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Molecular Testing in Anatomic Pathology and Adherence to Guidelines: A College of American Pathologists Q-Probes Study of 2230 Testing Events Reported by 26 Institutions.

With the rapid growth of specialized ancillary testing, laboratories are frequently asked to use anatomic pathology material to perform molecular testing. Such testing may be conducted either in-house or as a send-out to a reference laboratory, and the testing may be quite costly. In some cases, laboratories perform reflex molecular tests as initiated by pathologists. While there are some guidelines on clinical relevance and performance of these tests, there is currently limited information in the literature about adherence to these guidelines.

There are several chemotherapeutic regimens that rely upon ancillary testing to guide therapy. The National Comprehensive Cancer Network (NCCN) guidelines (1) are widely used and they provide recommendations for the use of ancillary testing in various tumor types. Guidelines for lung carcinoma, (2) colorectal carcinoma, (3) and melanoma (4) (current at the time this study was conducted [2013]) are briefly summarized herein. For metastatic or locally advanced nonsquamous, non-small cell lung carcinoma, the NCCN guidelines include epidermal growth factor receptor gene (EGFR) mutation analysis and anaplastic lymphoma kinase gene (ALK) rearrangement testing by fluorescence in situ hybridization (FISH), with testing for ROS1 gene rearrangement by FISH listed as an additional consideration. For metastatic colorectal adenocarcinoma, KRAS and BRAF mutation testing appears on the NCCN guidelines, but EGFR mutation testing is not recommended. In metastatic melanoma, NCCN guidelines include BRAF mutation analysis, as the V600E or V600K mutations of the BRAF gene guide vemurafenib therapy. In addition, KIT-mutated melanomas may be treated with imatinib. A recently published guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology (CAP/IASLC/AMP) specifically addresses EGFR and ALK testing for lung carcinomas. (5)

This Q-Probes study aimed to assess how frequently molecular testing in anatomic pathology adhered to NCCN guidelines and to determine if any practice or demographic characteristics were related to this rate. In addition, data were collected to determine testing turnaround times and adequacy of various specimen types for molecular testing.

MATERIALS AND METHODS Data Collection

The study consisted of 2 data collections. One was a retrospective collection limited to cases of lung primary carcinoma, colorectal primary carcinoma, and melanoma for which molecular testing was performed or attempted during the prior year, or until 40 cases were collected, whichever came first. The second was a prospective collection of all cases of solid tumors for which molecular testing was requested during a period of 2 months or until 30 cases were collected, whichever came first. For both data collections participants recorded the following for each case: primary tumor site; tumor histology; ordering provider; specimen type; extent of clinical disease; which molecular tests were requested, performed, or attempted; and the primary rationale for the test request. The study authors then compared these data points to the NCCN guidelines as were current at the time of data collection (beginning early 2013) and assessed each molecular test as either (1) strictly meeting the guideline, (2) loosely meeting the guideline, or (3) not meeting the guideline. In addition, turnaround time information and specimen adequacy were reported for the retrospective study. Both data collections excluded breast primary carcinomas, hematolymphoid tumors, and gynecologic cytology. Lynch syndrome screening was excluded from the retrospective study but included in the prospective study. Both data collections included in-house and send-out testing.

Definitions

To classify the molecular testing events and to assess adherence to guidelines, the following definitions were applied.

Molecular Test.--Analysis for the presence or quantitation of nucleic acids (either DNA or RNA) and proteins with the aim to guide therapy, predict prognosis, diagnose disease, or predict occurrence of disease. Examples applied to anatomic pathology specimens include gene sequencing, DNA hybridization techniques (eg, fluorescence in situ hybridization, chromogenic in situ hybridization, microarrays), and amplification methods (eg, polymerase chain reaction).

Strict Adherence to Guidelines.--The test is included in the NCCN guideline as an integral part of the decision-making algorithm (eg, EGFR testing in metastatic or locally advanced lung adenocarcinoma, KRAS testing in metastatic colorectal adenocarcinoma).

Loose Adherence to Guidelines.--The test is not part of the NCCN decision-making algorithm but it falls into either of the following categories: (1) the test is directly related to other standard tests in the guideline, making its performance reasonable in certain situations (eg, KRAS or ROS1 testing in metastatic or locally advanced lung adenocarcinoma) or (2) the test is mentioned in the guideline as a consideration for certain patients (eg, Lynch syndrome screening in colon adenocarcinoma, BRAF testing in metastatic colorectal adenocarcinoma).

Data Analysis

For both data collections the primary performance indicators were the percentage of tests that strictly met the NCCN guidelines and the percentage of tests that at least loosely met the guidelines. There were 2 additional performance indicators for the retrospective study of lung carcinoma, colon carcinoma, and melanoma: the percentage of cases with adequate tissue for molecular testing and the median turnaround time from molecular test request to test result.

Statistical analysis was performed to determine which factors were significantly associated with the performance indicators. Participant results were excluded from the analysis for those indicators based on fewer than 5 tests. Associations between the performance indicators with the demographic and practice variables were analyzed by using Kruskal-Wallis tests for discrete-valued independent variables and regression analysis for the continuous independent variables. Variables with significant associations (any P value < .10) identified by this initial analysis were then included in a forward selection multivariate regression model for which a significance level of .05 was used. The distributions of the aggregate test characteristics were compared by using the [chi square] tests and Fisher exact test; a significance level of .05 was used for these tests. All statistical tests were performed with SAS 9.2 (SAS Institute, Cary, North Carolina).

RESULTS Demographics

Twenty-six institutions submitted data for this Q-Probes study. Twenty-five (97%) were located in the United States and 1 in Brazil. Sixteen (62%) were teaching hospitals and 12 (46%) had pathology residency training programs.

Participant Characteristics

Within the past 2 years, all 26 participating laboratories had been inspected by the CAP, and 3 (11%) had been inspected by The Joint Commission. Seventeen (65%) institutions were urban, 5 (19%) were suburban, and 4 (15%) were rural. Fifteen (58%) were voluntary nonprofit hospitals, 6 (23%) were nongovernmental university hospitals, and there was 1 laboratory from each of the following categories: governmental nonfederal university, other nongovernmental, proprietary hospital, system/integrated delivery network, and veterans hospital. Distribution of bed size was as follows: 0-150, 8 (31%); 151-300, 7 (27%); 301450, 2 (8%); 451-600, 5 (19%); and greater than 600, 4 (15%).

