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Toward Improving the Delivery of Oral Anticancer Drugs in the VA: Work IN PROGRESS
Purpose: An Innovation Network Spark award was received to develop “My Chemo Calendar,” a tool aimed at providing veterans with easy to understand critical information (eg drug name, schedule, side effects), to optimize the benefits of their oral anticancer drugs (OADs). Using a human-centered design approach, we are first obtaining insight from patients and providers on tools (including “my Chemo Calendar”) and strategies that may improve experiences with OADs.
Background: OADs often have complex dosing schedules, toxicity risk, and special handling precautions. Best tools and practices for ensuring safe and effective care for veterans who are prescribed OADs are not yet well established.
Methods: Surveys, focus groups, and semi-structured interviews are being conducted with patients and providers. Topics included: OAD education and knowledge, medication handling and adherence, and symptom management.
Data Analysis: Descriptive statistics will be used to summarize the survey data. Audio files from focus groups and semi-structured interviews will be transcribed and analyzed using NVivo.
Results: To date, data has been collected from two patients and eighteen oncology care providers. Both patients were ‘very satisfied’ with the information they received to successfully and safely take their OADs. They preferred to receive information from multiple sources (eg physician, internet, hand-outs). The majority of providers reported that they never/rarely/sometimes spoke about digesting an OAD with/without food, necessary diet modifications (e.g. no grapefruit), missed doses, medication storage temperatures, and refills. Most usually spoke about side effects, timing (eg morning), adverse effects, phone number to report side effects, and reporting concerning symptoms. Most were not/slightly/moderately confident that the patients were receiving all the necessary instructions to use the OAD properly. The oncology pharmacist was identified as the most appropriate oncology team member to provide patient education. Although, it was noted that it would be best for patients to receive information at various touch points from different team members. The concept of “My Chemo Calendar” was well received but how best to integrate it into care was unclear.
Implications: Data collection and analysis is still ongoing. This information will be used create and pilot new strategies and tools to improve experiences with OADs.
Purpose: An Innovation Network Spark award was received to develop “My Chemo Calendar,” a tool aimed at providing veterans with easy to understand critical information (eg drug name, schedule, side effects), to optimize the benefits of their oral anticancer drugs (OADs). Using a human-centered design approach, we are first obtaining insight from patients and providers on tools (including “my Chemo Calendar”) and strategies that may improve experiences with OADs.
Background: OADs often have complex dosing schedules, toxicity risk, and special handling precautions. Best tools and practices for ensuring safe and effective care for veterans who are prescribed OADs are not yet well established.
Methods: Surveys, focus groups, and semi-structured interviews are being conducted with patients and providers. Topics included: OAD education and knowledge, medication handling and adherence, and symptom management.
Data Analysis: Descriptive statistics will be used to summarize the survey data. Audio files from focus groups and semi-structured interviews will be transcribed and analyzed using NVivo.
Results: To date, data has been collected from two patients and eighteen oncology care providers. Both patients were ‘very satisfied’ with the information they received to successfully and safely take their OADs. They preferred to receive information from multiple sources (eg physician, internet, hand-outs). The majority of providers reported that they never/rarely/sometimes spoke about digesting an OAD with/without food, necessary diet modifications (e.g. no grapefruit), missed doses, medication storage temperatures, and refills. Most usually spoke about side effects, timing (eg morning), adverse effects, phone number to report side effects, and reporting concerning symptoms. Most were not/slightly/moderately confident that the patients were receiving all the necessary instructions to use the OAD properly. The oncology pharmacist was identified as the most appropriate oncology team member to provide patient education. Although, it was noted that it would be best for patients to receive information at various touch points from different team members. The concept of “My Chemo Calendar” was well received but how best to integrate it into care was unclear.
Implications: Data collection and analysis is still ongoing. This information will be used create and pilot new strategies and tools to improve experiences with OADs.
Purpose: An Innovation Network Spark award was received to develop “My Chemo Calendar,” a tool aimed at providing veterans with easy to understand critical information (eg drug name, schedule, side effects), to optimize the benefits of their oral anticancer drugs (OADs). Using a human-centered design approach, we are first obtaining insight from patients and providers on tools (including “my Chemo Calendar”) and strategies that may improve experiences with OADs.
Background: OADs often have complex dosing schedules, toxicity risk, and special handling precautions. Best tools and practices for ensuring safe and effective care for veterans who are prescribed OADs are not yet well established.
Methods: Surveys, focus groups, and semi-structured interviews are being conducted with patients and providers. Topics included: OAD education and knowledge, medication handling and adherence, and symptom management.
Data Analysis: Descriptive statistics will be used to summarize the survey data. Audio files from focus groups and semi-structured interviews will be transcribed and analyzed using NVivo.
Results: To date, data has been collected from two patients and eighteen oncology care providers. Both patients were ‘very satisfied’ with the information they received to successfully and safely take their OADs. They preferred to receive information from multiple sources (eg physician, internet, hand-outs). The majority of providers reported that they never/rarely/sometimes spoke about digesting an OAD with/without food, necessary diet modifications (e.g. no grapefruit), missed doses, medication storage temperatures, and refills. Most usually spoke about side effects, timing (eg morning), adverse effects, phone number to report side effects, and reporting concerning symptoms. Most were not/slightly/moderately confident that the patients were receiving all the necessary instructions to use the OAD properly. The oncology pharmacist was identified as the most appropriate oncology team member to provide patient education. Although, it was noted that it would be best for patients to receive information at various touch points from different team members. The concept of “My Chemo Calendar” was well received but how best to integrate it into care was unclear.
Implications: Data collection and analysis is still ongoing. This information will be used create and pilot new strategies and tools to improve experiences with OADs.
Evaluation of the Implementation of a 90-Minute Rituximab Infusion Protocol at the Richard L. Roudebush VA Medical Center
Background: The utilization of rituximab for a variety of different indications has historically been associated with logistical challenges related to time and labor. Institutions across the country have implemented protocols to shorten the infusion time of rituximab in order to help alleviate these challenges. The purpose of this study was to support the safe implementation of a 90-minute rapid infusion protocol for rituximab at the Richard L. Roudebush VA Medical Center and improve staff perception regarding similar initiatives in the future with other therapies.
Methods: Proactive measures were taken to educate physicians, pharmacists, and nurses about their role in the implementation of the protocol. A weekly report of patients receiving rituximab was generated from November 1st, 2018 to April 1st, 2019. Patients were then screened for future eligibility for rapid infusions of the drug based on prespecified criteria and providers were notified regarding potential candidates. After patients received their rapid infusions, a retrospective chart review was performed to evaluate patient tolerability and assess for any safety concerns.
Data Analysis: The primary endpoint for this study was the incidence of grade 3 and 4 infusion related reactions associated with the rapid infusions of rituximab based on criteria from CTCAE version 5.0. Secondary endpoints were savings in infusion clinic chair time and the proportion of patients experiencing a grade 3 or 4 infusion related reaction to the rapid infusion that received proper treatment according to the institution’s hypersensitivity protocol. All endpoints were analyzed using descriptive statistics.
Results: During the study period, 11 patients received a total of 24 rapid infusions of rituximab. One out of 24 infusions (4.17%) resulted in a grade 3 infusion related reaction. This patient was treated appropriately by nurses according to the institution’s hypersensitivity protocol. The average savings in infusion clinic chair time by rapid infusions was 39.3 minutes.
Conclusion: This study proved that a rapid infusion protocol for rituximab can be successfully implemented at the Richard L. Roudebush VA Medical Center. The proactive measures utilized to implement the protocol improved provider prescribing rates and nursing satisfaction. Future plans involve implementing a rapid infusion protocol for daratumumab.
