Cytologic Features of Epithelioid Hemangioendothelioma

Anatomic Pathology / Epithelioid Hemangioendothelioma Cytology

Cytologic Features of Epithelioid Hemangioendothelioma Rajmohan Murali, MBBS, MD, FRCPA,* Matthew A. Zarka, MD, Idris T. Ocal, MD, and Henry D. Tazelaar, MD Key Words: Cytology; Diagnosis; Epithelioid hemangioendothelioma; Fine-needle biopsy; Pathology; Vascular tumors DOI: 10.1309/AJCP5NK0FJCGHTFM

Abstract To determine cytologic features of epithelioid hemangioendothelioma (EHE) that would enable accurate diagnosis, we evaluated fine-needle aspiration biopsy (FNAB) smears from 11 histologically confirmed EHEs. The variably cellular smears comprised dispersed single cells and occasional cell aggregates. Dense stromal fragments were present in association with some tissue fragments. The cells were epithelioid, containing moderate or large amounts of dense cytoplasm. Nuclei exhibited mild pleomorphism, and nuclear grooves were identified in all cases. At least occasional intranuclear pseudoinclusions (INPIs) and intracytoplasmic lumina (ICLs) were present in all cases and in 9 cases (82%), respectively, and rare erythrocytes were seen within ICLs in 5 cases (45%). Mitotic figures were identified in 4 cases (36%). The background was bloody in 6 cases (55%) and contained hemosiderin and/or hemosiderin-laden macrophages in 5 cases (45%). The combination of the following features in FNAB samples should raise strong suspicion for EHE: predominantly dispersed single cells with occasional cohesive cell clusters; epithelioid cytomorphology; dense cytoplasm with well-defined cytoplasmic borders; ICLs (with or without erythrocytes), INPIs, and nuclear grooves. The presence of these features should prompt correlation with clinical, radiologic, and histologic features and immunohistochemical evaluation using vascular markers.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit ™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 818. Exam is located at www.ascp.org/ajcpcme.

Epithelioid hemangioendothelioma (EHE) is a vascular tumor of intermediate malignancy that may occur in a variety of sites, including soft tissues,1,2 bone,3,4 lung,5 liver,6 pleura and peritoneum,7,8 skin,2,9 lymph nodes,10,11 stomach,12 and brain.13 It occurs over a broad age range, but predominantly in middle-aged adults. Soft tissue EHE equally affects both sexes, but liver and lung tumors often occur more commonly in females. Although considered a tumor of low-grade malignancy, metastasis has been reported in up to 30% of soft tissue cases,2,13 and mortality rates vary by anatomic location of the tumors, for example, 13% for soft tissue,2 31% for bone,4 43% for liver,6 and 65% for lung.13 Owing to the epithelioid morphologic features of their constituent cells, EHEs may be mistaken for epithelial tumors, including carcinoma, melanoma, and mesothelioma. Distinction of EHE from epithelial neoplasms may be particularly difficult in cytologic material, usually obtained by fine-needle aspiration biopsy (FNAB), in which characteristic histoarchitectural features are not assessable. The cytologic features of approximately 30 cases of EHE have been reported in the English language literature, usually in the form of single case reports.11,14-38 In this report, we describe the largest cytologic study of EHE to date. The aim of the study was to determine the cytologic features of EHE that would enable accurate cytologic diagnosis and distinction of EHE from other entities in the differential diagnosis.

Materials and Methods The files of Mayo Clinic Scottsdale, Scottsdale, AZ, and Mayo Clinic Rochester, Rochester, MN, were searched for cases of histologically confirmed EHE, in which the tumors

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DOI: 10.1309/AJCP5NK0FJCGHTFM

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CME/SAM

Upon completion of this activity you will be able to: • describe the cytologic features of epithelioid hemangioendothelioma. • apply knowledge of these features to diagnose epithelioid hemangioendothelioma accurately. • distinguish epithelioid hemangioendothelioma from other entities in the differential diagnosis.

