New immunohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors.* Context.--Immunohistochemistry (IHC) has become an important tool in the diagnosis of brain tumors.
Objective.--To review the latest advances in IHC in the diagnostic neuro-oncologic pathology.
Data Sources.--Original research and review articles and the authors' personal experiences.
Data Synthesis.--We review the features of new, useful or potentially applicable marker antibodies as well as the new uses of already established antibodies in the area of diagnostic neuro-oncologic pathology, focusing on the use of IHC for differential diagnosis and prognosis. We discuss (1) placental alkaline phosphatase, c-Kit, and OCT OCT ornithine carbamoyltransferase; oxytocin challenge test.
ornithine carbamoyl transferase, a liver specific enzyme.
OCT Oxytocin stress test, see there 4 for germinoma, (2) [alpha]-inhibin and D2-40 for capillary hemangioblastoma, (3) phosphohistone-H3 (PHH3), MIB-1/Ki-67, and claudin-1 for meningioma meningioma /me·nin·gi·o·ma/ (me-nin?je-o´mah) a benign, slow-growing tumor of the meninges, usually next to the dura mater, which may invade the skull or cause hyperostosis, and often causes increased intracranial pressure; it is usually , (4) PHH3, MIB-1/Ki-67, and p53 for astrocytoma astrocytoma /as·tro·cy·to·ma/ (as?tro-si-to´mah) a tumor composed of astrocytes; the most common type of primary brain tumor and also found throughout the central nervous system, classified on the basis of histology or in order of , (5) synaptophysin, microtubule-associated protein 2, neurofilament neurofilament /neu·ro·fil·a·ment/ (-fil´ah-ment) an intermediate filament occurring with neurotubules in the neurons and having cytoskeletal, and perhaps transport, functions.
n. protein, and neuronal nuclei for medulloblastoma, (6) INI1 for atypical teratoid/ rhabdoid tumor, and (7) epithelial membrane antigen for ependymoma. All the markers presented here are used mainly for supporting or confirming the diagnosis, with the exception of the proliferation markers (MIB-1/Ki-67 and PHH3), which are primarily used to support grading and are reportedly associated with prognosis in certain categories of brain tumors.
Conclusions.--Although conventional hematoxylin-eosin staining is the mainstay for pathologic diagnosis, IHC has played a major role in differential diagnosis and in improving diagnostic accuracy not only in general surgical pathology but also in neuro-oncologic pathology. The judicious use of a panel of selected immunostains is unquestionably helpful in diagnostically challenging cases. In addition, IHC is also of great help in predicting the prognosis for certain brain tumors.
(Arch Pathol Lab Med. 2007;131:234-241)
Although conventional hematoxylin-eosin (H&E) staining is crucial for diagnosis, diagnostic neuropathology neuropathology /neu·ro·pa·thol·o·gy/ (-pah-thol´ah-je) pathology of diseases of the nervous system.
The study of diseases of the nervous system. has benefited in the last 2 decades from the incorporation of, and recent advances in, immunohistochemistry (IHC). A number of markers for IHC have been developed in the area of diagnostic neuro-oncology, since glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) protein that is found in glial cells such as astrocytes. First described in 1971, GFAP is a type III IF protein that maps, in humans, to 17q21. (GFAP GFAP glial fibrillary acidic protein. ), the antibody against which is currently most commonly used in practice, was found by Eng et al (1) in 1971 and was later reported as a useful marker antigen for astroglial cells by Kleihues et al (2) in 1987.
In general, brain tumors are classified into 2 major groups, primary and metastatic, and the primary brain tumors can be classified further into 3 groups: neuroepithelial neuroepithelial
pertaining to the neuroepithelium.
an APUD respiratory system cell occurring in the bronchiolar mucosa either singly or as small aggregates. (eg, astrocytic as·tro·cyte
A star-shaped cell, especially a neuroglial cell of nervous tissue.
astro·cyt , oligodendroglial, ependymal, choroid plexus, neuronal, and pineal parenchymal pa·ren·chy·ma
1. Anatomy The tissue characteristic of an organ, as distinguished from associated connective or supporting tissues.
2. tumors), nonneuroepithelial (eg, meningioma, nerve sheath tumors, malignant lymphoma, pituitary adenoma, and germ cell tumors), and others (ie, tumors of unknown origin, eg, capillary hemangioblastoma). In neuropathology practice, we routinely use several useful IHC markers that are relatively sensitive and specific for some of these tumors (eg, GFAP for astrocytomas, synaptophysin for neuronal tumors); however, none of these are diagnostic (ie, no absolute sensitivity and specificity).
There have been many recent publications in the area of IHC in brain tumor pathology, with several articles relating to new specific antibodies. (3-10) This review will discuss the features of new, reportedly sensitive and specific marker antibodies as well as new uses of already established antibodies in the areas of adult and pediatric pediatric /pe·di·at·ric/ (pe?de-at´rik) pertaining to the health of children.
Of or relating to pediatrics. , diagnostic neuro-oncology practice, based on recently published reports and our own experience.
GERMINOMA: PLACENTAL ALKALINE PHOSPHATASE, C-KIT (CD117), AND OCT4
Germinoma occurs predominantly in the pineal and suprasellar regions and is composed of lobules or sheets of uniform cells with large vesicular vesicular /ve·sic·u·lar/ (ve-sik´u-ler)
1. composed of or relating to small, saclike bodies.
2. pertaining to or made up of vesicles on the skin.
3. nuclei, prominent nucleoli nucleoli
plural form of nucleolus. , well-defined cell boundaries, and abundant clear cytoplasm, admixed with lymphoplasmacytic infiltrates. Given that, characteristically, intracranial germinomas are highly radiosensitive ra·di·o·sen·si·tive
Sensitive to the action of radiation. Used especially of living structures.
ra and chemosensitive, allowing for a high cure rate with radiation alone or cisplatin-based chemotherapy followed by low-dose radiotherapy, an accurate diagnosis is critical for patient management. The histologic features are virtually diagnostic when the specimens are sufficient for evaluation and are well preserved without artifact. Immunohistochemistry is of particular use in cases when either the specimen is very small or the lymphocytic infiltrate is predominant. (11) As with ovarian dysgerminomas and testicular seminomas, intracranial germinomas are known to show immunoreactivity for placental alkaline phosphatase (PLAP) in a surface membrane or, somewhat less commonly, diffuse cytoplasmic distribution. (12) This antigen is a cell surface glycoprotein and is normally expressed in syncytiotrophoblasts and primordial germ cells. (13) Although this marker is the mainstay in current neuropathology practice, it has its shortcoming in that PLAP labeling is not a constant feature with variable sensitivity, intensity, and extent of reactivity, (3,12,14) and it can sometimes be difficult to interpret, especially in the cases with heavy inflammatory cell infiltrates and in specimens that were previously frozen. (12)
The c-kit proto-oncogene encodes a receptor tyrosine kinase Receptor tyrosine kinases (RTK)s are the high affinity cell surface receptors for many polypeptide growth factors, cytokines and hormones. Of the ninety unique tyrosine kinase genes idenitified in the human genome, 58 encode receptor tyrosine kinase proteins. that is required in normal spermatogenesis. (15) Expression of c-Kit (CD117) has been reported on the cell surface in almost all gonadal gonadal
pertaining to or arising from a gonad. See also testicular, ovarian.
cords formed by epithelial cells which migrate from the mesonephric tubules in the embryo to the gonadal ridge and establish the indifferent seminomas/dysgerminomas (Figure 1, A) but very rarely in nonseminomatous germ cell tumors. (15,16) Takeshima et al (17) and Sakuma et al (18) reported that they studied 16 cases of intracranial germinomas, respectively, and c-Kit was diffusely expressed on the surface of germinoma cells in all cases examined. In addition, Takeshima et al (17) reported that stem cell factor stem cell factor
A cytokine that promotes the differentiation and growth of hematopoietic stem cells into other types of cells. (SCF), a specific ligand of c-Kit, was also expressed on the cell surface, the staining pattern of which was identical to that of c-Kit. CD30 and c-Kit (CD117) used in combination are known to be useful to distinguish between embryonal carcinoma and seminoma seminoma /sem·i·no·ma/ (-no´mah) a radiosensitive, malignant neoplasm of the testis, thought to be derived from primordial germ cells of the sexually undifferentiated embryonic gonad. Cf. germinoma. in the gonads. (15) However, to our knowledge, the expression of these markers has not been studied in combination in their intracranial counterparts.
