Home | Main | Meningiomas | Neurosurgical Encyclopaedia| Video Gallery | Contact
 
 
 
 
 
 
 neurosurgery.co
 e-neurosurgery.com
 humanneurophysiology.com
 neurosurgery.tv
 neurooncology.ws
 acousticschwannoma.com
 pituitaryadenomas.com
 pinealomas.com
 glioma.ws
 vascularneurosurgery.com
 e-neuroradiology.com
 mesencephalon.org
 brainstem.cc
 spinesurgeries.org
 spondylolisthesis.info
 paraplegia.co
 munir.ws
e-neurosurgery.com
 
 

 
TABLE-1 World Health Organization (WHO) Classification of Tumors of the Meninges (1993)

I. Tumors of Meningothelial Cells
A. Meningioma
1. Meningothelial
2. Fibrous (fibroblastic)
3. Transitional (mixed)
4. Psammomatous
5. Angiomatous
6. Microcystic
7.Secretory 
8. Clear cell
9. Chordoid
10. Lymphoplasmacyte-rich
11. Metaplastic
B. Atypical meningioma
C. Papillary meningioma
D. Anaplastic (malignant) meningioma

II Mesenchymal, Non-Meningothelial Tumors
A. Benign neoplasms
1. Osteocartilaginous tumors
2. Lipoma
3. Fibrous histiocytoma
4. Others
B. Malignant neoplasms
1. Hemangiopericytoma
2. Chondrosarcoma
       Variant: mesenchymal chondrosarcoma
3. Malignant fibrous histiocytoma
4.Rhabdomyosarcoma
5. Meningeal sarcomatosis
6. Others
C. Primary melanocytic lesions
1. Diffuse melanosis
2. Melanocytoma
3. Malignant melanoma
    Variant: meningeal    melanomatosis   
D. Tumors of uncertain histogenesis
1. Hemangioblastoma
(Capillary hemangioblastoma)

 

TABLE -2 Previous WHO Classification of Tumors of the Meninges (1979)

I. Meningiomas
A. Meningotheliomatous (endotheliomatous, syncytial, arachnotheliomatous)
B. Fibrous (fibroblastic)
C. Transitional (mixed
D. Psammomatous
E. Angiomatous
F. Hemangioblastic
G. Hemangiopericytic
H. Papillary
I. Anaplastic (malignant)
II. Meningeal Sarcomas
A. Fibrosarcoma
B. Polymorphic cell sarcoma
C. Primary meningeal sarcomatosis
III. Xanthomatous Tumors
A. Fibroxanthoma
B. Xanthosarcoma (malignant fibroxanthoma)
IV. Primary Melanotic Tumors
A. Melanoma
B. Meningeal melanomatosis
V. Others

TOPICS COVERED IN THIS SITE

Introduction
Surgical treatment in meningiomas.
Histological aspects in meningiomas.
Supratentorial meningiomas in general.
Parasagittal meningiomas.
Falx meningiomas.
Convexital meningiomas
Olfactory groove meningiomas.
Tuberculum sellae meningiomas.
Sphenoid wing meningiomas.
Optic sheath meningiomas.
Middle fossa meningiomas.
Cavernous sinus meningiomas.
Intraventricular meningiomas.
Malignant meningiomas.
Peritorcular meningiomas.
Tentorial meningiomas.
Infratentorial meningiomas.

 

 