Murali et al / Epithelioid Hemangioendothelioma Cytology

❚Table 1❚ Clinical Features and Histopathologic Findings Case No./ Sex/Age (y)

Anatomic Site and Relevant History

1/M/31 2/F/56 3/M/64

Soft tissue/bone; paravertebral Liver Lung

4/M/48

Bone, humerus; multiple previous EHEs, low-grade vascular lesions on arm

5/F/73

Bone, iliac crest; previous EHE, anterior mediastinum Soft tissue, left lower neck; previous left mediastinal EHE Liver, probable infection, ?granulomatous; less likely malignant; previous EHE, lung Bone, pubis; previous EHE, right forearm Bone, ilium Soft tissue, peritoneum; previous EHE, liver, February 2003 Bone, ischium; previous EHE, liver Soft tissue, shoulder, ?liposarcoma vs ossifying lipoma Posterior chest wall; previous primary lung EHE Liver Liver Liver

6/M/77 7/F/46 8/M/53 9/F/69 10/F/46 11/M/48 12/M/77 13/F/44 14/M/73 15/F/79 16/F/74

Original Cytologic Diagnosis*

Method of Histologic Confirmation

Immunohistochemical Findings

Surgical excision Core biopsy Core biopsy

— CD31+/CD34+/FLI1+/CK– CD31+/CK–

Atypical cells; consistent with EHE Nondiagnostic Malignant cells consistent with adenocarcinoma Positive for malignancy; metastatic sarcoma consistent with low-grade angiosarcoma with features of composite hemangioendothelioma Atypical, predominantly blood and rare atypical cells Positive for malignancy; melanoma

Core biopsy

CD31+/FVIII–/CK–

Core biopsy and surgical excision Surgical excision

CD31+/CD34+/CK–

Negative for malignancy

Core biopsy

CD31+/FVIII+/CK–

Atypical, rare atypical spindle cells

Core biopsy

—

Positive; malignant cells identified Atypical, rare atypical cells present; “suspicious” for recurrent EHE

Core biopsy Core biopsy

— CD31+/CD34+

Atypical cells present

Core biopsy

CD31+/CD34+/FVIII+/FLI1+/CK–

Suspicious, a few spindle cells present Suspicious; rare atypical cells suspicious for recurrent EHE Negative for malignant cells Atypical Negative for malignancy

Core biopsy

CD31+/FVIII+

Surgical excision

—

Core biopsy Core biopsy Core biopsy

— — CD31+/CD34+/CK–

CD31+/FVIII+/S-100–/CK–

CK, cytokeratin; EHE, epithelioid hemangioendothelioma; FVIII, factor VIII. * Diagnosis made following initial examination of fine-needle aspiration smears (before evaluation of histologic sections or immunochemical studies).

❚Table 2❚ Cytologic Features of Cases With Diagnostic Features Nuclear Characteristics Case No. Cellularity

Cell Arrangements

Location

Shape

Pleomorphism

Grooves

Predominantly single, small cell clusters; focally, fibrovascular stroma associated with groups; some spindle cells Predominantly single; some spindle cells

Often eccentric; occasionally central Eccentric; some central Eccentric and central

Oval; some round; some raisinoid

Moderate

Present

Round and oval

Mild

Rare

Round and oval; raisinoid

Moderate; occasional MNGCs

Occasional

Mainly eccentric

Round and oval

Mild

Rare

Predominantly central Mainly eccentric

Round and oval, raisinoid; some spindle Round, oval, raisinoid; occasional spindle Round and oval; irregular outlines

Moderate; occasional MNGCs Moderate

Present Occasional

Moderate

Rare

Moderate; occasional MNGCs Moderate; occasional MNGCs Moderate; occasional MNGCs Moderate; occasional MNGCs

Present

1

High

2

Moderate

3

High

4

High

5

Low

Singly and in small and large tissue fragments; dense stroma associated with some cell groups Several cohesive, crowded groups and some single cells; small rosette-like arrangements in some tissue fragments; some groups have fibrovascular cores Predominantly single; some spindle cells

6

Moderate

Predominantly single; some small groups

7

Moderate

Eccentric and central

8

Low

Singly and in small and large tissue fragments; dense stroma associated with some cell groups Predominantly single; many spindle cells

9

Moderate

10

Low

Single and some large 3-D groups; stroma associated with some groups Predominantly single; some small groups

11

Moderate

Eccentric and central Eccentric and central Eccentric

Predominantly single; some spindle and stellate cells

Eccentric

Oval, raisinoid; some spindle Oval and round, raisinoid; some spindle cells Round, oval; raisinoid Round and oval; raisinoid

Occasional Present Present

3-D, 3-dimensional; ICLs, intracytoplasmic lumina; INPIs, intranuclear pseudoinclusions; MNGCs, multinucleate giant cells.