[FIGURE 1 OMITTED]
OCT4, also known as POU5F1, OCT3, or OTF3, is a nuclear transcription factor expressed in early embryonic cells and germ cells. (19,20) This factor is involved in the regulation and maintenance of pluripotency of these cells (19-22) and has been shown to be essential for embryonic stem cell Embryonic stem cells (ES cells) are stem cells derived from the inner cell mass of an early stage embryo known as a blastocyst. Human embryos reach the blastocyst stage 4-5 days post fertilization, at which time they consist of 50-150 cells.
ES cells are pluripotent. formation and self-renewal. (23,24) Cheng et al (25) reported that OCT4 was expressed in all 33 cases of ovarian dysgerminomas examined, including metastases, while no immunoreactivity was noted in all 111 cases of ovarian nondysgerminomatous tumors with the exception of 4 of 14 clear cell carcinomas of ovary that showed focal (<10%) positivity. On the other hand, Jones et al (26) examined 91 cases of primary testicular neoplasms and reported that there was near 100% staining of the seminoma and embryonal carcinoma cells for OCT4 in all 64 cases of adult mixed germ cell tumors examined, while the other germ cell tumor Germ cell tumor (GCT) is a tumor (neoplasm) derived from germ cells. (Germ cells themselves are not pathogenic; i.e., they are not the viral and bacterial "germs" that cause illness.) Germ cell tumors can occur both inside and outside of the gonads (ovary and testis). components (yolk sac tumor, choriocarcinoma choriocarcinoma: see neoplasm. , and teratoma teratoma /ter·a·to·ma/ (ter?ah-to´mah) pl. terato´mata, teratomas a true neoplasm made up of different types of tissue, none of which is native to the area in which it occurs; usually found in the ovary or testis. ) showed no staining. In these 2 studies, the main finding is not only that OCT4 is a highly sensitive and specific marker of ovarian dysgerminoma, and testicular seminoma and embryonal carcinoma, respectively, but also that the OCT4 staining pattern was nuclear (in contrast to PLAP and c-Kit, which show characteristically cell membrane staining), with uniformly strong staining intensity and staining extent of greater than 90%. Hattab et al (3) conducted a comparative immunohistochemical study of intracranial germinomas using OCT4 and PLAP with control cases, and concluded that OCT4 is a highly specific and sensitive marker for primary intracranial germinomas (100% sensitivity for OCT4 vs 92% for PLAP). As with the ovarian and testicular counterparts in the previous studies cited above, OCT4 demonstrated characteristically diffuse and strong nuclear staining in the germinoma cells (Figure 1, B), (3) which is more easily interpreted than the membranous membranous /mem·bra·nous/ (mem´brah-nus) pertaining to or of the nature of a membrane.
1. Relating to, made of, or similar to a membrane.
2. pattern seen with PLAP immunostaining, especially in very small specimens. Since no intracranial embryonal carcinomas were included in this study, (3) OCT4 may not be specific for intracranial germinomas; in other words Adv. 1. in other words - otherwise stated; "in other words, we are broke"
put differently , intracranial embryonal carcinomas should be excluded with H&E-stained sections and probably with CD30 immunostaining if the tumor is OCT4 positive.
CAPILLARY HEMANGIOBLASTOMA: [alpha]-INHIBIN (INHIBIN in·hib·in
A peptide hormone secreted by the follicular cells of the ovary and the Sertoli cells of the testis that inhibits secretion of follicle stimulating hormone from the anterior pituitary. A) AND D2-40
Capillary hemangioblastomas (CHBs) are considered by the World Health Organization (WHO) to be grade 1 tumors of uncertain histogenesis histogenesis /his·to·gen·e·sis/ (-jen´e-sis) the formation or development of tissues from the undifferentiated cells of the germ layers of the embryo.histogenet´ic
n. , composed of stromal Stromal
A type of tissue that is associated with the support of an organ.
Mentioned in: Wilms' Tumor cells and abundant capillaries and commonly involving the cerebellum and spinal cord. (27) The histological differential diagnosis of CHB includes metastatic clear cell renal cell carcinoma renal cell carcinoma
Malignant tumour of the cells that cover and line the kidney. It usually affects persons over age 50 who have vascular disorders of the kidneys. It seldom causes pain, unless it is advanced. (CRCC), paraganglioma, angiomatous an·gi·o·ma·tous
Relating to or resembling an angioma. meningioma, (28) and capillary hemangioma. The histological distinction of CHB from metastatic CRCC has long been recognized as a particular difficulty because of striking morphologic similarities between them. This difficulty may be compounded in patients with von Hippel-Lindau (VHL) disease, an autosomal dominant disorder Noun 1. autosomal dominant disorder - a disease caused by a dominant mutant gene on an autosome
autosomal dominant disease
congenital disease, genetic abnormality, genetic defect, genetic disease, genetic disorder, hereditary condition, hereditary disease, caused by germ-line mutations of the VHL tumor suppressor gene tumor suppressor gene
A gene that suppresses cellular proliferation. When inherited in a mutated state, it is associated with the development of various cancers, including most familial cancers. Also called antioncogene. , in which both CHB and CRCC are among the most commonly encountered tumors. In view of the possibility of both CHB and metastatic CRCC to the central nervous system (CNS See Continuous net settlement.
See continuous net settlement (CNS). ) occurring synchronously, metachronously, or both, and tumor-to-tumor metastasis (CRCC metastasizing to CHB) (29-31) in patients with VHL disease, their distinction is of particular importance and cannot be overemphasized, since the prognostic and therapeutic significance is completely different. Capillary hemangioblastoma is a benign tumor and generally has a benign course following resection, whereas metastatic CRCC in the brain carries a dismal prognosis (32) and may require more aggressive treatment after surgery. Given that medical history and conventional histological examination with H&E staining alone cannot reliably distinguish between these 2 entities, IHC is crucial for differential diagnosis, and there have been a number of IHC studies to address these concerns.
In general, renal cell carcinomas are immunoreactive for epithelial markers, such as epithelial membrane antigen (EMA) and low-molecular-weight cytokeratins (eg, CAM 5.2), (33) whereas CHBs are negative. On the other hand, the stromal cells of CHB have been reported to show variable patterns of immunoreactivity for neuron-specific enolase enolase /eno·lase/ (e´no-las) an enzyme that catalyzes the dehydration of 2-phosphoglycerate to form phospho, a step in the pathway of glucose metabolism. (NSE NSE - Network Software Environment: a proprietary CASE framework from Sun Microsystems. ), S100 protein, VHL protein, and several growth factors (27,34,35); however, all of these immunohistochemical reactions are nonspecific and would not exclude other possibilities in the differential diagnosis of CHB. (29) The combined use of the immunohistochemical markers mentioned above is of help for differential diagnosis and often allows for a definitive diagnosis. Since loss of immunophenotype is sometimes encountered during tumor progression, and a definite subset (10%-30%) of CRCC is negative for EMA and CAM 5.2, (36,37) other more "specific" immunohistochemical markers for CHB are needed.
Inhibin, a dimeric 32-kd glycoprotein belonging to the transforming growth factor [beta] family and composed of an [alpha] (inhibin A) and a [beta] subunit, is produced mainly by ovarian granulosa cells and testicular Sertoli cells. (38) Inhibin A is expressed in the sex cord-stromal tumors and adrenal cortical tumors. (39,40) Hoang and Amirkhan (4) reported in 2003 that immunoreactivity for inhibin A was demonstrated in all 25 cases of hemangioblastoma with cytoplasmic expression in the stromal cells (Figure 2), in contrast to all 19 cases of renal cell carcinoma, including both primary and metastatic, none of which were positive, and concluded that inhibin A was a helpful marker in distinguishing CHB from metastatic CRCC. In addition, this study included 11 cases of CHB from 8 patients with VHL disease, and there was no difference in the inhibin A staining pattern between the sporadic CHB and those associated with VHL disease. A recent study performed by Jung and Kuo (5) demonstrated that CD10 membranous immunoreactivity was seen in all 21 cases of CRCC (5 metastatic, 16 primary) examined, whereas all 22 cases of CHB were negative. They also showed that 91% (20/22) of cases of CHB and 24% (5/21) of cases of CRCC expressed inhibin A, and concluded that, in addition to inhibin A, CD10 was a superior marker for the differential diagnosis of CHB (negative) and metastatic CRCC (positive).
