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Clear cell tumors of the central nervous system: a case-based review.

Clear cell tumors (CCT) of the central nervous system (CNS) share similar morphologic features that have led to misdiagnosis in the past. With the advent of electron microscopy and immunohistochemical stains, some of those tumors have been reclassified later. (1-4) The CCT case studies that follow are taken in part (cases 1-3) from a breakout session held at the 2011 New Frontiers in Pathology meeting hosted by the University of Michigan in Ann Arbor. Two complementary cases are also presented to provide a comprehensive picture of the most common CCTs in the CNS and to illustrate the morphologic similarities that pose challenges to practicing pathologists.

To illustrate the similar morphologic features on light microscopy and the challenges to accurately diagnose CCT, Figure 1, A through F, shows representative hematoxylineosin images of the cases presented in this review in the absence of any clinical or radiologic data. Description of the clinical, radiologic, and pathologic features associated with the cases and their relevance to the accurate diagnosis of these tumors is then discussed.

REPORT OF CASES

Case 1

Clinical History.--A 52-year-old, right-handed woman complained of right-sided numbness and an inability to hold a cigarette with her right hand. Past medical history was relevant for squamous supraglottic carcinoma (T3N2c, M0), following chemotherapy and radiation 4 years before the current symptoms. Her tumor was thought to be in remission. Recent brain magnetic resonance imaging showed high T2 and fluid-attenuated inversion recovery signal with loss of brain parenchyma, prominence of the sulci and encephalomalacia in the left paramedial frontal region, consistent with a left anterior cerebral artery stroke. In addition, another incidental lesion was found on the right frontal lobe, which had an increased fluid-attenuated inversion recovery and a T2 signal abnormality with very minimal contrast enhancement. The right frontal lesion had expanded some of the gyri and blurred the grey white mater junction, changes suggestive of a primary neoplasm (Figure 2, A). An excisional biopsy was performed on the right side of the frontal lobe.

Brain Biopsy Findings.--At low power, marked distention of the cortical ribbon, with loss of cortical layering and normal cytoarchitecture, was observed (Figure 2, B). Higher magnification showed increased cellularity, composed of cells with round nuclei. Overall, the chromatin was open, and one or more small nucleoli were present. Nuclear pleomorphism was minimal with no overt nuclear atypia. The cytoplasm was clear, and discrete cytoplasmic borders were present. Specific structures, such as rosettes or canals, were not seen. In addition, there was a delicate, thin vasculature running throughout the tumor ("chicken-wire pattern"). Although occasional mitoses were present, mitotic activity was not brisk. Entrapped, healthy neurons were evident within the tumor, suggesting a diffusely infiltrating neoplasm (Figure 2, C). Immunohistochemical stains demonstrated that the tumor was diffusely immunoreactive for glial fibrillary acidic protein (GFAP) and for a mutant variant of isocitrate dehydrogenase 1 (IDH1) (Figure 2, D and E). Neurofilament highlighted entrapped axons within the tumor, confirming the infiltrating nature of the tumor (Figure 2, F). Synaptophysin staining was negative, and the proliferation index (Ki-67) was low, approximately 3%.

Diagnosis.--The diagnosis was oligodendroglioma, World Health Organization (WHO) grade II. Subsequent molecular studies showed codeletion of 1p and 19q chromosomal material.

[FIGURE 1 OMITTED]

COMMENT

Histologic features of the incidentally found lesion of the right side of the frontal lobe demonstrated that the lesion expanded the gyri, blurred the grey-white mater junction, and distorted the normal cortical cytoarchitecture, indicating that the lesion was infiltrative. At high power, the tumor infiltrated the cortex, as illustrated by the presence of entrapped neurons within the tumor. These features are key characteristics that differentiate this tumor from other CCTs. Oligodendrogliomas are part of the infiltrating glial neoplasms and, as such, are characterized by secondary structures of Scherer, which are perineuronal satellitosis, perivascular satellitosis, subpial aggregation, and infiltration of white matter tracts. Oligodendrogliomas often display a delicate capillary network (chicken-wire vasculature), which makes them prone to hemorrhage. Areas of microcalcification are commonly observed and illustrate the slow growing nature of the tumor. When sufficient tissue is available for evaluation, tumor growth in a nodular pattern is often detected. Smear preparations often reveal regular, round nuclei with relatively short glial processes, which can help guide the pathologist toward the glial nature of the tumor during frozen-section analysis. The rounded nuclei morphology is lost once the tissue is frozen. In addition, the clear cytoplasm becomes more evident once the specimen has been embedded in paraffin sections.