Practice Characteristics

In the prior year (2012), participating laboratories had accessioned a median of 16 963 surgical pathology cases (10th to 90th percentile range, 4832-40 425) and a median of 2507 nongynecologic cytology cases (10th to 90th percentile range, 276-11 530).

Retrospective Study of Lung, Colon, and Melanoma

The retrospective portion of the study consisted of a collection of testing that had been either performed or attempted on cases of colon primary carcinoma, lung primary carcinoma, and melanoma. Twenty-six institutions reported data on 1508 testing events. In aggregate, 996 of 1508 (66%) strictly adhered to NCCN guidelines and 1319 of 1508 (87%) at least loosely met guidelines. For all institutions the median for strict adherence was 71% and median for loose adherence was 95% (Table 1). The median turnaround time was 8 days, with a 10th to 90th percentile range of 4 to 13 days. The aggregate turnaround time was wide, ranging from same day to 127 days. There was adequate tissue to obtain a test result in a median 98%, with a 10th to 90th percentile range of 86% to 100%. Details of the individual cases are listed in Table 2. Pathologist-initiated reflex testing accounted for 483 of 1508 of testing (32%), while medical oncologist orders accounted for 56%. The tested specimen was an excision in a minority of cases (498 of 1508, 33%), with the remainder of specimens consisting of smaller biopsy samples. The molecular tests performed or attempted are listed in Table 3; EGFR, ALK, and KRAS were the most common by a large margin. Details regarding adequacy of material by specimen type are in Table 4; cell blocks showed a significantly lower adequacy rate than other specimen types (P < .001). Lynch syndrome screening was to be excluded from the retrospective study, but some participants did include such cases (93 of 1508 test events, 6.2% of total).

Prospective Study of All Case Types

The prospective portion of the study consisted of a collection of requests for molecular testing regardless of organ site. Twenty-three institutions reported data on 722 testing events. In aggregate, 360 of 722 (50%) strictly adhered to NCCN guidelines and 645 of 722 (89%) at least loosely met guidelines. For all institutions the median for strict adherence was 53% and the median for loose adherence was 94% (Table 1). Details for the individual cases are listed in Table 5. The most common organ sites were the lower gastrointestinal tract and lung. Pathologist-initiated reflex testing accounted for 303 of 722 tests (42%) and medical oncologists accounted for 325 of 722 test requests (45%). Again, excision specimens were in the minority (303 of 722, 42%). Details regarding the molecular tests requested are listed in Table 6. The most common requests were for EGFR, KRAS, ALK, Lynch syndrome screening, and BRAF.

General Questionnaire

Participants also completed a general questionnaire regarding various aspects of institutional practices and handling of some specific testing situations (Tables 7 through 12). Most laboratories do not have a written policy for turnaround time goals in molecular testing. There was variation in how molecular test orders are handled, including 4 of 23 participants (17%) reporting that neither MD nor PhD personnel are involved in the process. Slightly more than half of participants require pathology department approval for some molecular testing, and generally such approval is required for send-out testing, proprietary tests, and testing for inpatients. One institution required pathology approval for all molecular tests. It appears that some effort is made to have block and slide selection performed by a pathologist familiar with the case, though a small minority of laboratories (2 of 23, 9%) have designated a specific pathologist for this function. In terms of creating an integrated report, 15 of 23 laboratories (65%) routinely incorporate molecular test results into anatomic pathology reports, and two-thirds of those participants routinely include correlative information as to the significance of the test results. Participation in tumor boards was common, with general tumor boards (18 of 23, 78%) and breast conferences (18 of 23, 78%) the most common. Nearly all of the participating institutions (19 of 21, 90%) hold cancer accreditation of some form. Additional practice details are listed in Table 7.

Pathologist-initiated reflex testing is performed in slightly more than half of participating laboratories (13 of 23, 57%), and most (8 of 13, 62%) of these institutions do not require a standing written order for such reflex testing. The most commonly performed reflex tests were immunohistochemistry for mismatch repair proteins (12 of 13, 92%), followed by ALK and EGFR testing on lung tumors with appropriate histology (8 of 13, 62% each) and KRAS testing on colon cancers (8 of 13, 62%). A minority of laboratories (5 of 13, 39%) use a sequential or algorithmic approach to reflex testing. Most laboratories (18 of 23, 78%) are able to meet the 10-day turnaround time goal for EGFR and ALK testing on lung cases. Additional details are listed in Table 8.

Participants reported details on special handling techniques for small biopsy samples and cytology specimens in anticipation of molecular testing. Roughly half of laboratories handle lung biopsy samples differently from other specimen types, including cutting additional unstained slides or making fewer initial levels for hematoxylin-eosin staining. Preliminary adequacy assessment for fine-needle aspiration specimens is provided in 21 of 23 laboratories (91%). Additional details are listed in Table 9.

Laboratories reported which molecular tests were performed in-house versus send-out in their practices (Table 10). Most tests are send-outs, and 10 laboratories do not perform any in-house molecular tests. For in-house testing, participants reported various details regarding micro-dissection and reporting. The Medicare 14-day rule was not consistently followed, as more than half of participants (6 of 11, 55%) disregard the rule for in-house testing and 9 of 22 (41%) disregard the rule for send-out testing. Additional details are listed in Table 11.

There was variation in the approach to screening for Lynch syndrome, with 6 of 23 (26%) using an algorithm involving reflex immunohistochemistry and polymerase chain reaction testing and an equal proportion routinely performing both tests concurrently. The remainder varied by clinician request and individual pathologist practice. Similarly, there was wide variation in how patients were selected for testing. Additional details are provided in Table 12.

