| Abstract|| |
The newest revision of the WHO classification of tumors of the central nervous system, also known as WHO 5th edition, introduces substantial changes, especially within the glial tumor category and separates adult-type and pediatric-type glial tumors into different categories for the first time. In addition, another category of glial tumors, “Circumscribed Astrocytic Gliomas” were also created. This group includes pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, astroblastoma, and the highly nebulous novel entity high-grade astrocytoma with piloid features. We present a brief and critical review of the pathological and molecular characteristics of these often well-demarcated tumors that can occur in adults as well as in the pediatric population.
Keywords: Astroblastoma, chordoid glioma, circumscribed glioma, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma
|How to cite this article:|
Köy Y, Tihan T. Circumscribed astrocytic gliomas: Contribution of molecular analyses to histopathology diagnosis in the WHO CNS5 classification. Indian J Pathol Microbiol 2022;65, Suppl S1:33-41
|How to cite this URL:|
Köy Y, Tihan T. Circumscribed astrocytic gliomas: Contribution of molecular analyses to histopathology diagnosis in the WHO CNS5 classification. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 May 28];65, Suppl S1:33-41. Available from: https://www.ijpmonline.org/text.asp?2022/65/5/33/345027
| Introduction|| |
Classification schemes are evolving efforts in an attempt to create some form of order in a natural world that often defies such attempts. Therefore, any classification is imperfect and primed for changes and modifications with advancing knowledge. The most recent attempt by a group of experts selected by the World Health Organization (WHO) for improving classification of central nervous system (CNS) tumors is such an effort. This classification attempt requires a much more comprehensive analysis of molecular features of CNS tumors and more elaborate assessment through genomics and methylomics, and therefore it falls short of creating a universally applicable and practical scheme that can be employed by all pathologists worldwide. This version of WHO CNS tumor classification will invariably divide the neuropathology world into “haves” and “have-nots,” particularly when some diagnoses only require advanced techniques available in a small minority of advanced medical centers. Yet, one can convincingly argue that this attempt is a significant improvement over the previous classification effort published in 2016.
One of the welcome improvements of this classification is regrouping of gliomas that distinguish pediatric from adult gliomas as well as diffuse from circumscribed astrocytomas or “astrocytic gliomas.” The choice of the term “astrocytic glioma” instead of “astrocytoma” probably stems from the fact that two neoplasms in the circumscribed category, astroblastoma and chordoid glioma, have more of an ependymal character and may not be purely astrocytic. Nevertheless, this group of tumors consist of entities (tumor types) with less aggressive behavior, well recognized morphological features and characteristics genetic alterations [Table 1]. There is one exception to this description in this group, high-grade astrocytoma with piloid features, which will not be discussed in this paper and probably does not belong in this category. In the following pages, we will summarize the salient clinicopathological features including pathological diagnostic criteria [Table 2] for these well-defined astrocytomas/astrocytic gliomas.
|Table 2: Essential and desirable diagnostic criteria for circumscribed astrocytic gliomas WHO 5th edition|
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Pilocytic astrocytoma and its subtype pilomxyoid astrocytoma
Pilocytic astrocytoma (PA) is one of the most common gliomas in children and young adults. The overwhelming majority of PAs are indolent with long overall survival probability and often cure, especially with gross total resection. The genetic signature of PA is well characterized, and understanding of some molecular alterations allowed explanation of unusual behavior of some examples. Such unusual behaviors include oncogene-induced senescence and associated spontaneous regression, unpredictable radiotherapy response, anaplastic transformation, and cerebrospinal dissemination.,,, Despite this progress, there are still challenges in our understanding of these indolent neoplasms.
PA can occur anywhere within the CNS, and most often occur in the posterior fossa. In adults, there appears to be no significant difference in incidence between infra- and supratentorial locations. PAs can arise in association in neurofibromatosis type 1 (NF1), wherein they most commonly manifest as “optic glioma,” a nonspecific term that implies involvement of the optic nerve proper. Progression-free and overall survival probabilities are influenced by a number of factors including tumor location, extent of resection, and may also be modified by access to healthcare. Patients who undergo gross total resection of their tumors have excellent prognosis, while those with deeply situated lesions and receive subtotal resections may experience recurrence. Yet, even subtotally resected tumors may not progress over time.