[FIGURE 2 OMITTED]

Immunohistochemical studies are helpful in distinguishing oligodendrogliomas from other CCTs of the CNS. As glial neoplasms, they are diffusely immunoreactive for GFAP. Oligodendrogliomas can have 3 different staining patterns: strong cytoplasmic staining with short, stubby processes; perinuclear staining with a clear cytoplasm; and/ or membranous staining with a clear cytoplasm. Given its infiltrative nature, the use of additional markers is helpful to highlight that feature. For example, neurofilament staining will highlight entrapped axons in the middle of an infiltrative tumor. Synaptophysin staining is negative in oligodendrogliomas, although you may see it in the background neuropil. Caution is needed when interpreting synaptophysin results to ensure that the immunoreactivity is not within the tumor cells. Finally, staining for a mutantspecific antibody against IDH1 can be diagnostically helpful and informative as a prognostic marker.

IDH1 is a mitochondrial protein that is mutated in most infiltrating gliomas: astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. In contrast, mutant IDH is rarely detected in other primary CNS tumors: neuronal, circumscribed gliomas, ependymomas, meningiomas, or systemic malignancies, with the exception of a subset of acute myeloid leukemias. (5-10) Mutations can occur in IDH1 and IDH2; however, IDH1 mutations are more frequently observed. Approximately 70% to 80% of all oligodendrogliomas harbor IDH mutations. (6,11 The most common IDH1 mutation involves codon 132, where arginine is replaced by histidine (R132H). (6-8,11) A monoclonal antibody for the most-common mutant form of IDH1 (R132H) has been recently developed. (12) This mutant-specific antibody has proven to be very helpful in the differential diagnosis of infiltrating gliomas from other primary CNS tumors and from reactive conditions that can mimic low-grade gliomas. (13,14) Similarly, the mutant-specific IDH1 antibody can be used to distinguish various CNS tumors with clear cell morphology. (15) Recent studies have suggested that glial tumors harboring IDH mutations have a more favorable outcome, which may soon help stratify patient status and to tailor therapy. (16,17) In addition, a molecular marker in oligodendrogliomas that carries a favorable prognosis is codeletion of 1p and 19q material. An oligodendroglioma with those molecular alterations has a better response to PCV (procarbazine hydrochloride, lomustine [CCNU; CeeNU], and vincristine sulfate) chemotherapy. (18,19) In our practice, all oligodendrogliomas are studied for their 1p 19q status.

Case 2

Clinical History.--A 25-year-old woman complained of headaches that had been worsening in the previous 1 to 2 months. The patient did not mention any visual symptoms, focal neurologic deficits, nausea, or vomiting. Magnetic resonance imaging of the brain showed a large mass on the right lateral ventricle extending into the third ventricle, with concomitant dilation of the third ventricle and both lateral ventricles (Figure 3, A). A tumor resection was performed.

Brain Biopsy Findings.--Smear preparations performed in the frozen-section room showed a homogenous population of small, round cells with scant cytoplasm; round nuclei; and salt-and-pepper chromatin. Some of the cells clustered around a central area of eosinophilic granular material, forming so-called Homer-Wright rosettes (Figure 3, B). Paraffin-embedded sections show a relatively well-circumscribed tumor with monomorphous, round cells, some of which had clear cytoplasm (Figure 3, C). A thin, delicate vasculature network was also present. No mitotic activity was identified (Figure 3, D). The tumor staining was diffusely immunoreactive for synaptophysin and negative for GFAP (Figure 3, E). Some of the tumor cells showed nuclear immunoreactivity for neuronal nuclear antigen (NeuN) stain (Figure 3, F). The proliferation index (Ki-67) was less than 1%.

Diagnosis.--The diagnosis was a central neurocytoma, WHO grade II.

COMMENT

Central neurocytomas are benign tumors that commonly arise in the midline of the cerebral ventricular system. The lateral ventricles and foramen of Monroe are the most common locations for central neurocytomas. Attachment to the septum pellucidum is frequently seen. Their peak incidence is in the third decade of life. Symptoms are due to cerebrospinal fluid obstruction and associated increased intracranial pressure. Central neurocytomas are enhanced by magnetic resonance imaging and computed tomography scan.