Practice Characteristics and the Effect on the Performance Indicators

The performance indicators were tested for associations with institutional demographic and practice variables. A P value below .05 was considered statistically significant. Although no associations were identified between the performance indicators and the demographic or practice characteristics, 2 observations were found for the retrospective study of lung, colon, and melanoma cases. First, institutions holding a higher number of multidisciplinary conferences tended to have a higher rate of molecular testing at least loosely meeting guidelines (P = .07). Second, compared to colon cancer and melanoma, lung cancer testing more often strictly met guidelines (74% lung, 44% colon, 61% melanoma, P < .001) and more often at least loosely met guidelines (90% lung, 81% colon, 82% melanoma, P < .001). Two similar observations were found for the prospective study of all case types. First, testing on lung cancer more often strictly met guidelines when compared to other specimen sites, such as melanoma and lower gastrointestinal tract (71% lung, 63% melanoma, 29% colon, 39% aggregate other, P < .001). Second, testing on lung, colon, brain/spinal cord, and skin/melanoma more often at least loosely met guidelines when compared to all other sites (96% lung, 87% colon, 96% melanoma, 96% brain/spinal cord, 82% aggregate other, P < .001), based on the aggregate test results. Rural institutions had a longer molecular testing turnaround time than institutions located in city/suburban areas. This observation was not formally tested because of the low sample size (4 rural and 22 city/ suburban institutions), but the rural turnaround time was a median 13 days (range, 8-16 days), whereas city/suburban turnaround time was a median 7 days (range, 1-12 days).

COMMENT

This Q-Probes study examined the rate of adherence to NCCN guidelines for molecular testing, the turnaround time for molecular tests, and the adequacy of specimens for testing. The study included both in-house and send-out testing on anatomic pathology specimens. Excluded from the study were cases of hematolymphoid neoplasia, breast primary carcinomas, and gynecologic cytology specimens.

The study consisted of 2 data collections: 1 retrospective and 1 prospective. The retrospective collection consisted of testing that had been previously performed or attempted and was restricted to lung carcinoma, colorectal carcinoma, and melanoma. In addition to allowing a more focused assessment of solid tumors that are commonly tested, the retrospective collection enabled assessment of turnaround time and adequacy of material for test completion. The retrospective data collection revealed that a median 71% of cases strictly met guidelines and a median 95% at least loosely met guidelines. In the retrospective collection the most common tests were for EGFR, ALK, and KRAS, in aggregate comprising 74% (1111 of 1508) of tests.

The prospective data collection consisted of requests for molecular testing and included a broader spectrum of organ sites. This data collection enabled assessment of the breadth of molecular test requests, the distribution of tumor types and organ sites undergoing testing, and allowed capture of any test requests that, for various reasons, ultimately may not have been completed. For the prospective collection, a median of 53% of cases strictly met guidelines and a median 94% at least loosely met guidelines. The most common tests requested were for EGFR, KRAS, ALK, Lynch syndrome screening, and BRAF, in aggregate comprising 86% (621 of 722) of the test requests.

Ranges of guideline adherence were quite broad among the participating institutions. Institutions holding a higher number of multidisciplinary conferences tended to have a higher percentage of testing that met guidelines. Tests were most frequently requested and/or performed on lung and lower gastrointestinal tract specimens. Testing on lung carcinomas more often met NCCN guidelines than for other organ sites. Perhaps this is related to the higher profile and increased emphasis on molecular testing of lung cancers through both the NCCN and the recently published CAP/ IASLC/AMP guideline for EGFR and ALK testing. (5) Median turnaround time for molecular tests was 8 days, which meets the recommended 10-day turnaround time goal set by the CAP/IASLC/AMP guideline. From our study's general questionnaire, 78% of participants report they are able to routinely meet the 10-day turnaround time goal for EGFR and ALK testing in lung cancer. Thus, the 10-day goal seems reasonable. A sequential or algorithmic approach to lung testing has potential to reduce the number of tests performed, but only a minority (5 of 13, 39%) of our study participants reported such an approach, and this was likely because of turnaround time concerns. In a recent survey of National Cancer Institute-designated cancer centers, average turnaround time for lung cancer testing with a sequential approach was 22.8 days, as compared to 7.6 days when tests were performed concurrently. (6) Most laboratories (18 of 23, 78%) in our study do not have a formal written goal for turnaround time in molecular testing in anatomic pathology.

This study provides some insights into pathologist involvement in molecular testing and the important function of the pathologist as gatekeeper. In our study most specimens used for molecular testing were small biopsy samples, highlighting the pathologist's continuing challenge to accomplish ever more with ever less material. In aggregate, 96% (751 of 785) of specimens had adequate material for testing, but there were statistically significant differences for the specimen type, with a cytology cell block adequacy rate of only 84% (80 of 95). It is notable that 91% (21 of 23) of participants routinely perform preliminary adequacy assessments for fine-needle aspiration specimens, thus the cell block adequacy rate in our study may actually be higher than typical. There were too few data points to link specimen adequacy to molecular laboratory dissection practices. Although pathologist-initiated reflex testing comprised a minority of the testing in our study, 57% (13 of 23) of laboratories reported that they routinely provide some form of either reflex or algorithmic testing, and most of those laboratories (8 of 13, 62%) do not require a standing written order for the testing. Perhaps the other laboratories require written orders as a means to avoid any appearance of inappropriate self-referral. The most common reflex testing was for Lynch syndrome screening in colon carcinomas, followed by ALK and EGFR for lung carcinomas, and KRAS for colon carcinomas. Similar to other studies, (7-9) we found considerable variability in both the selection of patients for Lynch syndrome screening and in the performance of the various test components, highlighting the need for standardization in this area.

More than half of participants report that pathology department approval is required for at least a subset of molecular tests, with approval most often required for send-out testing, tests for inpatients, and proprietary tests. There was inconsistent consideration of the 14-day rule for Medicare patients; for in-house testing, 55% (6 of 11) of laboratories ignore the rule and perform testing at the time of request, but only 41% (9 of 22) ignore the rule for send-out testing. This likely reflects an attempt to balance financial concerns with turnaround time pressures, but laboratories must tread lightly since inadvertent submission of inappropriate charges to Medicare may risk false claims accusations. In most practices orders for molecular testing are handled by a pathologist or PhD scientist, but 17% (4 of 22) of laboratories reported that such orders are typically handled by non-MD, non-PhD personnel. Most laboratories (15 of 23, 65%) incorporate molecular testing into a comprehensive anatomic pathology report, with 67% (10 of 15) of those laboratories routinely adding correlative information regarding the significance of the molecular testing results.