In the 1993 World Health Organization (WHO) classification of tumors of the central nervous system. tumors of the meninges (Table 1) are divided into two major groups: (1) tumors arising from meningothelial (or arachnoid cap) cells. which are called meningiomas. and (2) tumors arising from mesenchymal. non­meningothelial cells. which are classified using criteria for soft tissue tumors. such as those outlined in the textbook by Enzinger and Weiss. Here focus directed on meningiomas and will discuss significant revisions in the 1993 WHO classification from the previous 1979 classification system (Table 2).
Several notable changes are incorporated into the 1993 classification. First, the list of recognized histologic variants of meningioma has been expanded. further emphasizing the well-known capability of meningothelial cells to express both mesenchymal and epithelial characteristics. New subtypes include microcystic, secretory. clear cell (glycogen-rich). chordoid. Iymphoplasmacyte-rich, and metaplastic. Meningothelial (syncytial), fibrous (fibroblastic), transitional (mixed). psammomatous, and angiomatous types are retained from the 1979 classification. The papillary type has been moved into its own separate category in acknowledgment of its aggressive behaviour.
Second, the term angioblastic has been eliminated in the 1993 classification. The designation of a meningioma as angiomatous or angioblastic has been a source of controversy and confusion in past (vide infra). The term angiomatous refers to a highly vascular meningioma. Angioblastic meningioma of the Hemangiopericytic type or Hemangiopericytic meningioma is now called hemangiopericytoma to reflect growth in understanding that this tumor shows greater similarity to soft tissue hemangiopericytoma than meningioma. Angioblastic meningioma of the hemangioblastic type or hemangioblastic meningioma is now classified as hemangioblastoma, a tumor of uncertain histogenesis. along with its cerebellar counterpart which it resembles.
Third. the 1993 classification recognizes three forms of meningioma that were included to reflect three levels of biological behaviour: benign. atypical. and anaplastic (malignant).


Histologic Subtypes of Meningiomas

Meningothelial, transitional, and psammomatous meningiomas usually present no diagnostic difficulty because these tumors exhibit features of non-neoplastic arachnoid cap cells, particularly the tendency to form whorls. The nuclei of many meningiomas (especially the meningothelial types) show intranuclear vacuoles of two types. One type is formed by invagination of cytoplasm into the nucleus, the other by clearing of chromatin material from the center of the nucleus. The latter type is more common and is of diagnostic help.

The ultrastructural features of the meningothelial cell are reflected in the tumor cells of meningiomas. The most important of these are (I) formation of complex and intertwining cell processes, (2) formation of variable numbers of intercellular junctional complexes, especially desmosomes, and (3) presence of numerous fine fibrils in the cytoplasm of these cells. The nuclei of some tumor cells may show invagination of cytoplasm. A nucleolus is often recognized. Usual cell organelles like mitochondria, as well as rough-surfaced endoplasmic reticulum, are found between the cytoplasmic filaments. An electron­dense granular material is often found between some of the tumor cells. Unusually the meningothelial tumor cells may show formation of basal bodies and cilia.

The other subtypes of meningioma may be more difficult to recognize as meningioma on first glance by light microscopy. Fortunately, more often than not histologic patterns are mixed so that foci that are clearly meningothelial or transitional are present in a tumor that may otherwise look more epithelial or mesenchymal or hematopoietic. Some meningiomas contain bloated cells with well-defined cytoplasmic borders, mimicking gemistocytic astrocytes. Some meningiomas (focally at least) may mimic the "fried egg" pattern of 0ligodendrogliomas. If doubt still remains after careful examination with the light microscope, the meningothelial nature of the tumor will be revealed by performing electron microscopy and demonstrating the characteristic ultrastructural features noted above. In view of the histologic diversity of meningiomas. it is imperative that the requisition for frozen-section diagnosis be accompanied by information about the patient's age. the characteristics of the tumor on imaging studies. the exact location of the tumor. i.e. whether intra-axial or extra-axial. and the structures invaded by it. In addition. specimens obtained with the CUSA system show crushing of cells mimicking necrosis. This form of pseudonecrosis does not have the grave implication of true necrosis seen in malignant meningiomas. Additional information and photomicrographs of tumors not illustrated here may be found in the WHO manual, the article by uniform cells with round or oval nuclei, ample light pink cytoplasm, and indistinct cytoplasmic borders. It is that indistinctness of the cytoplasmic borders, which is due to interdigitations between adjacent cell membranes as noted above in the description of ultrastructural features of meningothelial cells, that gave rise to the term syncytial. Slight to moderate tendency to whorling of the cells may be observed in these tumors.

Meningothelial (Syncytial) Meningioma

The meningothelial (also called syncytial or endothelial) type is characterized by broad sheets or medium-size lobules of fairly uniform cells with round or oval nuclei, ample light pink cytoplasm, and indistinct cytoplasmic borders . It is that indistinctness of the cytoplasmic borders, which is due to interdigitations between adjacent cell membranes as noted above in the description of ultrastructural features of meningothelial cells, that gave rise to the term syncytial. Slight to moderate tendency to whorling of the cells may be observed in these tumors.