Histologically, central neurocytomas are composed of sheets of uniform cells with small, round nuclei; salt-and-pepper chromatin; and fine, granular eosinophilic cytoplasm that stains positive for synaptophysin. Homer-Wright rosettes may be present. Occasionally, ganglionic cells with Nissl substance can be detected. The tumor cells express neuronal markers, such as class III-[beta] tubulin, microtubule associated protein 2 (MAP2), NeuN, and neurofilament protein. Of note, GFAP may be focally positive, which has been interpreted as reactive astroglia. Because of their capillary network, central neurocytomas may present with bleeding. Microcalcifications can also be observed. Mitoses, nuclear atypia, or hyperchromasia are usually not detected. Tumors that show microvascular proliferation, necrosis, and mitotic activity have been designated as atypical neurocytomas. (20-22) Recurrence is associated with incomplete surgical resection and a proliferation index (Ki-67) more than 2%. (21,23)

Neurocytomas were misdiagnosed as oligodendrogliomas or ependymomas until their neuronal nature was elucidated by electron microcopy and immunohistochemistry. (1,3,24-26) Extraventricular neurocytomas (EVNs) are neurocytic tumors located within the brain parenchyma or in areas of the neuroaxis other than ventricles. Given its unusual location, EVNs pose a greater challenge in differentiating from other CCTs. (27,28) One diagnostic clue lies in the radiologic appearance. Indeed, EVNs are usually well circumscribed and cystic with several mural nodules, thus sharing radiologic characteristics with other low-grade neoplasms of the CNS. However, EVNs, like their central counterpart, can have nuclear atypia, mitotic activity, vascular proliferation, and necrosis, making it difficult to differentiate from a primary, high-grade, glial neoplasm in the diagnosis. The EVN or atypical EVN is also considered a WHO grade II tumor. The most important predictive features for recurrence of EVN are subtotal resection, a high proliferation index, atypical features, and older age of the patient; in those cases concomitant radiation is required. (28)

[FIGURE 3 OMITTED]

Central neurocytomas and EVNs have not been associated with IDH mutations. Therefore, the presence of a CCT that harbors IDH mutations, as observed either by mutation analysis or immunohistochemistry, favors the diagnosis of an oligodendroglioma. (15,29) Finally, another ancillary test to aid in distinguishing this tumor from oligodendroglioma is immuno histochemistry for Olig-2. This transcription factor is expressed highly in oligodendroglial tumors and to a lesser degree in other glial neoplasms but is not expressed in neurocytomas. (30)

[FIGURE 4 OMITTED]

Case 3

Clinical History.--A 13-year-old girl presented with a 2-month history of back pain, followed by right leg pain, and a few days of leg weakness. The patient had 2 episodes of decreased urination. She has normal sacral sensation and good rectal tone. Magnetic resonance imaging of the brain and spine were performed, which revealed a heterogeneous intrathecal lesion extending from T12 to the most distal aspect of the conus medullaris, which caused significant compression of the conus and the cauda equina (Figure 4, A). The lesion was resected.

Spinal Cord Biopsy Findings.--Histologic sections showed a nodular, well circumscribed tumor with a thick, fibrous capsule. Most of the tumor cells had ample, clear cytoplasm. The nuclei were round to oval with moderate pleomorphism and occasional prominent nucleoli (Figure 4, B). Traversing, thick, hyalinized collagen bands were commonly present (Figure 4, C). In some areas, cytoplasmic borders were well defined, giving the appearance of polygonal cells. However, in other areas, a syncytial growth pattern was present. Focally, meningothelial whorls were noted (Figure 4, D). Mitotic activity reached up to 3 mitoses per 10 high-power fields. There were multiple small areas of tumor necrosis (Figure 4, E). Immunohistochemistry demonstrated that the tumor was diffusely immunoreactive for epithelial membrane antigen (EMA) and vimentin but negative for GFAP and synaptophysin staining (Figure 4, F). The proliferation index (Ki-67) was 22%.

Diagnosis.--The diagnosis was clear cell meningioma, WHO grade II.