There are limitations to the data we report. We chose NCCN guidelines because they are comprehensive and widely used, but we recognize that other treatment guidelines exist. The field of molecular pathology is rapidly evolving, thus the appropriateness of testing on specific tumors or organ sites is fluid and ongoing clinical trials will continue to alter practice patterns. The NCCN guidelines have been updated multiple times since the data collection for this study began. Assessing adherence to NCCN guidelines was not always clear cut and there were some gray areas involved, hence the designations of "strict adherence" and "loose adherence" to guidelines. In some cases the ambiguity was related to the guidelines themselves, in others it was due to limitations in our data collection, and in others it was due to limitations in what participants reported. One example of guideline ambiguity is screening for Lynch syndrome. While NCCN encourages testing of all patients with colorectal carcinoma who are younger than 50 years or patients with stage II disease, it does not state specific criteria for Lynch syndrome testing. Some centers have implemented screening of all colorectal and endometrial cancers, regardless of age at diagnosis or family history, and this approach has been endorsed for colorectal cancer by the Evaluation of Genomic Applications in Practice and Prevention Working Group from the Centers for Disease Control. (9) Similarly, ROS1 testing for lung cancer is a "consideration" in patients who are ALK negative. For melanoma, KIT mutation analysis is listed as part of "other active regimens" without strict guidance as to which patients should be tested.

To keep the data collection manageable for participants, the required data points for each submitted case were kept to a minimum and, in some instances, this affected assessment of guideline adherence. For example, we did not ask for tumor grade; O-6-methylguanine-DNA-methyltransferase gene (MGMT) testing is not appropriate for all gliomas but is restricted to high-grade tumors. We also did not delineate specific locations of head and neck squamous cell carcinomas; human papilloma virus testing is not necessarily appropriate for every site in the head and neck. We did not collect data regarding prior treatment regimens; KIT and platelet-derived growth factor receptor a gene (PDGFRa) mutation testing is not necessarily warranted for every patient with gastrointestinal stromal tumor. We also did not collect data regarding appropriateness of specific testing methodologies (eg, EGFR mutation analysis versus EGFR amplification by fluorescence in situ hybridization). Assessment of testing appropriateness is not possible for tumors of unknown primary site.

Limitations in participants' submitted data included some cases with clearly inaccurate data entered (eg, "bone primary adenocarcinoma") and some write-in responses for test names that were unrecognizable. For lung primary carcinomas, the study input form listed all possible carcinoma histologic subtypes, but some cases were submitted with histology of "other," making it likely that at least some of the data were reported by nonpathologists.

Our data collection did not ascertain if molecular testing was performed on all cases that could have potentially undergone testing, thus we do not have a denominator or any means of measuring underutilization of molecular testing. Our data also do not address what inappropriate testing may have been performed despite objection by the pathologist. Particularly in the community setting, where a pathologist's livelihood depends on providing good customer service, it can be difficult to deny insistent clinicians. We also do not know if the results of the molecular tests were acted upon, which could be the focus of a future study. Finally, considering our small sample size of 26 institutions, nearly all of which held cancer center accreditation, our data are likely not generalizable to all of pathology practice.

In summary, this Q-Probes study aimed to assess the proportion of anatomic pathology molecular testing that adheres to NCCN guidelines. We are not aware of any prior multi-institutional study of this topic. The study is limited by a low number of participants, but it does provide useful benchmarking data and important information regarding how laboratories are handling this rapidly growing facet of pathology practice.

The authors thank the participating institutions for their time and diligence in collecting the data for this study.

References

(1.) National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. 2013. http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp#site. Accessed March 30, 2013.

(2.) National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology--non small cell lung carcinoma. Version 2. 2013. http://www nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed March 30, 2013.

(3.) National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology-colon cancer. Version 3. 2013. http://www.nccn.org/ professionals/physician_gls/pdf/colon.pdf. Accessed March 30, 2013.

(4.) National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology--melanoma. Version 2. 2013. http://www.nccn.org/ professionals/physician_gls/pdf/melanoma.pdf. Accessed March 30, 2013.

(5.) Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013; 137(6):828-1174.

(6.) Schink JC, Trosman JR, Weldon, CB, et al. Biomarker testing methods in breast, gastric, and lung cancers: a benchmarking survey of NCI cancer centers. / Clin Oncol. 2013; 31(suppl):Abstract e22093.

(7.) Beamer LC, Grant ML, Espenschied CR, et al. Reflex immunohistochemistry and microsatellite instability testing of colorectal tumors for Lynch syndrome among US cancer programs and follow-up of abnormal results. J Clin Oncol. 2012; 30:1058-1063.

(8.) Bellcross CA, Bedrosian SR, Daniels E, et al. Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting. Genet Med. 2012; 14(1):152-162.

(9.) Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1):35-41.

Keith E. Volmar, MD; Michael O. Idowu, MD, MPH; Rhona J. Souers, MS; Raouf E. Nakhleh, MD

Accepted for publication November 24, 2014.

From the Department of Pathology, Rex Pathology Associates, Raleigh, North Carolina (Dr Volmar); the Department of Pathology, Virginia Commonwealth University, Richmond (Dr Idowu);the Department of Biostatistics, College of American Pathologists, Northfield, Illinois (Ms Souers); and the Department of Pathology, Mayo Clinic Jacksonville, Jacksonville, Florida (Dr Nakhleh).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Keith E. Volmar, MD, Rex Pathology Associates, 4420 Lake Boone Trail, Raleigh, NC 27607 (e-mail: keith.volmar@ rexhealth.com).
Table 1. Molecular Testing Adherence to National
Comprehensive Cancer Network Guidelines

                               All Institutions Percentiles

                       n    10th   25th   Median   75th    90th
Retrospective study
  (lung, colorectal,
  melanoma)
Percentage of tests    26   32.6   64.7    70.9    82.7    89.7
  that strictly meet
  the guideline
Percentage of tests    26   57.4   90.7    95.1    98.9    100.0
  that at least
  loosely meet the
  guideline
Prospective study
  (all case types)
Percentage of tests    23   20.0   31.4    53.3    66.7    70.5
  that strictly meet
  the guideline
Percentage of tests    23   75.0   87.0    94.3    100.0   100.0
  that at least
  loosely meet the
  guideline

Table 2. Details of Retrospective Study
(Lung, Colon, Melanoma)