Background: The utilization of rituximab for a variety of different indications has historically been associated with logistical challenges related to time and labor. Institutions across the country have implemented protocols to shorten the infusion time of rituximab in order to help alleviate these challenges. The purpose of this study was to support the safe implementation of a 90-minute rapid infusion protocol for rituximab at the Richard L. Roudebush VA Medical Center and improve staff perception regarding similar initiatives in the future with other therapies.
Methods: Proactive measures were taken to educate physicians, pharmacists, and nurses about their role in the implementation of the protocol. A weekly report of patients receiving rituximab was generated from November 1st, 2018 to April 1st, 2019. Patients were then screened for future eligibility for rapid infusions of the drug based on prespecified criteria and providers were notified regarding potential candidates. After patients received their rapid infusions, a retrospective chart review was performed to evaluate patient tolerability and assess for any safety concerns.
Data Analysis: The primary endpoint for this study was the incidence of grade 3 and 4 infusion related reactions associated with the rapid infusions of rituximab based on criteria from CTCAE version 5.0. Secondary endpoints were savings in infusion clinic chair time and the proportion of patients experiencing a grade 3 or 4 infusion related reaction to the rapid infusion that received proper treatment according to the institution’s hypersensitivity protocol. All endpoints were analyzed using descriptive statistics.
Results: During the study period, 11 patients received a total of 24 rapid infusions of rituximab. One out of 24 infusions (4.17%) resulted in a grade 3 infusion related reaction. This patient was treated appropriately by nurses according to the institution’s hypersensitivity protocol. The average savings in infusion clinic chair time by rapid infusions was 39.3 minutes.
Conclusion: This study proved that a rapid infusion protocol for rituximab can be successfully implemented at the Richard L. Roudebush VA Medical Center. The proactive measures utilized to implement the protocol improved provider prescribing rates and nursing satisfaction. Future plans involve implementing a rapid infusion protocol for daratumumab.
Background: The utilization of rituximab for a variety of different indications has historically been associated with logistical challenges related to time and labor. Institutions across the country have implemented protocols to shorten the infusion time of rituximab in order to help alleviate these challenges. The purpose of this study was to support the safe implementation of a 90-minute rapid infusion protocol for rituximab at the Richard L. Roudebush VA Medical Center and improve staff perception regarding similar initiatives in the future with other therapies.
Methods: Proactive measures were taken to educate physicians, pharmacists, and nurses about their role in the implementation of the protocol. A weekly report of patients receiving rituximab was generated from November 1st, 2018 to April 1st, 2019. Patients were then screened for future eligibility for rapid infusions of the drug based on prespecified criteria and providers were notified regarding potential candidates. After patients received their rapid infusions, a retrospective chart review was performed to evaluate patient tolerability and assess for any safety concerns.
Data Analysis: The primary endpoint for this study was the incidence of grade 3 and 4 infusion related reactions associated with the rapid infusions of rituximab based on criteria from CTCAE version 5.0. Secondary endpoints were savings in infusion clinic chair time and the proportion of patients experiencing a grade 3 or 4 infusion related reaction to the rapid infusion that received proper treatment according to the institution’s hypersensitivity protocol. All endpoints were analyzed using descriptive statistics.
Results: During the study period, 11 patients received a total of 24 rapid infusions of rituximab. One out of 24 infusions (4.17%) resulted in a grade 3 infusion related reaction. This patient was treated appropriately by nurses according to the institution’s hypersensitivity protocol. The average savings in infusion clinic chair time by rapid infusions was 39.3 minutes.
Conclusion: This study proved that a rapid infusion protocol for rituximab can be successfully implemented at the Richard L. Roudebush VA Medical Center. The proactive measures utilized to implement the protocol improved provider prescribing rates and nursing satisfaction. Future plans involve implementing a rapid infusion protocol for daratumumab.
Improving Oral Chemotherapy Documentation Using QOPI Audit, Plan-Do-Study-Act Cycles, and the Electronic Medical Record
Background: The use of oral chemotherapy in cancer patients continues to increase and proper documentation of patient adherence, duration of treatment and side effects while on these medications is important. The Quality Oncology Practice Initiative (QOPI) identified oral chemotherapy documentation as an area in need of improvement.
Methods: We used the QOPI audit to create a quality improvement project with the goal of improving our provider oral chemotherapy documentation including cycle number, adherence and side effects. An existing oral chemotherapy best practice alert template in our electronic medical record had already been created to help our providers document oral chemotherapy administration, and we sought to improve our documentation by increasing our provider compliance in completing this template. We utilized Plan-Do-Study- Act (PDSA) cycles to accomplish our goal. For the first PDSA cycle, we made bypassing the oral chemotherapy documentation template in our electronic medical record more difficult for our providers. Our providers were required to acknowledge the template by either following the link to complete the template or documenting a reason why the template was not completed. Requiring the provider to document a reason why the template was not completed made bypassing the template more difficult.
Results: By making this change to the template, we successfully improved our provider compliance with following the link to complete the template from 38% (83/220) to 71% (121/169). For the second PDSA cycle, we educated our medical oncology providers via email about the importance of utilizing the template to improve our oral chemotherapy documentation. By educating our providers, we improved our provider compliance with following the link to complete the template to 86.5% (155/179).
Conclusion: Our project showed how the QOPI audit can be used to create a quality improvement project. Our project also demonstrated how templates within the electronic medical record can be utilized to complete a successful quality improvement project.
Background: The use of oral chemotherapy in cancer patients continues to increase and proper documentation of patient adherence, duration of treatment and side effects while on these medications is important. The Quality Oncology Practice Initiative (QOPI) identified oral chemotherapy documentation as an area in need of improvement.
Methods: We used the QOPI audit to create a quality improvement project with the goal of improving our provider oral chemotherapy documentation including cycle number, adherence and side effects. An existing oral chemotherapy best practice alert template in our electronic medical record had already been created to help our providers document oral chemotherapy administration, and we sought to improve our documentation by increasing our provider compliance in completing this template. We utilized Plan-Do-Study- Act (PDSA) cycles to accomplish our goal. For the first PDSA cycle, we made bypassing the oral chemotherapy documentation template in our electronic medical record more difficult for our providers. Our providers were required to acknowledge the template by either following the link to complete the template or documenting a reason why the template was not completed. Requiring the provider to document a reason why the template was not completed made bypassing the template more difficult.
Results: By making this change to the template, we successfully improved our provider compliance with following the link to complete the template from 38% (83/220) to 71% (121/169). For the second PDSA cycle, we educated our medical oncology providers via email about the importance of utilizing the template to improve our oral chemotherapy documentation. By educating our providers, we improved our provider compliance with following the link to complete the template to 86.5% (155/179).
Conclusion: Our project showed how the QOPI audit can be used to create a quality improvement project. Our project also demonstrated how templates within the electronic medical record can be utilized to complete a successful quality improvement project.
Background: The use of oral chemotherapy in cancer patients continues to increase and proper documentation of patient adherence, duration of treatment and side effects while on these medications is important. The Quality Oncology Practice Initiative (QOPI) identified oral chemotherapy documentation as an area in need of improvement.
Methods: We used the QOPI audit to create a quality improvement project with the goal of improving our provider oral chemotherapy documentation including cycle number, adherence and side effects. An existing oral chemotherapy best practice alert template in our electronic medical record had already been created to help our providers document oral chemotherapy administration, and we sought to improve our documentation by increasing our provider compliance in completing this template. We utilized Plan-Do-Study- Act (PDSA) cycles to accomplish our goal. For the first PDSA cycle, we made bypassing the oral chemotherapy documentation template in our electronic medical record more difficult for our providers. Our providers were required to acknowledge the template by either following the link to complete the template or documenting a reason why the template was not completed. Requiring the provider to document a reason why the template was not completed made bypassing the template more difficult.
