Recommendations for Performance Evaluation of Machine Learning in Pathology: A Concept Paper From the College of American Pathologists.

CONTEXT.­: Machine learning applications in the pathology clinical domain are emerging rapidly. As decision support systems continue to mature, laboratories will increasingly need guidance to evaluate their performance in clinical practice. Currently there are no formal guidelines to assist pathology laboratories in verification and/or validation of such systems. These recommendations are being proposed for the evaluation of machine learning systems in the clinical practice of pathology. OBJECTIVE.­: To propose recommendations for performance evaluation of in vitro diagnostic tests on patient samples that incorporate machine learning as part of the preanalytical, analytical, or postanalytical phases of the laboratory workflow. Topics described include considerations for machine learning model evaluation including risk assessment, predeployment requirements, data sourcing and curation, verification and validation, change control management, human-computer interaction, practitioner training, and competency evaluation. DATA SOURCES.­: An expert panel performed a review of the literature, Clinical and Laboratory Standards Institute guidance, and laboratory and government regulatory frameworks. CONCLUSIONS.­: Review of the literature and existing documents enabled the development of proposed recommendations. This white paper pertains to performance evaluation of machine learning systems intended to be implemented for clinical patient testing. Further studies with real-world clinical data are encouraged to support these proposed recommendations. Performance evaluation of machine learning models is critical to verification and/or validation of in vitro diagnostic tests using machine learning intended for clinical practice.

Pathologist-performed ultrasound-guided fine-needle aspirations of the thyroid: A single institution observational study.

BACKGROUND: Ultrasound-guided fine-needle aspiration biopsies (USFNAs) are increasingly performed by pathologists. This study was designed to assess the diagnostic yield and characterization of thyroid nodules biopsied at a teaching hospital setting in which both attending physicians and trainees are involved in the performance of USFNAs. METHODS: A retrospective study of pathologist-performed USFNAs of thyroid cases was performed over a period of 9 years at a tertiary medical center. Data collected included patient characteristics and The Bethesda System diagnostic categories. RESULTS: Over the study period, 1531 USFNAs of thyroid nodules were performed in the pathology-based clinic, with 1209 lesions in females and 322 in males. Ninety-three percent of samples were sufficient for diagnosis (n = 1420). The majority of nodules biopsied were benign (65.4%, n = 1002). Overall, 3.1% of nodules biopsied were diagnostic of malignancy (n = 47). The number of USFNAs over the years showed a rapid increase initially, with a coronavirus disease 2019-related decrease in 2020. CONCLUSIONS: The authors report their experience with thyroid USFNA over nearly a decade. The most common diagnosis was benign and the second most common was Bethesda category III. Lesions that were diagnostic of malignancy were relatively uncommon. Over the study period, the results showed that at a large tertiary care center in which USFNAs were performed by trainees as well as attending physicians, the diagnostic yield was good with a majority of thyroid nodules biopsied associated with a definitive diagnosis.

Performance of repeat cytology with reflex ThyroSeq genomic classifier for indeterminant thyroid cytology.

BACKGROUND: The American Thyroid Association recommends either repeat fine-needle aspiration biopsy (FNAB) or molecular testing (eg, ThyroSeq) of Bethesda category III (atypia of undetermined significance/follicular lesion of undetermined significance [AUS/FLUS]) nodules to provide further risk stratification. How a testing algorithm that uses ancillary molecular tests performs as a reflex test for repeat sampling of indeterminant nodules remains unclear. METHODS: Thyroid FNABs performed over a 24-month period that received a diagnosis of AUS/FLUS and underwent subsequent FNAB were analyzed. RESULTS: In total, 187 patients were identified who received an FNAB diagnosis of AUS/FLUS and had repeat sampling. Of these patients, 64% received a subsequent indeterminant diagnosis on repeat biopsy: 7 (3.7%) repeat biopsies were diagnosed as nondiagnostic/unsatisfactory, 104 (55.6%) were diagnosed as AUS/FLUS, and 8 (4.3%) were diagnosed as follicular neoplasm/suspicious for follicular neoplasm. Of the repeat biopsied nodules, 63% underwent subsequent testing with ThyroSeq version 3. The diagnostic performance was calculated using only surgically confirmed nodules (sensitivity, 100%; specificity, 30%; positive predictive value, 41%; negative predictive value, 100%) and by assigning nonresected nodules with negative ThyroSeq or benign cytology results as benign (sensitivity, 100%; specificity, 88%; positive predictive value, 41%; negative predictive value, 100%). CONCLUSIONS: In the majority of patients, repeat FNAB for AUS/FLUS did not preclude subsequent molecular ancillary testing because of the high rate of indeterminant results on repeat biopsy. The diagnostic performance of the testing algorithm reported here was very similar to other reports using either repeat biopsy or molecular testing alone. Ultimately, the algorithm of performing molecular testing on repeat indeterminant nodules increased the number of biopsies performed and lengthened the time to definitive risk stratification without a disproportionate decrease in the use of molecular testing or an appreciable improvement in diagnostic performance.