Fibrous (Fibroblastic) Meningioma

Another frequent type of meningioma is called the fibroblastic meningioma because the cells mimic fibroblasts in appearance  and also form true reticulin and collagen fibrils. The cells of the fibroblastic meningioma are usually arranged in fascicles crossing other fascicles. The amount of reticulin and collagen fibers formed varies from one place to another. Reticulin fibers are often easily seen with special stains. The pink collagen bundles seen in hematoxylin-eosin stained sections vary from place to place.

Transitional (Mixed) Meningioma

Whorling is more common in transitional meningioma. The cells in this type are more elongated and separated from one another and thus appear less syncytial. Bundles of several cells sweep in different directions. and a few elongated fascicles can also be seen. The most important feature of this type of meningioma is the propensity of the cells to form small whorls by partly encircling other cells: this whorl formation is an important feature for intraoperative diagnosis of these tumors. The number of whorls formed varies from tumor to tumor and from one place to another in the same tumor. Some whorling is also observed around small blood vessels. but most whorls contain tumor cells in the center. When a whorl in a meningioma undergoes degeneration of the cells in the middle followed by calcium deposition, a rounded, partly or totally calcified structure called the psammoma body is formed.

Psammomatous Meningioma

The number of psammoma bodies in a meningioma varies from nil to tumors wholly composed of these bodies with a few cells in between the psammomatous meningiomas. These are basically a variant of transitional meningiomas. The presence of psammoma bodies in abundance indicates slow growth and good prognosis. Psammomatous meningiomas are more common in the spinal canal, orbit, and olfactory groove than elsewhere in the nervous system.

Angiomatous Meningioma

The term angiomatous meningioma denotes a richly vascularized meningioma. The meningothelial component of the tumor may be difficult to discern amidst the vessels, which may be large or small. When the vessels are capillary size, the tumor may resemble a hemangioblastoma.

Microcystic Meningioma

This variant can be grossly cystic and display a wet glistening cut surface, but these features are not necessarily present. It has been referred to as humid meningioma in previous descriptions. Microscopically, the tumor has a loose, lace-like pattern due to the presence of extracellular fluid collections. The fluid may contain plasma proteins, and areas of fibrosis may be present. In particular, hyalinized blood vessels may be conspicuous. Whorls and psam­moma bodies may be present, but are not a prominent feature. The cells are stellate and have delicate processes. The cell nuclei are meningothelial, many with intranuclear inclusions, and may show hyperchromatism and pleomorphism, a feature that does not imply a worse prognosis in this setting.

Secretory Meningioma

The formation of glands and the presence of intraluminal and intracytoplasmic hyaline, periodic acid-Schiff (PAS)-positive inclusions are characteristic of secretory meningiomas. This variant clearly illustrates the ability of meningothelial cells to exhibit epithelial features, which is further confirmed by staining of the cells for cytokeratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). The inclusions may stain for CEA, EMA, secretory component of IgA, IgM, or alpha-I-antitrypsin. These inclusions have been called pseudopsammoma bodies. In addition to positive CEA immunoreactivity in the cells and inclusions, the patient may have elevated serum CEA values, which may confound differentiating this tumor from metastatic carcinoma. Proliferation of small dark cells, believed to be pericytes around blood vessels is also a feature of secretory meningiomas, and is not ordinarily seen in other variants. This pathologic change may be responsible for the severe edema that surrounds many secretory meningiomas.

Clear Cell (Glycogen-Rich) Meningioma

This tumor consists of sheets of polygonal cells with clear cytoplasm due to the accumulation of glycogen. Whorls are subtle or vague. Hyalinization of the stroma and perivascular regions may result in extensive areas of fibrosis in older tumors. These tumors show a proclivity for the cerebellopontine angle and cauda equina region. The histologic appearance and high glycogen content are very similar to those seen in renal cell carcinoma, with which clear cell meningioma may be confused.

Chordoid Meningioma

This rare variant derives its name from its histologic resemblance to chordoma. It has a lobar pattern and contains cells, occasionally vacuolated, surrounded by a myxoid matrix. Lymphoplasmacytic infiltrates may be pronounced and may include the formation of follicles with germinal centers. These cells are polyclonal, consistent with being reactive rather than neoplastic. The inflammatory infiltrate may extend into the adjacent brain, which could result in an erroneous diagnosis of encephalitis. Clinically, this tumor may be seen in children in whom it may be accompanied by a Castleman-like syndrome with anaemia and/or hypergammaglobulinemia being the most consistent features. In adults there may be few systemic problems. In patients with anaemia or hypergammaglobulinemia, these manifestations may reappear if the tumor recurs.