Results: By making this change to the template, we successfully improved our provider compliance with following the link to complete the template from 38% (83/220) to 71% (121/169). For the second PDSA cycle, we educated our medical oncology providers via email about the importance of utilizing the template to improve our oral chemotherapy documentation. By educating our providers, we improved our provider compliance with following the link to complete the template to 86.5% (155/179).
Conclusion: Our project showed how the QOPI audit can be used to create a quality improvement project. Our project also demonstrated how templates within the electronic medical record can be utilized to complete a successful quality improvement project.
Radiation Therapy Treatment Breaks and Weight Changes in Head and Neck Cancer Patients in a Veterans Affairs Radiation Oncology Clinic
Background: Unplanned radiation treatment breaks are shown to be related to increased risk of local recurrence, lower survival rates and reduced tumor control rates. Weight loss, along with other side effects, can be a major factor in radiation treatment breaks. This quality improvement project aimed to review weight changes and treatment breaks via retrospective chart review to better understand how to improve the combined nutritional and radiation oncology care of head and neck cancer (HNC) patients.
Methods: Utilizing the Lean Six Sigma Project Management approach to ensure critical components were assessed, this quality improvement project reviewed HNC cases via retrospective chart review that started and/or completed definitive radiation treatment from January 1, 2014 - December 31, 2018. Weights were assessed during the timeframe of treatment and limited to weights obtained within the same unit. Treatment breaks were confirmed via Electronic Medical Records (EMR) systems and defined as one or more missed or cancelled treatments, excluding those missed for nonclinical reasons. Charts were reviewed for documented dysphagia, mucositis, and skin reactions. Information on nutrition visits were assessed.
Results: The incidence of patients who experienced treatment breaks was 47.8%. Patients averaged 5.5 missed treatments. More than half of the patients who experienced treatment breaks had Stage IV disease and 62.5% experienced clinically significant weight loss within their treatment time frame. Approximately 15% of patients were seen within a designated oncology nutrition clinic. Side effects, such as mucositis, dysphagia, and skin reactions, were documented to have contributed to weight changes and treatment breaks.
Conclusion: This project highlighted the multifactorial nature associated with radiotherapy treatment of HNC patients. Based on prior experience with integration of nutrition and radiation oncology services and understanding expected treatment side effects, we recommend that nutrition services are integrated as part of the initial radiation consultation process to proactively approach the known weight loss and nutritionally relevant side effects. It is imperative to integrate medical informatics infrastructure to modernize the process of documenting treatment side effects and outcomes. Continued in-depth review of this data will facilitate us in creating a comprehensive multidisciplinary treatment approach for HNC patients undergoing radiation therapy.
Background: Unplanned radiation treatment breaks are shown to be related to increased risk of local recurrence, lower survival rates and reduced tumor control rates. Weight loss, along with other side effects, can be a major factor in radiation treatment breaks. This quality improvement project aimed to review weight changes and treatment breaks via retrospective chart review to better understand how to improve the combined nutritional and radiation oncology care of head and neck cancer (HNC) patients.
Methods: Utilizing the Lean Six Sigma Project Management approach to ensure critical components were assessed, this quality improvement project reviewed HNC cases via retrospective chart review that started and/or completed definitive radiation treatment from January 1, 2014 - December 31, 2018. Weights were assessed during the timeframe of treatment and limited to weights obtained within the same unit. Treatment breaks were confirmed via Electronic Medical Records (EMR) systems and defined as one or more missed or cancelled treatments, excluding those missed for nonclinical reasons. Charts were reviewed for documented dysphagia, mucositis, and skin reactions. Information on nutrition visits were assessed.
Results: The incidence of patients who experienced treatment breaks was 47.8%. Patients averaged 5.5 missed treatments. More than half of the patients who experienced treatment breaks had Stage IV disease and 62.5% experienced clinically significant weight loss within their treatment time frame. Approximately 15% of patients were seen within a designated oncology nutrition clinic. Side effects, such as mucositis, dysphagia, and skin reactions, were documented to have contributed to weight changes and treatment breaks.
Conclusion: This project highlighted the multifactorial nature associated with radiotherapy treatment of HNC patients. Based on prior experience with integration of nutrition and radiation oncology services and understanding expected treatment side effects, we recommend that nutrition services are integrated as part of the initial radiation consultation process to proactively approach the known weight loss and nutritionally relevant side effects. It is imperative to integrate medical informatics infrastructure to modernize the process of documenting treatment side effects and outcomes. Continued in-depth review of this data will facilitate us in creating a comprehensive multidisciplinary treatment approach for HNC patients undergoing radiation therapy.
Background: Unplanned radiation treatment breaks are shown to be related to increased risk of local recurrence, lower survival rates and reduced tumor control rates. Weight loss, along with other side effects, can be a major factor in radiation treatment breaks. This quality improvement project aimed to review weight changes and treatment breaks via retrospective chart review to better understand how to improve the combined nutritional and radiation oncology care of head and neck cancer (HNC) patients.
Methods: Utilizing the Lean Six Sigma Project Management approach to ensure critical components were assessed, this quality improvement project reviewed HNC cases via retrospective chart review that started and/or completed definitive radiation treatment from January 1, 2014 - December 31, 2018. Weights were assessed during the timeframe of treatment and limited to weights obtained within the same unit. Treatment breaks were confirmed via Electronic Medical Records (EMR) systems and defined as one or more missed or cancelled treatments, excluding those missed for nonclinical reasons. Charts were reviewed for documented dysphagia, mucositis, and skin reactions. Information on nutrition visits were assessed.
Results: The incidence of patients who experienced treatment breaks was 47.8%. Patients averaged 5.5 missed treatments. More than half of the patients who experienced treatment breaks had Stage IV disease and 62.5% experienced clinically significant weight loss within their treatment time frame. Approximately 15% of patients were seen within a designated oncology nutrition clinic. Side effects, such as mucositis, dysphagia, and skin reactions, were documented to have contributed to weight changes and treatment breaks.
Conclusion: This project highlighted the multifactorial nature associated with radiotherapy treatment of HNC patients. Based on prior experience with integration of nutrition and radiation oncology services and understanding expected treatment side effects, we recommend that nutrition services are integrated as part of the initial radiation consultation process to proactively approach the known weight loss and nutritionally relevant side effects. It is imperative to integrate medical informatics infrastructure to modernize the process of documenting treatment side effects and outcomes. Continued in-depth review of this data will facilitate us in creating a comprehensive multidisciplinary treatment approach for HNC patients undergoing radiation therapy.
Benefits of Psychosocial Participation in a Head and Neck Cancer Tumor Board at the VA Palo Alto Health Care System: Two Case Examples
Background: Multidisciplinary tumor boards (MTBs) have been shown to positively impact the assessment and treatment of cancer patients (Pillay et al, 2016) and increase referrals to specialty services present at the meetings (eg genetic testing in breast cancer, Cohen et al, 2016). However, no research to date has explored the impact of involvement of psychosocial providers on MTBs. The following two cases are presented as examples of multidisciplinary cancer care that was facilitated by psychology/social work involvement in the Head and Neck Cancer MTB at VAPAHCS.
Case Report 1: Mr. T is an 86-year-old veteran who was referred to the Oncology and ENT services in May 2017 for a recurrent squamous cell carcinoma in the neck, presumably from prior lip primary. The patient evaluated by Oncology, KC, and ENT who recommended surgical resection. The veteran consented but later cancelled his surgery due to beliefs that God would cure him. The MTB reviewed his case, and the veteran agreed to return for a visit to the Oncology clinic. SD met with the veteran first, and then accompanied him to a meeting with the Oncologist who arranged a same day appointment with an ENT surgeon and an anesthesiologist. SD integrated the veteran’s belief systems (eg, that God would cure his cancer) to help facilitate his decisions. The veteran’s surgery was expedited and completed 3 days later. At present, he has no evidence of recurrent disease.