An interesting but widely reported feature of PA is the propensity to undergo spontaneous regression. This phenomenon can be observed after subtotal resection and in the absence of any adjuvant treatment. The underlying biological mechanisms underpinning tumor regression may actually be associated with alteration in the mitogen-activated protein kinase (MAPK). Radiologically, PA is a typically a solid-cystic mass with an enhancing mural nodule, and often demonstrates calcifications. The solid component is usually iso-or hypointense to gray matter on T1-weighted images and hyperintense on T2-weighted images., Hypothalamic tumors are mostly solid, and the only recognized subtype of PA, pilomyxoid astrocytoma (PMA) typically occurs in this region.
PAs are noninfiltrating tumors with moderate cellularity and a variety of histological patterns. The cells often have bipolar processes within a rich fibrillary network. PAs typically contain Rosenthal fibers [Figure 1]a and [Figure 1]b. Some PAs may show oligodendroglioma-like features, which has been associated with FGFR1 alterations., PAs usually show a variable degree of infiltration into the adjacent brain parenchyma despite radiologic circumscription. PAs are often strongly and diffusely positive with GFAP, Vimentin, Olig-2, Sox-10, and S100 protein, and often diffusely and weakly positive with synaptophysin, which may be misleading.,,, Tumors do not harbor mutations associated with adult diffuse gliomas including IDH and TP53 mutations. Immunostaining for BRAF V600E-mutant protein may be positive in a rare tumor, but more often this antibody elicits no staining. There is still much controversy on the histological designation of anaplastic PA and such a tumor is a rare occurrence. A significant proportion of tumors with anaplasia have occurred in the setting of prior radiation therapy even though anaplastic transformation is not always associated with a history of irradiation.,, Anaplastic PA has not been well-characterized and a WHO grade was not assigned to these tumors. PMA is the only recognized subtype of PA, and there is a strong possibility that the prevalence of PMA is overestimated. Histologically, PMA is quite distinct from PA, in that the tumor is homogenously myxoid, has a much more monomorphic appearance, and is characterized by a distinct angiocentric arrangement of tumor cells. There is virtually no difference between PA and PMA in terms of immunohistochemical staining.
|Figure 1: (a) Typical histological appearance of pilocytic astrocytoma with abundant Rosenthal fibers. While Rosenthal fibers within the tumor tissue is a critical histological feature, it has not been considered an essential criterion per se. Thus, diagnosis of pilocytic astrocytoma can be made without finding Rosenthal fibers (original magnification ×200). b) “Pennies-on-a-plate” sign originally described by late Dr. Bernd W. Scheithauer, implies clustered tumor nuclei that may, at times, give the impression of multinucleated giant cells (original magnification ×400). c) Typical pleomorphic xanthoastrocytoma with giant, bizarre cells with vacuolated nuclei and xanthomatous cells (original magnification X400). d) Typical gemistocyte-like cells of subependymal giant cell astrocytoma may be mistaken for a gemistocytic astrocytoma, a tumor that is considered within adult-type diffuse gliomas (original magnification ×400). e) Characteristic myxoid background and spindle cells of chordoid glioma (original magnification ×200). f) The “astroblastic” rosette was defined as perivascular arrangement of tumor cells that are often cuboidal and with a limited fibrillary phenotype, reminiscent but somewhat distinct from ependymal pseudorosettes (original magnification ×400)|
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Molecular and genetic characteristics