Lymphoplasmacyte-Rich Meningioma

The presence of a prominent polyclonal infiltrate of histologically benign lymphocytes and plasma cells characterizes this uncommon variant of meningioma. Germinal centers, Russell bodies, and amyloid deposits may also be present. The proportion of the tumor which is recognizable as meningothelial or transitional meningioma varies from case to case, and may be hard to detect. This tumor can occur at any age but more often has been described in children and young adults. It may be associated with a polyclonal hypergammaglobulinemia that remits after surgical resection of the tumor.

Metaplastic Meningioma

These are meningiomas, usually meningothelial, transitional, or fibroblastic, with osseous, cartilaginous, lipomatous, lipoblastic, xanthomatous, or myxomatous foci, thought to represent metaplastic transformation of arachnoidal cells to mesenchymal cells.

Papillary Meningioma

Fortunately, these tumors that tend to occur in children and young adults are uncommon. They are often large, invasive, and necrotic, and may be cystic. In addition to the papillary structures consisting of tapering cells with meningothelial nuclei radially arranged around fibrovascular cores, malignant histologic features are invariably present, such as hypercellularity, numerous mitotic figures, and necrosis. The papillary pattern is not always predominant, and in some instances it is more obvious in recurrences or metastases than in the original tumor. Sites of metastasis include the lung (most common), mediastinal lymph nodes, liver, kidneys, pancreas, adrenal glands, femur, and peritoneum, sites where metastatic meningiomas of any type are usually found. The high rates of recurrence (55 percent), extraneural metastasis (20 percent), and tumor-related death (50 percent) warrant the classification of this variant as malignant.

The extent to which a meningioma is resectable because of its topography, invasiveness, or multifocality is a critical determinant in its likelihood of recurrence. Although the majority of meningiomas can be totally excised, do not recur, and thus are clinically benign, the correlation between the clinical behaviour and the histologic appearance of a meningioma in an individual patient is not precise, because a histologically benign tumor may recur following apparent gross total resection. However, when series of cases are studied there seem to be three tiers of clinical behaviour that correspond to benign, intermediate, and malignant histologic findings. The intermediate histologic grade is called atypical. (The WHO histologic grading system with designated grades I-IV, which is widely used, particularly in Europe, the relationship of those grades to other grading systems for brain tumors).

Atypical Meningioma

Histologic features associated with atypical meningioma, as listed in the 1993 WHO manual, include frequent mitoses, increased cellularity, high nuclear/cytoplasmic ratio, prominent nucleoli, sheetlike (rather than lobular) pattern of growth, and zones of necrosis. The problem is that there is no consensus on which or how many of these are necessary or sufficient for the diagnosis of atypical meningioma. Intermediate biological behaviour associated with atypical meningiomas using only increased cellularity and at least five mitotic figures per 10 high-power (400 X) fields are necessary criteria, a system that is simple and reproducible. Nuclear atypia alone is not enough to make the diagnosis of "atypical" meningioma, nor is invasion of dura or bone, although invasion of bone is more common in tumors that later recur than in those that do not. Atypical meningiomas can be of any histologic subtype, with the exception of papillary meningioma, and histologic subtype is not related to recurrence. Atypical changes may be focal, which emphasizes the importance of thorough sampling of a tumor for histologic examination.

Molecular Genetics of Meningioma

Abnormalities of chromosome 22, usually monosomy or partial deletions, are commonly found in meningiomas. Using restriction fragment length polymorphism (RFLP) analysis, most meningiomas show some loss of heterozygosity (LOH) for loci in the 22q. 3-qter region of the chromosome. This has been interpreted as evidence for the presence of a tumor suppressor gene that is inactivated in meningiomas. Loss of alleles on chromosome 22 correlates with histologic features predictive of recurrence (e.g., prominent nucleoli, mitoses, and nuclear pleomorphism). In astrocytomas, the acquisition of LOH on chromosome 10 is associated with progression in malignancy. LOH on chromosome 10 was found in 50% of atypical meningiomas and 30% malignant meningiomas but in none of benign meningiomas suggesting that a similar mechanism of tumor progression may apply to meningiomas. Abnormalities on chromosome 22 may also shed some light on the biology of meningiomas. The gene for neurofibromatosis (NF) type 2, a condition associated with an increased incidence of meningiomas, is near the meningioma locus. Although these two genes are most likely not identical, alterations in the NF-2 gene could affect expression of the meningioma gene. The c-sis protooncogene, which codes for the beta subunit of platelet-derived growth factor (PDGF), is also on chromosome 22. Meningiomas express both c-sis/PDGF proteins and PDGF receptors, raising the possibility that tumor growth may be controlled by autocrine cell stimulation, which may in turn be turned on by alterations in chromosome