Integrating the Health-care Enterprise Pathology and Laboratory Medicine Guideline for Digital Pathology Interoperability.

Integrating the health-care enterprise (IHE) is an international initiative to promote the use of standards to achieve interoperability among health information technology systems. The Pathology and Laboratory Medicine domain within IHE has brought together subject matter experts, electronic health record vendors, and digital imaging vendors, to initiate development of a series of digital pathology interoperability guidelines, called "integration profiles" within IHE. This effort begins with documentation of common use cases, followed by identification of available data and technology standards best utilized to achieve those use cases. An integration profile that describes the information flow and technology interactions is then published for trial use. Real world testing occurs in "connectathon" events, in which multiple vendors attempt to connect their products following the interoperability guidance parameters set forth in the profile. This paper describes the overarching set of integration profiles, one of which has been published, to support key digital pathology use cases.

A Model Information Management Plan for Molecular Pathology Sequence Data Using Standards: From Sequencer to Electronic Health Record.

Incorporating genetic variant data into the electronic health record (EHR) in discrete computable fashion has vexed the informatics community for years. Genetic sequence test results are typically communicated by the molecular laboratory and stored in the EHR as textual documents. Although text documents are useful for human readability and initial use, they are not conducive for data retrieval and reuse. As a result, clinicians often struggle to find historical gene sequence results on a series of oncology patients within the EHR that might influence the care of the current patient. Second, identification of patients with specific mutation results in the EHR who are now eligible for new and/or changing therapy is not easily accomplished. Third, the molecular laboratory is challenged to monitor its sequencing processes for nonrandom process variation and other quality metrics. A novel approach to address each of these issues is presented and demonstrated. The authors use standard Health Level 7 laboratory result message formats in conjunction with international standards, Systematized Nomenclature of Medicine Clinical Terms and Human Genome Variant Society nomenclature, to represent, communicate, and store discrete gene sequence data within the EHR in a scalable fashion. This information management plan enables the support of the clinician at the point of care, enhances population management, and facilitates audits for maintaining laboratory quality.

Flow cytometry immunophenotyping of vitreous specimens does not contribute to diagnosis of lymphoma without supporting morphologic features.

BACKGROUND: Diagnostic vitrectomy with flow cytometry immunophenotyping (FCI) is being increasingly used as part of screening for diagnostically challenging cases. We aim to evaluate the utility of combined cytopathology and FCI in diagnostic pars plana vitrectomy. We also aim to evaluate cytologic features that could potentially predict FCI outcomes. This study provides clearer indications for use of FCI in diagnostic vitrectomy. METHODS: A case series of diagnostic pars plana vitrectomy specimens from 2010 to 2016 from a single institution was retrospectively evaluated. Associations between cytologic features and FCI were analyzed statistically. RESULTS: Ninety-nine vitrectomy specimens (90 patients) were evaluated. Evaluation was diagnostic in 39 of 99 (39.4%) specimens. FCI was performed in 66 of 73 (90.4%) specimens collected for lymphoma indication, and 9 of those 66 FCIs (13.6%) demonstrated abnormal lymphocytes. FCI was performed in 10 of 26 (38.5%) specimens collected for non-lymphomatous indications; all 10 FCIs failed to demonstrate lymphocyte abnormality. The absence of large lymphocytes frequently demonstrated negative FCI (negative predictive value = 97.7%), and was the sole cytologic feature significantly associated with a negative FCI result [OR, 14.0; 95% CI, 1.65-635.6; P = .034]. CONCLUSIONS: Diagnostic vitrectomy with cytopathology evaluation is valuable, and concomitant FCI is useful to confirm intraocular lymphoma. However, the absence of large lymphocytes on cytologic examination is the single significant predictor of a negative FCI, and this finding should preclude the use of FCI.