The association of PA with neurofibromatosis 1 (NF1) has been recognized for many years, and PA constitutes one of the most common types of gliomas in this patient population. PMAs have also been reported in some patients with NF1. The NF1 germline mutation is inherited in an autosomal dominant manner, but about half of all patients have a sporadic or de novo NF1 mutations. There has been limited information about the genetic and molecular characteristics of non-NF1 associated PA or PMA until a decade ago when several independent studies found that the majority of PAs demonstrated oncogenic tandem duplication at 7q34, resulting in a KIAA1549-BRAF fusion gene with constitutive activation of the MAPK pathway.,, KIAA1549-BRAF fusions are significantly more frequent in cerebellar tumors, compared to those arising at other sites. Multiple different exonic fusion combinations have been reported, all resulting in loss of autoregulatory N-terminal domain and activation of the oncogenic MAPK pathway. A number of other BRAF fusion partners are reported, including FAM131B, RNF130, CLCN6, MKRN1, GNA11, QKI, FXR1, and MACF1.,,, The second most common alteration in PAs is BRAF V600E mutation, which was found in about 10% of PAs and more often in extra-cerebellar tumors. Other alterations in the MAPK pathway include FGFR1 mutations, fusions/duplication, NTRK2 fusions, RAF1 fusions, KRAS mutations, and rarely PTPN11 mutation., These MAPK pathway alterations appear to be mutually exclusive. PMAs also harbor BRAF fusions and mutations and also other MAPK pathway alterations. Gene expression array studies have shown significant differences between PMA versus PA, where PMAs showed a higher expression of developmental genes H19, DACT2, extracellular matrix collagens (COL2A1; COL1A1), and IGF2BP3 (IMP3). Anaplastic examples of PA often harbor additional alteration such as CDKN2A/B deletion, ATRX protein loss, and H3K27M mutation., Other genetic alterations that appear to adversely affect prognosis in PA include whole chromosome 7 gain and loss of heterozygosity on 17p13, both of which were found to be associated with an increased risk of recurrence. It is critical to note that PA and PMA are mostly indolent tumors and may have a protracted clinical course as well as regression. DNA methylation profile has not been useful in PA or PMA.
We would like to mention a few words about the subtype PMA as well the anaplastic pilocytic astrocytoma categories. WHO working group accepts PMA as the only subtype due to sufficient differences between PMA and the main type, PA. However, the 5th edition of WHO classification does not create a separate section for PMA, and we have also kept the discussion of these tumors together. Likewise, anaplastic pilocytic astrocytoma was considered not to be a subtype, simply due to the limited evidence in the literature, and the task of defining the grade and nature of placing anaplastic pilocytic astrocytomas was left for the future WHO classification efforts. One clear line of evidence for anaplasia for pilocytic astrocytoma has been the presence of additional molecular alterations such as ATRX or H3K27M mutations or CDKN2A loss, as well as complex chromosomal copy number variations. Yet, specific criteria for such alterations to designate subtype and grade await further studies.
Extent of resection seems to be the most relevant prognostic factor for PA/PMA and this should be attempted as much as possible. Other clinical factors have also been suggested such as exophytic or invasive appearance radiologically but these have been variably reproducible. Molecular markers associated with aggressive growth have been reported in the context of “anaplastic” category.,,
Pleomorphic xanthoastrocytoma (PXA) is an astrocytoma with large pleomorphic (frequently multinucleated) cells, spindle cells, and lipidized cells, numerous eosinophilic granular bodies, reticulin deposition, and characteristically with BRAF V600E mutation (or other MAPK pathway gene alterations) and homozygous CDKN2A/B deletion. The majority of tumors occur supratentorially, and there is predilection to the temporal lobe. PXAs involving the cerebellum and spinal cord have been reported., PXA can be either WHO grade 2 or 3.
Many patients present with a long history of seizures. Cerebellar and spinal cord tumors have symptoms reflecting their location. While many tumors can be safely removed totally, in deep-seated lesions such as those in the brainstem gross total resection may not be achieved. Radiologically, PXA is cerebral, peripherally located and frequently cystic, often involving the leptomeninges. The tumor cysts are hypodense to gray matter on T1-weighted images. The solid portion of the tumor is either hypointense or isointense to gray matter on T1-weighted images and shows a hyperintense or mixed signal on T2- modalities.