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Anatomic Pathology / Original Article

had been sampled using FNAB between 1994 and 2010. Histologic confirmation of the diagnosis was achieved by means of core biopsy (generally performed concurrently with the FNAB) or subsequent excision of the tumor. All available FNAB slides were retrieved from the Mayo Clinic archives, and the cytologic features were reviewed. The available slides included a mixture of Romanowsky-stained and Papanicolaou-stained smears. Cytologic features assessed were cellularity (estimated as low, moderate, or high by an overview of the slides), cell arrangement/architecture (single cells or aggregates; shapes of cell aggregates and association with stroma), cell shape, cytoplasmic appearance and cytoplasmic border, presence of intracytoplasmic lumina (ICLs), presence of erythrocytes within ICLs, nuclear size and shape, degree of nuclear pleomorphism, presence of nuclear grooves, presence and prominence of nucleoli, presence of intranuclear pseudoinclusions (INPIs), presence of mitoses, and background composition. Histologic sections of core biopsy specimens and excision specimens were also reviewed for confirmation of the diagnoses.

Results There were 19 patients (10 women and 9 men) with histologically confirmed EHE who underwent FNAB. The mean and median ages were 57 and 56 years, respectively (range, 31-77 years). Cytologic slides were available for

review in 16 (84%; 8 women and 8 men) cases ❚Table 1❚, ❚Table 2❚, and ❚Table 3❚. In 5 cases (2 from liver and 3 from soft tissue of the shoulder; cases 12-16), the FNAB slides contained insufficient cellular material to permit a confident cytologic diagnosis (Table 3). The FNAB slides in 1 of the liver tumors showed only benign hepatocytes, whereas the slides in 2 other tumors (1 from liver and 1 from soft tissue) were paucicellular and showed small numbers of atypical cells, some with INPIs. The cytologic features of the remaining 11 tumors (from 5 women and 6 men; mean age, 56 years; median age, 53 years; range, 31-77 years) were sufficient for diagnosis (cases 1-11, Table 2). The smears were variably cellular and composed of dispersed single cells and occasional cell aggregates ❚Image 1A❚ with some branching tissue fragments, the edges of some of which exhibited a frayed appearance. Stromal fragments were present in association with some tissue fragments, sometimes ❚Table 3❚ Cytologic Features of Nondiagnostic Cases Case No.

Features

12 13 14 15 16

Only a few spindle cells Very small numbers of stripped atypical nuclei Only normal hepatocytes; no tumor cells Very small numbers of cells Atypical; small numbers of pleomorphic hyperchromatic cells, some with intranuclear pseudoinclusions

Nucleoli

INPIs

Mitoses

ICLs

Erythrocytes in ICLs

Background

Small, single

Present

Rare

Small numbers

Not seen

Bloody

Small or inconspicuous

Present

Rare

Present

Very occasional

Prominent; single or multiple

Present; few

Rare

Present

Very rare

Bloody; hemosiderin, some siderophages, hepatocytes Bloody; several siderophages

≥1, small

Rare

Not seen

Scant; occasional signet ring forms

Not seen

—

Single

Present

Not seen

Occasional

Not seen

Bloody

Small, single

Numerous

Not seen

Not seen

Not seen

Single; prominent

Present

Not seen

Focal

Very occasional

Variably conspicuous

Present

Not seen

Rare

Not seen

Hemosiderin pigment and siderophages Hemosiderin pigment; some tumor cells intimately associated with hepatocytes Bloody