                                         No.   Percentage
Case type
Lung carcinoma                           499         60.7
Colon carcinoma                          251         30.5
Melanoma                                  72          8.8
Histology
Adenocarcinoma (invasive)                598         73.4
Melanoma                                  73          9.0
Non-small cell carcinoma, not
otherwise specified                       49          6.0
Carcinoma, not otherwise specified        26          3.2
Squamous cell carcinoma                   20          2.5
Adenocarcinoma in situ                    15          1.8
Adenosquamous carcinoma                    5          0.6
Large cell neuroendocrine
carcinoma                                  5          0.6
Large cell carcinoma, not otherwise
specified                                  3          0.4
Small cell carcinoma                       3          0.4
Carcinoid/low-grade neuroendocrine
tumor                                      1          0.1
Other                                     17          2.1
Ordering provider
Medical oncologist                       451         56.4
Pathologist (reflex test)                257         32.1
Surgeon                                   61          7.6
Radiology oncologist                       6          0.8
Generalist                                 3          0.4
Other                                     22          2.8
Specimen type
Excision                                 268         32.6
Core biopsy                              186         22.6
Incisional or open biopsy                163         19.8
Cytology cell block                       96         11.7
Cytology smear                             5          0.6
Other small biopsies (eg, forceps
biopsies)                                104         12.7
Extent of clinical disease
Metastasis proven                        354         43.1
Not known                                247         30.0
Locally confined                         120         14.6
Metastasis suspected                      51          6.2
Locally advanced                          44          5.4
Recurrence or refractory                   6          0.7
Primary reason for test request
Predictive/guide therapy                 515         62.8
Not known                                138         16.8
Diagnostic                                91         11.1
Prognostic                                74          9.0
Patient request                            1          0.1
Research/clinical trial                    1          0.1
Adequate material for testing
Yes                                      752         95.7
No                                        34          4.3
No. of molecular tests performed or
attempted per case
1                                        387         47.4
2                                        261         32.0
3                                        110         13.5
4                                         27          3.3
5                                         25          3.1
6                                          6          0.7

Table 3. Tests Performed or Attempted
in Retrospective Study (Lung, Colon, Melanoma)

Molecular Test Performed
or Attempted                            No.   Percentage

EGFR                                    446         29.6
ALK (EML4-ALK)                          358         23.7
KRAS                                    307         20.4
BRAF                                    114          7.6
Lynch syndrome screening (MMR/MSI)       93          6.2
NRAS                                     39          2.6
PIK3CA                                   39          2.6
ROS1                                     24          1.6
KIT                                      22          1.5
HER2/ERBB2 (only nonbreast cases)         5          0.3
ERCC1                                     3          0.2
HRAS                                      2          0.1
MET                                       2          0.1
Other                                    54          3.6
Other molecular test, submitted text
response
Proprietary tests (45)                  ...          ...
Unrecognized tests (9)                  ...          ...

Abbreviations: ALK, anaplastic lymphoma receptor
tyrosine kinase (anaplastic lymphoma kinase);BRAF,
B-Raf proto-oncogene, serine-threonine kinase
(v-raf murine sarcoma viral oncogene homolog B);
EGFR, epidermal growth factor receptor;EML4,
echinoderm microtu-bule-associated protein-like 4;
ERCC1, excision repair cross-comple-mentation
group 1; HER2-ERBB2, v-erb-b2 avian erythroblastic
leukemia viral oncogene homolog 2 (human epidermal
growth factor receptor 2); HRAS, Harvey rat
sarcoma viral oncogene homolog;KIT, v-kit
Hardy-Zuckerman 4 feline sarcoma viral oncogene
homolog;KRAS, Kirsten rat sarcoma viral oncogene
homolog; MET, MET proto-oncogene, receptor
tyrosine kinase;MMR, mismatch repair protein; MSI,
microsatellite instability; NRAS, neuroblastoma
rat sarcoma viral (v-ras) oncogene homolog;
PIK3CA, phosphatidylinositol-4,5-bisphos-phate
3-kinase, catalytic subunit a; ROS1, ROS
protooncogene 1, receptor tyrosine kinase.

Table 4. Specimen Type and Adequacy
for Molecular Testing (Retrospective Study
of Lung, Colon, Melanoma)

                              No. of    No. With Adequate
Specimen Type (a)           Specimens      Material (%)

Excision                          251          250 (99.6)
Core biopsy                       176          163 (92.6)
Incisional or open biopsy         155          152 (98.1)
Cytology cell block                95           80 (84.2)
Cytology smear                      5            4 (80.0)
Other small biopsies
  (eg, forceps biopsies)          103          102 (99.0)

(a) Statistically significant difference between
cytology cell block and all other types (Fisher
exact test;P < .001).

Molecular Testing in Anatomic Pathology-Volmar et
al 1118

Table 5. Details of Prospective Study (All Case
Types)
                                        No.   Percentage
Tumor site
  Lower gastrointestinal tract (small
    bowel, colon)                       177         35.8
  Lung                                  171         34.6
  Skin                                   24          4.9
  Brain and spinal cord                  19          3.8
  Genital, female                        19          3.8
  Lymph node                             14          2.8
  Upper gastrointestinal tract
    (esophagus, stomach, duodenum)       14          2.8
  Thyroid                                11          2.2
  Liver and biliary tract                 9          1.8
  Nasopharynx-oropharynx-
    hypopharynx                           7          1.4
  Unknown primary                         7          1.4
  Soft tissue                             6          1.2
  Kidney                                  5          1.0
  Genital, male                           2          0.4
  Breast (exclude primary carcinoma)      1          0.2
  Salivary gland                          1          0.2
  Other                                   7          1.4
Histology
  Adenocarcinoma (invasive)             359         72.7
  Melanoma                               30          6.1
  Carcinoma, not otherwise specified     27          5.5
  Glioma                                 18          3.6
  Non-small cell carcinoma, not
    otherwise specified                  16          3.2
  Squamous cell carcinoma                14          2.8
  Adenocarcinoma in situ                  5          1.0
  Large cell neuroendocrine
    carcinoma                             4          0.8
  Sarcoma                                 3          0.6
  Gastrointestinal stromal tumor          1          0.2
  Large cell carcinoma, not otherwise
  specified                               1          0.2
  Small cell carcinoma                    1          0.2
  Other                                  15          3.0
Ordering provider
  Medical oncologist                    216         45.0
  Pathologist (reflex test)             201         41.9
  Surgeon                                50         10.4
  Radiology oncologist                    7          1.5
  Geneticist                              2          0.4
  Other                                   4          0.8
Specimen type
  Excision                              208         42.3
  Core biopsy                            82         16.7
  Incisional or open biopsy              76         15.4
  Cytology cell block                    47          9.6
  Other small biopsies (eg, forceps
    biopsies)                            79         16.1
Extent of clinical disease
  Metastasis proven                     202         40.9
  Not known                             138         27.9
  Locally confined                       90         18.2
  Locally advanced                       36          7.3
  Metastasis suspected                   23          4.7
  Recurrence or refractory                5          1.0
Primary reason for test request
  Predictive/guide therapy              285         57.9
  Prognostic                            117         23.8
  Diagnostic                             70         14.2
  Not known                              19          3.9
  Research/clinical trial                 1          0.2
No. of requested molecular tests per
  case
  1                                     254         55.8
  2                                     142         31.2
  3                                      52         11.4
  4                                       7          1.5