The College of American Pathologists Biorepository Accreditation Program: Results from the First 5 Years.

The College of American Pathologists (CAP) developed the Biorepository Accreditation Program (BAP) in 2012. This program integrates best practices from the International Society for Biological and Environmental Biorepositories, the National Cancer Institute, the Organisation for Economic Cooperation and Development, the Center for Medicare and Medicaid Services, and the CAP Laboratory Accreditation Program. The goal of this elective program is to provide requirements for standardization in biorepository processes that will result in high-quality specimens that can be used to support research, drug discovery, and personalized medicine. CAP uses a peer inspection model to ensure the inspectors have proper expertise and to promote educational efforts through information sharing. Lead inspectors are comprised of pathologists, PhDs, and managers of biorepositories and they are often supported by CAP staff inspectors. Accreditation is a 3-year continuous cycle of quality with a peer inspection occurring at the start of year 1 and a self-inspection and CAP desk assessment at the start of year 2 and 3. At this time 53 biorepositories are fully CAP BAP accredited and 13 are in the process of obtaining accreditation. There are currently 273 established standards with requirement lists customized based on the scope of activities performed by a biorepository. A total of 90 inspections were completed between May 2012 and December 2016. Sixty-one were initial inspections and 29 were reinspections. A total of 527 deficiencies were identified in the areas of Equipment/Instrumentation (22%), Information Technology (18%), Specimen Handling and QC (15%), Quality Management (16%), Personnel (11%), Safety (10%), Facilities (6%), and Regulatory (2%). Assessment of common deficiencies identifies areas of focus for continuous improvement and educational opportunities. Overall success of the program is high based on the current enrollment of 66 biorepositories, anecdotal participant feedback and increasing national recognition of the BAP in federal documents.

A call to standardize preanalytic data elements for biospecimens.

CONTEXT: Biospecimens must have appropriate clinical annotation (data) to ensure optimal quality for both patient care and research. Clinical preanalytic variables are the focus of this study. OBJECTIVE: To define the essential preanalytic variables (data fields) that should be attached to every collected biospecimen and to provide a complete list of such variables, along with their relative importance, which can vary, depending on downstream use, institutional needs, and information technology capabilities. DESIGN: The College of American Pathologists Diagnostic Intelligence and Health Information Technology Committee sponsored a Biorepository Working Group to develop a ranked list of the preanalytic variables for annotating biospecimens. Members of the working group were experts in anatomic, clinical, and molecular pathology; biobanking; medical informatics; and accreditation. Several members had experience with federal government programs, such as the National Cancer Institute's Biospecimens and Biorepository Branch and the National Cancer Institute's Community Cancer Center Program. Potential preanalytic variables were identified and ranked along with available supporting evidence, definitions, and potential negative effects if the variable was not attached to the biospecimen. Additional national and international stakeholders reviewed the draft manuscript. RESULTS: The ranked listing of 170 preanalytic variables produced can be used as a guide for site-specific implementation into patient care and/or research biorepository processes. Conclusions.-In our collective experience, it is often difficult to choose which of the many preanalytic variables to attach to any specific set of biospecimens used for patient care and/or research. The provided ranked list should aid in the selection of preanalytic variables for a given biospecimen collection.

Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy.

Aerobic exercise training (AET) is an effective adjunct therapy to attenuate the adverse side-effects of adjuvant chemotherapy in women with early breast cancer. Whether AET interacts with the antitumor efficacy of chemotherapy has received scant attention. We carried out a pilot study to explore the effects of AET in combination with neoadjuvant doxorubicin-cyclophosphamide (AC+AET), relative to AC alone, on: (i) host physiology [exercise capacity (VO2 peak), brachial artery flow-mediated dilation (BA-FMD)], (ii) host-related circulating factors [circulating endothelial progenitor cells (CEP) cytokines and angiogenic factors (CAF)], and (iii) tumor phenotype [tumor blood flow ((15)O-water PET), tissue markers (hypoxia and proliferation), and gene expression] in 20 women with operable breast cancer. AET consisted of three supervised cycle ergometry sessions/week at 60% to 100% of VO2 peak, 30 to 45 min/session, for 12 weeks. There was significant time × group interactions for VO2 peak and BA-FMD, favoring the AC+AET group (P < 0.001 and P = 0.07, respectively). These changes were accompanied by significant time × group interactions in CEPs and select CAFs [placenta growth factor, interleukin (IL)-1ß, and IL-2], also favoring the AC+AET group (P < 0.05). (15)O-water positron emission tomography (PET) imaging revealed a 38% decrease in tumor blood flow in the AC+AET group. There were no differences in any tumor tissue markers (P > 0.05). Whole-genome microarray tumor analysis revealed significant differential modulation of 57 pathways (P < 0.01), including many that converge on NF-κB. Data from this exploratory study provide initial evidence that AET can modulate several host- and tumor-related pathways during standard chemotherapy. The biologic and clinical implications remain to be determined.