Malignant Meningioma

The definition of malignancy is also vague: "histological features of frank malignancy far in excess of the abnormalities noted in atypical meningioma. These include obviously malignant cytology, a high mitotic index and conspicuous necrosis. Two additional features are noteworthy. Papillary meningiomas are considered malignant. Gross or deep cortical brain invasion is considered a sign of malignancy and is usually associated with other histologic features of malignancy. However, the significance of superficial cortical invasion or invasion into the Virchow-Robin spaces that does not breach the pia is less clear, as this may be seen in otherwise benign meningiomas. Brain invasion, when present, may not be represented in the tissue examined by the pathologist, a point that should be kept in mind by the surgeon when interpreting the pathologist's report.

Other Tests of Possible Value in Prognostication

Because of the relative imprecision of prognostications based on histologic findings alone, other techniques may yield clinically useful data. No one of these measures is an absolutely reliable predictor of outcome in an individual case; therefore, the results must be interpreted in light of the clinical history, imaging studies, intraoperative findings, and histologic diagnosis.

  Measures of DNA Ploidy and Cell Proliferation

Aneuploidy has been suggested to be related to aggressive clinical characteristics such as moderate to severe peritumoral edema and large tumor size, as well as atypical or malignant histologic features, a tendency to recur, and the occurrence of multiple tumors in some patients. However, many benign meningiomas are aneuploid, and likewise histologically malignant tumors may be diploid, causing some investigators to state that deoxyribonucleic acid (DNA) ploidy analysis adds no useful information over and above that obtained by knowing the histologic appearance and extent of resection of the tumor. Proliferative index (PI), obtained by calculating the percentage of cells in S phase plus G2/M phases on flow cytometry, is an indicator of increased probability of recurrence, especially if the PI is greater than 15 to 20 percent. Bromodeoxyuridine (BUdR), a thymidine analogue, can be used to assess the S phase in tumors by calculating the labeling index (LI), the percentage of cells counted with positive immunostaining for BUdR. The recurrence rates is 100 percent for LIs greater than or equal to 5 percent, 55.6 percent for LIs of 3 to 5 percent, and 30.6 percent for LIs of I to 3 percent; these groups contained 88, 78, and 19 percent histologically malignant tumors, respectively.44 Ki-67, a nuclear protein expressed during the G1, S, and G2 phases of the cell cycle, and proliferating cell nuclear antigen (PCNA), an auxiliary protein of DNA polymerase delta that is maximally expressed in early stages of histologic malignancy. The silver-staining nucleolar organizing region (AgNOR) technique is based on the fact that silver is taken up by nucleolar organizing region proteins. The number of nucleolar organizing regions in a nucleus is a reflection of the level of ribosomal ribonucleic acid (RNA) synthesis, and thus of protein synthesis and cell activity. In meningiomas, the number of AgNORs is related to histologic grade and recurrence, and correlates with BUdR LI. With the exception of flow cytometry, in which the cell counting is automated, all of these methods of assessing cell proliferation are labor intensive and tedious, and thus may not be available outside of academic centers.