Table 6. Test Requests From Prospective Study
(All Case Types)

Molecular Test Requested                   No.   Percentage

EGFR                                       163         22.6
KRAS                                       159         22.0
ALK (EML4-ALK)                             114         15.8
Lynch syndrome screening (MMR/MSI)         113         15.7
BRAF                                        74         10.2
HER2/ERBB2 (only nonbreast cases)           14          1.9
MGMT methylation                            14          1.9
K/T                                         13          1.8
HPV in situ hybridization (excluding
  GYN cytology)                              9          1.2
ROSI                                         8          1.1
1p and 19q deletion                          6          0.8
/DH1 and/or /DH2 mutation                    4          0.6
NRAS                                         2          0.3
PAX8-PPARA                                   2          0.3
HPV genotype (excluding GYN
  cytology)                                  1          0.1
HRAS                                         1          0.1
MET                                          1          0.1
PDGFRA                                       1          0.1
Other                                       23          3.2
Other molecular test, submitted text
    response
  Proprietary tests (19)                   ...          ...
  MSH6 (1)                                 ...          ...
  TP53 (1)                                 ...          ...
  Thymidylate synthase (1)                 ...          ...
  Unrecognized test (1)                    ...          ...

Abbreviations: ALK, anaplastic lymphoma receptor
tyrosine kinase (anaplastic lymphoma kinase);BRAF,
B-Raf proto-oncogene, serine-threonine kinase
(v-raf murine sarcoma viral oncogene homolog B);
EGFR, epidermal growth factor receptor;EML4,
echinoderm microtu-bule-associated protein-like
4;GYN, gynecologic; HER2-ERBB2, v-erb-b2 avian
erythroblastic leukemia viral oncogene homolog 2
(human epidermal growth factor receptor 2);HPV,
human papilloma virus; HRAS, Harvey rat sarcoma
viral oncogene homolog;-DH, isocitrate
dehydrogenase;K-T, v-kit Hardy-Zuckerman 4 feline
sarcoma viral oncogene homolog; KRAS, Kirsten rat
sarcoma viral oncogene homolog;MET, MET
protooncogene, receptor tyrosine kinase
(protooncogene-C-Met); MGMT,
O-6-methylguanine-DNA-methyltransfer-ase;MMR,
mismatch repair
protein;MSH6, mutS homolog 6;MSI, microsatellite
instability; NRAS, neuroblastoma rat sarcoma viral
oncogene homolog;PAX8-PPARA, paired box
8-peroxisome prolifer-ator-activated receptor a;
PDGFRA, platelet-derived growth factor receptor, a
polypeptide;ROSI, ROS proto-oncogene 1, receptor
tyrosine kinase (c-ros oncogene 1); TP53, tumor
protein p53.

Table 7. Laboratory Practices Related to
Management and Reporting of Molecular Tests

                                                No.   Percentage

Does your laboratory have a written
    policy for turnaround time goals for
    molecular testing on solid tumors in
    anatomic pathology?
  Yes                                             5         21.7
  No                                             18         78.3
Who typically manages orders for
    molecular testing on solid tumors in
    anatomic pathology in your department?
  Any available pathologist                      10         43.5
  Non-MD, non-PhD personnel                       4         17.4
  Select pathologist(s) specifically              4         17.4
  designated for this function
  Other                                           4         17.4
  Other category, submitted text response       ...          ...
    Case pathologist (2)
    Combination of MD, non-MD,                  ...          ...
    non-PhD personnel (1)
    PhD specifically assigned                   ...          ...
    for case (1)
  N/A, such orders are typically                  1          4.3
  managed through standing protocols
Is pathology department approval
    required for any molecular tests on
    solid tumors in anatomic pathology in
    your institution?
  Yes                                            12         52.2
  No                                             11         47.8
If yes, which of the following require
    pathology department approval? (a) (n = 12)
  Send-out molecular tests                       11         91.7
  Molecular tests on inpatients                   8         66.7
  Proprietary molecular tests                     7         58.3
  Molecular tests above a cost threshold          1          8.3
  Other                                           1          8.3
  Other category submitted text response
    All molecular testing (1)
Who typically chooses the blocks or
    slides used for molecular testing on
    solid tumors in anatomic pathology?
  Pathologist familiar with the case             14         60.9
  Any available pathologist                       7         30.4
  Select pathologist(s) specifically              2          8.7
  designated for this function
Do you incorporate the results of
    molecular testing for solid tumors into
    anatomic pathology reports?
  Yes, either an addendum or amendment is        15         65.2
  issued to the anatomic pathology report
  No                                              8         34.8
If yes, do you routinely provide
    correlative information regarding the
    significance of the molecular test
    results?
  Yes                                            10         66.7
  No                                              5         33.3
Which multidisciplinary conferences are
    held at your institution? (a) (n = 23)
  Breast                                         18         78.3
  General tumor board                            18         78.3
  Gastrointestinal                               11         47.8
  Genitourinary                                  11         47.8
  Gynecologic                                    11         47.8
  General surgical conference                     9         39.1
  Hematopathology                                 9         39.1
  Infectious disease                              9         39.1
  Liver                                           9         39.1
  Neurosurgery                                    9         39.1
  Renal                                           9         39.1
  Thoracic                                        9         39.1
  Endocrine                                       8         34.8
  Head and neck                                   7         30.4
  None                                            1          4.3
Does your institution hold accreditation
    as a recognized cancer program? (a) (n =
    21)
  Yes, American College of Surgeons              15         71.4
  Commission on Cancer
  Yes, other cancer program accreditation         5         23.8
  No, my institution is not a cancer center       2          9.5

Abbreviation: N/A, not applicable.