[FIGURE 2 OMITTED]
D2-40, a novel monoclonal antibody that was initially raised against an oncofetal antigen M2A, (41) was recently introduced to diagnostic pathology to help identify lymphatic endothelium. (42,43) Apart from lymphatic endothelium, D2-40 has been reported to be immunoreactive in mesotheliomas (44,45) and, in the CNS, in choroid plexus epithelium, ependymal cells, subependymal areas, and the leptomeninges leptomeninges /lep·to·me·nin·ges/ (lep?to-me-nin´jez) sing. leptome´ninx the pia mater and arachnoid taken together; the pia-arachnoid.leptomenin´geal
n. . (6) A recent study conducted by Roy et al (6) revealed that all 23 cases of CHB examined expressed D2-40 membranous immunoreactivity in the stromal cells with strong intensity in 19 cases (83%), whereas all 28 cases of CRCC (8 metastatic, 20 primary) failed to show immunoreactivity. There were 3 cases of CHB with VHL disease included in this study, and no difference was seen in D2-40 staining of CHB in patients with or without VHL disease. Although D2-40 appears to be a very useful marker, we have not experienced constant positivity in several cases of hemangioblastoma examined in our laboratory.
In summary, based on the recent studies, inhibin A and D2-40 are sensitive and specific markers for CHB, while EMA, CAM 5.2, and CD10 mark CRCC. Combined use of at least one of these markers from each group helps to distinguish CHB from metastatic CRCC in patients with or without VHL disease.
We have recently experienced a case of angiomatous meningioma, histologically closely mimicking CHB, which is generally considered to be one of the histological differential diagnoses of CHB. (34) Diffuse EMA immunoreactivity and negative inhibin A staining supported the diagnosis of a meningioma and excluded that of a CHB. Metastatic CRCC was included in the differential diagnosis based on the diffuse EMA staining; however, CD10 and CAM 5.2 were negative.
Paraganglioma may mimic CHB and is included in the differential diagnosis of CHB; however, neuroendocrine markers, such as chromogranin and synaptophysin, are usually positive in paragangliomas.
Capillary hemangiomas of the CNS are very rare and show histological features similar to those of lobular lob·ule
1. A small lobe.
2. A section or subdivision of a lobe.
lob capillary hemangiomas of the skin as well as the capillary hemangiomas of infancy, (46) with a fibrous pseudocapsule. (47) Most examples have been documented recently and appear to arise more commonly in spinal cord. (46-51) Central nervous system capillary hemangiomas may mimic CHB, especially a vascular dominant CHB, given that this subtype of CHB may feature a lobular architecture with feeding vessels and a compact growth pattern. (52) In order to exclude this unusual subtype of CHB in which the stromal cell component is small to minimal, we should use IHC with markers for the stromal cells (eg, S100 protein, NSE, inhibin A, D2-40) whenever making a diagnosis of CNS capillary hemangiomas. There were several recently reported cases of CNS capillary hemangiomas with no immunohistochemical analysis with these markers. (49-51)
MENINGIOMA: PHOSPHOHISTONE-H3, MIB-1/KI-67, AND CLAUDIN-1
Meningiomas are among the most common primary neoplasms of the CNS, comprising between 13% and 26% of intracranial tumors. (53) According to the WHO classification, most meningiomas are benign and can be graded into WHO grade 1, and certain histological subtypes are associated with greater likelihood of recurrence and/or aggressive behavior and correspond to WHO grades 2 and 3. (53) Quantifying the proliferative potential is of help in predicting the biologic behavior. One of the WHO criteria other than particular histological subtypes in the assignment of grade in meningiomas is the number of mitotic mitotic
pertaining to mitosis.
degree to which a cell population is proliferating; used as an index of tumor aggression. figures (MFs) per 10 high-power fields (HPFs, defined as 0.16 [mm.sup.2]) in the areas of highest mitotic activity; that is, no less than 4 mitoses per 10 HPFs in atypical (WHO grade 2) meningiomas, and no less than 20 mitoses per 10 HPFs in anaplastic an·a·plas·tic
1. Relating to the surgical restoration of a lost or absent part.
2. Of, relating to, or characterized by cells that have become less differentiated.
1. (WHO grade 3) meningiomas. (53)
Given that it is difficult to distinguish MFs on H&E-stained slides from similar chromatin changes occurring in apoptotic cells or secondary to crush, distortion, pyknosis, or necrosis, (54) as the diagnostic criterion, MF is not as subjective as usually considered. Ribalta et al (7) studied a mitosis-specific antibody against phosphorylated histone histone (hĭs`tōn), any of a class of protein molecules found in the chromosomes of eukaryotic cells. They complex with the DNA (see nucleic acid) and pack the DNA into tight masses of chromatin, which have the structure of coiled coils, much H3 (PHH3) (which is negligible during interphase but reaches a maximum during mitosis (55,56)) in 54 cases of meningiomas and showed a robust positive correlation between MF counts performed on traditional H&E-stained slides and those performed on anti-PHH3-immunostained slides. Labeled nuclei are characterized by multiple finger-like projections of immunoreactivity (Figure 3, A). This robust staining of mitoses with a negative background makes mitoses "stand out." They concluded that anti-PHH3 immunostaining facilitated rapid reliable grading of meningiomas according to WHO 2000 criteria by permitting quick focus of attention on the most mitotically active tumor area(s) for quantitation and by allowing easy and objective differentiation of MFs from apoptotic and distorted/pyknotic nuclei. (7) Although it is uncertain whether or not this seemingly more sensitive and specific method is more useful than the conventional method to predict the biological behavior of meningiomas and further studies are required for this issue, there is no doubt that this immunostaining allows for rapid and accurate identification of MF.
[FIGURE 3 OMITTED]
Apart from MFs, an anti-Ki-67 monoclonal antibody MIB-1, which is immunoreactive for the nuclei of cells in non-G0 phases (ie, G1, S, G2, and M phases) of the cell cycle, is commonly used as a useful ancillary study in routine surgical/neuropathological practice to assess the proliferative potential in a given neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. . The MIB-1 labeling index (MIB-1 LI), which is calculated as a percentage of the MIB-1-positive cells to the total number of tumor cells, in meningiomas has been reported to correlate well with histologic grade (57,58) and clinical tumor recurrence. (58,59) Although MIB-1 LI is not included in the WHO criteria to grade the meningiomas, it is of particular help in tumors that are histologically "on the fence" with regard to tumor grade. Amatya et al (57) studied 146 cases of meningiomas immunohistochemically and reported that the mean MIB-1 LI of benign, atypical, and anaplastic meningiomas was 1.5%, 8.1%, and 19.5%, respectively. They also reported that p53 immunoreactivity (p53 labeling index) correlated with the histologic grade as well. Nakasu et al (58) investigated the predictability of tumor growth, assessed radiologically by tumor doubling time, and recurrence in 139 cases of meningiomas by MIB-1 IHC, using 2 different counting methods; that is, counting in the area of the highest MIB-1 labeling (HL method) and counting in randomly selected fields (RS method). They reported that the MIB-1 LI measured by both methods showed a significant correlation with tumor grade, growth speed, and recurrence rate. Interestingly, they pointed out that focal accumulation of MIB-1-positive cells in meningiomas was not likely to correlate with their biologic aggressiveness and concluded that the RS method was a better predictor of recurrence and tumor growth in meningiomas than the HL method when counting manually. There have been several studies describing the cutoff point of MIB-1 LI for recurrence, although it varied from report to report. (58-61) Nakasu et al (58) suggested approximately 2% and 3% in the RS and HL methods, respectively. Matsuno et al (60) studied the MIB-1 LI of recurrent (n = 54) and non-recurrent (n = 73) groups of meningiomas using the HL method, and mentioned that a MIB-1 LI of 3% was a cutoff point for recurrence, especially within the first 10-year follow-up periods, although there was a marked overlap of values between the groups. Ho et al (61) studied 83 cases of meningiomas with at least a 10-year follow-up by IHC using the HL method and reported that the MIB-1 LI of 10% was a cutoff point for recurrence. Perry et al (59) studied prognostic significance of variable parameters by IHC using image analysis in 425 cases of meningiomas, and reported that the MIB-1 LI of 4.2% or more was strongly associated with a decreased recurrence-free survival rate in gross, totally resected meningiomas.
