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H&N cancer may be undertreated in women
CHICAGO – Sex disparities in the treatment of head and neck cancer may be leading to poorer outcomes for women, according to a retrospective registry-based cohort study of 884 patients reported at annual meeting of the American Society of Clinical Oncology.
“The treatment of head and neck cancer often requires intensive treatment that can have lasting side effects,” senior study author Jed A. Katzel, MD, a medical oncologist at Kaiser Permanente in Santa Clara, Calif., said in a press briefing. “Our goal was to review data from a large group of patients in Northern California to determine which patients are most likely to benefit from aggressive therapy, while minimizing toxicity for those likely to die from competing events.”
The reasons for the observed sex disparities are not known, according to Dr. Katzel. However, they may include patient preferences, physician practices, and the higher proportion among men of oropharynx tumors, as those tumors are more commonly associated with human papillomavirus (HPV), which carries a more favorable prognosis.
“Further investigation is needed to determine if there is an actual difference in treatment and outcomes for women, compared with men,” he said. “To this end, we have planned a chart-by-chart review, as well as a prospective analysis that will be performed in the currently enrolling NRG HN004 clinical trial.”
“The outcome of this study was very surprising to us, the idea that there are disparities in both the treatment that women receive relative to men, but also in the rate of death from head and neck cancer for women compared to men,” commented ASCO Expert Joshua Jones, MD, MA, who is also a radiation oncologist at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia.
Dr. Katzel and his colleagues used the Kaiser Permanente Northern California registry to identify patients with stage II to IVB head and neck cancer diagnosed during 2000-2015.
Analyses were based on 223 women and 661 men, relative numbers that are not surprising given the known demographics of this cancer. Oropharyngeal tumors accounted for 38% of the cancers in the former, but 55% in the latter. (HPV status was not directly ascertained.)
The rate of receipt of intensive chemotherapy was 35% for women and 46% for men (adjusted odds ratio, 0.68; 95% CI, 0.48-0.98; P = .006). Similarly, the rate of receipt of radiation therapy was 60% for women and 70% for men (AOR, 0.79; 95% CI, 0.56-1.11; P = .008). Receipt of surgery was similar for the sexes.
The investigators analyzed deaths according to type using a GCE model that controlled for age, sex, tumor site, and Charlson Comorbidity Index. “The GCE model essentially describes the degree to which cancer is the patient’s problem,” Dr. Katzel explained.
Results showed that both women and men were more likely to die from cancer than from other causes; however, the ratio was 7 for women, compared with just 3.8 for men, a difference translating to a relative hazard ratio of 1.92 (95% CI, 1.07-3.43).
In terms of potential confounding, there were only 19 noncancer deaths among the women studied, suggesting that they may have been more healthy than the men, which could have influenced the calculations, according to Dr. Katzel.
“This GCE model has been validated in head and neck cancer, but also in breast cancer, prostate cancer, and endometrial cancer, so we are using a validated model to do this evaluation,” he noted. “So I would say we are confident in our findings.”
Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
SOURCE: Park A et al. ASCO 2018 Abstract LBA6002.
CHICAGO – Sex disparities in the treatment of head and neck cancer may be leading to poorer outcomes for women, according to a retrospective registry-based cohort study of 884 patients reported at annual meeting of the American Society of Clinical Oncology.
“The treatment of head and neck cancer often requires intensive treatment that can have lasting side effects,” senior study author Jed A. Katzel, MD, a medical oncologist at Kaiser Permanente in Santa Clara, Calif., said in a press briefing. “Our goal was to review data from a large group of patients in Northern California to determine which patients are most likely to benefit from aggressive therapy, while minimizing toxicity for those likely to die from competing events.”
The reasons for the observed sex disparities are not known, according to Dr. Katzel. However, they may include patient preferences, physician practices, and the higher proportion among men of oropharynx tumors, as those tumors are more commonly associated with human papillomavirus (HPV), which carries a more favorable prognosis.
“Further investigation is needed to determine if there is an actual difference in treatment and outcomes for women, compared with men,” he said. “To this end, we have planned a chart-by-chart review, as well as a prospective analysis that will be performed in the currently enrolling NRG HN004 clinical trial.”
“The outcome of this study was very surprising to us, the idea that there are disparities in both the treatment that women receive relative to men, but also in the rate of death from head and neck cancer for women compared to men,” commented ASCO Expert Joshua Jones, MD, MA, who is also a radiation oncologist at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia.
Dr. Katzel and his colleagues used the Kaiser Permanente Northern California registry to identify patients with stage II to IVB head and neck cancer diagnosed during 2000-2015.
Analyses were based on 223 women and 661 men, relative numbers that are not surprising given the known demographics of this cancer. Oropharyngeal tumors accounted for 38% of the cancers in the former, but 55% in the latter. (HPV status was not directly ascertained.)
The rate of receipt of intensive chemotherapy was 35% for women and 46% for men (adjusted odds ratio, 0.68; 95% CI, 0.48-0.98; P = .006). Similarly, the rate of receipt of radiation therapy was 60% for women and 70% for men (AOR, 0.79; 95% CI, 0.56-1.11; P = .008). Receipt of surgery was similar for the sexes.
The investigators analyzed deaths according to type using a GCE model that controlled for age, sex, tumor site, and Charlson Comorbidity Index. “The GCE model essentially describes the degree to which cancer is the patient’s problem,” Dr. Katzel explained.
Results showed that both women and men were more likely to die from cancer than from other causes; however, the ratio was 7 for women, compared with just 3.8 for men, a difference translating to a relative hazard ratio of 1.92 (95% CI, 1.07-3.43).
In terms of potential confounding, there were only 19 noncancer deaths among the women studied, suggesting that they may have been more healthy than the men, which could have influenced the calculations, according to Dr. Katzel.
“This GCE model has been validated in head and neck cancer, but also in breast cancer, prostate cancer, and endometrial cancer, so we are using a validated model to do this evaluation,” he noted. “So I would say we are confident in our findings.”
Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
SOURCE: Park A et al. ASCO 2018 Abstract LBA6002.
CHICAGO – Sex disparities in the treatment of head and neck cancer may be leading to poorer outcomes for women, according to a retrospective registry-based cohort study of 884 patients reported at annual meeting of the American Society of Clinical Oncology.
“The treatment of head and neck cancer often requires intensive treatment that can have lasting side effects,” senior study author Jed A. Katzel, MD, a medical oncologist at Kaiser Permanente in Santa Clara, Calif., said in a press briefing. “Our goal was to review data from a large group of patients in Northern California to determine which patients are most likely to benefit from aggressive therapy, while minimizing toxicity for those likely to die from competing events.”
The reasons for the observed sex disparities are not known, according to Dr. Katzel. However, they may include patient preferences, physician practices, and the higher proportion among men of oropharynx tumors, as those tumors are more commonly associated with human papillomavirus (HPV), which carries a more favorable prognosis.
“Further investigation is needed to determine if there is an actual difference in treatment and outcomes for women, compared with men,” he said. “To this end, we have planned a chart-by-chart review, as well as a prospective analysis that will be performed in the currently enrolling NRG HN004 clinical trial.”
“The outcome of this study was very surprising to us, the idea that there are disparities in both the treatment that women receive relative to men, but also in the rate of death from head and neck cancer for women compared to men,” commented ASCO Expert Joshua Jones, MD, MA, who is also a radiation oncologist at the Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia.
Dr. Katzel and his colleagues used the Kaiser Permanente Northern California registry to identify patients with stage II to IVB head and neck cancer diagnosed during 2000-2015.
Analyses were based on 223 women and 661 men, relative numbers that are not surprising given the known demographics of this cancer. Oropharyngeal tumors accounted for 38% of the cancers in the former, but 55% in the latter. (HPV status was not directly ascertained.)
The rate of receipt of intensive chemotherapy was 35% for women and 46% for men (adjusted odds ratio, 0.68; 95% CI, 0.48-0.98; P = .006). Similarly, the rate of receipt of radiation therapy was 60% for women and 70% for men (AOR, 0.79; 95% CI, 0.56-1.11; P = .008). Receipt of surgery was similar for the sexes.
The investigators analyzed deaths according to type using a GCE model that controlled for age, sex, tumor site, and Charlson Comorbidity Index. “The GCE model essentially describes the degree to which cancer is the patient’s problem,” Dr. Katzel explained.
Results showed that both women and men were more likely to die from cancer than from other causes; however, the ratio was 7 for women, compared with just 3.8 for men, a difference translating to a relative hazard ratio of 1.92 (95% CI, 1.07-3.43).
In terms of potential confounding, there were only 19 noncancer deaths among the women studied, suggesting that they may have been more healthy than the men, which could have influenced the calculations, according to Dr. Katzel.
“This GCE model has been validated in head and neck cancer, but also in breast cancer, prostate cancer, and endometrial cancer, so we are using a validated model to do this evaluation,” he noted. “So I would say we are confident in our findings.”
Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
SOURCE: Park A et al. ASCO 2018 Abstract LBA6002.
REPORTING FROM ASCO 2018
Key clinical point: Women with head and neck cancer may be relatively undertreated and therefore are more likely to die from the disease.
Major finding: Compared with male counterparts, female patients had lower rates of receiving intensive chemotherapy (35% vs. 46%) and radiation therapy (60% vs. 70%) and a higher ratio of cancer to noncancer mortality (adjusted relative hazard ratio, 1.92).
Study details: Retrospective, registry-based, cohort study of 884 patients with stage II to IVB H&N cancer diagnosed during 2000-2015.
Disclosures: Dr. Katzel disclosed that he had no relevant conflicts of interest. The study received funding from Kaiser Permanente Northern California Graduate Medical Education Department.
Source: Park A et al. ASCO 2018, Abstract LBA6002.
Head and neck cancers: Women less commonly receive intensive chemo
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Women with head and neck cancer less commonly receive intensive chemotherapy (35% vs. 46%) and radiation therapy (60% vs. 70%) than do their male counterparts, finds an analysis of 223 female patients and 661 male patients with stage II-IVB disease treated at Kaiser Permanente Northern California. And this apparent undertreatment may be compromising survival for women, as their ratio of cancer deaths to other deaths is nearly twice that of men (adjusted relative hazard ratio, 1.92; 95% CI, 1.07-3.43).
In this video interview from the annual meeting of the American Society of Clinical Oncology, senior study author Jed A. Katzel, MD, of Kaiser Permanente in Santa Clara, Calif., described the new statistical approach used to assess outcomes and discussed ongoing research to pin down the reasons for the apparent treatment disparities, including patient preferences and the influences of tumor site and HPV status.
Dr. Katzel reported no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Women with head and neck cancer less commonly receive intensive chemotherapy (35% vs. 46%) and radiation therapy (60% vs. 70%) than do their male counterparts, finds an analysis of 223 female patients and 661 male patients with stage II-IVB disease treated at Kaiser Permanente Northern California. And this apparent undertreatment may be compromising survival for women, as their ratio of cancer deaths to other deaths is nearly twice that of men (adjusted relative hazard ratio, 1.92; 95% CI, 1.07-3.43).
In this video interview from the annual meeting of the American Society of Clinical Oncology, senior study author Jed A. Katzel, MD, of Kaiser Permanente in Santa Clara, Calif., described the new statistical approach used to assess outcomes and discussed ongoing research to pin down the reasons for the apparent treatment disparities, including patient preferences and the influences of tumor site and HPV status.
Dr. Katzel reported no financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
CHICAGO – Women with head and neck cancer less commonly receive intensive chemotherapy (35% vs. 46%) and radiation therapy (60% vs. 70%) than do their male counterparts, finds an analysis of 223 female patients and 661 male patients with stage II-IVB disease treated at Kaiser Permanente Northern California. And this apparent undertreatment may be compromising survival for women, as their ratio of cancer deaths to other deaths is nearly twice that of men (adjusted relative hazard ratio, 1.92; 95% CI, 1.07-3.43).