COMMENT

Imaging studies suggested that the lesion was intradural and intra-axial. The original radiologic differential diagnosis included an ependymoma, myxopapillary ependymoma, infiltrating glioma, or, less likely, a primary nerve sheath tumor.

Histologic sections showed a clear cell neoplasm. The key histologic features toward reaching the diagnosis included the presence of meningothelial differentiation, such as whorls, and areas with a syncytial growth pattern where cytoplasmic borders could not be elucidated. However, the typical meningothelial features may be focal or ill defined. In addition, the classic psammoma bodies are not expected in this meningioma variant. Meningiomas usually show membranous EMA staining, which can be diffuse or focal. Vimentin was positive but is also detected in other neoplasms. Cytokeratin, GFAP, and synaptophysin were negative, which can be helpful in excluding other tumors in the differential diagnosis. If histologic and immunohistochemical features are not sufficient to reach the diagnosis, ultrastructural studies can be performed, where the tumor cells should demonstrate intercellular junctions, interdigitating cell processes, and intermediate filaments (10 nm) of vimentin.

Clear cell meningioma is a variant of meningiomas classified as WHO grade II for its propensity to recur. Similar to atypical meningiomas, recurrence can be local or distant and may have a mortality rate of up to 23%. (31,32) It commonly affects children and young adults. Clear cell meningiomas are often rich in glycogen, which gives them their clear cell appearance. Collagen bands are common, and sometimes, the tumor has a sclerotic appearance with only sparse clear cells in between the collagen bands. Clear cell meningioma diagnoses are challenging because the defining meningothelial features are usually focal or ill defined. It is important to differentiate this tumor from other CCTs, such as ependymomas, oligodendrogliomas, and central neurocytomas. (33) Clear cell meningiomas are often found in the cerebellopontine angle and the cauda equina. Although rare, meningiomas can occur in the ventricles, and if the morphology has clear cells, a diagnostic challenge arises in differentiating these tumors from central neurocytomas or clear cell ependymomas. (34,35)

Case 4

Clinical History.--An 85-year-old woman who complained of back pain was found to have on imaging studies an enhancing, expansile mass in the spinal cord at T7-8 level. The tumor was resected in an outside institution and sent for histopathologic consultation.

Spinal Cord Biopsy Findings.--Histologic sections showed a densely packed tumor composed of clear cells with rounded nuclei and minimal nuclear pleomorphism. The tumor had areas devoid of nuclei, predominately around blood vessels. Instead, eosinophilic processes that extended from the tumor cells toward the vessel wall, forming pseudorosettes were observed (Figure 5, A). At high power, areas of tumor cells with eosinophilic processes forming true rosettes were also noted (Figure 5, B). Mitoses were not common, and microvascular proliferation or necrosis was not identified. GFAP was diffusely immunoreactive, with increased staining of the glial processes extending toward the vessels (pseudorosettes) (Figure 5, C). EMA showed only focal perinuclear dot positivity (Figure 5, D). Neurofilament was present, predominately at the edge of the tumor, suggesting a relatively wellcircumscribed tumor. Synaptophysin and mutant-specific IDH1 immunostaining were negative. The proliferation index (Ki-67) was 2%.

Diagnosis.--The diagnosis was clear cell ependymoma, WHO grade II.

COMMENT

Clear cell ependymoma is a rare variant that commonly occurs in a supratentorial location in children and young adults, although they can be seen at any age. Other locations in the neuroaxis, such as the cauda equina are also reported. (36) Histologically, clear cell ependymomas can resemble any of the CCTs discussed here. Clear cell ependymomas have round to oval nuclei, clear cytoplasm, and occasional microcalcifications. Identifying the presence of perivascular pseudorosettes or true ependymal rosettes is instrumental in the diagnosis. Ependymomas are immunoreactive for GFAP; however, GFAP expression may be variable. The GFAP expression is strongest in areas forming pseudorosettes, with cell processes radiating toward the vessels. EMA is often focal and consists of perinuclear dot positivity, or, less frequently, a ringlike pattern, lining the lumens of the ependymal rosettes. In addition, ependymomas are relatively well-circumscribed tumors. Absence of infiltrative characteristics (neurofilament) is helpful in differentiating clear cell ependymomas from oligodendrogliomas. Ependymomas are negative for neuronal markers (neurofilament, synaptophysin, NeuN) and mutant IDH1.