(a) Multiple responses allowed.

Table 8. Laboratory Practices Related to
Reflex Testing and Turnaround Time

                                                 No.   Percentage

Does your laboratory routinely initiate
    reflex molecular testing on solid tumors
    in anatomic pathology?
  Yes                                             13         56.5
  No, we do not perform reflex                    10         43.5
  molecular testing
If yes, do you require a standing order
    for reflex testing?
Yes                                                5         38.5
No                                                 8         61.5
If yes, what reflex molecular testing
    do you routinely perform on solid tumors
    in anatomic pathology? (a) (n = 13)
  MMR immunohistochemistry for colon cancers      12         92.3
  ALK (EML4-ALK) for lung cancers with             8         61.5
  appropriate histology
  EGFR for lung cancers with                       8         61.5
  appropriate histology
  KRAS for colon cancers with                      8         61.5
  appropriate histology
  KRAS for lung cancers with                       7         53.8
  appropriate histology
  MSI polymerase chain reaction                    7         53.8
  for colon cancers
  BRAF for melanomas                               5         38.5
  BRAF for colon cancers with                      3         23.1
  appropriate histology
  ROS1 for lung cancers with                       1          7.7
  appropriate histology
If yes, does any of your reflex
    testing on solid tumors follow a
    sequential or algorithmic approach?
  Yes                                              5         38.5
  No                                               8         61.5
What is your most common approach for
    EGFR and EML4-ALK testing in
    non-small cell lung carcinomas?
  Both tests are performed at the same            15         65.2
  time (only EGFR and EML4-ALK
  are performed)
  These 2 tests are performed as part              7         30.4
  of a broader test panel
  A sequential/algorithmic approach is             1          4.3
  used (involving only EGFR and EML4-ALK)
Are you able to consistently meet the
    recommended turnaround time
    goal of 10 working days for EGFR
    and EML4-ALK testing in non-small
    cell lung carcinomas?
  Yes                                             18         78.3
  No                                               5         21.7

Abbreviations: ALK, anaplastic lymphoma receptor
tyrosine kinase (anaplastic lymphoma kinase);BRAF,
B-Raf proto-oncogene, serine-threonine kinase
(v-raf murine sarcoma viral oncogene homolog B);
EGFR, epidermal growth factor receptor;EML4,
echinoderm microtubule-associated protein-like
4;KRAS, Kirsten rat sarcoma viral oncogene
homolog;MMR, mismatch repair protein;MSI,
microsatellite instability; ROS1, ROS
protooncogene 1, receptor tyrosine kinase (c-ros
oncogene 1).

(a) Multiple responses allowed.

Table 9. Laboratory Practices Related to Small
Biopsy and Cytology Specimens

                                                   No.    Percentage
Do you routinely use techniques to
    preserve tissue for molecular testing
    for small biopsy and FNA specimens?
  Yes, lung tumor biopsy specimens are              12          52.2
  handled differently
  No, all specimens are handled in                  11          47.8
  basically the same manner
If applicable, how are lung tumor biopsy
    specimens handled differently? (a) (n = 12)
  Additional unstained slides are                    9          75.0
  initially cut from biopsy specimens
  Fewer initial levels are made compared             3          25.0
  to other biopsy specimens
  Immunohistochemical study is typically             2          16.7
  limited to a certain number of stains
  Additional unstained FNA smears are made           1           8.3
Other                                                4          33.3
Other category submitted text response
  Dual stains used (1)
  EGFR ordered before immunohistochemistry (1)
For lung biopsy specimens, what is the
    number of additional unstained slides
    initially cut?
  3                                                  1          11.1
  5                                                  4          44.4
  6                                                  2          22.2
  9                                                  1          11.1
  15                                                 1          11.1
For lung biopsy specimens, what is the
    typical limit of the number of slides
    for immunohistochemical study?
2                                                    1          50.0
3                                                    1          50.0
For fine-needle aspiration specimens,
    does your department provide preliminary
    adequacy assessment?
Yes, routinely                                      21          91.3
No, we do not provide on-site assessment             2           8.7

Abbreviations: EGFR, epidermal growth
factor receptor; FNA, fine-needle
aspiration.

(a) Multiple responses allowed.

Abbreviations: ALK, anaplastic lymphoma receptor
tyrosine kinase (anaplastic lymphoma kinase);BRAF,
v-raf murine sarcoma viral oncogene homolog B;
EGFR, epidermal growth factor receptor;EML4,
echinoderm microtubule-associated protein-like 4;
HER2-ERBB2, v-erb-b2 avian erythroblastic leukemia
viral oncogene homolog 2 (human epidermal growth
factor receptor 2);K-T, v-kit Hardy-Zuckerman 4
feline sarcoma viral oncogene homolog;KRAS,
Kirsten rat sarcoma viral oncogene homolog;MMR,
mismatch repair protein;MSI, microsatellite
instability; RET, RET proto-oncogene.

Table 10. Laboratory Practices Related to Molecular Testing Location

                                      In-House           Send-Out

Where are each of the            No.   Percentage   No.   Percentage
following  molecular
tests performed in
your practice?

MMR immunohistochemistry         12       54.5      10       45.5
HER2/ERBB2 fluorescence           9       39.1      14       60.9
  in situ hybridization
KRAS mutation analysis            8       34.8      15       65.2
BRAF mutation analysis            7       30.4      16       69.6
EGFR mutation analysis            5       21.7      18       78.3
ALK (EML4-ALK) fluorescence       5       21.7      18       78.3
  in situ hybridization
MSI polymerase chain reaction     5       23.8      16       76.2
K/T mutation analysis             2       11.1      16       88.9
RET mutation analysis             0        0.0      17      100.0

Table 11. Laboratory Practices Related
to Technical Aspects of Molecular
Testing

                                                           No.