In this video interview from the annual meeting of the American Society of Clinical Oncology, senior study author Jed A. Katzel, MD, of Kaiser Permanente in Santa Clara, Calif., described the new statistical approach used to assess outcomes and discussed ongoing research to pin down the reasons for the apparent treatment disparities, including patient preferences and the influences of tumor site and HPV status.
Dr. Katzel reported no financial disclosures.
REPORTING FROM ASCO 2018
Positivity Rates in Oropharyngeal and Nonoropharyngeal Head and Neck Cancer in the VA
Head and neck cancer (HNC) continues to be a major health issue with an estimated 51,540 cases in the US in 2018, making it the eighth most common cancer among men with an estimated 4% of all new cancer diagnoses.1 Over the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor for survival in squamous cell carcinomas of the oropharynx. Patients who are HPV-positive (HPV+) have a much higher survival rate than patients who have HPV-negative (HPV-) cancers of the oropharynx. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual has 2 distinct stagings for HPV+ and HPV- oropharyngeal tumors using p16-positivity (p16+) as a surrogate marker.2
Squamous cell carcinomas of the oropharynx that are HPV+ have about half the risk of death of HPV- tumors, are highly responsive to treatment, and are more often seen in younger and healthier patients with little to no tobacco use.2,3 As such, there also is a movement to de-escalate HPV+ oropharyngeal cancers with multiple trials by either replacing cytotoxic chemotherapy with a targeted agent (cisplatin vs cetuximab in RTOG 1016) or reducing the radiation dose (ECOG 1308, NRG HN002, Quarterback, and OPTIMA trials).3
The focus of many epidemiologic studies has been in the HNC general population. A recent epidemiologic analysis of the HNC general population found a p16 positivity rate of 60% in oropharyngeal squamous cell carcinomas (OPSCC) and 10% in nonoropharyngeal squamous cell carcinomas (NOPSCC).4 There has been a lack of studies focusing on the US Department of Veterans Administration (VA) population. The VA HNC population consists mostly of older white male smokers; whereas the rise of OPSCC in the general population consists primarily of males aged < 60 years often with little or no tobacco use.5 Furthermore, the importance of p16 positivity in NOPSCC also may be prognostic.6 Population data on this subset in the VA are lacking as well.This study’s purpose is to analyze the p16 positivity rate in both the OPSCC and NOPSCC in the VA population. Elucidation of epidemiologic factors that are associated with these groups may bring to light important differences between the VA and general HNC populations.
Methods
A review of the Kansas City VA Medical Center database for patients with HNC was performed from 2011 to 2017. The review consisted of 183 patient records (second primaries were scored separately), and 123 were deemed eligible for the study. Epidemiologic data were collected, including site, OPSCC vs NOPSCC, age, race, education level, tobacco use, alcohol use, TNM stage, and marital status (Table). 
Results
The NOPSCC p16+ group had the greatest mean pack-year use (57). The lowest was in the OPSCC p16+ group (29). The OPSCC p16+ group had 37% never smokers compared with ≤ 10% for the other groups. Both the OPSCC and NOPSCC p16- groups had much more alcohol use per week than that of the p16+ groups. The differences in marital status included a lower rate of never married individuals in the p16+ group and a higher rate of marriage in the NOPSCC p16- group. The T stage distribution within the OPSCC groups was similar, but NOPSCC groups saw more T1 lesions in the NOPSCC p16- group (42% p16- vs 18% p16+). Conversely, more T4 lesions were found in the NOPSCC p16+ patients (7% p16- vs 29% p16+).
Discussion
The overall HPV positivity rate in the general population of patients with HNC has been reported as between 57% and 72% for OPSCC and between 1.3% and 7% for NOPSCC.6 One study, however, examined the p16 positivity rate in NOPSCC patients enrolled in major trials (RTOG 0129, 0234, and 0522 studies) and found that up to 19.3% of NOPSCC patients had p16 positivity.6 Even with the near 20% rate in those aforementioned trials that are above the reported norm, the current study found that nearly 30% of its VA population had p16+ NOPSCC. It has been shown that regardless of site, HPV-driven head and neck tumors share a similar gene expression and DNA methylation profiles (nonkeratinizing, basaloid histopathologic features, and lack of TP53 or CDKN2A alterations).5 p16+ NOPSCC has a different immune microenvironment with less lymphocyte infiltration, and there is some debate in the literature about the effects on tumor outcomes for NOPSCC cancer.5
In the aforementioned RTOG trials, p16- NOPSCC had worse outcomes compared with those of p16+ NOPSCC.6 This result is in contrast to the Danish Head and Neck Cancer Group (DAHANCA) and the combined Johns Hopkins University (JHU) and University of California, San Francisco (UCSF) data that found no difference between p16+ NOPSCC or p16- NOPSCC.7,8 In regards to race, this study did not find any differences. Another UCSF and JHU study showed lower p16+ rates in African American patients with OPSCC, but no distinction between race in the NOPSCC group. This result is consistent with the data in the current study as the distribution of race was no different among the 4 groups; however, this study's cohort was 90% white, 10% African American, and only < 1% Native American.4 This study's cohort population also was consistent with HPV-positive tumors presenting with earlier T, but higher N staging.9
Smoking is known to decrease survival in HPV-positive HNC, with the RTOG 0129 study separating head and neck tumors into low, medium, and high risk, based on HPV status, smoking, and stage.10 Although the average smoking pack-years in the current study’s OPC p16+ group was high at 29 pack-years, there was still a significant number of nonsmokers in that same group (37%). The University of Michigan conducted a study that had a similar profile of patients with an average age of 56.5 and 32.4% never smokers in their p16+ OPSCC cohort; thus, the VA p16+ OPSCC group in this study may be similar to the general population's p16+ OPSCC group.11 Nonmonogamous relationships also have been shown to be a risk factor for HPV positivity, and there was a difference in marital status (assuming it was a surrogate for monogamy) between the 4 groups; however, in contrast, the p16+ group in the current study had a high number of married patients, 45% in OPC p16+ group, and may not have been a good surrogate for monogamy in this VA population.