If light microscopy and immunohistochemical stains are inconclusive, one can resort to electron microscopy studies. The main features of ependymal differentiation include the presence of intermediate glial filaments (10 im in diameter), surface microvilli and cilia, and complex intercellular junctions. (37,38)

Grading is usually done as with conventional ependymomas; however, some studies have shown that clear cell ependymomas have a more aggressive behavior. (39)

Case 5

Clinical History.--A 66-year-old woman complained of headaches, which were exacerbated when leaning forward. In addition, the patient felt out of balance. The symptoms started 2 weeks before her presentation to medical attention. Recent thyroid ultrasound identified 2 nodules in the left thyroid. Family history was significant for breast and ovarian cancer in her mother, pancreatic cancer in her father, breast cancer in a sister, and colon cancer in a brother. Brain magnetic resonance imaging demonstrated an enhancing intraparenchymal mass in the right cerebellar hemisphere, partially cystic, with surrounding vasogenic edema and mass effect. The cerebellar lesion was resected.

[FIGURE 5 OMITTED]

Cerebellar Biopsy Findings.--The tumor was a well-circumscribed lesion with displacement of the cerebellar folia at the periphery, and no evidence of infiltration (Figure 6, A). The tumor was composed of clear cells with round to oval nuclei in a rich vascular network with vessels of different calibers (Figure 6, B). Some areas of the tumor showed clear cells with a bubbly cytoplasm and more nuclear pleomorphism (Figure 6, C). Mitoses were not prominent. Oil red O in frozen tissue showed numerous lipid globules of different sizes within the tumor cells (Figure 6, D). Permanent sections showed the tumor was positive for S100 and inhibin A, focally positive for D2-40, and negative for GFAP (Figure 6 E and F).

Diagnosis.--The diagnosis was hemangioblastoma, WHO grade I.

COMMENT

Given the prominent family history of carcinomas, the possibility of a metastatic lesion was high in the differential diagnosis. The resection of the tumor showed a clear cell tumor embedded in a rich capillary network, similar to previously described cases in this review. Focally, however, some of those clear cells showed prominent vacuolated and bubbly cytoplasm, indicating the possibility of a hemangioblastoma. Oil red O staining, performed on frozen tissue, showed the rich lipid content of the tumor, which is characteristic of this entity. Unfortunately, fat globules disappear on processing and embedding the tissue in paraffin sections; therefore, if frozen tissue is not available, one might have to use other ancillary studies to confirm the diagnosis.

Hemangioblastomas are relatively uncommon neoplasms that can occur sporadically or in the setting of von HippelLindau disease. Sporadic cases are usually seen in the cerebellum as a single lesion in patients with a mean age of 45 years. Tumors associated with von Hippel-Lindau disease present at a younger age (mean, 36 years), they can be multiple, and they can occur in unusual locations, such as retina, brain, and spinal cord. Patients with von Hippel-Lindau disease may develop renal cell carcinomas (RCCs). In such cases, assessing whether the brain lesion is a primary hemangioblastoma, a metastatic clear cell variant of RCC, or, in some rare instances, an RCC metastatic to a hemangioblastoma, is challenging. (40)

[FIGURE 6 OMITTED]

Radiologically, a hemangioblastoma is frequently cystic with a mural nodule. Intratumoral bleeding is not uncommon and can be the presenting sign. Grossly, the tumor is red because of the rich capillary network. Histologically, the tumor is well circumscribed and may have a thin capsule. The cells can range from clear cytoplasm with minimal nuclear pleomorphism to very bubbly cytoplasm with moderate or even marked nuclear atypia. Despite areas of nuclear pleomorphism, mitoses are seldom found. The tumor is embedded in a rich anastomosing network of capillaries. Extramedullary hematopoiesis and mast cells can be part of the tumor, and, in some instances, patients may have increased erythropoietin that normalizes after the tumor is resected. (41) Immunohistochemically, the tumor cells, also called stromal cells, have variable reactivity for neuron-specific enolase (NSE), S100, and CD56. Vimentin and vascular endothelial growth factor (VEGF) are usually diffusely positive. Staining with GFAP is generally negative but can be seen in some cells. (42-44) Recently, inhibin A, D240, and brachyury have been found to be present in hemangioblastomas and may be helpful in differentiating them from other CCTs. (45-47)

[FIGURE 7 OMITTED]

When the clear cell variant of RCC is in the differential diagnosis or suspected to be metastatic within the hemangioblastoma, the use of ancillary studies is helpful. Staining with CD10 and PAX2 is more sensitive and specific in differentiating RCC with hemangioblastoma than are other markers, such as RCC, D2-40, or inhibin A (Figure 6, G and H) (48)

CONCLUSIONS

Accurate diagnosis of CCTs in the CNS can be difficult, especially in the absence of comprehensive clinical and radiologic data. Histologically, CCTs of the CNS have similar morphologic features, and often, ancillarystudies are required to accurately diagnose these lesions.