Case Report 2: Mr. M is a 62-year-old veteran who was referred to the ENT and Oncology Services in October 2017 for squamous cell carcinoma of base of tongue. He was first seen by ENT, discussed in MTB, then seen by KC and BA. Significant psychosocial issues were identified that could complicate his care, including homelessness and PTSD symptoms that directly impacted his ability to stay in VA housing and interact with the medical system. A multidisciplinary treatment plan was created to meet the veteran’s housing/ hygiene needs and provide interventions to assist him in managing PTSD symptoms enough to proceed through treatment. The veteran was able to complete treatment, has no evidence of recurrent disease, and has returned to his goal of hiking the Pacific Crest.
Background: Multidisciplinary tumor boards (MTBs) have been shown to positively impact the assessment and treatment of cancer patients (Pillay et al, 2016) and increase referrals to specialty services present at the meetings (eg genetic testing in breast cancer, Cohen et al, 2016). However, no research to date has explored the impact of involvement of psychosocial providers on MTBs. The following two cases are presented as examples of multidisciplinary cancer care that was facilitated by psychology/social work involvement in the Head and Neck Cancer MTB at VAPAHCS.
Case Report 1: Mr. T is an 86-year-old veteran who was referred to the Oncology and ENT services in May 2017 for a recurrent squamous cell carcinoma in the neck, presumably from prior lip primary. The patient evaluated by Oncology, KC, and ENT who recommended surgical resection. The veteran consented but later cancelled his surgery due to beliefs that God would cure him. The MTB reviewed his case, and the veteran agreed to return for a visit to the Oncology clinic. SD met with the veteran first, and then accompanied him to a meeting with the Oncologist who arranged a same day appointment with an ENT surgeon and an anesthesiologist. SD integrated the veteran’s belief systems (eg, that God would cure his cancer) to help facilitate his decisions. The veteran’s surgery was expedited and completed 3 days later. At present, he has no evidence of recurrent disease.
Case Report 2: Mr. M is a 62-year-old veteran who was referred to the ENT and Oncology Services in October 2017 for squamous cell carcinoma of base of tongue. He was first seen by ENT, discussed in MTB, then seen by KC and BA. Significant psychosocial issues were identified that could complicate his care, including homelessness and PTSD symptoms that directly impacted his ability to stay in VA housing and interact with the medical system. A multidisciplinary treatment plan was created to meet the veteran’s housing/ hygiene needs and provide interventions to assist him in managing PTSD symptoms enough to proceed through treatment. The veteran was able to complete treatment, has no evidence of recurrent disease, and has returned to his goal of hiking the Pacific Crest.
Background: Multidisciplinary tumor boards (MTBs) have been shown to positively impact the assessment and treatment of cancer patients (Pillay et al, 2016) and increase referrals to specialty services present at the meetings (eg genetic testing in breast cancer, Cohen et al, 2016). However, no research to date has explored the impact of involvement of psychosocial providers on MTBs. The following two cases are presented as examples of multidisciplinary cancer care that was facilitated by psychology/social work involvement in the Head and Neck Cancer MTB at VAPAHCS.
Case Report 1: Mr. T is an 86-year-old veteran who was referred to the Oncology and ENT services in May 2017 for a recurrent squamous cell carcinoma in the neck, presumably from prior lip primary. The patient evaluated by Oncology, KC, and ENT who recommended surgical resection. The veteran consented but later cancelled his surgery due to beliefs that God would cure him. The MTB reviewed his case, and the veteran agreed to return for a visit to the Oncology clinic. SD met with the veteran first, and then accompanied him to a meeting with the Oncologist who arranged a same day appointment with an ENT surgeon and an anesthesiologist. SD integrated the veteran’s belief systems (eg, that God would cure his cancer) to help facilitate his decisions. The veteran’s surgery was expedited and completed 3 days later. At present, he has no evidence of recurrent disease.
Case Report 2: Mr. M is a 62-year-old veteran who was referred to the ENT and Oncology Services in October 2017 for squamous cell carcinoma of base of tongue. He was first seen by ENT, discussed in MTB, then seen by KC and BA. Significant psychosocial issues were identified that could complicate his care, including homelessness and PTSD symptoms that directly impacted his ability to stay in VA housing and interact with the medical system. A multidisciplinary treatment plan was created to meet the veteran’s housing/ hygiene needs and provide interventions to assist him in managing PTSD symptoms enough to proceed through treatment. The veteran was able to complete treatment, has no evidence of recurrent disease, and has returned to his goal of hiking the Pacific Crest.
Immune-related toxicities, hospitalization common with checkpoint inhibitor therapy
, according to a retrospective cohort study.
In addition, the majority of the immune-related toxicities were high-grade events of grade 3 or higher (65%), necessitated multidisciplinary care (91%), and eventually improved or resolved (65%). The results highlight potential risk factors for hospitalizations due to immune-related toxicities in oncology patients.
“[We aimed to] characterize the spectrum of toxicities, management, and outcomes of hospitalizations for immune-related adverse events,” wrote Aanika Balaji, BS, of Johns Hopkins University, Baltimore, and colleagues. The findings were reported in the Journal of Oncology Practice.
The researchers studied 443 patients admitted to solid tumor oncology service at an oncology center over a period of 6-months. Of these, 100 patients had at any point received checkpoint inhibitor therapy.
The proportion of hospital admissions for patients with confirmed immune-related toxicities and associations between hospitalizations due to immune-related toxicity and patient characteristics were assessed by the team. Nearly half of the patients admitted with immune-related toxicities had thoracic or head and neck cancers.
In the analysis, patients treated with combination checkpoint inhibitor therapy (odds ratio, 6.8; 95% confidence interval, 2.0-23.2), in addition to those aged 65 years and over (OR, 5.4; 95% CI, 1.6-17.8), were more likely to be hospitalized for immune-related toxicities.
Overall, 5% of all hospitalizations were the result of immune-related toxicities. Furthermore, 87% of patients discontinued checkpoint inhibitor therapy post discharge.
“We found that the most common immune-related adverse events warranting hospital admission were pneumonitis (26%) and colitis (17%),” they wrote.
The researchers acknowledged two key limitations of the study were the small sample size and lack of generalizability in community settings. Future studies that include patients from community oncology settings could improve the generalizability of the results.
“These data indicate potential risk factors for immune-related adverse event hospitalization and are likely to indicate future service needs” they concluded.
Financial support was provided by Jarushka Naidoo. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Compugen, Genentech, GlaxoSmithKline, Exelixis, MedImmune, and several others.
SOURCE: Balaji A et al. J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703.
, according to a retrospective cohort study.
In addition, the majority of the immune-related toxicities were high-grade events of grade 3 or higher (65%), necessitated multidisciplinary care (91%), and eventually improved or resolved (65%). The results highlight potential risk factors for hospitalizations due to immune-related toxicities in oncology patients.
“[We aimed to] characterize the spectrum of toxicities, management, and outcomes of hospitalizations for immune-related adverse events,” wrote Aanika Balaji, BS, of Johns Hopkins University, Baltimore, and colleagues. The findings were reported in the Journal of Oncology Practice.
The researchers studied 443 patients admitted to solid tumor oncology service at an oncology center over a period of 6-months. Of these, 100 patients had at any point received checkpoint inhibitor therapy.