Limitations
Limitations of this study include all the caveats that come with a retrospective study, such as confounding variables, unbalanced groups, and selection bias. A detailed sexual history was not included, although it is well known that sexual activity is linked with oral HPV positivity.12 Human papillomavirus positivity based on p16 immunohistochemical analysis also was used as a surrogate marker for HPV instead of DNA in situ hybridization. The data also may be skewed due to the study patient’s being predominantly white and male: Both groups have a higher predilection for HPV-driven HNCs.13
Conclusion
The proportion of p16+ VA OPSCC cases was similar to that of the general population at 75% with 37% never smokers, but the percentage in NOPSCC was higher at 29% with only 10% never smokers. The p16+ NOPSCC also presented with more T4 lesions and a higher overall stage compared with p16- NOPSCC. Further studies are needed to compare these subgroups in the VA and in the general HNC populations.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137.
3. Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol. 2017;8:4-11.
4. D’Souza G, Westra WH, Wang SJ, et al. Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncol. 2017;3(2):169-177.
5. Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132-4141.
6. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930-3938.
7. Lassen P, Primdahl H, Johansen J, et al; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310-316.
8. Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566-1575.
9. Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.
10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.
11. Maxwell, JH, Kumar B, Feng FY, et al. Tobacco use in HPV-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226-1235.
12. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703.
13. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574.
Head and neck cancer (HNC) continues to be a major health issue with an estimated 51,540 cases in the US in 2018, making it the eighth most common cancer among men with an estimated 4% of all new cancer diagnoses.1 Over the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor for survival in squamous cell carcinomas of the oropharynx. Patients who are HPV-positive (HPV+) have a much higher survival rate than patients who have HPV-negative (HPV-) cancers of the oropharynx. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual has 2 distinct stagings for HPV+ and HPV- oropharyngeal tumors using p16-positivity (p16+) as a surrogate marker.2
Squamous cell carcinomas of the oropharynx that are HPV+ have about half the risk of death of HPV- tumors, are highly responsive to treatment, and are more often seen in younger and healthier patients with little to no tobacco use.2,3 As such, there also is a movement to de-escalate HPV+ oropharyngeal cancers with multiple trials by either replacing cytotoxic chemotherapy with a targeted agent (cisplatin vs cetuximab in RTOG 1016) or reducing the radiation dose (ECOG 1308, NRG HN002, Quarterback, and OPTIMA trials).3
The focus of many epidemiologic studies has been in the HNC general population. A recent epidemiologic analysis of the HNC general population found a p16 positivity rate of 60% in oropharyngeal squamous cell carcinomas (OPSCC) and 10% in nonoropharyngeal squamous cell carcinomas (NOPSCC).4 There has been a lack of studies focusing on the US Department of Veterans Administration (VA) population. The VA HNC population consists mostly of older white male smokers; whereas the rise of OPSCC in the general population consists primarily of males aged < 60 years often with little or no tobacco use.5 Furthermore, the importance of p16 positivity in NOPSCC also may be prognostic.6 Population data on this subset in the VA are lacking as well.This study’s purpose is to analyze the p16 positivity rate in both the OPSCC and NOPSCC in the VA population. Elucidation of epidemiologic factors that are associated with these groups may bring to light important differences between the VA and general HNC populations.
Methods
A review of the Kansas City VA Medical Center database for patients with HNC was performed from 2011 to 2017. The review consisted of 183 patient records (second primaries were scored separately), and 123 were deemed eligible for the study. Epidemiologic data were collected, including site, OPSCC vs NOPSCC, age, race, education level, tobacco use, alcohol use, TNM stage, and marital status (Table).
Results
The NOPSCC p16+ group had the greatest mean pack-year use (57). The lowest was in the OPSCC p16+ group (29). The OPSCC p16+ group had 37% never smokers compared with ≤ 10% for the other groups. Both the OPSCC and NOPSCC p16- groups had much more alcohol use per week than that of the p16+ groups. The differences in marital status included a lower rate of never married individuals in the p16+ group and a higher rate of marriage in the NOPSCC p16- group. The T stage distribution within the OPSCC groups was similar, but NOPSCC groups saw more T1 lesions in the NOPSCC p16- group (42% p16- vs 18% p16+). Conversely, more T4 lesions were found in the NOPSCC p16+ patients (7% p16- vs 29% p16+).