The key diagnostic histopathological features of PXA are well established., PXAs are hypercellular tumors composed of pleomorphic cells with spindled morphology and abundant cytoplasm [Figure 1]c. The cells are often arranged in fascicles or in a storiform pattern imparting a mesenchymal appearance. Xanthomatous cells (“xanthoastrocytes”) with foamy cytoplasm are also diagnostically helpful, but are only encountered in about a quarter of the cases. Intranuclear inclusions and eosinophilic granular bodies are almost constant findings. Focal perivascular or intratumoral collections of lymphocytes and plasma cells are also frequent. One of the most characteristic features of PXAs is the deposition of reticulin around tumor cells, either diffusely or in a patchy fashion. Rare tumor cells contain pigment. Although cellular pleomorphism is a common feature of PXA, the absence of mitoses and necrosis helps their distinction from adult diffuse gliomas. PXA is typically noninfiltrative with only marginal incursions into the surrounding brain parenchyma. WHO grade 3 tumors have more anaplastic features and infiltrative patterns compared to WHO grade 2 tumors. In anaplastic examples, rhabdoid cells are particularly more common. Mitotic rate for WHO grade 2 tumors is low, but tumors with greater than 5 mitoses per 2 mm2 or 5 mitoses per 10 high power magnification fields are considered WHO grade 3 neoplasms. Necrosis is common in WHO grade 3 tumors, but its significance in isolation is unknown. PXA shows diffuse and strong positivity with the antibodies against GFAP, OLIG2, SOX2, and S100 protein, supporting an astrocytic cell of origin. Many individual tumor cells are also positive with the antibodies against neuronal markers including synaptophysin, neurofilament, class III B-tubulin, and MAP2 with variable frequency. The hematopoietic progenitor/vascular endothelial cell associated antigen CD34 is expressed in many tumors focally. The p53 labelling index is variable, most tumors being negative. Majority of tumors are positive with the mutant BRAF V600E antibody. Focal SMARCB1 (INI1) loss has been reported in rare tumors, especially with rhabdoid features.
Molecular and genetic characteristics
PXA typically harbors BRAF V600E mutation combined with CDKN2A and/or CDKN2B homozygous deletion. Rarely, anaplastic examples may also harbor TERT alterations., TP53 mutations are rare. Alterations in other genes have been described, but currently the significance of these findings is unclear. Therefore, the combination of BRAF V600E mutation and CDKN2A/B homozygous deletion constitutes the molecular signature of PXA. A word of caution is warranted because the combination of these two alterations is by no means specific to PXA and may be seen in other glial and glioneuronal tumors. A specific DNA methylation profile has been reported for PXA.
PXAs are low grade but recurrence is often expected. Anaplastic PXAs are clearly more aggressive even though they may not be as aggressive as IDH-wildtype glioblastomas. PXAs in the elderly appear to carry an adverse prognosis. In addition, extent of resection and anaplastic histology remain the key determinants of prognosis.,
Subependymal giant cell astrocytoma
Subependymal giant cell astrocytoma (SEGA) is an intraventricular tumor composed partly of large gemistocyte-like cells, often encountered in the setting of tuberous sclerosis complex (TSC) even though sporadic examples are equally common. The tumor is considered a WHO grade 1 neoplasm.
Most patients with SEGA present with signs and symptoms of increased intracranial pressure. Tumor growth at the foramen of Monro often leads to obstructive hydrocephalus. Spontaneous hemorrhage has been reported. SEGAs may also be incidental. Radiologically SEGAs are solid intraventricular masses that often show punctate calcifications, often associated with the foramen of Monro. Ventriculomagaly is often seen. MRI studies reveal a solid mass that is hyperintense on T2 modalities, iso or hypointense to gray matter on T1-weighted image with marked contrast enhancement.
SEGAs are well-circumscribed cellular tumors that are often composed of large gemistocyte-like cells with ample cytoplasm. There is a spectrum of cytomorphology but the typical cell is a large polygonal cell with abundant glassy cytoplasm [Figure 1]d. The tumor cells are often arranged in a swirling patterns and sweeping fascicles and occasionally demonstrate nests with poorly formed septations. The gemistocyte-like cells have large nuclei with prominent nucleoli and occasional inclusions. These cells often have ganglion-cell like features. There is focal hyalinization of tumor vessels and occasional collection of lymphocytes, plasma cells, and scattered mastocytes. Mitotic figures are present but rare, and occasionally there is significant hemorrhage and necrosis. Vascular proliferation other than degenerative-type linear vascular proliferation is rare. The tumor cells are variably positive with the glial and neuronal antibodies such as GFAP, synaptophysin, NEUN, neurofilament, and S100 protein. However, almost all SEGAs are diffusely negative with OLIG2 and CD34 antibodies. Some commercially available Hamartin or Tuberin antibodies may reveal loss of expression of these proteins, but often there is significant background rendering the results difficult to interpret. The antibodies against downstream proteins such as 4EP1 and phospho-S6 antibodies are often diffusely and strongly positive. SEGAs are diffusely positive with the antibody against thyroid transcription factor 1 (TTF1), a feature they share with some sellar tumors.
