroblastomas, and ependymomas. GFAP-positive cells were also found in oligodendrogliomas and choroid plexus papillomas, and they were interpreted as being astroglial or ependymal differentiations. Stromal cells in cerebellar hemangioblastomas were negative. However, engulfed astrocytes were found at the periphery of such tumors and often adjacent to the proliferate blood vessels. In meningiomas, neurinomas, metastatic carcinomas, pituitary adenomas and other non-glial tumors, GFAP-positive cells were not identified.     

Role of sex hormones in development of pituitary adenoma

Role of sex hormones in the development of pituitary adenomas was investigated by analyzing the content of nuclear estradiol and testosterone receptors in different tumors of the anterior pituitary: prolactinomas, meningiomas, growth hormone-producing adenomas, astrocytomas, neurinomas, and ependymomas. The concentration of nuclear estrogen and androgen receptors in prolactin-secreting pituitary adenomas was much higher than in growth hormone-producing adenomas and other pituitary tumors.     

A marker for primary choroid plexus neoplasms.

Primary choroid plexus (CP) tumors are rare neoplasms that present in childhood or, less frequently, in adult life. The majority are benign and amenable to complete surgical excision, but occasionally more invasive variants are encountered. Although generally pathologically distinct, occasionally primary CP neoplasms may be difficult to distinguish from metastatic papillary carcinomas or papillary ependymomas. Conventional cytologic markers are not sufficiently specific to permit accurate diagnosis of primary CP tumors. The authors have reported that the CP is the unique site of synthesis within the brain of transthyretin (TTR, prealbumin), a transport protein for thyroxine and retinol. They therefore investigated the utility of TTR as a biochemical marker for CP tumors. They detected intense immunoreactivity for TTR at high dilutions of primary antiserum in the neoplastic epithelium of all of nine primary CP tumors (six papillomas and three carcinomas), but not in eight cellular or three papillary intracerebral ependymomas, meningiomas, oligodendrogliomas, astrocytomas, primary extracerebral papillary carcinomas (three thyroid, two breast) or five of six cerebral metastases from systemic papillary carcinomas. In one case of cerebral metastasis from papillary thyroid carcinoma, rare isolated immunoreactive cells were observed. Faint staining of the stromal-ependymal junction was seen in myxopapillary ependymomas of the filum terminale, which were otherwise nonreactive. By in situ hybridization, TTR mRNA was abundant in neoplastic CP epithelium, confirming local TTR synthesis. The authors conclude that TTR is synthesized by neoplastic CP epithelium and is an excellent marker for primary CP neoplasms.     

Significance of immunohistochemistry in neuro-oncology. V. Keratin as a marker for epithelial differentiation of primary and secondary intracranial and intraspinal tumors

Intermediate filament keratin is regarded as a good marker for epithelial and mesothelial tumors. In the intracranial and intraspinal spaces keratin has been demonstrated only in the endocrine cells of the adenohypophysis, squamous epithelial islands in the pars tuberalis of the hypophysis and in the choroid plexus epithelium. Since gliomas and meningiomas do not express keratin, this marker provides an additional help for differentiating between primary and secondary CNS tumors. Indirect immunofluorescence using an anti-keratin serum was used in a retrospective search for keratin in 80 tumors of the cranium and intraspinal space. Of the primary CNS tumors keratin positivity occurred in craniopharyngiomas, epidermoid tumors, pituitary adenomas, chordomas, a plexus papilloma as well as in the majority of germ cell tumors. Only 3 renal cell carcinoma metastases of 21 metastatic epithelial cell tumors (7 bronchial carcinomas, 6 breast cancers, 6 renal carcinomas, 1 rectum carcinoma, 1 cervix carcinoma) were keratin-negative. Similar findings were made in two melanoma metastases which we examined, whereas in a seminoma metastasis a few keratin expressing cells were found. Primary CNS tumors such as myxopapillary ependymomas, medulloepitheliomas, malignant meningiomas and paragangliomas which are often difficult to distinguish from these metastases proved to be keratin negative.     

Clinicopathological correlations in pituitary adenomas

Pituitary adenomas are common neuroendocrine neoplasms arising from adenohypophysial cells. Recent progress in our understanding of pituitary tumorigenesis as well as pathways involved in molecular cytodifferentiation of the adenohypophysis has impacted on the classification of pituitary adenomas. The detailed comprehensive classification of pituitary adenomas is now well recognized to reflect specific clinical features and genetic changes that predict targeted treatments, as well as prognostic information for patients with pituitary adenomas. Therefore, the clinical responsibility of pathologists is not only limited to the distinction of pituitary adenomas from other sellar lesions, but also to provide a comprehensive subtype classification using appropriate ancillary tools. In this article, we highlight an approach to clinical diagnosis and pitfalls in the classification of these common neoplasms.     

Intracerebral granular cell tumor. Case report

The authors report a case of intracerebral granular cell tumor. These neoplasms are uncommon and, particularly, the intracerebral location has been reported only in ten previous cases. The authors discuss the clinical and histological features of these lesions, the histogenesis of which is still controversial. Our data seem furthermore to support the theory that at least in most cases, granular cell tumors are derived from Schwann cells.     