Meningiomas, particularly the fibroblastic type, may be difficult to distinguish from schwannomas with routine H&E-stained sections, especially when located in the cerebellopontine angles and intradural, extramedullary regions of spinal canal. In these tumors, EMA immunoreactivity may be faint and/or focal. Winek et al (62) mentioned that because of overlap in S100 protein and EMA reactivity, these markers were unreliable in differentiating meningioma from acoustic schwannoma.
Claudin-1, an integral structural protein of tight junctions, has recently been used as a marker of perineurial per·i·neu·ri·um
n. pl. per·i·neu·ri·a
The sheath of connective tissue enclosing a bundle of nerve fibers.
[New Latin : peri- + Greek neuron, nerve; see neuron. cells and has been reported to be often a more robust marker than EMA to distinguish soft tissue perineuriomas from its mimics. (63) Bhattacharjee et al (8) conducted a comparative IHC study using claudin-1 and EMA in 20 and 10 cases of meningioma and schwannoma, respectively. They reported that claudin-1 and EMA expression was observed in 85% and 100% of meningiomas, respectively, and of the 10 schwannomas, 2 cases showed focal, nonmembranous staining for EMA, while none were positive for claudin-1. They also stressed that the immunoreactive pattern of claudin-1 was unique in the crisp, punctate/ granular membranous reaction (Figure 3, B), which was visually more favorable in contrast to the faint or weak membranous pattern of expression seen in EMA. They concluded that claudin-1 was a very useful adjunct to EMA in meningiomas with equivocal morphologic features or with weak/focal EMA expression, and that the lack of claudin-1 expression by schwannomas was very useful in the context of differential diagnosis with fibroblastic meningiomas, particularly of cerebellopontine angle tumors. A recent report by Hahn et al (9) showed similar results, although the sensitivity was lower, with 21 (53%) of 40 meningiomas being immunoreactive and all other tumors being negative.
ASTROCYTOMA: PHH3, MIB-1/KI-67, AND p53
Diffusely infiltrating astrocytomas include (low-grade) diffuse astrocytoma (WHO grade 2), anaplastic astrocytoma (WHO grade 3), and glioblastoma (WHO grade 4), according to the current WHO classification. (64) Distinguishing between WHO grade 2 and 3 infiltrating astrocytomas is particularly important for patient management as well as for prognosis. By current WHO guidelines, this distinction is made primarily by assessment of the proliferation activity of neoplastic neoplastic /neo·plas·tic/ (ne?o-plas´tik)
1. pertaining to a neoplasm.
2. pertaining to neoplasia.
pertaining to neoplasia or a neoplasm. cells. There are a few studies demonstrating a significant positive correlation between MIB-1 LI and tumor grade in diffusely infiltrating astrocytomas, classified according to the WHO 2000 classification system. (65,66) A recent large retrospective study of grade 2 and 3 astrocytomas by Colman et al, evaluating the utility of PHH3 staining for determining proliferative activity, demonstrated that the PHH3 mitotic index (per 1000 cells) was significantly associated with the standard mitotic count (mitoses per 10 HPFs) and with the MIB-1 LI and had specific technical advantages over the MIB-1 LI (67) because the latter showed significant interlaboratory variability, depending on staining conditions. (68) For a practical usage of this marker, they pointed out that the antigenicity seemed to have decreased after 3 to 5 years in their samples. With regard to prognosis, they reported that the PHH3 index was an independent predictor of survival after adjusting for relevant clinical variables in multivariate analysis. Interestingly, they listed specific cutoffs to separate the patients into 2 groups with survival times similar to those established in a previously reported series for grade 2 and grade 3 astrocytomas. The cutoffs (grade 2 vs 3, respectively) were as follows: PHH3 index ([less than or equal to]4 vs >4 per 1000 cells), MIB-1 LI ([less than or equal to]9% vs >9%), and mitoses per 10 HPFs ([less than or equal to]3 vs >3). (67) Although the current WHO guidelines do not define such a cutoff to distinguish between grade 2 and 3 astrocytomas, this information on the proliferation markers, in addition to the variable morphologic parameters, can be very useful to grade the tumors.
One of the most common diagnostic dilemmas in neuro-oncologic pathology is a distinction between benign reactive astrocytic lesions (ie, gliosis) and low-grade astrocytomas, especially with small biopsies (eg, stereotactic stereotactic /ster·eo·tac·tic/ (-tak´tik)
1. characterized by precise positioning in space; said especially of discrete areas of the brain that control specific functions.
2. pertaining to stereotactic surgery. biopsies). In general, there should be negligible or very low levels of Ki-67/MIB-1 immunoreactivity in the setting of gliosis. (68) This pattern of immunoreactivity in gliosis and that seen in some low-grade astrocytomas may overlap. Wild-type p53 is involved in regulation of the cell cycle as well as apoptosis, (69) and it has been demonstrated to suppress cell transformation. (70) The wild-type p53 protein has a short half-life (5-30 minutes) because of its rapid turnover, and is not normally detectable by standard immunohistochemical methods. (71) Mutation of the gene usually leads to the production of a functionally impaired or altered protein, which retards degradation and thus can be detected via immunohistochemical staining. On the other hand, p53 immunoreactivity is sometimes unaccompanied by gene mutations. This pattern can be seen in the settings, such as binding of wild-type p53 by various oncoproteins (eg, mdm-2) (72) and the result of epigenetic epigenetic /epi·ge·net·ic/ (-je-net´ik)
1. pertaining to epigenesis.
2. altering the activity of genes without changing their structure. changes. (73,74) Yaziji et al (75) reported that p53 (monoclonal antibody, DO-7; Dako, Carpinteria, Calif; dilution, 1:60) immunoreactivity was seen in 12 (54%) of 22 low-grade astrocytomas and 5 (9%) of 56 reactive astrocytic lesions, all 5 being cases of progressive multifocal leukoencephalopathy Progressive Multifocal Leukoencephalopathy Definition
Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive neuromuscular disease caused by opportunistic infection of brain cells (oligodendrocytes and astrocytes) by the JC virus . Given unusual p53 immunoreactivity seen in astrogliosis in their study, they concluded that p53 immunostain can help to differentiate reactive from neoplastic astrocytic lesions. In contrast, Kurtkaya-Yapicier et al (76) conducted a similar study of 60 nonneoplastic lesions, including gliosis, infarction, demyelination, progressive multifocal leukoencephalopathy, and herpes simplex virus Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.
Mentioned in: Conjunctivitis
herpes simplex virus encephalitis, and 50 astrocytomas of WHO grades 2 to 4, using p53 antibody (monoclonal, DO-7; Dako; dilution, 1:200). They showed p53 immunoreactivity in all lesions examined, although the reactivity was low-level in most instances, and concluded that it was not a reliable indicator of astrocytic neoplasia. We believe that this distinction is still best handled on histologic grounds with the clinical, radiologic, and operative findings, although immunohistochemical staining for Ki-67 and p53 may be of help if the expression is significantly high.
MEDULLOBLASTOMA: SYNAPTOPHYSIN, MICROTUBULE-ASSOCIATED PROTEIN 2, NEUROFILAMENT PROTEIN, AND NEURONAL NUCLEI
The medulloblastoma (MDB) is defined as a malignant, invasive embryonal tumor of the cerebellum, preferentially occurring in children and adolescents, with a propensity for leptomeningeal dissemination. Medulloblastomas are the second most frequent brain tumors in childhood after pilocytic astrocytomas, and account for approximately 15% of all pediatric brain tumors. (77) The median age at diagnosis is 9 years. (77) Medulloblastomas have been chiefly subtyped as classic, nodular nodular
marked with, or resembling, nodules.
see nodular fasciitis (below).
a firm painless nodular swelling, 0. (desmoplastic), and large cell/anaplastic based on histologic appearances. (78) Of these, the large cell/ anaplastic variant is known to be associated with worse prognosis. (78,79)
Although MDBs are derived from embryonal precursor cells with a capacity for divergent differentiation, neuronal differentiation is most consistently seen. (80,81) This is usually incipient in that it is restricted to the expression of neuronal markers, with rare cases showing overt ganglionic or mature neuronal cells. Synaptophysin has proven to be a reliable marker of neuronal differentiation and is detected in virtually all cases on frozen sections, (80,81) with 70% to 80% of cases being positive in paraffin sections. (82) Microtubule-associated protein 2 antibody mirrors synaptophysin but has a more intense granular or punctate punctate /punc·tate/ (punk´tat) spotted; marked with points or punctures.