Discussion
The overall HPV positivity rate in the general population of patients with HNC has been reported as between 57% and 72% for OPSCC and between 1.3% and 7% for NOPSCC.6 One study, however, examined the p16 positivity rate in NOPSCC patients enrolled in major trials (RTOG 0129, 0234, and 0522 studies) and found that up to 19.3% of NOPSCC patients had p16 positivity.6 Even with the near 20% rate in those aforementioned trials that are above the reported norm, the current study found that nearly 30% of its VA population had p16+ NOPSCC. It has been shown that regardless of site, HPV-driven head and neck tumors share a similar gene expression and DNA methylation profiles (nonkeratinizing, basaloid histopathologic features, and lack of TP53 or CDKN2A alterations).5 p16+ NOPSCC has a different immune microenvironment with less lymphocyte infiltration, and there is some debate in the literature about the effects on tumor outcomes for NOPSCC cancer.5
In the aforementioned RTOG trials, p16- NOPSCC had worse outcomes compared with those of p16+ NOPSCC.6 This result is in contrast to the Danish Head and Neck Cancer Group (DAHANCA) and the combined Johns Hopkins University (JHU) and University of California, San Francisco (UCSF) data that found no difference between p16+ NOPSCC or p16- NOPSCC.7,8 In regards to race, this study did not find any differences. Another UCSF and JHU study showed lower p16+ rates in African American patients with OPSCC, but no distinction between race in the NOPSCC group. This result is consistent with the data in the current study as the distribution of race was no different among the 4 groups; however, this study's cohort was 90% white, 10% African American, and only < 1% Native American.4 This study's cohort population also was consistent with HPV-positive tumors presenting with earlier T, but higher N staging.9
Smoking is known to decrease survival in HPV-positive HNC, with the RTOG 0129 study separating head and neck tumors into low, medium, and high risk, based on HPV status, smoking, and stage.10 Although the average smoking pack-years in the current study’s OPC p16+ group was high at 29 pack-years, there was still a significant number of nonsmokers in that same group (37%). The University of Michigan conducted a study that had a similar profile of patients with an average age of 56.5 and 32.4% never smokers in their p16+ OPSCC cohort; thus, the VA p16+ OPSCC group in this study may be similar to the general population's p16+ OPSCC group.11 Nonmonogamous relationships also have been shown to be a risk factor for HPV positivity, and there was a difference in marital status (assuming it was a surrogate for monogamy) between the 4 groups; however, in contrast, the p16+ group in the current study had a high number of married patients, 45% in OPC p16+ group, and may not have been a good surrogate for monogamy in this VA population.
Limitations
Limitations of this study include all the caveats that come with a retrospective study, such as confounding variables, unbalanced groups, and selection bias. A detailed sexual history was not included, although it is well known that sexual activity is linked with oral HPV positivity.12 Human papillomavirus positivity based on p16 immunohistochemical analysis also was used as a surrogate marker for HPV instead of DNA in situ hybridization. The data also may be skewed due to the study patient’s being predominantly white and male: Both groups have a higher predilection for HPV-driven HNCs.13
Conclusion
The proportion of p16+ VA OPSCC cases was similar to that of the general population at 75% with 37% never smokers, but the percentage in NOPSCC was higher at 29% with only 10% never smokers. The p16+ NOPSCC also presented with more T4 lesions and a higher overall stage compared with p16- NOPSCC. Further studies are needed to compare these subgroups in the VA and in the general HNC populations.
Head and neck cancer (HNC) continues to be a major health issue with an estimated 51,540 cases in the US in 2018, making it the eighth most common cancer among men with an estimated 4% of all new cancer diagnoses.1 Over the past decade, human papillomavirus (HPV) has emerged as a major prognostic factor for survival in squamous cell carcinomas of the oropharynx. Patients who are HPV-positive (HPV+) have a much higher survival rate than patients who have HPV-negative (HPV-) cancers of the oropharynx. The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual has 2 distinct stagings for HPV+ and HPV- oropharyngeal tumors using p16-positivity (p16+) as a surrogate marker.2
Squamous cell carcinomas of the oropharynx that are HPV+ have about half the risk of death of HPV- tumors, are highly responsive to treatment, and are more often seen in younger and healthier patients with little to no tobacco use.2,3 As such, there also is a movement to de-escalate HPV+ oropharyngeal cancers with multiple trials by either replacing cytotoxic chemotherapy with a targeted agent (cisplatin vs cetuximab in RTOG 1016) or reducing the radiation dose (ECOG 1308, NRG HN002, Quarterback, and OPTIMA trials).3
The focus of many epidemiologic studies has been in the HNC general population. A recent epidemiologic analysis of the HNC general population found a p16 positivity rate of 60% in oropharyngeal squamous cell carcinomas (OPSCC) and 10% in nonoropharyngeal squamous cell carcinomas (NOPSCC).4 There has been a lack of studies focusing on the US Department of Veterans Administration (VA) population. The VA HNC population consists mostly of older white male smokers; whereas the rise of OPSCC in the general population consists primarily of males aged < 60 years often with little or no tobacco use.5 Furthermore, the importance of p16 positivity in NOPSCC also may be prognostic.6 Population data on this subset in the VA are lacking as well.This study’s purpose is to analyze the p16 positivity rate in both the OPSCC and NOPSCC in the VA population. Elucidation of epidemiologic factors that are associated with these groups may bring to light important differences between the VA and general HNC populations.
Methods
A review of the Kansas City VA Medical Center database for patients with HNC was performed from 2011 to 2017. The review consisted of 183 patient records (second primaries were scored separately), and 123 were deemed eligible for the study. Epidemiologic data were collected, including site, OPSCC vs NOPSCC, age, race, education level, tobacco use, alcohol use, TNM stage, and marital status (Table).
Results
The NOPSCC p16+ group had the greatest mean pack-year use (57). The lowest was in the OPSCC p16+ group (29). The OPSCC p16+ group had 37% never smokers compared with ≤ 10% for the other groups. Both the OPSCC and NOPSCC p16- groups had much more alcohol use per week than that of the p16+ groups. The differences in marital status included a lower rate of never married individuals in the p16+ group and a higher rate of marriage in the NOPSCC p16- group. The T stage distribution within the OPSCC groups was similar, but NOPSCC groups saw more T1 lesions in the NOPSCC p16- group (42% p16- vs 18% p16+). Conversely, more T4 lesions were found in the NOPSCC p16+ patients (7% p16- vs 29% p16+).