Molecular and genetic characteristics
Biallelic inactivation of either TSC1 or TSC2 defines SEGA. The consequence of inactivation of either gene is the activation of the mTOR pathway. The second hit is often deletion or loss of heterozygosity. Tumors without alterations in TSC1 or TSC2 have been reported, but the presumption is the presence of currently undetectable alterations in these genes. Alternately, inactivation of these genes through other mechanisms or other genes along the mTOR pathway may be responsible. DNA methylation-based classification studies support SEGA as a distinct tumor entity.
The outcome of SEGA is essentially excellent, especially after total resection. The outcome of patients with TSC depends on the complexity of pathology in these patients. Some partially resected and recurrent tumors were successfully treated using mTOR inhibitors.
Chordoid glioma (CG) is a discrete, chordoma-like glial neoplasm typically in the anterior third ventricle. CG is defined by its myxoid and chordoid architecture and a recurrent PRKCA D463H mutation recently described as its genetic signature. CG is a WHO grade 2 neoplasm, but grading criteria for CG have not been clearly described.
CG presents as a solid mass and displaces the surrounding structures, causing signs and symptoms related to this mass effect. Signs and symptoms of obstructive hydrocephalus, gait disturbances, headache, nausea, and vomiting have been reported. Their expansion from the third ventricle may also be associated with endocrine anomalies (such as diabetes insipidus) and personality changes. Radiologically, the tumors are solid and are isointense to gray matter on T1-weighted images with homogenous contrast enhancement.
CG is a solid, noninfiltrative mass often composed of cords or ribbons of epithelioid cells with vaguely fibrillary processes in a myxoid background. The tumor cells may be markedly spindled and tumors often have variable fibrous or hyalinized stroma [Figure 1]e. While most tumors appear monomorphous, some degree of cellular pleomorphism may be seen. Mitoses are often rare or absent, and high-grade features such as vascular proliferation or necrosis are exceptional. The tumor contains variable number of lymphoplasmacytic cells including rare mast cells and occasional Russell bodies, imparting an inflamed appearance. The surrounding tissue often demonstrates reactive gliosis and occasional Rosenthal fibers, which may be misinterpreted. CG is positive with the antibodies against GFAP, S100 protein, and thyroid transcription factor TTF1., Most examples also show diffuse strong positivity with the antibodies against CD34 and Vimentin, and focal or weak staining with the antibodies against epithelial membrane antigen (EMA). Neuronal markers are typically negative with rare exceptions, and the proliferative markers show low labeling.,,,
Molecular and genetic characteristics
Recent studies demonstrated a typical D463H mutation in PRKCA gene as the molecular signature of CG., This specific mutation is unique to CG, even though other types of PRKCA mutations were reported in other tumors. The exact effect of this mutation and how it changes the activity of the gene product is not clear, but is presumed to activate the MAPK signaling pathway. No other consistent mutation or genetic alteration has been detected in CG. A DNA methylation profile has been reported.
There is very little data on the outcome and prognosis of chordoid glioma. Of course, extent of resection can be associated with better outcome, but data on this are also very limited. Recurrent tumors have been reported.
The original term “astroblastoma” was used to describe an infiltrating astrocytoma intermediate between astrocytoma and the obsolete term spongioblastoma. The term has been applied in a nonspecific manner to a disparate group of tumors linked only by the presence of glial cells that radiate from the blood vessels (astroblastic rosettes). Recent studies suggest a more restricted definition of “astroblastoma” that conforms to a better and definable clinicopathological entity characterized with MN1 alterations. The current term Astroblastoma, MN1-altered, defines a circumscribed glial tumor composed of cuboidal to fibrillary astrocytic cells with a typical perivascular arrangement of tumor cells and MN1 alterations that are often fusions with partner such as BEND2 or CXXC5. The tumor is typically located supratentorially but examples have been reported in the posterior fossa and the spinal cord.