Prominent; usually single ≥1

Present

Not seen

Very occasional

Very occasional

Bloody

Present

Not seen

Not seen

Not seen

—

Single, small

Present

Present; quite a few

Present

Occasional

Bloody; hemosiderin and siderophages


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in the form of stromal cores ❚Image 1B❚. The stromal fragments were thick and had a dense, hyaline appearance. The cells were round or oval epithelioid cells containing moderate or abundant amounts of cytoplasm. The cytoplasm in most of the tumor cells was dense, and the cytoplasmic borders were well defined; occasional tumor cells in some cases exhibited granular cytoplasm ❚Image 1C❚ and ❚Image 1D❚. The cell groups in 1 case showed pseudoacinar rosette-like arrangements ❚Image 2A❚. Nuclei were located centrally or eccentrically within cells and exhibited mild to moderate pleomorphism. Nuclear

grooves were identified in all cases and in 8 cases (73%), the nuclei had a “raisinoid” appearance. At least occasional INPIs ❚Image 2B❚ and ICLs (Image 1D) were present in all cases and in 9 cases (82%), respectively, and rare erythrocytes were seen within ICLs in 5 cases (45%; Image 1D). Mitotic figures were identified in 4 cases (36%) and were prominent in 1 of the 4 cases. The background was bloody in 6 cases (55%) and contained hemosiderin and/or hemosiderin-laden macrophages in 5 cases (45%). Occasional multinucleate tumor giant cells (Image 1C) were present in 6 cases (55%; Table 2).

A

B

C

D

❚Image 1❚ (Case 3) Fine-needle aspiration cytology smears. A, Smears composed of dispersed single cells and some aggregates. B, Branching tissue fragments, the edges of which have a frayed appearance. Dense hyaline stromal fragments (arrow) and fibrovascular cores (arrowhead) are intimately associated with some tissue fragments (A and B, Papanicolaou, ×100). C, Cells are epithelioid-shaped and contain moderate amounts of cytoplasm. Note intranuclear pseudoinclusions (arrowhead) and cytoplasmic hemosiderin (arrow). Inset shows multinucleated giant cell with multiple cytoplasmic vacuoles (C and inset, Papanicolaou, ×400). D, Epithelioid cells have dense cytoplasm, well-defined cytoplasmic borders, and intracytoplasmic vacuoles (arrows), one of which contains an erythrocyte. Note intranuclear pseudoinclusions (arrowheads) (Papanicolaou, ×400).

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Histologically, the tumors were relatively circumscribed nodules exhibiting areas (often prominent) of hyaline sclerosis, within which epithelioid cells were arranged in clusters and singly. The cells contained moderate amounts of cytoplasm and mildly pleomorphic nuclei. ICLs containing variably degenerate erythrocytes were present ❚Image 3A❚. Immunohistochemically, the tumor cells were positive for vascular markers such as factor VIII, CD31 ❚Image 3B❚, CD34, and FLI-1 and negative for cytokeratin (Table 1).

A

Discussion EHE falls within the category of epithelioid endothelial tumors.39 The FNAB cytologic features of EHE were first described by Pettinato and colleagues15 in 1986. Since then, a few additional single case reports have described the cytologic features, which are similar to those described in the present study. The smears were reported to be moderately cellular and to contain round, polygonal, or slightly spindle-shaped epithelioid tumor cells arranged as single cells and pseudopapillary

B

❚Image 2❚ Fine-needle aspiration cytology smears. A (Case 4), Cell aggregates containing numerous rosette-like pseudoacinar arrangements (Papanicolaou, ×100). B, Left (Case 6), Epithelioid and oval cells containing numerous intranuclear pseudoinclusions (arrows). Right (Case 11), Epithelioid tumor cells with eccentrically located nuclei and abundant dense cytoplasm; one cell has an intracytoplasmic vacuole that contains an erythrocyte (arrow) (left and right, Papanicolaou, ×400). A

B

❚Image 3❚ (Case 3) Histologic features of core biopsy specimens of tumor. A, Epithelioid cells with intracytoplasmic vacuoles containing variably degenerate erythrocytes (arrows) (H&E, ×200). B, CD31 immunohistochemistry decorates the epithelioid cells (left, H&E, ×100; right, CD31, ×100).