Discussion
The overall HPV positivity rate in the general population of patients with HNC has been reported as between 57% and 72% for OPSCC and between 1.3% and 7% for NOPSCC.6 One study, however, examined the p16 positivity rate in NOPSCC patients enrolled in major trials (RTOG 0129, 0234, and 0522 studies) and found that up to 19.3% of NOPSCC patients had p16 positivity.6 Even with the near 20% rate in those aforementioned trials that are above the reported norm, the current study found that nearly 30% of its VA population had p16+ NOPSCC. It has been shown that regardless of site, HPV-driven head and neck tumors share a similar gene expression and DNA methylation profiles (nonkeratinizing, basaloid histopathologic features, and lack of TP53 or CDKN2A alterations).5 p16+ NOPSCC has a different immune microenvironment with less lymphocyte infiltration, and there is some debate in the literature about the effects on tumor outcomes for NOPSCC cancer.5
In the aforementioned RTOG trials, p16- NOPSCC had worse outcomes compared with those of p16+ NOPSCC.6 This result is in contrast to the Danish Head and Neck Cancer Group (DAHANCA) and the combined Johns Hopkins University (JHU) and University of California, San Francisco (UCSF) data that found no difference between p16+ NOPSCC or p16- NOPSCC.7,8 In regards to race, this study did not find any differences. Another UCSF and JHU study showed lower p16+ rates in African American patients with OPSCC, but no distinction between race in the NOPSCC group. This result is consistent with the data in the current study as the distribution of race was no different among the 4 groups; however, this study's cohort was 90% white, 10% African American, and only < 1% Native American.4 This study's cohort population also was consistent with HPV-positive tumors presenting with earlier T, but higher N staging.9
Smoking is known to decrease survival in HPV-positive HNC, with the RTOG 0129 study separating head and neck tumors into low, medium, and high risk, based on HPV status, smoking, and stage.10 Although the average smoking pack-years in the current study’s OPC p16+ group was high at 29 pack-years, there was still a significant number of nonsmokers in that same group (37%). The University of Michigan conducted a study that had a similar profile of patients with an average age of 56.5 and 32.4% never smokers in their p16+ OPSCC cohort; thus, the VA p16+ OPSCC group in this study may be similar to the general population's p16+ OPSCC group.11 Nonmonogamous relationships also have been shown to be a risk factor for HPV positivity, and there was a difference in marital status (assuming it was a surrogate for monogamy) between the 4 groups; however, in contrast, the p16+ group in the current study had a high number of married patients, 45% in OPC p16+ group, and may not have been a good surrogate for monogamy in this VA population.
Limitations
Limitations of this study include all the caveats that come with a retrospective study, such as confounding variables, unbalanced groups, and selection bias. A detailed sexual history was not included, although it is well known that sexual activity is linked with oral HPV positivity.12 Human papillomavirus positivity based on p16 immunohistochemical analysis also was used as a surrogate marker for HPV instead of DNA in situ hybridization. The data also may be skewed due to the study patient’s being predominantly white and male: Both groups have a higher predilection for HPV-driven HNCs.13
Conclusion
The proportion of p16+ VA OPSCC cases was similar to that of the general population at 75% with 37% never smokers, but the percentage in NOPSCC was higher at 29% with only 10% never smokers. The p16+ NOPSCC also presented with more T4 lesions and a higher overall stage compared with p16- NOPSCC. Further studies are needed to compare these subgroups in the VA and in the general HNC populations.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137.
3. Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol. 2017;8:4-11.
4. D’Souza G, Westra WH, Wang SJ, et al. Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncol. 2017;3(2):169-177.
5. Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132-4141.
6. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930-3938.
7. Lassen P, Primdahl H, Johansen J, et al; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310-316.
8. Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566-1575.
9. Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.
10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.
11. Maxwell, JH, Kumar B, Feng FY, et al. Tobacco use in HPV-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226-1235.
12. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703.
13. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574.
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(2):122-137.
3. Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol. 2017;8:4-11.
4. D’Souza G, Westra WH, Wang SJ, et al. Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncol. 2017;3(2):169-177.
5. Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. J Clin Oncol. 2016;34(34):4132-4141.
6. Chung CH, Zhang Q, Kong CS, et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol. 2014;32(35):3930-3938.
7. Lassen P, Primdahl H, Johansen J, et al; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310-316.
8. Fakhry C, Westra WH, Wang SJ, et al. The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer. 2017;123(9):1566-1575.
9. Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol Ital. 2014;34(5):299-309.
10. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24-35.
11. Maxwell, JH, Kumar B, Feng FY, et al. Tobacco use in HPV-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res. 2010;16(4):1226-1235.
12. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703.
13. Benson E, Li R, Eisele D, Fakhry C. The clinical impact of HPV tumor status upon head and neck squamous cell carcinomas. Oral Oncol. 2014;50(6):565-574.
New remote monitoring system lessens symptoms in head and neck cancer
A new system for remotely assessing and transmitting selected vitals and self-reported measures reduces symptom severity among patients with head and neck cancer receiving radiation therapy, in a randomized trial reported at a press briefing held before the annual meeting of the American Society of Clinical Oncology.
“Head and neck cancer patients who receive radiation treatment have a high symptom burden and also are at increased risk for dehydration during treatment,” said lead study author Susan K. Peterson, PhD, a professor in the department of behavioral science at the University of Texas MD Anderson Cancer Center, Houston. “Previously, we have shown that it was feasible to use mobile and sensor technology to identify treatment-related symptoms and early dehydration risk in patients receiving radiation treatment as part of their outpatient care.”
In the new trial, the investigators tested the CYCORE system (Cyberinfrastructure for Comparative Effectiveness Research), which consists of a Bluetooth-enabled weight scale and blood pressure cuff, and a mobile tablet with a symptom-tracking app that sends information directly to the physician each weekday. A network hub/router was set up in patients’ homes to transmit their sensor readouts, and the mobile app transmitted their symptom data to secure firewall-protected computers. “CYCORE also included a software infrastructure that enabled the analysis and viewing of data in near-real time and was compliant with safety and security and confidentiality standards,” Dr. Peterson noted.
Main trial results showed that compared with peers receiving only usual care (weekly visits with the radiation oncologist), patients receiving usual care augmented with the CYCORE system had lower mean scores on a 10-point scale for general symptoms (0.5-point difference) and for symptoms specific to head and neck cancer (0.6-point difference). In addition, daily remote tracking of patient well-being allowed clinicians to more rapidly detect and respond to symptoms.