Risk of invasive breast cancer and ductal carcinoma in situ in women with atypical papillary lesions of the breast.

Benign papillary lesions of the breast include papilloma and papillomatosis. A retrospective analysis of patients with a papillary breast lesion diagnosed between October 1992 and December 2009 was performed. Patients were excluded if they had a previous or concurrent diagnosis of invasive or in situ cancer or less than 6 months of follow-up. The Kaplan-Meier method was used to determine the risk of developing subsequent malignancy. The log rank test was used to compare groups of patients. Median follow-up for the 167 patients included in the study was 4.6 years. Fifty-one patients had a papillary lesion with atypia and 116 patients had a papillary lesion without atypia. Patients with a papillary lesion with atypia were more likely to develop invasive or in situ breast cancer with a 5 year risk of 13.0% versus 4.6% in patients with no atypia (p = 0.03).

Biospecimens and biorepositories for the community pathologist.

Pathologists have long served as custodians of human biospecimens collected for diagnostic purposes. Rapid advancements in diagnostic technologies require that pathologists change their practices to optimize patient care. The proper handling of biospecimens creates opportunities for pathologists to improve their diagnoses while assessing prognosis and treatment. In addition, the growing need for high-quality biorepositories represents an opportunity for community pathologists to strengthen their role within the health care team, ensuring that clinical care is not compromised while facilitating research. This article provides a resource to community pathologists learning how to create high-quality biorepositories and participating in emerging opportunities in the biorepository field. While a variety of topics are covered to provide breadth of information, the intent is to facilitate a level of understanding that permits community pathologists to make more informed choices in identifying how best their skills and practice may be augmented to address developments in this field.

Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer.

The purpose of this study is to investigate the effects of exercise on cancer progression, metastasis, and underlying mechanisms in an orthotopic model of murine prostate cancer. C57BL/6 male mice (6-8 wk of age) were orthotopically injected with transgenic adenocarcinoma of mouse prostate C-1 cells (5 × 10(5)) and randomly assigned to exercise (n = 28) or a non-intervention control (n = 31) groups. The exercise group was given voluntary access to a wheel 24 h/day for the duration of the study. Four mice per group were serially killed on days 14, 31, and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Before death, MRI was performed to assess tumor blood perfusion. Primary tumor growth rate was comparable between groups, but expression of prometastatic genes was significantly modulated in exercising animals with a shift toward reduced metastasis. Exercise was associated with increased activity of protein kinases within the MEK/MAPK and PI3K/mTOR signaling cascades with subsequent increased intratumoral protein levels of HIF-1α and VEGF. This was associated with improved tumor vascularization. Multiplex ELISAs revealed distinct reductions in plasma concentrations of several angiogenic cytokines in the exercise group, which was associated with increased expression of angiogenic and metabolic genes in the skeletal muscle. Exercise-induced stabilization of HIF-1α and subsequent upregulation of VEGF was associated with "productive" tumor vascularization with a shift toward suppressed metastasis in an orthotopic model of prostate cancer.

Recurrence risk and margin status in granular cell tumors of the breast: a clinicopathologic study of 13 patients.