Hormone Receptors

 

Epidemiologic features that suggest a role for sex hormones in the genesis or growth of meningiomas include the predilection of these tumors for women (although the peak age is past child-bearing years), the observation that these tumors can become symptomatic and enlarge during the second and third trimester of pregnancy with improvement postpartum (although some of these changes may be due to changes in edema), and nonrandom association of meningioma and breast cancer in some women. After the initial report of the presence of estrogen receptors in meningiomas in 1979, numerous other papers concerning the status of hormone receptors in meningioma have appeared. Although understanding the collective data derived from these studies is made difficult by differences in methodology and in interpretation of the signifi­cance of the results, the majority view is that progesterone recep­tors are present in most meningiomas, but estrogen receptor levels are variable and usually undetectable. Further studies demon­strated that hormones can modulate the growth of meningioma cells in vitro, but not always in a consistent or predictable manner. These data were taken as an encouraging sign that hormones could be used to treat meningiomas, especially tumors not amenable to total surgical excision. However, the results of clinical trials to date using estrogen antagonists (tamoxifen) and progesterone ago­nists (medroxyprogesterone acetate and megestrol acetate) have been disappointing. Recent reviews by Grunbergl5 and Schrell and Fahlbusch43 are recommended for more detailed information.

 

Mesenchymal, Nonmeningothelial Tumors

 

The incidence of mesenchymal, nonmeningothelial tumors arising in the central nervous system is very low but difficult to estimate accurately because of the prior use of a classification scheme for these tumors that bore little resemblance to that used for tumors arising in other organs or tissues, and because hemangiopericytomas were formerly classified as meningiomas and were thus not counted in this category. Hemangiopericytomas comprise I to 7 percent of meningeal tumors,20 which in turn comprise about 15 percent of intracranial tumors, thus yielding an estimated inci­dence for hemangiopericytoma of less than I percent of intracra­nial tumors. If hemangiopericytomas are excluded, primary intra­cranial sarcomas account for less than 0.1 percent of intracranial tumors,37 and before the diagnosis of primary intracranial sarcoma can be made, the more likely diagnoses of gliosarcoma and meta­static sarcoma must be excluded. Because they are so rare, the nonmeningothelial tumors will not be described here, with the ex­ception of hemangiopericytoma and hemangioblastoma; these two are included because of their historic relationship to meningiomas, having been classified formerly as variants of angioblastic menin­gioma. Information on other nonmeningothelial tumors can be ob­tained elsewhere.

Hemangiopericytoma

This tumor resembles its soft tissue counterpart on light and electron microscopic examination, in its pattern of immunoreactivity, and in its clinical behaviour in that it is more common in males (unlike meningioma) and behaves in a decidedly aggressive fashion with a much greater incidence of recurrence and extraneural metastasis than most meningiomas. These are the major reasons this tumor is no longer considered a meningioma. This decision for all practical purposes lays to rest a long controversy concerning the classification of this tumor.

The tumor is a solitary, solid, pink-tan, firm to rubbery mass with a smooth, lobulated but unencapsulated surface. It has promi­nent blood vessels and tends to bleed copiously when cut. Microscopically, it is highly cellular and composed of rather monoto­nous, plump, polygonal cells with oval nuclei and scant cytoplasm. Reticulin deposits may be dense, especially around blood vessels. Pale hypocellular zones may be seen as well as patchy areas of spindle cells and fibrosis. The solid cellular background is broken up by vascular spaces, classically called staghorn because of a characteristic shape the spaces may assume. Mitotic figures are usually present and may be numerous. Tight whorls and psammoma bodies are not typical in this tumor.

Hemangioblastoma

This tumor is also called capillary hemangioblastoma and is histologically identical to the tumor typically located in the cerebellum. Unlike meningioma, males are more often affected than females. Hemangioblastoma may occur as part of von Hippel-Lindau syndrome, although cerebral meningeal hemangioblastoma rarely have this association. The tumor often has a cystic component and is highly vascular.
Microscopically, the predominant cell is the stromal cell, which has a variable number of lipid-containing vacuoles and eosinophilic cytoplasm. The cells may be in clusters or oriented around the numerous capillaries. The nature of the stromal cell is poorly understood; hence, the classification of this tumor as one of uncertain histogenesis. Important clinical features of this tumor are its ability to produce erythropoietin, and its resemblance to renal cell carcinoma. This latter point is important because renal cell carcinoma is a part of von Hippel-Lindau syndrome and may be a source of brain metastases in that setting. Immunohistochemical studies, especially using epithelial membrane antigen (EMA) and antigens to cytokeratins, may help make the important distinction between metastatic carcinoma and hemangioblastoma, as the latter should be unreactive.

Back Home!

 
Home | Main | Meningiomas | Neurosurgical Encyclopaedia| Video Gallery | Contact