“This is important because symptoms can affects patients’ ability to tolerate treatment and can also impact their quality of life during treatment,” Dr. Peterson said.
The mean age of the patients was 60 years; the oldest was 86 years old. “This supports the notion that the use of technology-based interventions can be feasible in older patients,” she maintained. In addition, patients in the CYCORE group showed at least 80% adherence to the daily monitoring tasks.
“We believe that good patient adherence plus the fact that this imposed minimal burden on clinicians for the monitoring supports the use of systems like CYCORE during intensive treatment periods in cancer care, and that using sensor and mobile technology to monitor patients during critical periods of outpatient care can provide a timely source of information for clinical decision making and may ultimately improve quality of life and health outcomes,” Dr. Peterson concluded. “Our next steps would be to explore ways to implement this as part of clinical care, including in community cancer centers, where most patients receive their care.”
“This is yet another application of technology-enabled sharing of information generated at home,” said ASCO President Bruce E. Johnson, MD, FASCO, noting that a similar study last year showed better patient-reported experience and overall survival.
Such technology will likely be increasingly used to obtain timely information that ultimately leads to a reduction in complications, he speculated.
“This information in head and neck cancer is particularly important because patients commonly get a lot of side effects when attempting to swallow enough fluids, such that some centers end up putting a feeding tube into the stomach because it’s so difficult to swallow,” added Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, Boston. “So this is a particularly important clinical application in cancer.”
Study details
The trial population consisted of 357 patients undergoing radiation therapy for head and neck cancer. “We believe that this is the first and largest study of its kind in head and neck cancer,” Dr. Peterson said.
The severity of symptoms and their interference with daily activities were assessed at serial time points with the MD Anderson Symptom Inventory.
In the CYCORE group, 87% of patients measured their blood pressure daily, 86% measured their weight daily, and 80% used the symptom-tracking app daily.
At the end of radiation therapy, the CYCORE patients had lower (i.e., better) mean scores for general symptoms (e.g., pain, nausea, fatigue) relative to usual care counterparts (2.9 vs. 3.4), with a difference still evident 6-8 weeks later (1.6 vs. 1.9) (P = .007).
In addition, the CYCORE patients had lower mean scores for symptoms specific to head and neck cancer (e.g., dysphagia, pain, rash) at the end of radiation therapy (4.2 vs. 4.8), with a difference still evident 6-8 weeks later (1.7 vs. 2.1) (P = .009).
The groups fared essentially the same with respect to scores assessing interference of symptoms with activities of daily living.
Dr. Peterson disclosed that she had no relevant conflicts of interest. The study received funding from the National Institutes of Health.
SOURCE: Peterson et al. ASCO 2018, Abstract 6063.
A new system for remotely assessing and transmitting selected vitals and self-reported measures reduces symptom severity among patients with head and neck cancer receiving radiation therapy, in a randomized trial reported at a press briefing held before the annual meeting of the American Society of Clinical Oncology.
“Head and neck cancer patients who receive radiation treatment have a high symptom burden and also are at increased risk for dehydration during treatment,” said lead study author Susan K. Peterson, PhD, a professor in the department of behavioral science at the University of Texas MD Anderson Cancer Center, Houston. “Previously, we have shown that it was feasible to use mobile and sensor technology to identify treatment-related symptoms and early dehydration risk in patients receiving radiation treatment as part of their outpatient care.”
In the new trial, the investigators tested the CYCORE system (Cyberinfrastructure for Comparative Effectiveness Research), which consists of a Bluetooth-enabled weight scale and blood pressure cuff, and a mobile tablet with a symptom-tracking app that sends information directly to the physician each weekday. A network hub/router was set up in patients’ homes to transmit their sensor readouts, and the mobile app transmitted their symptom data to secure firewall-protected computers. “CYCORE also included a software infrastructure that enabled the analysis and viewing of data in near-real time and was compliant with safety and security and confidentiality standards,” Dr. Peterson noted.
Main trial results showed that compared with peers receiving only usual care (weekly visits with the radiation oncologist), patients receiving usual care augmented with the CYCORE system had lower mean scores on a 10-point scale for general symptoms (0.5-point difference) and for symptoms specific to head and neck cancer (0.6-point difference). In addition, daily remote tracking of patient well-being allowed clinicians to more rapidly detect and respond to symptoms.
“This is important because symptoms can affects patients’ ability to tolerate treatment and can also impact their quality of life during treatment,” Dr. Peterson said.
The mean age of the patients was 60 years; the oldest was 86 years old. “This supports the notion that the use of technology-based interventions can be feasible in older patients,” she maintained. In addition, patients in the CYCORE group showed at least 80% adherence to the daily monitoring tasks.
“We believe that good patient adherence plus the fact that this imposed minimal burden on clinicians for the monitoring supports the use of systems like CYCORE during intensive treatment periods in cancer care, and that using sensor and mobile technology to monitor patients during critical periods of outpatient care can provide a timely source of information for clinical decision making and may ultimately improve quality of life and health outcomes,” Dr. Peterson concluded. “Our next steps would be to explore ways to implement this as part of clinical care, including in community cancer centers, where most patients receive their care.”
“This is yet another application of technology-enabled sharing of information generated at home,” said ASCO President Bruce E. Johnson, MD, FASCO, noting that a similar study last year showed better patient-reported experience and overall survival.
Such technology will likely be increasingly used to obtain timely information that ultimately leads to a reduction in complications, he speculated.
“This information in head and neck cancer is particularly important because patients commonly get a lot of side effects when attempting to swallow enough fluids, such that some centers end up putting a feeding tube into the stomach because it’s so difficult to swallow,” added Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, Boston. “So this is a particularly important clinical application in cancer.”
Study details
The trial population consisted of 357 patients undergoing radiation therapy for head and neck cancer. “We believe that this is the first and largest study of its kind in head and neck cancer,” Dr. Peterson said.
The severity of symptoms and their interference with daily activities were assessed at serial time points with the MD Anderson Symptom Inventory.