CONTEXT: Granular cell tumors (GCTs) of the breast are rare neoplasms that mimic epithelial malignancy clinically and rarely occur in association with it. Granular cell tumors of the breast are not infrequently excised with positive margins. Reports describing risk of recurrence including data on margin status and follow-up are lacking. OBJECTIVE: To review our series of GCTs of the breast to determine the risk of recurrence if excised with positive or close margins. DESIGN: Cases of GCT of the breast were reviewed. Margin status of specimens was recorded as positive, close (<1 mm), and negative. RESULTS: Thirteen female patients with GCT of the breast were identified. Mean patient age at presentation was 45 years. Seventy-seven percent of patients were African American and 23% were white. African American patients presented on average 13 years earlier than white patients. Average tumor size was 1.22 cm. Fifteen percent of lesions had positive margins on excisional biopsy or lumpectomy and 31% had tumor cells within 1 mm of the margin. One of 13 patients (8%) had coexistent invasive ductal carcinoma. Average follow-up for the entire group was 77 months. Patients with positive margins remained free of tumor progression or recurrence for 89 months and patients with close margins also remained disease free during a 64-month follow-up period. No tumors recurred out of the entire group. CONCLUSION: Granular cell tumors of the breast have little long-term risk for recurrence, even when excised with positive margins. Surgical evaluation after nonexcisional biopsy may still be indicated to assess for the possible association of colocalized carcinoma.

The cancer translational research informatics platform.

BACKGROUND: Despite the pressing need for the creation of applications that facilitate the aggregation of clinical and molecular data, most current applications are proprietary and lack the necessary compliance with standards that would allow for cross-institutional data exchange. In line with its mission of accelerating research discoveries and improving patient outcomes by linking networks of researchers, physicians, and patients focused on cancer research, caBIG (cancer Biomedical Informatics Grid) has sponsored the creation of the caTRIP (Cancer Translational Research Informatics Platform) tool, with the purpose of aggregating clinical and molecular data in a repository that is user-friendly, easily accessible, as well as compliant with regulatory requirements of privacy and security. RESULTS: caTRIP has been developed as an N-tier architecture, with three primary tiers: domain services, the distributed query engine, and the graphical user interface, primarily making use of the caGrid infrastructure to ensure compatibility with other tools currently developed by caBIG. The application interface was designed so that users can construct queries using either the Simple Interface via drop-down menus or the Advanced Interface for more sophisticated searching strategies to using drag-and-drop. Furthermore, the application addresses the security concerns of authentication, authorization, and delegation, as well as an automated honest broker service for deidentifying data. CONCLUSION: Currently being deployed at Duke University and a few other centers, we expect that caTRIP will make a significant contribution to further the development of translational research through the facilitation of its data exchange and storage processes.

Desmoplastic small round cell tumor: using FISH as an ancillary technique to support cytologic diagnosis in an unusual case.

Desmoplastic small round cell tumor is a rare and aggressive neoplasm that predominantly affects young males. In almost all cases, a reciprocal translocation is present resulting in the fusion of the Ewing sarcoma gene with the Wilms' tumor gene. Here we describe an unusual case occurring in a 59-year-old male, in which fluorescence in situ hybridization (FISH) was used in conjunction with immunohistochemical studies to confirm the diagnosis. To our knowledge, this is the first reported case of using FISH as an ancillary technique to confirm the cytologic diagnosis of this tumor.

The value of fluorescence in situ hybridization and polymerase chain reaction in the diagnosis of B-cell non-Hodgkin lymphoma by fine-needle aspiration.

CONTEXT: Molecular genetic analyses have been predicted to improve the diagnostic accuracy of fine-needle aspiration of B-cell non-Hodgkin lymphoma. OBJECTIVE: To determine the value of routine molecular genetic assays, polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), in the diagnosis of B-cell non-Hodgkin lymphoma by fine-needle aspiration (FNA). DESIGN: A multiparametric method, including cytology, flow cytometry, PCR, and FISH, was prospectively evaluated in the diagnosis of B-cell non-Hodgkin lymphoma by FNA. Aspirates from 30 consecutive patients with suspected hematolymphoid malignancies were collected. All aspirates were triaged through a uniform program including cell-size analysis, B- and T-cell clonality studies, flow cytometric immunophenotyping, and bcl-1 and bcl-2 gene rearrangements by PCR and FISH. After completion of FNA evaluations, FNA results were compared with diagnoses from prior or subsequent surgical biopsies. RESULTS: Monoclonal B-cell populations were detected in 18 of 20 B-cell non-Hodgkin lymphomas by flow cytometry and PCR. bcl-1 gene rearrangement was detected in 2 of 2 cases of mantle cell lymphoma. bcl-2 rearrangement was detected in 5 cases including 4 of 4 low-grade follicular lymphomas and 1 transformed follicular lymphoma. By incorporating the results of molecular genetic and ancillary diagnostics, a definitive classification was reached in 12 cases of B-cell non-Hodgkin lymphoma by FNA, including all cases of low-grade follicular lymphoma (4/4) and mantle cell lymphoma (2/2) and approximately 50% of small lymphocytic lymphoma (2/4) and large B-cell lymphoma (4/8). Ten of the 12 cases with a final classification reached by FNA had either prior or follow-up surgical biopsies, and all 10 cases showed agreement between the diagnoses rendered on FNA and surgical biopsies. CONCLUSIONS: With proper handling and management of specimens, FNA can routinely provide samples adequate for molecular genetic studies, in addition to cytomorphology and flow cytometry, making it possible to consistently render accurate and definitive diagnoses in a subset of B-cell non-Hodgkin lymphomas. By incorporating FISH and PCR methods, FNA may assume an expanded role for the primary diagnosis of B-cell non-Hodgkin lymphoma.