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and pseudoglandular structures of varying size.15,33 In the present study, some cases were also characterized by complex branching cell groups with central stromal cores. Dense stromal material was attached to some tissue fragments, which correlates with the presence of varying degrees of hyaline sclerosis in intimate association with tumor cells, characteristically seen in histologic sections of EHE.1-3 In the present study, tissue fragments and cell groups in EHE showed a disorganized arrangement of their constituent epithelioid cells, with a frayed appearance at the edges of many cell groups. The cell aggregates lacked sharp “anatomic” borders or scalloped outlines. In the reported cytologic features of EHE, the cells contained moderate amounts of dense cytoplasm with welldefined cytoplasmic borders, and the nuclei exhibited mild pleomorphism and inconspicuous nucleoli. Mitotic figures were infrequent. Rare cells exhibited signet ring morphologic features. Intranuclear cytoplasmic invaginations (pseudoinclusions) and ICLs (some of which contain erythrocytes) were rarely identified. Immunohistochemical studies performed on cytologic material revealed reactivity of tumor cells with vascular markers such as factor VIIIa, CD31, and CD34.15 Focal reactivity for cytokeratin has also been reported.33 In this study, immunocytochemical studies were not performed on the cytologic smears. Single, sharply demarcated ICLs are typical of EHE and were identified in 11 cases (85%) in the current study. In some cells, numerous distinct cytoplasmic vacuoles were seen. These observations are similar to those described previously.15,30 In occasional cells, the ICLs were so large that the nucleus was compressed, occasionally presenting a signet-ring appearance. The ICLs were usually clear and empty, although rarely (in 3 cases), an erythrocyte or a fragment of erythrocyte cytoplasm was identified within the ICL; the rarity of identifiable erythrocytes is also evident in previous reports of EHE.17,18,25 This is in contrast with histologic preparations, in which erythrocytes and erythrocyte fragments are more readily identified within ICLs.6 Therefore reliance on the presence of erythrocytes within ICLs to make a cytologic diagnosis of EHE will potentially result in many cases being overlooked. The cytologic differential diagnosis of EHE includes other epithelioid tumors that may be seen in the anatomic sites in which EHE tends to occur. These include adenocarcinoma, epithelioid mesothelioma, melanoma, epithelioid angiosarcoma (EAS), and epithelioid sarcoma (ES). Because the prognosis and therapeutic approaches to EHE and its differential diagnoses are quite distinct, accurate diagnosis is critical. The recognition of EHE and its distinction from adenocarcinoma in FNAB samples is difficult because both tumors may exhibit similar morphologic features, such as 3-dimensional cell aggregates, epithelioid cytomorphologic features, and cytoplasmic vacuolation, and because the latter is far more commonly encountered than EHE. Therefore, a 744 744


high index of suspicion for EHE is required, along with an appreciation of some distinguishing cytologic features. For example, the cell aggregates in EHE typically lack sharp anatomic borders or scalloped outlines, which are more commonly identified in adenocarcinoma. Acinar structures are far more common in adenocarcinoma cell groups, although we identified pseudoacinar/rosette-like structures in 1 case of EHE. Dense cytoplasm and cytoplasmic ICLs (occasionally containing erythrocytes) are features seen in EHE but not in adenocarcinoma, which are often characterized by pale, foamy, or cyanophilic cytoplasm.21,22,25,30 Cytoplasmic vacuoles may be seen in adenocarcinoma but do not contain erythrocytes. In some types of adenocarcinoma, such as lobular carcinoma of the breast and mucinous bronchioloalveolar carcinoma of the lung, the sharp cytoplasmic mucin vacuoles may be difficult to distinguish from those of EHE. In contrast with the ICLs in EHE, mucin vacuoles in adenocarcinoma are often positive for mucin stains such as periodic acid–Schiff or mucicarmine. The presence of more than an occasional INPI favors EHE over most subtypes of adenocarcinoma,15,17,25 although some types of adenocarcinoma, such as pulmonary bronchioloalveolar carcinoma and papillary thyroid carcinoma, may exhibit several INPIs. Nuclear pleomorphism and nucleolar prominence are variable in adenocarcinoma; although they are reported to be generally more pronounced than in EHE,30 there is overlap, and they are not reliable discriminating features. The presence of dense stroma intimately associated with tissue fragments and in the background is more often associated with EHE than adenocarcinoma.26 Finally, although rare cases of EHE may show weak and focal positivity for cytokeratin,33 they lack the strong and often diffuse positivity for cytokeratin and epithelial membrane antigen seen in adenocarcinoma. In the majority of our cases, although adenocarcinoma was considered in the differential diagnosis, the cytologic features (in conjunction with immunochemical studies for vascular markers) permitted distinction from adenocarcinoma. In pleural or peritoneal effusions or in FNAB specimens, malignant mesothelioma may manifest as 3-dimensional epithelioid cell clusters showing relatively little cytologic atypia, along with occasional papillary formations and amorphous stromal cores, similar to EHE. However, in contrast with EHE, mesotheliomas have two-toned cytoplasm (“fuzzy cytoplasmic borders”) and intercellular spaces (“windows”) and lack cytoplasmic vacuoles and INPIs. An immunohistochemical panel including vascular markers and mesothelial markers (such as calretinin, cytokeratin 5/6, or WT-1) may be necessary to distinguish the 2 entities.8 Melanoma is often composed of predominantly dispersed epithelioid cells with moderate to abundant amounts of cytoplasm and eccentrically located nuclei. In contrast with EHE, melanomas often show greater amounts of cytologic atypia, and mitoses may be more frequent. INPIs may be © American Society for Clinical Pathology