Having tiny spots, points, or depressions. pattern of reactivity. It is often helpful in those cases where the synaptophysin staining is weak or equivocal. Neurofilament proteins of low and intermediate molecular masses (68 kd and 160 kd, respectively), are expressed in proliferating medulloblastoma cells, (80) but high-molecular-mass neurofilament protein (200 kd) is only expressed in the tumor cells with advanced neuronal differentiation and overt ganglionic or neuronal morphology. (83) Neuronal nuclei immunoreactivity is seen focally in the nuclei of cells with advanced neuronal differentiation. (84)
Glial glial /gli·al/ (gli´'l) of or pertaining to the neuroglia.
of or pertaining to glia or neuroglia.
a dense network of glial processes at the pia mater. (astrocytic) cell differentiation in MDBs is restricted to small foci of tumor cells without evidence of progressive differentiation to mature astrocytes. When strict criteria are applied for true tumor cells with glial (astrocytic) differentiation, excluding entrapped reactive astrocytes, the incidence is seen in up to 13% of cases. (83) True tumor cell glial differentiation is defined as a typical medulloblastoma cell with hyperchromatic nucleus and scant cytoplasm, showing GFAP immunoreactivity restricted to perinuclear perinuclear /peri·nu·cle·ar/ (-noo´kle-ar) near or around a nucleus. cytoplasm, and is associated with a poor prognosis. (85)
Mesenchymal, epithelial, and melanotic melanotic /mel·a·not·ic/ (mel?ah-not´ik)
1. pertaining to or characterized by the presence of melanin.
2. characterized by melanosis. markers are seen in rare variants of MDBs. It should be noted that focal expression of epithelial markers (keratins and EMA) is otherwise rare in MDBs, and in particular, in the case of large cell/anaplastic subtype, raises the possibility of atypical teratoid/rhabdoid tumor. (86)
ATYPICAL TERATOID/RHABDOID TUMOR: INI1
Atypical teratoid/rhabdoid tumors (ATRTs) may form a histological spectrum from pure rhabdoid to atypical teratoid/ rhabdoid tumors, (87,88) and occur most commonly in young children (Figure 4). More than 90% of cases are diagnosed before age 5 years. (89) Since their initial description, they have been reported to occur throughout the neuraxis, but the posterior fossa remains a preferred site, in particular the cerebellopontine angle. Neither clinical presentation nor neuroimaging distinguishes the ATRT from medulloblastoma. (90) Microscopically, ATRTs are very cellular tumors that show marked regional heterogeneity, with primitive neuroepithelial, rhabdoid, epithelial, and mesenchymal components. There is often a fibrovascular fibrovascular
both fibrous and vascular.
see malignant fibrous histiocytoma. stroma stroma /stro·ma/ (stro´mah) pl. stro´mata [Gr.] the matrix or supporting tissue of an organ.stro´malstromat´ic
n. pl. stro·ma·ta
1. separating lobules and sheets of tumor cells. The cellular morphology varies from smaller, primitive neuroepithelial type cells, with hyperchromatic nuclei resembling those of a medulloblastoma, to large cells with eosinophilic eosinophilic /eo·sin·o·phil·ic/ (-fil´ik)
1. readily stainable with eosin.
2. pertaining to eosinophils.
3. pertaining to or characterized by eosinophilia. , pale, or clear cytoplasm and large round nuclei with more open chromatin and prominent nucleoli. Immunohistochemistry reflects the morphological heterogeneity of the tumor. There is immunoreactivity for a range of mesenchymal, epithelial, and neuroectodermal markers, but the tumors are consistently negative for the germ cell markers. Vimentin is consistently expressed. Expression of EMA, keratin keratin (kĕr`ətĭn), any one of a class of fibrous protein molecules that serve as structural units for various living tissues. The keratins are the major protein components of hair, wool, nails, horn, hoofs, and the quills of feathers. , smooth muscle actin, and GFAP is also frequently observed. S100 protein, synaptophysin, chromogranin, neurofilament protein, desmin, and HMB-45 may be variably and focally expressed in ATRTs. Glucose transporter protein 1 (GLUT-1) is expressed by ATRTs, and suggests origin from a stem cell. (91) There is a high frequency of monosomy 22 in CNS ATRTs. Molecular cytogenetic cytogenetic /cy·to·ge·net·ic/ (-je-net´ik)
1. pertaining to chromosomes.
2. pertaining to cytogenetics.
pertaining to or originating from the origin and development of the cell. screening has shown deletions of chromosome 22q11.2; this region contains the hSNF5/INI1 gene. Most CNS, renal, and extrarenal rhabdoid tumors show homozygous ho·mo·zy·gous
Having the same alleles at one or more gene loci on homologous chromosome segments.
Identical genes controlling a specified inherited trait. inactivation of INI1 by deletion and/or mutation of the INI gene, with decreased or absent expression at the RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic or protein level. Immunohistochemistry with antibody to INI1 (with absent nuclear staining in tumor cells in ATRT) has been shown to correlate with molecular findings in ATRT. (10) The INI antibody may be more useful in analysis of tumors with indeterminate histologic and immunophenotypic profiles, since negative staining (albeit with preserved nuclear expression in normal components such as endothelial cells) is intuitively not as desirable an end result as compared with positive staining. In the diagnosis of ATRTs, a panel of immunohistochemical markers which include vimentin, EMA, keratins, smooth muscle actin, GFAP, and synaptophysin is likely to help confirm the diagnosis in the context of the appropriate morphological appearance. INI1 immunostaining can be used in those cases having indeterminate histological features, or in small biopsies which may not be representative of the morphological heterogeneity typical of ATRTs.
[FIGURE 4 OMITTED]
Ependymomas account for 3% to 9% of all neuroepithelial tumors. (92) They are most often seen in children, adolescents, and young adults, but can be seen in older age groups. In children, they are the third most common CNS tumors after astrocytomas and medulloblastomas. (77) Posterior fossa tumors are more frequent than supratentorial, and spinal cord ependymomas occur in older age groups than pediatric tumors. Ependymomas of the fourth and lateral ventricles occur in a ratio of 6:4; their location and growth pattern in the fourth ventricle may influence prognosis. (93) Microscopically, ependymomas are well-demarcated, moderately cellular tumors with a monomorphic monomorphic /mono·mor·phic/ (-mor´fik) existing in only one form; maintaining the same form throughout all developmental stages.
mon·o·mor·phic or mon·o·mor·phous
1. nuclear morphology. Characteristic features include perivascular perivascular /peri·vas·cu·lar/ (-vas´ku-lar) near or around a vessel.
around a vessel.
perivascular cellulitis pseudorosettes, which are nearly always seen in these tumors, and "true" ependymal rosettes. The latter feature is much less frequently seen in ependymomas and is characterized by clusters of ependymal cells arranged around a lumen with some resemblance to the central canal of the spinal cord. Immunohistochemistry in ependymomas reveals their dual nature with glial fibrillogenesis and GFAP expression, and epithelial with EMA expression. GFAP is variably positive in ependymomas, with the tumor cells and processes forming the perivascular pseudorosettes being most consistently positive. Normal mature ependymal cells do not express GFAP, but reactive and neoplastic ependymal cells reacquire the developmentally repressed ability to express GFAP which occurs from the 15th week of gestation, but is lost in adulthood. Other intermediate filaments such as vimentin and desmin are also expressed in neoplastic ependymal cells. EMA expression is useful in that it is consistently and widely expressed in well-differentiated tumors; anaplastic examples were not immunoreactive in one study, (94) but in our experience are at least focally expressed. The pattern of EMA immunoreactivity typically is seen as dotlike perinuclear cytoplasmic reaction. Histological features by themselves are not reliable predictors of biological behavior, likely due to tumor heterogeneity. However, ependymomas with 2 or more of the features of hypercellularity, mitotic figures, elevated MIB-1 LI, microvascular proliferation, and necrosis are likely to show aggressive behavior. (95) According to the recent study of ependymomas from 103 consecutive patients, Wolfsberger et al (96) demonstrated that extent of resection and MIB-1 LI were independent prognostic factors on multivariate analysis. They defined its median value of 20.5% as cutoff point, and showed low (<20.5%) or high ([greater than or equal to]20.5) MIB-1 LI predicted favorable ([greater than or equal to]5 years' survival) or unfavorable (<5 years) patient outcome at 79% and 70%, respectively.