In some instances, morphologic features may direct us toward one diagnosis or the other. For example, the presence of pseudorosettes and ependymal rosettes is consistent with ependymal differentiation. In the presence of whorls and intranuclear inclusions, clear cell meningioma is the most likely diagnosis. A bubbly cytoplasm in a tumor that was cystic with a mural nodule will suggest a hemangioblastoma. However, when such features are not found, ancillary studies are needed to achieve an accurate diagnosis.

Figure 7 proposes an immunohistochemical algorithm for differentiating CCTs in the CNS. The first step is identifying whether the lesion is infiltrative or not. Good evidence of infiltration is the entrapment of normal brain structures. Other infiltrative features of gliomas, especially oligodendrogliomas, are the presence of secondary structures of Scherer: perineuronal satellitosis, perivascular satellitosis, subpial aggregation, and infiltration of white matter tracts. If the sample is small or these features are not evident, observation of entrapped axons with neurofilaments in the middle of the tumor is a reliable indicator that the lesion is infiltrative and likely oligodendroglial in nature. In addition, if the tumor is immunoreactive for mutant-specific IDH1 (a signature for infiltrating gliomas) and negative for synaptophysin and other neuronal markers, the presence of an oligodendroglioma is highly suspected.

If the tumor is well circumscribed or axons are only seen at the periphery of the tumor, identifying the origin of the lesion by combining GFAP, EMA, and synaptophysin is important. If the tumor shows diffuse immunoreactivity for GFAP or focal staining with an accentuation of the staining in glial processes toward vessels (pseudorosettes), it is most consistent with a clear cell ependymoma. In addition, focal staining with EMA in a perinuclear dot or ringlike pattern may support such a diagnosis. If GFAP is negative and EMA shows a diffuse membranous pattern of staining, then a diagnosis of clear cell meningioma is more likely. Staining with GFAP can be focally positive in other CCTs, and additional studies will be necessary, such as in the case of neurocytoma and hemangioblastoma. Synaptophysin should be diffusely positive in neurocytomas and generally negative in hemangioblastomas. Hemangioblastoma, however, is immunoreactive for S100, VEGF, D2-40, and inhibin A, among other markers. Also, close space between this and previos sentence. Finally, if all of the above markers are negative and a metastatic clear cell carcinoma, sarcoma, or melanoma is suspected, specific stains for those entities should be performed.

In some cases, histology and immunohistochemical studies are not sufficient to elucidate the etiology of the tumor. Ultrastructural studies may identify specific features; for example, cilia or microvilli in ependymomas, interdigitating junctions in meningiomas, and neurosecretory granules in central neurocytoma. Ultrastructural studies can be done from paraffin-embedded tissue but are best from tissue fixed in glutaraldehyde.

When performed, comprehensive assessment of the clinical and radiologic presentation of the case is crucial for correlation with the histologic findings and essential to guide the pathologist to a cost-effective and finally accurate diagnosis of CCTs in the CNS.

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Sandra Camelo-Piragua, MD

Accepted for publication April 17, 2012.

From the Department of Pathology, University of Michigan, Ann Arbor.

The author has no relevant financial interest in the products or companies described in this article.

Presented in part at the New Frontiers in Pathology: An Update for Practicing Pathologists meeting; University of Michigan; October 13, 2011; Ann Arbor, Michigan.

Reprints: Sandra Camelo-Piragua, MD, Department of Pathology, University of Michigan, 1301 Catherine Rd, MSB1, Room M4213, Ann Arbor, MI 48108 (e-mail: sandraca@umich.edu).
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Author:Camelo-Piragua, Sandra
Publication:Archives of Pathology & Laboratory Medicine
Date:Aug 1, 2012
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