quite common in melanoma, but ICLs are not seen. Necrotic debris may be seen in the background in melanoma but not in EHE.40 Melanin pigment may be seen in the cytoplasm of tumor cells or in macrophages in melanoma and may present difficulties in distinction from hemosiderin. The latter is often more coarsely granular and refractile than melanin, and histochemical stains (Fontana-Masson for melanin and Perls for hemosiderin) may be helpful.41 Confirmatory immunochemical positivity for vascular and melanocytic markers assists distinction of EHE and melanoma, respectively. EAS is also composed of epithelioid cells that may contain distinct ICLs and is immunochemically positive for vascular markers, similar to EHE. However, in contrast with EHE, smears of EAS are characterized by greater cellularity, larger cells, more prominent mitotic activity, greater nuclear and nucleolar pleomorphism, and more frequent tightly cohesive cell clusters.18,42 ES is a tumor occurring in soft tissue, which may be mistaken for EHE. Smears of ES are composed predominantly of singly dispersed cells with only rare disorganized cell groups. The tumor cells in ES are most often large, round, or polyhedral with abundant cytoplasm and eccentrically placed nuclei. Binucleate and multinucleate tumor cells may be seen. Nuclei are usually round and smooth and hyperchromatic and usually contain small nucleoli. A paranuclear pale zone in the cytoplasm may be present, but discrete ICLs are not identified. No INPIs or nuclear grooves are present. The tumor cells are immunoreactive for vimentin and cytokeratin and negative for vascular markers.43 In addition to careful evaluation of the cytologic features (as described) and judicious use of ancillary immunochemical studies, correlation with clinical and radiologic findings is important in arriving at the correct diagnosis. In cases presenting diagnostic difficulty or when insufficient cytologic material is obtained for definitive diagnosis, consideration should be given to histologic examination of tumor samples obtained by core biopsy or surgical excision. The combination of the following features in FNAB samples should raise strong suspicion for EHE: predominantly dispersed single cells with occasional cohesive cell clusters; epithelioid cytomorphologic features; dense cytoplasm with well-defined cytoplasmic borders; ICLs (with or without erythrocytes), INPIs, and nuclear grooves. The presence of the aforementioned cytologic features should prompt correlation with clinical, radiologic, and histologic features and immunohistochemical evaluation using vascular markers. From the Department of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, AZ. Supported by a Geraldine C. Zeiler Scholarship for the Study of Lung Pathology and Cytopathology (to Dr Murali, a visiting clinician at Mayo Clinic in June-July 2010).

Presented at the 100th Annual Meeting of the United States and Canadian Academy of Pathology; February 26 to March 4, 2011; San Antonio, TX. Address reprint requests to Dr Murali: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. * Dr Murali is currently with the Memorial Sloan-Kettering Cancer Center, New York, NY. Acknowledgments: We thank our colleagues in the Departments of Pathology and Laboratory Medicine, Mayo Clinic, Scottsdale, AZ, and Mayo Clinic, Rochester, MN, for assistance with this study.

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