We presented several new IHC markers for supporting and at times confirming the morphologic diagnosis of adult and pediatric brain tumors. These include OCT4 for germinoma, [alpha]-inhibin (inhibin A) and D2-40 for CHB, claudin-1 for meningioma, microtubule-associated protein 2 and neuronal nuclei for MDB, and INI1 for ATRT. Of particular importance is the differential diagnosis of CHB from metastatic CRCC because of completely different prognostic as well as therapeutic significance. We stressed the combined use of inhibin A (and D2-40) and epithelial markers (EMA, CAM 5.2, and CD10) for this distinction. INI1 is unique in its negative nuclear staining in ATRTs, and can be used in those cases having indeterminate histological features or in small biopsies that may not be representative of the morphological heterogeneity typical of ATRTs. Another new marker, PHH3, is a mitosis-specific marker, and enables us to provide a quick focus on the most mitotically active areas within the tumor and to facilitate rapid, reliable grading in meningiomas. In astrocytomas, this antibody can be of particular help to differentiate between grade 2 and 3 tumors, compared with MIB-1/Ki-67. With this particular marker, mitotic index will be further investigated in the neoplasms, for which proliferation potential is of relevance to tumor grading and prognosis. We also showed the current data on MIB-1/Ki-67 LI in prognosis in meningioma, astrocytoma, and ependymoma.
From a practical point of view, an accurate diagnosis of brain tumors is usually possible after careful assessment of routine microscopic features with sufficient clinical and radiological information. Although conventional H&E staining is a mainstay for pathologic diagnosis, IHC has played a major role in differential diagnosis and in improving the diagnostic accuracy in neuro-oncologic pathology. The judicious use of a panel of IHC, whose selection was based on the differential diagnosis rendered after the initial assessment, is unquestionably helpful in diagnostically challenging cases. In addition, IHC is also reportedly of great help to grade and to predict the prognosis in certain brain tumors.
(1.) Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B. An acidic protein isolated form fibrous astrocytes. Brain Res. 1971;28:351-354.
(2.) Kleihues P, Kiessling M, Janzer RC. Morphological markers in neuro-oncology. Curr Top Pathol. 1987;77:307-338.
(3.) Hattab EM, Tu PH, Wilson JD, Cheng L. OCT4 immunohistochemistry is superior to placental alkaline phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol. 2005;29:368-371.
(4.) Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol. 2003;27:1152-1156.
(5.) Jung SM, Kuo TT. Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central nervous system from metastatic clear renal cell carcinoma. Mod Pathol. 2005;18:788-794.
(6.) Roy S, Chu A, Trojanowski JQ, Zhang PJ. D2-40, a novel monoclonal antibody against the M2A antigen as a marker to distinguish hemangioblastomas from renal cell carcinomas. Acta Neuropathol. 2005;109:497-502.
(7.) Ribalta T, McCutcheon IE, Aldape KD, Bruner JM, Fuller GN. The mitosis-specific antibody anti-phosphohistone-H3 (PHH3) facilitates rapid reliable grading of meningiomas according to WHO 2000 criteria. Am J Surg Pathol. 2004; 28:1532-1536.
(8.) Bhattacharjee MB, Adesina AM, Goodman JC, Powell SZ. Claudin-1 expression in meningiomas and schwannomas: possible role in differential diagnosis [abstract]. J Neuropathol Exp Neurol. 2003;62:581.
(9.) Hahn HP, Bundock EA, Hornick JL. Immunohistochemical staining for claudin-1 can help distinguish meningiomas from histologic mimics. Am J Clin Pathol. 2006;125:203-208.
(10.) Judkins AR, Mauger J, Rorke LB, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol. 2004;28:644-650.
(11.) McLendon RE, Tien RD. Tumors and tumor-like lesions of maldevelopmental origin. In: Bigner DD, McLendon RE, Bruner JM, eds. Russell and Rubinstein's Pathology of Tumors of the Nervous System. 6th ed. London, England: Arnold; 1998:304-312.
(12.) Rosenblum MK, Matsutani M, van Meir EG. CNS germ cell tumours. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:208-210. World Health Organization Classification of Tumours.
(13.) Millan JL, Fishman WH. Biology of human alkaline phosphatases with special reference to cancer. Crit Rev Clin Lab Sci. 1995;32:1-39.
(14.) Kraichoke S, Cosgrove M, Chandrasoma PT. Granulomatous inflammation in pineal germinoma: a cause of diagnostic failure at stereotactic brain biopsy. Am J Surg Pathol. 1988;12:655-660.
(15.) Leroy X, Augusto D, Leteurtre E, Gosselin B. CD30 and CD117 (c-kit) used in combination are useful for distinguishing embryonal carcinoma from seminoma. J Histochem Cytochem. 2002;50:283-285.
(16.) Tian Q, Frierson HF Jr, Krystal GW, Moskaluk CA. Activating c-kit gene mutations in human germ cell tumors. Am J Pathol. 1999;154:1643-1647.
(17.) Takeshima H, Kaji M, Uchida H, Hirano H, Kuratsu J. Expression and distribution of c-kit receptor and its ligand in human CNS germ cell tumors: a useful histological marker for the diagnosis of germinoma. Brain Tumor Pathol. 2004;21:13-16.
(18.) Sakuma Y, Sakurai S, Oguni S, Satoh M, Hironaka M, Saito K. c-kit gene mutations in intracranial germinomas. Cancer Sci. 2004;95:716-720.
(19.) Hansis C, Grifo JA, Krey LC. Oct-4 expression in inner cell mass in·ner cell mass
The mass at the embryonic pole of the blastocyst concerned with the formation of the body of the embryo. and trophectoderm troph·ec·to·derm
The cell layer from which the trophoblast differentiates.
the earliest trophoblast. of human blastocysts. Mol Hum Reprod. 2000;6:999-1004.
(20.) Rosner MH,Vigano MA, Ozato K, et al. A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature. 1990;345: 686-692.
(21.) Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H. A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell. 1990;60:461-472.
(22.) Scholer HR, Dressler GR, Balling R, Rohdewohld H, Gruss P. Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J. 1990;9:2185-2195.
(23.) Nichols J, Zevnik B, Anastassiadis K, et al. Formation of pluripotent plu·rip·o·tent or plu·ri·po·ten·tial
1. Capable of affecting more than one organ or tissue.
2. Not fixed as to potential development. Used of an embryonic cell. stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95:379-391.
(24.) Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation dedifferentiation /de·dif·fer·en·ti·a·tion/ (de-dif?er-en?she-a´shun) anaplasia.
Regression of a specialized cell or tissue to a simpler unspecialized form. or self-renewal of ES cells. Nat Genet. 2000;24: 372-376.
(25.) Cheng L, Thomas A, Roth LM, Zheng W, Michael H, Karim FW. OCT4, a novel biomarker for dysgerminoma of the ovary. Am J Surg Pathol. 2004;28:1341-1346.
(26.) Jones TD, Ulbright TM, Eble JN, Baldridge LA, Cheng L. OCT staining in testicular tumors, a sensitive and specific marker for seminoma and embryonal carcinoma. Am J Surg Pathol. 2004;28:935-940.
(27.) Bohling T, Plate KH, Haltia MJ, Alitalo K, Neumann HPH.Von Hippel-Lindau disease von Hip·pel-Lindau disease or von Hippel-Lindau syndrome
See Lindau's disease.
von Hippel-Lindau disease and capillary haemangioblastoma. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:223-226. World Health Organization Classification of Tumours.