The proportion of hospital admissions for patients with confirmed immune-related toxicities and associations between hospitalizations due to immune-related toxicity and patient characteristics were assessed by the team. Nearly half of the patients admitted with immune-related toxicities had thoracic or head and neck cancers.
In the analysis, patients treated with combination checkpoint inhibitor therapy (odds ratio, 6.8; 95% confidence interval, 2.0-23.2), in addition to those aged 65 years and over (OR, 5.4; 95% CI, 1.6-17.8), were more likely to be hospitalized for immune-related toxicities.
Overall, 5% of all hospitalizations were the result of immune-related toxicities. Furthermore, 87% of patients discontinued checkpoint inhibitor therapy post discharge.
“We found that the most common immune-related adverse events warranting hospital admission were pneumonitis (26%) and colitis (17%),” they wrote.
The researchers acknowledged two key limitations of the study were the small sample size and lack of generalizability in community settings. Future studies that include patients from community oncology settings could improve the generalizability of the results.
“These data indicate potential risk factors for immune-related adverse event hospitalization and are likely to indicate future service needs” they concluded.
Financial support was provided by Jarushka Naidoo. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Compugen, Genentech, GlaxoSmithKline, Exelixis, MedImmune, and several others.
SOURCE: Balaji A et al. J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703.
, according to a retrospective cohort study.
In addition, the majority of the immune-related toxicities were high-grade events of grade 3 or higher (65%), necessitated multidisciplinary care (91%), and eventually improved or resolved (65%). The results highlight potential risk factors for hospitalizations due to immune-related toxicities in oncology patients.
“[We aimed to] characterize the spectrum of toxicities, management, and outcomes of hospitalizations for immune-related adverse events,” wrote Aanika Balaji, BS, of Johns Hopkins University, Baltimore, and colleagues. The findings were reported in the Journal of Oncology Practice.
The researchers studied 443 patients admitted to solid tumor oncology service at an oncology center over a period of 6-months. Of these, 100 patients had at any point received checkpoint inhibitor therapy.
The proportion of hospital admissions for patients with confirmed immune-related toxicities and associations between hospitalizations due to immune-related toxicity and patient characteristics were assessed by the team. Nearly half of the patients admitted with immune-related toxicities had thoracic or head and neck cancers.
In the analysis, patients treated with combination checkpoint inhibitor therapy (odds ratio, 6.8; 95% confidence interval, 2.0-23.2), in addition to those aged 65 years and over (OR, 5.4; 95% CI, 1.6-17.8), were more likely to be hospitalized for immune-related toxicities.
Overall, 5% of all hospitalizations were the result of immune-related toxicities. Furthermore, 87% of patients discontinued checkpoint inhibitor therapy post discharge.
“We found that the most common immune-related adverse events warranting hospital admission were pneumonitis (26%) and colitis (17%),” they wrote.
The researchers acknowledged two key limitations of the study were the small sample size and lack of generalizability in community settings. Future studies that include patients from community oncology settings could improve the generalizability of the results.
“These data indicate potential risk factors for immune-related adverse event hospitalization and are likely to indicate future service needs” they concluded.
Financial support was provided by Jarushka Naidoo. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Compugen, Genentech, GlaxoSmithKline, Exelixis, MedImmune, and several others.
SOURCE: Balaji A et al. J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703.
FROM JOURNAL OF ONCOLOGY PRACTICE
Prevalence of Cancer in Thyroid Nodules In the Veteran Population (FULL)
Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.1 The most common form of cancer is papillary carcinoma followed by follicular carcinoma.2 Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.3 Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.3
Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.3
Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.9
The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.
Methods
The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.
All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.
Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.
Results
A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 
Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 
When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 
Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.
There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.
Discussion
The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).
The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.11 They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).10 This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.1
Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.5 Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.
Limitations
This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.
Conclusion
This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.8 Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.8 Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.
1. Kamran SC, Marqusee E, Kim MI, et al. Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab. 2013;98(2):564-570.
2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-33.
3. Popoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am. 2012;96(2):329-349.
4. Amrikachi M, Ramzy I, Rubenfeld S, Wheeler TM. Accuracy of fine needle aspiration of thyroid. Arch Pathol Lab Med. 2001;125(4):484-488.
5. Kuru B, Gulcelik NE, Gulcelik MA, Dincer H. Predictive index for carcinoma of thyroid nodules and its integration with fine-needle aspiration cytology. Head Neck. 2009;31(7):856-866.
6. Kim JH, Kim NK, Oh YL, et al. The validity of ultrasonography-guided fine needle aspiration biopsy in thyroid nodules 4 cm or larger depends on ultrasound characteristics. Endocrinol Metab (Seoul). 2014;29(4):545-552.
7. Wharry LI, McCoy KL, Stang MT, et al. Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer? World J Surg. 2014;38(3):614-621.
8. Pinchot SN, Al-Wagih H, Schaefer S, Sippel R, Chen H. Accuracy of fine needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg. 2009;144(7):649-655.
9. Megwalu UC. Risk of malignancy in thyroid nodules 4 cm or larger. Endocrinol Metab (Seoul). 2017;32(1):77-82.
10. Magister MJ, Chaikhoutdinov I, Schaefer E, et al. Association of thyroid nodule size and Bethesda class with rate of malignant disease. JAMA Otolaryngol Head Neck Surg. 2015;141(12):1089-1095.
11. Shrestha M, Crothers BA, Burch HB. The impact of thyroid nodule size on the risk of malignancy and accuracy of fine needle aspiration: a 10-year study from a single institution. Thyroid. 2012;22(12):1251-1256.
Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.1 The most common form of cancer is papillary carcinoma followed by follicular carcinoma.2 Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.3 Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.3
Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.3
Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.9
The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.
Methods
The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.
All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.
Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.
Results
A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1).
Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2).
When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3).
Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.
There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.
Discussion
The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).
The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.11 They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).10 This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.1
Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.5 Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.
Limitations
This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.
Conclusion
This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.8 Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.8 Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.
Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.1 The most common form of cancer is papillary carcinoma followed by follicular carcinoma.2 Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.3 Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.3
Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.3
Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.9
The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.
Methods
The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.
All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.
Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.
Results
A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1).
Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2).
When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3).
Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.
There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.
Discussion
The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).
The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.11 They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).10 This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.1
Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.5 Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.
Limitations
This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.
Conclusion
This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.8 Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.8 Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.
1. Kamran SC, Marqusee E, Kim MI, et al. Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab. 2013;98(2):564-570.
2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-33.
3. Popoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am. 2012;96(2):329-349.
4. Amrikachi M, Ramzy I, Rubenfeld S, Wheeler TM. Accuracy of fine needle aspiration of thyroid. Arch Pathol Lab Med. 2001;125(4):484-488.
5. Kuru B, Gulcelik NE, Gulcelik MA, Dincer H. Predictive index for carcinoma of thyroid nodules and its integration with fine-needle aspiration cytology. Head Neck. 2009;31(7):856-866.
6. Kim JH, Kim NK, Oh YL, et al. The validity of ultrasonography-guided fine needle aspiration biopsy in thyroid nodules 4 cm or larger depends on ultrasound characteristics. Endocrinol Metab (Seoul). 2014;29(4):545-552.
7. Wharry LI, McCoy KL, Stang MT, et al. Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer? World J Surg. 2014;38(3):614-621.
8. Pinchot SN, Al-Wagih H, Schaefer S, Sippel R, Chen H. Accuracy of fine needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg. 2009;144(7):649-655.
9. Megwalu UC. Risk of malignancy in thyroid nodules 4 cm or larger. Endocrinol Metab (Seoul). 2017;32(1):77-82.
10. Magister MJ, Chaikhoutdinov I, Schaefer E, et al. Association of thyroid nodule size and Bethesda class with rate of malignant disease. JAMA Otolaryngol Head Neck Surg. 2015;141(12):1089-1095.