For in-house molecular testing on solid tumors,
    do you perform microdissection of
    specimens for molecular
    testing? (a)  (n = 22)
  Yes, manual microdissection                                6
  Yes, laser capture microdissection                         1
  No, do not perform microdissection                         5
  of specimens
  N/A, we do not perform in-house molecular                 10
  testing on solid tumors
If applicable, which personnel type typically
    performs laser capture
    microdissection of specimens?
  Personnel other than                                       1
  histotechnologist/histotechnician,
  pathologist, or pathologist assistant
If applicable, which personnel type typically performs
    manual microdissection of specimens?
  Histotechnologist/histotechnician                          2
  Personnel other than                                       5
  histotechnologist/histotechnician,
  pathologist, or pathologist assistant
For in-house molecular testing on solid tumors,
    does your molecular report
    include an assessment of the
    amount of tumor in the specimen?
  Yes                                                        5
  No                                                         7
If yes, how is an assessment of the amount of tumor
    in the specimen reported? (a) (n = 5)
  Percentage of tumor cellularity is reported                4
  Other                                                      1
For in-house molecular testing on solid tumors,
    which of the following best
   reflects how your laboratory
    typically handles the 14-day rule
    for Medicare patients?
  Rule is disregarded; testing is initiated                  6
  at the time of request
  Request is held; testing is initiated                      2
    after appropriate
    time interval has passed
  Other                                                      3
  Other category submitted text response
    Immunohistochemistry performed
    in-house, no requisition (1)
    Rule is followed; testing initiated
    upon request (1)
    Test is performed as soon as possible (1)
For send-out molecular testing on
     solid tumors, which of the
     following best reflects how your laboratory
     typically handles the 14-day rule
     for Medicare patients?
  Rule is disregarded; testing is initiated at               9
    the time of request
  Request is held; material is sent out after                8
    the appropriate time interval has passed
  N/A, we do not send out molecular tests                    1
    on solid tumors
  Reference laboratory holds the specimen                    1
    then runs the test at the appropriate time
  Other                                                      3
  Other category submitted text response
    Ask oncologist if result is needed (1)
    Rule is followed; testing
    initiated upon request (1)

                                                           Percentage

For in-house molecular testing on solid tumors,
    do you perform microdissection of
    specimens for molecular
    testing? (a)  (n = 22)
  Yes, manual microdissection                                    27.3
  Yes, laser capture microdissection                              4.5
  No, do not perform microdissection                             22.7
  of specimens
  N/A, we do not perform in-house molecular                      45.5
  testing on solid tumors
If applicable, which personnel type typically
    performs laser capture
    microdissection of specimens?
  Personnel other than                                            100
  histotechnologist/histotechnician,
  pathologist, or pathologist assistant
If applicable, which personnel type typically performs
    manual microdissection of specimens?
  Histotechnologist/histotechnician                              28.6
  Personnel other than                                           71.4
  histotechnologist/histotechnician,
  pathologist, or pathologist assistant
For in-house molecular testing on solid tumors,
    does your molecular report
    include an assessment of the
    amount of tumor in the specimen?
  Yes                                                            41.7
  No                                                             58.3
If yes, how is an assessment of the amount of tumor
    in the specimen reported? (a) (n = 5)
  Percentage of tumor cellularity is reported                    80.0
  Other                                                          20.0
For in-house molecular testing on solid tumors,
    which of the following best
   reflects how your laboratory
    typically handles the 14-day rule
    for Medicare patients?
  Rule is disregarded; testing is initiated                      54.5
  at the time of request
  Request is held; testing is initiated                          18.2
    after appropriate
    time interval has passed
  Other                                                          27.3
  Other category submitted text response
    Immunohistochemistry performed
    in-house, no requisition (1)
    Rule is followed; testing initiated
    upon request (1)
    Test is performed as soon as possible (1)
For send-out molecular testing on
     solid tumors, which of the
     following best reflects how your laboratory
     typically handles the 14-day rule
     for Medicare patients?
  Rule is disregarded; testing is initiated at                   40.9
    the time of request
  Request is held; material is sent out after                    36.4
    the appropriate time interval has passed
  N/A, we do not send out molecular tests                         4.5
    on solid tumors
  Reference laboratory holds the specimen                         4.5
    then runs the test at the appropriate time
  Other                                                          13.6
  Other category submitted text response
    Ask oncologist if result is needed (1)
    Rule is followed; testing
    initiated upon request (1)

Abbreviation: N/A, not applicable.

(a) Multiple responses allowed.

Table 12. Laboratory Practices Related to Lynch
Syndrome Screening

                                                    No.    Percentage
For colorectal carcinomas, how does your practice
    typically handle requests for Lynch
    syndrome screening
    (MMR/MSI testing) by IHC and PCR?
  No algorithm, IHC and PCR are typically             6          26.1
  performed concurrently
  Depends on clinician/geneticist request             6          26.1
  Algorithm starting with IHC, with reflex PCR        5          21.7
  Depends on pathologist                              2           8.7
  Algorithm starting with PCR, with reflex IHC        1           4.3
  Other                                               3          13.0
  Other category submitted text response
    IHC no reflex PCR (2)
    IHC performed first, then reflex PCR if
    applicable (1)
How are patients typically selected for Lynch
  All (or nearly all) patients with colorectal       11          47.8
  cancer are tested
  Depends on clinician request                        7          30.4
  Bethesda guidelines                                 1           4.3
  Amsterdam criteria                                  0           0.0
  Other                                               2           8.7
  Other category submitted text response
    Amsterdam criteria, Bethesda guidelines,
    clinician request and findings (1)
    Histology with/without Bethesda
    guidelines (1)
  Do not know                                         2           8.7
For Lynch syndrome screening in colorectal
    carcinomas, does your department require
    informed consent
from the patient for MMR/MSI testing by
    IHC and/or PCR?
  Yes                                                 2           8.7
  No                                                 18          78.3
  Do not know                                         3          13.0
Does your department perform Lynch syndrome
    screening tests on colorectal
    biopsy material?
  Yes                                                12          52.2
  No                                                 11          47.8
If yes, how is this typically handled? (a) (n = 12)
  IHC is performed                                   12         100.0
  PCR is performed                                    4          33.3
If yes and PCR is performed, what is typically
    used for the patient's normal DNA? (n = 4)
  Normal tissue is microdissected from the            3          75.0
  tumor biopsy block
  Additional normal tissue is purposely               1          25.0
  obtained at the time of biopsy

Abbreviations: IHC,
immunohistochemistry;MMR, mismatch
repair protein;MSI, microsatellite
instability; PCR, polymerase chain
reaction.

(a) Multiple responses allowed.
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Author:Volmar, Keith E.; Idowu, Michael O.; Souers, Rhona J.; Nakhleh, Raouf E.
Publication:Archives of Pathology & Laboratory Medicine
Date:Sep 1, 2015
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