(28.) Taraszewska A, Bogucki J. A case of cystic form of angiomatous meningioma with prominent microvascular pattern mimicking haemangioblastoma. Folia fo·li·a
Plural of folium. Neuropathol. 2001;39:119-123.
(29.) Hamazaki S, Nakashima H, Matsumoto K, Taguchi K, Okada S. Metastasis of renal cell carcinoma to central nervous system hemangioblastoma in two patients with von Hippel-Lindau disease. Pathol Int. 2001;51:948-953.
(30.) Mottolese C, Stan H, Giordano F, Frappaz D, Alexei D, Streichenberger N. Metastasis of clear cell renal cell carcinoma to cerebellar hemangioblastoma in von Hippel Lindau disease: rare or not investigated? Acta Neurochir (Wien). 2001;143:1059-1063.
(31.) Abou-Hamden A, Koszyca B, Carney PG, Sandhu N, Blumbergs PC. Metastasis of renal cell carcinoma to haemangioblastoma of the spinal cord in von Hippel-Lindau disease: case report and review of the literature. Pathology. 2003; 35:224-227.
(32.) Schoggl A, Kitz K, Ertl A, Dieckmann K, Saringer W, Koos WT. Gammaknife radiosurgery for brain metastases of renal cell carcinoma: results in 23 patients. Acta Neurochir (Wien). 1998;140:549-555.
(33.) Grignon DJ, Eble JN, Bonsib SM, Moch H. Clear cell renal cell carcinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, eds. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004:23-25. World Health Organization Classification of Tumours.
(34.) Bruner JM, Tien RD, McLendon RE. Tumors of vascular origin. In: Bigner DD, McLendon RE, Bruner JM, eds. Russell and Rubinstein's Pathology of Tumors of the Nervous System. 6th ed. London, England: Arnold; 1998:239-293.
(35.) Los M, Jansen GH, Kaelin WG, Lips CJ, Blijham GH, Voest EE. Expression pattern of the von Hippel-Lindau protein in human tissue. Lab Invest. 1996;75: 231-238.
(36.) Murakata LA, Ishak KG, Nzeako UC. Clear cell carcinoma of the liver: a comparative immunohistochemical study with renal clear cell carcinoma. Mod Pathol. 2000;13:874-881.
(37.) Sim SJ, Ro JY, Ordonez NG, Park YW, Kee KH, Ayala AG. Metastatic clear cell renal cell carcinoma to the bladder: a clinicopathologic and immunohistochemical study. Mod Pathol. 1999;12:351-355.
(38.) Anderson RA, Cambray N, Hartley PS, McNeilly AS. Expression and localization of inhibin alpha, inhibin/activin betaA and betaB and the activin activin /ac·ti·vin/ (ak´ti-vin) a nonsteroidal regulator synthesized in the pituitary glands and gonads that stimulates the secretion of follicle-stimulating hormone.
n. type II and inhibin beta-glycan receptors in the developing human testis testis (tĕs`tĭs) or testicle (tĕs`tĭkəl), one of a pair of glands that produce the male reproductive cells, or sperm. . Reproduction. 2002;123:779-788.
(39.) Fetsch PA, Powers CN, Zakowski MF, Abati A. Anti-alpha-inhibin: marker of choice marker of choice A lab parameter used to evaluate disease response to therapy and monitor for recurrence; MOCs include RNA for progression of HIV infection and CEA for colorectal cancer for the consistent distinction between adrenocortical carcinoma and renal cell carcinoma in fine-needle aspiration. Cancer. 1999;87:168-172.
(40.) Choi YL, Kim HS, Ahn G. Immunoexpression of inhibin alpha subunit, inhibin/activin beta A subunit and CD99 in ovarian tumors. Arch Pathol Lab Med. 2000;124:563-569.
(41.) Bailey D, Baumal R, Law J, et al. Production of a monoclonal antibody specific for seminomas and dysgerminomas. Proc Natl Acad Sci U S A. 1986;83: 5291-5295.
(42.) Kahn HJ, Marks A. A new monoclonal antibody, D2-40, for detection of lymphatic invasion in primary tumors. Lab Invest. 2002;82:1255-1257.
(43.) Galambos C, Nodit L. Identification of lymphatic endothelium in pediatric vascular tumors and malformation malformation /mal·for·ma·tion/ (-for-ma´shun)
1. a type of anomaly.
2. a morphologic defect of an organ or larger region of the body, resulting from an intrinsically abnormal developmental process. . Pediatr Dev Pathol. 2005;8:181-189.
(44.) Chu AY, Litzky LA, Pasha TL, Acs G, Zhang PJ. Utility of D2-40, a novel mesothelial mesothelial
pertaining to the mesothelium.
cover all serous membranes and normally found in fluid samples aspirated from the pleural or peritoneal cavities. marker, in the diagnosis of malignant mesothelioma. Mod Pathol. 2005;18:105-110.
(45.) Ordonez NG. D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid epithelioid /ep·i·the·li·oid/ (-the´le-oid) resembling epithelium.
Of or resembling epithelium.
resembling epithelium. malignant mesothelioma. Hum Pathol. 2005;36:372-380.
(46.) Abe M, Tabuchi K, Tanaka S, et al. Capillary hemangioma of the central nervous system. J Neurosurg. 2004;101:73-81.
(47.) Roncaroli F, Scheithauer BW, Krauss WE. Capillary hemangioma of the spinal cord: reports of four cases. J Neurosurg. 2000;93:148-151.
(48.) Nowak DA, Widenka DC. Spinal intradural capillary hemangioma: a review. Eur Spine J. 2001;10:464-472.
(49.) Bozkus H, Tanriverdi T, Kizilkilic, Tureci E, Oz B, Hanci M. Capillary haemangiomas of the spinal cord: report of two cases. Minim Invasive Neurosurg. 2003;46:41-46.
(50.) Abe M, Misago N, Tanaka S, Masuoka J, Tabuchi K. Capillary hemangioma of the central nervous system: a comparative study with lobular capillary hemangioma of the skin. Acta Neuropathol. 2005;109:151-158.
(51.) Simon SL, Moonis G, Judkins AR, et al. Intracranial capillary hemangioma: case report and review of the literature. Surg Neurol. 2005;64:154-159.
(52.) Tibbs RE Jr, Harkey HL, Raila FA. Hemangioblastoma of the filum terminale: case report. Neurosurgery. 1999;44:221-223.
(53.) Louis DN, Scheithauer BW, Budka H, von Deimling A, Kepes JJ. Meningiomas. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:176-184. World Health Organization Classification of Tumours.
(54.) Hendzel MJ, Nishioka WK, Raymond Y, Allis CD, Bazett-Jones DP, Th'ng JP. Chromatin condensation is not associated with apoptosis. J Biol Chem. 1998; 273:24470-24478.
(55.) Gurley LR, D'Anna JA, Barhan SS, Deaven LL, Tobey RA. Histone phosphorylation phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts. and chromatin structure during mitosis in Chinese hamster cells. Eur J Biochem. 1978;84:1-15.
(56.) Juan G, Traganos F, James WM, et al. Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis. Cytometry. 1998;32:71-77.
(57.) Amatya VJ, Takeshima Y, Sugiyama K, et al. Immunohistochemical study of Ki-67 (MIB-1), p53 protein, p21WAF1, and p27KIP1 expression in benign, atypical, and anaplastic meningiomas. Hum Pathol. 2001;32:970-975.
(58.) Nakasu S, Li DH, Okabe H, Nakajima M, Matsuda M. Significance of MIB-1 staining indices in meningiomas: comparison of two counting methods. Am J Surg Pathol. 2001;25:472-478.
(59.) Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. The prognostic significance of MIB-1, p53, and DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. flow cytometry in completely resected primary meningiomas. Cancer. 1998;82:2262-2269.
(60.) Matsuno A, Fujimaki T, Sasaki T, et al. Clinical and histopathological analysis of proliferative potentials of recurrent and non-recurrent meningiomas. Acta Neuropathol. 1996;91:504-510.
(61.) Ho DMT See DSL. , Hsu CY, Ting LT, Chiang H. Histopathology his·to·pa·thol·o·gy
The science concerned with the cytologic and histologic structure of abnormal or diseased tissue.
The study of diseased tissues at a minute (microscopic) level. and MIB-1 labeling index predicted recurrence of meningiomas: a proposal of diagnostic criteria for patients with atypical meningioma. Cancer. 2002;94:1538-1547.