11. Shrestha M, Crothers BA, Burch HB. The impact of thyroid nodule size on the risk of malignancy and accuracy of fine needle aspiration: a 10-year study from a single institution. Thyroid. 2012;22(12):1251-1256.
1. Kamran SC, Marqusee E, Kim MI, et al. Thyroid nodule size and prediction of cancer. J Clin Endocrinol Metab. 2013;98(2):564-570.
2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-33.
3. Popoveniuc G, Jonklaas J. Thyroid nodules. Med Clin North Am. 2012;96(2):329-349.
4. Amrikachi M, Ramzy I, Rubenfeld S, Wheeler TM. Accuracy of fine needle aspiration of thyroid. Arch Pathol Lab Med. 2001;125(4):484-488.
5. Kuru B, Gulcelik NE, Gulcelik MA, Dincer H. Predictive index for carcinoma of thyroid nodules and its integration with fine-needle aspiration cytology. Head Neck. 2009;31(7):856-866.
6. Kim JH, Kim NK, Oh YL, et al. The validity of ultrasonography-guided fine needle aspiration biopsy in thyroid nodules 4 cm or larger depends on ultrasound characteristics. Endocrinol Metab (Seoul). 2014;29(4):545-552.
7. Wharry LI, McCoy KL, Stang MT, et al. Thyroid nodules (≥4 cm): can ultrasound and cytology reliably exclude cancer? World J Surg. 2014;38(3):614-621.
8. Pinchot SN, Al-Wagih H, Schaefer S, Sippel R, Chen H. Accuracy of fine needle aspiration biopsy for predicting neoplasm or carcinoma in thyroid nodules 4 cm or larger. Arch Surg. 2009;144(7):649-655.
9. Megwalu UC. Risk of malignancy in thyroid nodules 4 cm or larger. Endocrinol Metab (Seoul). 2017;32(1):77-82.
10. Magister MJ, Chaikhoutdinov I, Schaefer E, et al. Association of thyroid nodule size and Bethesda class with rate of malignant disease. JAMA Otolaryngol Head Neck Surg. 2015;141(12):1089-1095.
11. Shrestha M, Crothers BA, Burch HB. The impact of thyroid nodule size on the risk of malignancy and accuracy of fine needle aspiration: a 10-year study from a single institution. Thyroid. 2012;22(12):1251-1256.
VHA Practice Guideline Recommendations for Diffuse Gliomas (FULL)
Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.1 One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.
In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.
Purpose
In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.
This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.2
Scope of Problem
The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.3 Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.3 Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).
Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.
Case Presentations
Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 
Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).
Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.4 Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.
Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 
Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).
Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.
A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.5,6
Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 
Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).
Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.7-9
New Diffuse Glioma Classification
Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.10 The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.11 Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.
As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.
Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 
Diagnostic Uses of Molecular Testing
While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.
Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.18,19
Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.20-26
Testing In the VA
The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 
The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.
Conclusion
In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).
Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 
Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.
Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.
Correspondence: Dr. Kulich ([email protected])
1. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820.
2. Wang-Rodriguez J, Yunes A, Phan R, et al. The challenges of precision medicine and new advances in molecular diagnostic testing in hematolymphoid malignancies: impact on the VHA. Fed Pract. 2017;34(suppl 5):S38-S49.
3. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol. 2017;19(suppl 5):v1-v88.
4. Nikiforova MN, Wald AI, Melan MA, et al. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. Neuro Oncol. 2016;18(3)379-387.
5. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90(19):1473-1479.
6. van den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res. 2013;19(19):5513-5522.
7. Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-466.
8. Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916-926.
9. van den Bent MJ, Kros JM. Predictive and prognostic markers in neuro-oncology. J Neuropathol Exp Neurol. 2007;66(12):1074-1081.
10. Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma subclassifications and their clinical significance. Neurotherapeutics. 2017;14(2):284-297.
11. Jordan JT, Sanders AE, Armstrong T, et al. Quality improvement in neurology: neuro-oncology quality measurement set. Neurology. 2018;90(14):652-658.
12. Chen L, Voronovich Z, Clark K, et al. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma. Neuro Oncol. 2014;16(11):1478-1483.
13. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
14. Wick W, Platten M, Meisner C, et al; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707-715.
15. Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319-1325.
16. Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Louis DN, Nutt CL. Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol. 2010;119(4):509-511.
17. Horbinski C, Kofler J, Yeaney G, et al. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 2011;21(5):564-574.
18. Berghoff AS, Preusser M. BRAF alterations in brain tumours: molecular pathology and therapeutic opportunities. Curr Opin Neurol. 2014;27(6):689-696.
19. Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009;118(3):401-405.
20. Fuller CE, Schmidt RE, Roth KA, et al. Clinical utility of fluorescence in situ hybridization (FISH) in morphologically ambiguous gliomas with hybrid oligodendroglial/astrocytic features. J Neuropathol Exp Neurol. 2003;62(11):1118-1128.
21. Horbinski C. Practical molecular diagnostics in neuropathology: making a tough job a little easier. Semin Diagn Pathol. 2010;27(2):105-113.
22. Fuller GN, Bigner SH. Amplified cellular oncogenes in neoplasms of the human central nervous system. Mutat Res. 1992;276(3):299-306.
23. Brennan CW, Verhaak RG, McKenna A, et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477.
24. Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):829-848.
25. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013;110(15):6021-6026.
26. Nikiforova MN, Hamilton RL. Molecular diagnostics of gliomas. Arch Pathol Lab Med. 2011;135(5):558-568.
Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.1 One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.
In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.
Purpose
In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.
This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.2
Scope of Problem
The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.3 Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.3 Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).
Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.
Case Presentations
Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C).
Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).
Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.4 Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.
Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C).
Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).
Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.
A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.5,6
Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C).
Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).
Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.7-9
New Diffuse Glioma Classification
Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.10 The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.11 Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.
As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.
Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points.
Diagnostic Uses of Molecular Testing
While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.
Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.18,19
Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.20-26
Testing In the VA
The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1).
The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.
Conclusion
In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).
Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas.
Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.
Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.
Correspondence: Dr. Kulich ([email protected])
Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.1 One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.
In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.
Purpose
In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.
This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.2
Scope of Problem
The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.3 Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.3 Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).
Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.
Case Presentations
Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C).
Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).
Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.4 Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.
Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C).
Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).
Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.
A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.5,6
Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C).
Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).
Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.7-9
New Diffuse Glioma Classification
Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.10 The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.11 Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.
As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.
Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points.
Diagnostic Uses of Molecular Testing
While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.
Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.18,19
Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.20-26
Testing In the VA
The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1).
The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.
Conclusion
In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).
Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas.
Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.
Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.
Correspondence: Dr. Kulich ([email protected])
1. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820.
2. Wang-Rodriguez J, Yunes A, Phan R, et al. The challenges of precision medicine and new advances in molecular diagnostic testing in hematolymphoid malignancies: impact on the VHA. Fed Pract. 2017;34(suppl 5):S38-S49.
3. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol. 2017;19(suppl 5):v1-v88.
4. Nikiforova MN, Wald AI, Melan MA, et al. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. Neuro Oncol. 2016;18(3)379-387.
5. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90(19):1473-1479.
6. van den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res. 2013;19(19):5513-5522.
7. Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-466.
8. Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916-926.
9. van den Bent MJ, Kros JM. Predictive and prognostic markers in neuro-oncology. J Neuropathol Exp Neurol. 2007;66(12):1074-1081.
10. Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma subclassifications and their clinical significance. Neurotherapeutics. 2017;14(2):284-297.
11. Jordan JT, Sanders AE, Armstrong T, et al. Quality improvement in neurology: neuro-oncology quality measurement set. Neurology. 2018;90(14):652-658.