Aneuploidy in oncocytic lesions of the thyroid gland: diffuse accumulation of mitochondria within the cell is associated with trisomy 7 and progressive numerical chromosomal alterations

Oncocytic cells are characterized by a greatly increased number of mitochondria that distend the cell cytoplasm and result in a distinctive granular appearance of the cell on conventional histology sections. Oncocytes are frequently found in metabolically active human tissues including the thyroid gland, and, as a general rule, when their proportion in a thyroid tumor is greater than 75% the tumor is referred to as oncocytic (Hürthle cell) adenoma or carcinoma. Such tumors represent a subset of thyroid lesions, and recently, both interphase fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH) studies reported that they may show aneuploidy, with widespread numerical chromosomal alterations. In contrast, very few cases have been studied by conventional cytogenetic analysis. Whether the cells with chromosomal changes are the same as those with mitochondrial accumulation or whether lesions only partially composed of oncocytic cells also have cytogenetic alterations is unclear. To investigate the relationship between acquisition of the oncocytic phenotype and numerical chromosomal changes, we analyzed a random selection of thyroid lesions with (18 cases) and without (11 cases) morphological evidence of oncocytic differentiation. Lesions with oncocytes included hyperplastic nodules, adenomas, Hürthle cell tumors, and papillary carcinomas with lymphocytic stroma (Whartin-like tumors of the thyroid). Karyotypic changes were analyzed by cytogenetic analysis, FISH, or CGH, and the results were compared with in situ analysis of mitochondrial accumulation by immunofluorescence. A striking correlation between the presence of oncocytes and the presence of aneuploid katyotypes was seen in the oncocytic follicular thyroid nodules, but not in the oncocytic papillary tumors. Structural chromosome changes or normal karyotypes were observed in the lesions lacking oncocytic features. Extending the FICTION technique to the evaluation of a cytoplasmic antigen (mitochondrial membrane antigen), we pursued the simultaneous visualization of both mitochondrial increase and numerical chromosomal alterations, and showed that oncocytes of follicular lesions are prone to become aneuploid. Our data support the contention that follicular tumors composed of oncocytes should be regarded as a distinct subset.     

Pathology of prolactin cell adenomas of the human pituitary

Prolactin (PRL) cell adenoma is the most common tumor type in the human pituitary. It accounts for 30% of surgically removed adenomas, while its prevalence is even higher (45%) among incidental pituitary tumors observed at autopsy. Most PRL cell adenomas are highly differentiated with a characteristic ultrastructure. Administration of bromocriptine, a dopaminergic agonist, evokes profound morphologic changes in responsive PRL cell adenomas, while it leaves the fine structure of unresponsive tumors unchanged. The importance of immunocytochemical and electron microscopic investigation of pituitary biopsies is emphasized as tumors with different cell derivation, biological behavior, and therapeutic responsiveness may mimic PRL cell adenomas clinically.     

SV40大T抗原在人脑肿瘤中与p53形成特异性复合物

目的 探讨SV40早期区域基因编码产物大T抗原（Tag) 表达及与抑癌蛋白p53的相互作用在人脑肿瘤发生发展中的意义。方法 采用免疫共沉淀及Western印迹法检测43例人脑肿瘤组织及5例正常人脑组织中Tag的表达，并对18例Tag阳性瘤组织检测Tag-p53复合物的存在。结果 Tag在5例室管膜瘤及2例脉络丛乳头状瘤中全部表达，垂体腺瘤（5／6）、星形胶质细胞瘤（7／10）、脑膜瘤（4／6）、多形性胶质母细胞瘤（3／5）及髓母细胞瘤（2／5）均有Tag的表达，3例少枝胶质细胞瘤、1例松果体瘤及5例正常人脑组织无Tag表达；检测18例Tag阳性瘤组织均发现Tag与p53形成特异性复合物。结论 在人脑肿瘤组织中Tag广泛表达，Tag可与p53形成特异性复合物，Tag-p53特异性复合物的形成导致p53失活，可能是SV40致人脑肿瘤发生的一个重要机理。     

Pituitary oncocytoma. Indispensable role of electron microscopy in its identification

Two surgically resected pituitary adenomas that appeared to be chromophobe or poorly granulated acidophil adenomas by light microscopy were correctly identified as oncocytomas by electron microscopy. The tumor cells ahd markedly hyperplastic, moderately pleomorphic mitochondria in the cytoplasm of virtually all cells. Scattered secretory granules were displaced to the periphery of the cytoplasm but the secretion type of pituitary cell remained obscure. Histochemical and immunocytochemical methods imperfectly characterized these unusual tumors. Even though these neoplasms have been considered rare, they are now being recognized more often after ultrastructural study. Eventually their pathobiologic features may be better understood. One of our patients was 24 years old and is the youngest patient, to our knowledge, in whom a pituitary oncocytoma has been documented.