Most patients present with mass effect, seizures, and/or focal neurological deficit, and headaches, focal paralysis, nausea, and vomiting have been reported. Radiologically, the solid component of astroblastoma has a bubbly appearance and a T2 signal that is isointense to gray matter. Punctate calcifications are often present. Occasionally, the solid component can be hypointense to gray matter on T1-weighted images and hyperintense on T2-weighted modalities. The solid component often enhances, but the enhancement could be quite variable.
Astroblastomas are essentially well-defined noninfiltrative neoplasms, and the distinctive histologic feature is the angiocentric arrangement of cells forming “astroblastic” pseudorosettes [Figure 1]e. There is a close relationship between the tumor cells that contain short and broad cellular processes and appear more cuboidal than the cells of ependymomas with vague epithelial appearance. However, the cytological resemblance is often striking. The astroblastic rosettes can resemble ependymal pseudorosettes, but are smaller, more uniform and better delineated. Astroblastomas show solid sheets of tumor cells around prominently hyalinized vessels. A distinctive feature of astroblastoma is vascular hyalinization, which could be quite pronounced. Dystrophic calcification can be seen in association with hyalinized regions. Some tumors may have cells with rhabdoid morphology. The tumor may appear partially infiltrative at its margin. Criteria for grading have not been established and a WHO grade has not been assigned to astroblastoma. Astroblastomas are typically positive with the antibodies against GFAP, OLIG2, EMA, D240 and negative with neuronal antibodies.,
Molecular and genetic characteristics
Two of the most common fusion partners for MN1 are BEND2 and CXXC5 that lead to a gain-of-function of the gene, but the specific mechanism is unknown. Astroblastoma, MN1-altered, is characterized by structural rearrangements of the MN1 gene at chromosome band 22q12.1. MN1 fusions appear to be the only pathogenetic change in most tumors, even though additional genetic alterations such as CDKN2A homozygous deletion have been reported.,, The most common chromosomal copy-number alterations to date involved monosomy 16 and partial losses of 22q and X. MN1 fusions demonstrate a high degree of correlation with the typical histological features of astroblastoma. Astroblastomas MN1 altered display a distinct DNA methylation pattern that could distinguish them from their mimics.
Examples of aggressive tumors have been reported, but there is a lack of good, long-term studies analyzing prognostic factors in this tumor type. One can safely assume extent of resection associates with prognosis and reported studies on this tumor type may contain different tumors.
| Summary|| |
The group of tumors within the “circumscribed astrocytic glioma” category include three very well-defined tumor types in which routine stains are sufficient for diagnosis of the majority of such cases. There are exceptional examples in which tumor typing is not clear, and there is no simple or single algorithm to work-up such cases. The most economical and practical approach is to seek the expertise of a tumor neuropathologist. It is very easy to expand the list on antibodies or genetic analyses ending up with large bill, but an informed and staged approach is often more realistic.
The two tumor types, chordoid glioma and astroblastomas, certainly require expert help much more commonly, and especially with the requirement of WHO, molecular assessment of PRKCA or MN1 alterations, the final diagnosis for these tumors could be quite challenging. In some cases, these molecular analyses are unavoidable, and may be critical, especially if and when targeted treatment for these genetic alterations are developed. We prefer to reserve comment on the last entity “high grade glioma with piloid features,” because there is much to learn about this tumor type before the neuropathology community can come to terms of the significance and value of this diagnosis.
The authors of this manuscript often do not follow a standard protocol or antibody panel, and consider clinical and radiological information essential in developing an approach to diagnosing circumscribed astrocytic gliomas. In many patients, we have not resorted to any additional studies in the light of the clinical and radiological realities. Yet, others have required multiple rounds of immunohistochemical stains, sequencing, and methylation analyses, and the results were occasionally less than satisfactory. In all of these cases, a healthy dose of common sense and understanding the practical realities of what can be done for the patient are also within the so-called “essential diagnostic criteria.”
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Conflicts of interest
There are no conflicts of interest.
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UCSF Department of Pathology, Neuropathology Division, Room M551, 505 Parnassus Avenue, San Francisco, CA 94143ö
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2]