12. Chen L, Voronovich Z, Clark K, et al. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma. Neuro Oncol. 2014;16(11):1478-1483.
13. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
14. Wick W, Platten M, Meisner C, et al; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707-715.
15. Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319-1325.
16. Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Louis DN, Nutt CL. Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol. 2010;119(4):509-511.
17. Horbinski C, Kofler J, Yeaney G, et al. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 2011;21(5):564-574.
18. Berghoff AS, Preusser M. BRAF alterations in brain tumours: molecular pathology and therapeutic opportunities. Curr Opin Neurol. 2014;27(6):689-696.
19. Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009;118(3):401-405.
20. Fuller CE, Schmidt RE, Roth KA, et al. Clinical utility of fluorescence in situ hybridization (FISH) in morphologically ambiguous gliomas with hybrid oligodendroglial/astrocytic features. J Neuropathol Exp Neurol. 2003;62(11):1118-1128.
21. Horbinski C. Practical molecular diagnostics in neuropathology: making a tough job a little easier. Semin Diagn Pathol. 2010;27(2):105-113.
22. Fuller GN, Bigner SH. Amplified cellular oncogenes in neoplasms of the human central nervous system. Mutat Res. 1992;276(3):299-306.
23. Brennan CW, Verhaak RG, McKenna A, et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477.
24. Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):829-848.
25. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013;110(15):6021-6026.
26. Nikiforova MN, Hamilton RL. Molecular diagnostics of gliomas. Arch Pathol Lab Med. 2011;135(5):558-568.
1. Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803-820.
2. Wang-Rodriguez J, Yunes A, Phan R, et al. The challenges of precision medicine and new advances in molecular diagnostic testing in hematolymphoid malignancies: impact on the VHA. Fed Pract. 2017;34(suppl 5):S38-S49.
3. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol. 2017;19(suppl 5):v1-v88.
4. Nikiforova MN, Wald AI, Melan MA, et al. Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. Neuro Oncol. 2016;18(3)379-387.
5. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst. 1998;90(19):1473-1479.
6. van den Bent MJ, Erdem-Eraslan L, Idbaih A, et al. MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951. Clin Cancer Res. 2013;19(19):5513-5522.
7. Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459-466.
8. Malmstrom A, Gronberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916-926.
9. van den Bent MJ, Kros JM. Predictive and prognostic markers in neuro-oncology. J Neuropathol Exp Neurol. 2007;66(12):1074-1081.
10. Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma subclassifications and their clinical significance. Neurotherapeutics. 2017;14(2):284-297.
11. Jordan JT, Sanders AE, Armstrong T, et al. Quality improvement in neurology: neuro-oncology quality measurement set. Neurology. 2018;90(14):652-658.
12. Chen L, Voronovich Z, Clark K, et al. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma. Neuro Oncol. 2014;16(11):1478-1483.
13. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003.
14. Wick W, Platten M, Meisner C, et al; NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 2012;13(7):707-715.
15. Horbinski C, Kofler J, Kelly LM, Murdoch GH, Nikiforova MN. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol. 2009;68(12):1319-1325.
16. Camelo-Piragua S, Jansen M, Ganguly A, Kim JC, Louis DN, Nutt CL. Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol. 2010;119(4):509-511.
17. Horbinski C, Kofler J, Yeaney G, et al. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 2011;21(5):564-574.
18. Berghoff AS, Preusser M. BRAF alterations in brain tumours: molecular pathology and therapeutic opportunities. Curr Opin Neurol. 2014;27(6):689-696.
19. Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 2009;118(3):401-405.
20. Fuller CE, Schmidt RE, Roth KA, et al. Clinical utility of fluorescence in situ hybridization (FISH) in morphologically ambiguous gliomas with hybrid oligodendroglial/astrocytic features. J Neuropathol Exp Neurol. 2003;62(11):1118-1128.
21. Horbinski C. Practical molecular diagnostics in neuropathology: making a tough job a little easier. Semin Diagn Pathol. 2010;27(2):105-113.
22. Fuller GN, Bigner SH. Amplified cellular oncogenes in neoplasms of the human central nervous system. Mutat Res. 1992;276(3):299-306.
23. Brennan CW, Verhaak RG, McKenna A, et al; TCGA Research Network. The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462-477.
24. Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A. Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol. 2015;129(6):829-848.
25. Killela PJ, Reitman ZJ, Jiao Y, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013;110(15):6021-6026.
26. Nikiforova MN, Hamilton RL. Molecular diagnostics of gliomas. Arch Pathol Lab Med. 2011;135(5):558-568.
FDA approves Keytruda for metastatic HNSCC
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).
FDA approval was based on results of the randomized, multicenter, three-arm, open‑label, active‑controlled KEYNOTE-048 trial. The 882 patients in the trial had metastatic HNSCC, and they received either single-agent pembrolizumab; pembrolizumab, carboplatin or cisplatin, and platinum and fluorouracil; or cetuximab, carboplatin or cisplatin, and platinum and fluorouracil.
Patients who received pembrolizumab plus chemotherapy had a mean overall survival of 13.0 months, compared with 10.7 months in the cetuximab plus chemotherapy group (hazard ratio, 0.77; 95% CI, 0.63-0.93; P = .0067).
In the patient subgroups that received single-agent pembrolizumab, overall survival was 12.3 months in patients with a Combined Positive Score of at least 1, compared with 10.3 months for the cetuximab plus chemotherapy group (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). In patients with a Combined Positive Score of at least 20, overall survival was 14.9 months in the pembrolizumab-only group and 10.7 months in the cetuximab plus chemotherapy group (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).
The most common adverse events in patients who received single-agent pembrolizumab were fatigue, constipation, and rash. In patients who received pembrolizumab plus chemotherapy, the most common adverse events were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.
Pembrolizumab is approved for use in combination with platinum and fluorouracil for all patients and as a single agent for patients whose tumors express programmed death–ligand 1, the FDA said.
The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.
Find the full press release on the FDA website.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).
FDA approval was based on results of the randomized, multicenter, three-arm, open‑label, active‑controlled KEYNOTE-048 trial. The 882 patients in the trial had metastatic HNSCC, and they received either single-agent pembrolizumab; pembrolizumab, carboplatin or cisplatin, and platinum and fluorouracil; or cetuximab, carboplatin or cisplatin, and platinum and fluorouracil.
Patients who received pembrolizumab plus chemotherapy had a mean overall survival of 13.0 months, compared with 10.7 months in the cetuximab plus chemotherapy group (hazard ratio, 0.77; 95% CI, 0.63-0.93; P = .0067).
In the patient subgroups that received single-agent pembrolizumab, overall survival was 12.3 months in patients with a Combined Positive Score of at least 1, compared with 10.3 months for the cetuximab plus chemotherapy group (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). In patients with a Combined Positive Score of at least 20, overall survival was 14.9 months in the pembrolizumab-only group and 10.7 months in the cetuximab plus chemotherapy group (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).
The most common adverse events in patients who received single-agent pembrolizumab were fatigue, constipation, and rash. In patients who received pembrolizumab plus chemotherapy, the most common adverse events were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.
Pembrolizumab is approved for use in combination with platinum and fluorouracil for all patients and as a single agent for patients whose tumors express programmed death–ligand 1, the FDA said.
The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.
Find the full press release on the FDA website.
The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).
FDA approval was based on results of the randomized, multicenter, three-arm, open‑label, active‑controlled KEYNOTE-048 trial. The 882 patients in the trial had metastatic HNSCC, and they received either single-agent pembrolizumab; pembrolizumab, carboplatin or cisplatin, and platinum and fluorouracil; or cetuximab, carboplatin or cisplatin, and platinum and fluorouracil.