(62.) Winek RR, Scheithauer BW, Wick MR. Meningioma, meningeal me·nin·ge·al
Of, relating to, or affecting the meninges.
pertaining to the meninges.
meningeal hemorrhage hemangiopericytoma (angioblastic meningioma), peripheral hemangiopericytoma, and acoustic schwannoma: a comparative immunohistochemical study. Am J Surg Pathol. 1989;13:251-261.
(63.) Folpe AL, Binnings SD, McKenney JK, Walsh SV, Nusrat A, Weiss SW. Expression of claudin-1, a recently described tight junction-associated protein, distinguishes soft tissue perineurioma from potential mimics. Am J Surg Pathol. 2002;26:1620-1626.
(64.) Cavenee WK, Furnari FB, Nagane M, et al. Diffusely infiltrating astrocytomas. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:10-21. World Health Organization Classification of Tumours.
(65.) Torp SH. Diagnostic and prognostic role of Ki67 immunostaining in human astrocytomas using four different antibodies. Clin Neuropathol. 2002;21:252-257.
(66.) Scott IS, Morris LS, Rushbrook SM, et al. Immunohistochemical estimation of cell cycle entry and phase distribution in astrocytomas: applications in diagnostic neuropathology. Neuropathol Appl Neurobiol. 2005;31:455-466.
(67.) Colman H, Giannini C, Huang L, et al. Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol. 2006;30:657-664.
(68.) Prayson RA. The utility of MIB-1/Ki-67 immunostaining in the evaluation of central nervous system neoplasms. Adv Anat Pathol. 2005;12:144-148.
(69.) Haffner R, Oren M. Biochemical and biological effects of p53. Curr Opin Genet Dev. 1995;5:84-90.
(70.) Levine AJ. The p53 tumor suppressor gene and product. Cancer Surv. 1992; 12:59-80.
(71.) Linden MD, Nathanson SD, Zarbo RJ. Evaluation of anti-p53 antibody staining immunoreactivity in benign tumors and nonneoplastic tissues. Appl Immunohistochem. 1995;3:232-238.
(72.) Haupt Y, Maya R, Kazaz A, Oren M. Mdm-2 promotes the rapid degradation of p53. Nature. 1997;387:296-299.
(73.) Hall PA, McKee PH, Menage HD, Dover R, Lane DP. High levels of p53 protein in UV-irradiated normal human skin. Oncogene. 1993;8:203-207.
(74.) Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB. Wild-type p53 is a cell cycle checkpoint Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. determinant following irradiation. Proc Natl Acad Sci U S A. 1992;89:7491-7495.
(75.) Yaziji H, Massarani-Wafai R, Gujrati M, Kuhns JG, Martin AW, Parker JC Jr. Role of p53 immunohistochemistry in differentiating reactive gliosis from malignant astrocytic lesions. Am J Surg Pathol. 1996;20:1086-1090.
(76.) Kurtkaya-Yapicier O, Scheithauer BW, Hebrink D, James CD. p53 in nonneoplastic central nervous system lesions: an immunohistochemical and genetic sequencing study. Neurosurgery. 2002;51:1246-1254.
(77.) Central Brain Tumor Registry of the United States (CBTRUS CBTRUS Central Brain Tumor Registry of the United States (Chicago, IL) ). 2005-2006 statistical report tables. Available at: http://www.cbtrus.org/2005-2006/2005-2006.html. Accessed May 13, 2006.
(78.) Giangaspero F, Bigner SH, Kleihues P, Pietsch T, Trojanowski JQ. Medulloblastoma. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:129-137. World Health Organization Classification of Tumours.
(79.) Brown HG, Kepner JL, Perlman EJ, et al. "Large cell/anaplastic" medulloblastomas: a Pediatric Oncology Group The Pediatric Oncology Group (POG) was a U.S. and Canadian clinical trial cooperative group created with the mission of studying childhood cancers. It was formed by the merger of the pediatric divisions of two other cooperative groups, the Southwest Oncology Group (SWOG) and the Study. J Neuropathol Exp Neurol. 2000; 59:857-865.
(80.) Gould VE, Rorke LB, Jansson DS, et al. Primitive neuroectodermal tumors of the central nervous system express neuroendocrine markers and may express all classes of intermediate filaments. Hum Pathol. 1990;21:245-252.
(81.) Gould VE, Lee I, Wiedenmann B, Moll R, Chejfec G, Franke WW. Synaptophysin: a novel marker for neurons, certain neuroendocrine cells, and their neoplasms. Hum Pathol. 1986;17:979-983.
(82.) Maraziotis T, Perentes E, Karamitopoulou E, et al. Neuron-associated class III beta-tubulin isotype i·so·type
An antigenic marker that occurs in all members of a subclass of an immunoglobulin class.
i , retinal S-antigen, synaptophysin, and glial fibrillary acidic protein in human medulloblastomas: a clinicopathological analysis of 36 cases. Acta Neuropathol (Berl). 1992;84:355-363.
(83.) Burger PC, Grahmann FC, Bliestle A, Kleihues P. Differentiation in the medulloblastoma: a histological and immunohistochemical study. Acta Neuropathol (Berl). 1987;73:115-123.
(84.) Wolf HK, Buslei R, Schmidt-Kastner R, et al. NeuN: a useful neuronal marker for diagnostic histopathology. J Histochem Cytochem. 1996;44:1167-1171.
(85.) Janss AJ, Yachnis AT, Silber JH, et al. Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors. Ann Neurol. 1996; 39:481-489.
(86.) Burger PC, Yu IT, Tihan T, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol. 1998;22:1083-1092.
(87.) Bhattacharjee MB, Hicks J, Dauser R, et al. Primary malignant rhabdoid tumor of the central nervous system. Ultrastruct Pathol. 1997;21:361-368.
(88.) Bhattacharjee MB, Hicks J, Langford L, et al. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. Ultrastruct Pathol. 1997; 21:369-378.
(89.) Rorke LB, Biegel JA. Atypical teratoid/rhabdoid tumour. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:145-148. World Health Organization Classification of Tumours.
(90.) Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/ rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996;85:56-65.
(91.) Loda M, Xu X, Pession A, Vortmeyer A, Giangaspero F. Membranous expression of glucose transporter-1 protein (GLUT-1) in embryonal neoplasms of the central nervous system. Neuropathol Appl Neurobiol. 2000;26:91-97.
(92.) Wiestler OD, Schiffer D, Coons SW, Prayson RA, Rosenblum MK. Ependymoma. In: Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous System. Lyon, France: IARC Press; 2000:72-80. World Health Organization Classification of Tumours.
(93.) Ikezaki K, Matsushima T, Inoue T, Yokoyama N, Kaneko Y, Fukui M. Correlation of microanatomical localization with postoperative survival in posterior fossa ependymomas. Neurosurgery. 1993;32:38-44.
(94.) Uematsu Y, Rojas-Corona RR, Llena JF, Hirano A. Distribution of epithelial membrane antigen in normal and neoplastic human ependyma. Acta Neuropathol (Berl). 1989;78:325-328.
(95.) Prayson RA. Clinicopathologic study of 61 patients with ependymoma including MIB-1 immunohistochemistry. Ann Diagn Pathol. 1999;3:11-18.
(96.) Wolfsberger S, Fischer I, Hoftberger R, et al. Ki-67 immunolabeling index is an accurate predictor of outcome in patients with intraspinal ependymoma. Am J Surg Pathol. 2004;28:914-920.
Accepted for publication July 7, 2006.
Hidehiro Takei, MD; Meenakshi B. Bhattacharjee, MD; Andreana Rivera, MD; Yeongju Dancer, MD; Suzanne Z. Powell, MD
From the Department of Pathology, Baylor College of Medicine Baylor College of Medicine is a private medical school located in Houston, Texas, USA on the grounds of the Texas Medical Center. It has been consistently rated the top medical school in Texas and among the best in the United States. , Houston, Tex (Drs Takei, Bhattacharjee, and Rivera); and the Department of Pathology, The Methodist Hospital, Houston, Tex (Drs Dancer and Powell).
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Hidehiro Takei, MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Suite 286A, Houston, TX 77030-3498 (e-mail: firstname.lastname@example.org).