A gammaGT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice.

To understand the physiological role of angiotensin type 1 (AT(1)) receptors in the proximal tubule of the kidney, we generated a transgenic mouse line in which the major murine AT(1) receptor isoform, AT(1A), was expressed under the control of the P1 portion of the gamma-glutamyl transpeptidase (gammaGT) promoter. In transgenic mice, this promoter has been shown to confer cell-specific expression in epithelial cells of the renal proximal tubule. To avoid random integration of multiple copies of the transgene, we used gene targeting to produce mice with a single-copy transgene insertion at the hypoxanthine phosphoribosyl transferase (Hprt) locus on the X chromosome. The physiological effects of the gammaGT-AT(1A) transgene were examined on a wild-type background and in mice with targeted disruption of one or both of the murine AT(1) receptor genes (Agtr1a and Agtr1b). On all three backgrounds, gammaGT-AT(1A) transgenic mice were healthy and viable. On the wild-type background, the presence of the transgene did not affect development, blood pressure, or kidney structure. Despite relatively low levels of expression in the proximal tubule, the transgene blunted the increase in renin expression typically seen in AT(1)-deficient mice and partially rescued the kidney phenotype associated with Agtr1a(-/-)Agtr1b(-/-) mice, significantly reducing cortical cyst formation by more than threefold. However, these low levels of cell-specific expression of AT(1) receptors in the renal proximal tubule did not increase the low blood pressures or abolish sodium sensitivity, which are characteristic of AT(1) receptor-deficient mice. Although our studies do not clearly identify a role for AT(1) receptors in the proximal tubules of the kidney in blood pressure homeostasis, they support a major role for these receptors in modulating renin expression and in maintaining structural integrity of the renal cortex.

Lymphomas and high-grade astrocytomas: comparison of water diffusibility and histologic characteristics.

PURPOSE: To determine if water diffusivity within lymphomas and high-grade astrocytomas correlates with cellularity. MATERIALS AND METHODS: Echo-planar diffusion-weighted magnetic resonance (MR) images obtained in 11 patients with brain lymphomas (19 lesions) and in 17 patients with astrocytomas (19 lesions) were retrospectively reviewed. Regions of interest were drawn on apparent diffusion coefficient (ADC) maps in enhancing tumor. ADC values were normalized by dividing ADC values of tumors by those of normal-appearing regions and expressing the quotient as a ratio. Histologic samples from 11 patients with astrocytomas (11 lesions) and seven patients with lymphoma (seven lesions) were reviewed. Cellularity was measured by calculating the percentage of nuclear area and the percentage of cytoplasmic area and expressing the results as the nuclear-to-cytoplasmic (N/C) ratio. The ADC and N/C ratios of both tumor types were compared by using a two-tailed t test. RESULTS: Mean ADC ratio of lymphomas was 1.15 (SD, 0.33; standard error of the mean [SEM], 0.10), and that of high-grade astrocytomas was 1.68 (SD, 0.48; SEM, 0.11) (P <.01). Mean N/C ratio of lymphoma was 1.45 (SD, 0.94; SEM, 0.36), and that of high-grade astrocytomas was 0.24 (SD, 0.18; SEM, 0.05) (P <.01). CONCLUSION: Measurements of water diffusivity and cellularity suggest that higher cellularity contributes to more restricted diffusion.