Patients who received pembrolizumab plus chemotherapy had a mean overall survival of 13.0 months, compared with 10.7 months in the cetuximab plus chemotherapy group (hazard ratio, 0.77; 95% CI, 0.63-0.93; P = .0067).
In the patient subgroups that received single-agent pembrolizumab, overall survival was 12.3 months in patients with a Combined Positive Score of at least 1, compared with 10.3 months for the cetuximab plus chemotherapy group (HR, 0.78; 95% CI, 0.64-0.96; P = .0171). In patients with a Combined Positive Score of at least 20, overall survival was 14.9 months in the pembrolizumab-only group and 10.7 months in the cetuximab plus chemotherapy group (HR, 0.61; 95% CI, 0.45-0.83; P = .0015).
The most common adverse events in patients who received single-agent pembrolizumab were fatigue, constipation, and rash. In patients who received pembrolizumab plus chemotherapy, the most common adverse events were nausea, fatigue, constipation, vomiting, mucosal inflammation, diarrhea, decreased appetite, stomatitis, and cough.
Pembrolizumab is approved for use in combination with platinum and fluorouracil for all patients and as a single agent for patients whose tumors express programmed death–ligand 1, the FDA said.
The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.
Find the full press release on the FDA website.
Ado-trastuzumab highly efficacious for rare HER2-amplified SGCs
CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.
In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.
“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.
The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”
Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.
Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.
Dr. Li described one patient who had bone and vertebral metastases.
“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”
Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.
SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.
“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.
In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.
Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.
“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”
Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.
Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.
“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.
“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.
Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.
“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”
Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.
“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.
Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.
SOURCE: Li B et al., ASCO 2019: Abstract 6001.
CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.
In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.
“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.
The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”
Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.
Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.
Dr. Li described one patient who had bone and vertebral metastases.
“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”
Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.
SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.
“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.
In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.
Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.
“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”
Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.
Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.
“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.
“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.
Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.
“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”
Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.
“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.
Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.
SOURCE: Li B et al., ASCO 2019: Abstract 6001.
CHICAGO – Ado-trastuzumab emtansine, previously known as T-DM1, is highly efficacious in patients with HER2-amplified salivary gland cancers, according to findings from an ongoing phase 2 multi-histology basket trial.
In fact, nine of 10 patients with this rare tumor responded to treatment with the HER2-targeted antibody drug conjugate after prior trastuzumab, pertuzumab, and anti-androgen therapy, and 5 of those had a complete response, Bob T. Li, MD, said at the annual meeting of the American Society of Clinical Oncology.
“We are reporting this study early because it has already met its primary endpoint,” said Dr. Li of Memorial Sloan Kettering Cancer Center, N.Y.
The 90% response rate was based on either Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) criteria; the latter was used because many patients with HER-amplified salivary gland cancer aren’t “RECIST measurable” due to presentation with only lymph node- and bone-only metastasis, he explained, adding that “many of the responses were quite durable, with some lasting 2 years.”
Even at a median of 12 months, neither duration of response nor median progression-free survival have been reached, he said.
Study subjects included nine men and one woman with salivary gland cancers (SGCs) and HER2 amplification identified by next-generation sequencing (NGS). They had a median age of 65 years and a median of 2 prior lines of systemic therapy.
Dr. Li described one patient who had bone and vertebral metastases.
“After just two doses, he had a complete metabolic response,” he said. “His symptoms improved, his pain went away, he feels well, and just recently he celebrated his 92nd birthday.”
Treatment, which included 3.6 mg/kg delivered intravenously every 3 weeks until disease progression or unacceptable toxicity, was well tolerated; toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and transaminitis. Two dose reductions were required, but no treatment-related deaths occurred, Dr. Li said.
SGCs are rare tumors accounting for only about 0.8% of malignancies. There is no approved therapy for metastatic disease, and due to the rarity of the disease there is no established standard of care, he said, noting, however, that chemotherapy and anti-androgen therapy are considered treatment options based on some retrospective case series.
“Now, coming in from a molecular angle, HER2 amplification turns out to be very common in this rare tumor,” he said.
In fact, NGS of more than 40,000 tumors using the MSK-IMPACT 468-gene oncopanel showed that HER2 amplification occurs in 8% of all SGC histologies, and additional published data show that it occurs in about 30% of those with “the very aggressive salivary duct carcinoma histologic subtype,” he said, adding that case reports and a phase 2 study reported at ASCO 2018 showed encouraging response rates with chemotherapy plus trastuzumab.
Ado-trastuzumab emtansine is a Food and Drug Administration-approved agent for the treatment HER2-positive breast cancer.
“It’s got the trastuzumab antibody, it has a linker which attaches the highly toxic DM1 chemotherapy to it, and ... it binds to the over-expressed HER2 receptor and uses that receptor to internalize the drug into the cancer cell and by lysosome deregulation release the highly toxic DM1 into the cell to cause cancer cell kill,” he explained. “We hypothesized that this drug, as a single agent, would be efficacious in HER2-amplified SGC tumors, and it turns out [that] recently there was a nice case series published from the University of Pennsylvania supporting this hypothesis in a group of patients.”
Indeed, the findings are encouraging and warrant cohort expansion to confirm the results, he said.
Of note, HER2 amplification by NGS (fold change 2.8 to 22.8) correlated with findings on fluorescence in situ hybridization (FISH) in 8 of 8 patients tested, and with immunohistochemistry (IHC) 3+ in 10 of 10 patients tested, thereby confirming the validity of this testing method for the biomarker and as a study entry criterion, he said, adding that ongoing correlative analyses are focusing on cell-free DNA NGS to look for acquired resistance, quantitative HER2 protein analysis by mass spectrometry, and also a dimerization assay looking at the degree of HER2-HER3 dimerization, which leads to receptor internalization that may predict response to HER2 antibody drug conjugates.
“We wanted to see why [HER2-amplified SGC patients] respond so well in contrast to the other diseases in the basket trial,” Dr. Li said, explaining that the trial also includes lung, bladder and urinary tract, endometrial, and colorectal cancer cohorts.
“However, to me as an oncologist, the most pressing thing is that with these kind of results and with this kind of response rate and progression-free survival ... there are patients in need of this treatment, so that is certainly the priority–to further accrue patients, complete the trial, publish the data, and hopefully have this new treatment approved to benefit all patients,” he concluded.
Discussant Vanita Noronha, MD, noted that the survival data are immature but “very clinically relevant and clinically significant,” and that they fulfill an unmet need.
“As much as we would like to have randomized trial, this is really a challenge in these kind of rare tumors,” said Dr. Noronha, a professor in the Department of Medical Oncology at Tata Memorial Hospital in Mumbai, India. “So my take-home message ... is that HER2neu is an important molecule driver in salivary gland tumors [and] all patients with salivary gland cancers should be tested for HER2neu amplification.”
Ado trastuzumab emtansine appears to be a good treatment option in those with HER2 amplified SGC, she added.
“Is this a practice changing study? Yes, potentially it is,” she said, noting that in patients with recurrent/metastatic SGC not amenable to radical therapy who are found to have HER2neu amplification, treatment options include either ado trastuzumab emtansine or the combination of trastuzumab and chemotherapy.
Dr. Li reported consulting or advisory roles with Biosceptre International, Guardant Health, Hengrui Therapeutics, Mersana, Roche, and Thermo Fisher Scientific. He reported research funding to his institution from AstraZeneca, BioMed Valley Discoveries, Daiichi Sankyo, GRAIL, Guardant Health, Hengrui Therapeutics, Illumina, and Roche/Genentech. Dr. Noronha has received research funding (to her institution) from Amgen,and Sanofi Aventis.
SOURCE: Li B et al., ASCO 2019: Abstract 6001.
REPORTING FROM ASCO 2019