In the CYCORE group, 87% of patients measured their blood pressure daily, 86% measured their weight daily, and 80% used the symptom-tracking app daily.
At the end of radiation therapy, the CYCORE patients had lower (i.e., better) mean scores for general symptoms (e.g., pain, nausea, fatigue) relative to usual care counterparts (2.9 vs. 3.4), with a difference still evident 6-8 weeks later (1.6 vs. 1.9) (P = .007).
In addition, the CYCORE patients had lower mean scores for symptoms specific to head and neck cancer (e.g., dysphagia, pain, rash) at the end of radiation therapy (4.2 vs. 4.8), with a difference still evident 6-8 weeks later (1.7 vs. 2.1) (P = .009).
The groups fared essentially the same with respect to scores assessing interference of symptoms with activities of daily living.
Dr. Peterson disclosed that she had no relevant conflicts of interest. The study received funding from the National Institutes of Health.
SOURCE: Peterson et al. ASCO 2018, Abstract 6063.
A new system for remotely assessing and transmitting selected vitals and self-reported measures reduces symptom severity among patients with head and neck cancer receiving radiation therapy, in a randomized trial reported at a press briefing held before the annual meeting of the American Society of Clinical Oncology.
“Head and neck cancer patients who receive radiation treatment have a high symptom burden and also are at increased risk for dehydration during treatment,” said lead study author Susan K. Peterson, PhD, a professor in the department of behavioral science at the University of Texas MD Anderson Cancer Center, Houston. “Previously, we have shown that it was feasible to use mobile and sensor technology to identify treatment-related symptoms and early dehydration risk in patients receiving radiation treatment as part of their outpatient care.”
In the new trial, the investigators tested the CYCORE system (Cyberinfrastructure for Comparative Effectiveness Research), which consists of a Bluetooth-enabled weight scale and blood pressure cuff, and a mobile tablet with a symptom-tracking app that sends information directly to the physician each weekday. A network hub/router was set up in patients’ homes to transmit their sensor readouts, and the mobile app transmitted their symptom data to secure firewall-protected computers. “CYCORE also included a software infrastructure that enabled the analysis and viewing of data in near-real time and was compliant with safety and security and confidentiality standards,” Dr. Peterson noted.
Main trial results showed that compared with peers receiving only usual care (weekly visits with the radiation oncologist), patients receiving usual care augmented with the CYCORE system had lower mean scores on a 10-point scale for general symptoms (0.5-point difference) and for symptoms specific to head and neck cancer (0.6-point difference). In addition, daily remote tracking of patient well-being allowed clinicians to more rapidly detect and respond to symptoms.
“This is important because symptoms can affects patients’ ability to tolerate treatment and can also impact their quality of life during treatment,” Dr. Peterson said.
The mean age of the patients was 60 years; the oldest was 86 years old. “This supports the notion that the use of technology-based interventions can be feasible in older patients,” she maintained. In addition, patients in the CYCORE group showed at least 80% adherence to the daily monitoring tasks.
“We believe that good patient adherence plus the fact that this imposed minimal burden on clinicians for the monitoring supports the use of systems like CYCORE during intensive treatment periods in cancer care, and that using sensor and mobile technology to monitor patients during critical periods of outpatient care can provide a timely source of information for clinical decision making and may ultimately improve quality of life and health outcomes,” Dr. Peterson concluded. “Our next steps would be to explore ways to implement this as part of clinical care, including in community cancer centers, where most patients receive their care.”
“This is yet another application of technology-enabled sharing of information generated at home,” said ASCO President Bruce E. Johnson, MD, FASCO, noting that a similar study last year showed better patient-reported experience and overall survival.
Such technology will likely be increasingly used to obtain timely information that ultimately leads to a reduction in complications, he speculated.
“This information in head and neck cancer is particularly important because patients commonly get a lot of side effects when attempting to swallow enough fluids, such that some centers end up putting a feeding tube into the stomach because it’s so difficult to swallow,” added Dr. Johnson, who is also a professor of medicine at the Dana-Farber Cancer Institute and a leader of the Dana-Farber/Harvard Cancer Center Lung Cancer Program, Boston. “So this is a particularly important clinical application in cancer.”
Study details
The trial population consisted of 357 patients undergoing radiation therapy for head and neck cancer. “We believe that this is the first and largest study of its kind in head and neck cancer,” Dr. Peterson said.
The severity of symptoms and their interference with daily activities were assessed at serial time points with the MD Anderson Symptom Inventory.
In the CYCORE group, 87% of patients measured their blood pressure daily, 86% measured their weight daily, and 80% used the symptom-tracking app daily.
At the end of radiation therapy, the CYCORE patients had lower (i.e., better) mean scores for general symptoms (e.g., pain, nausea, fatigue) relative to usual care counterparts (2.9 vs. 3.4), with a difference still evident 6-8 weeks later (1.6 vs. 1.9) (P = .007).
In addition, the CYCORE patients had lower mean scores for symptoms specific to head and neck cancer (e.g., dysphagia, pain, rash) at the end of radiation therapy (4.2 vs. 4.8), with a difference still evident 6-8 weeks later (1.7 vs. 2.1) (P = .009).
The groups fared essentially the same with respect to scores assessing interference of symptoms with activities of daily living.
Dr. Peterson disclosed that she had no relevant conflicts of interest. The study received funding from the National Institutes of Health.
SOURCE: Peterson et al. ASCO 2018, Abstract 6063.
REPORTING FROM ASCO 2018
Key clinical point: .
Major finding: Compared with usual care, the system for tracking and transmitting vitals and self-reported measures through sensor and mobile devices was associated with milder general symptoms (0.5-point difference) and head and neck cancer symptoms (0.6-point difference).
Study details: A randomized controlled trial among 357 patients with head and neck cancer undergoing radiation therapy.
Disclosures: Dr. Peterson disclosed that she had no conflicts of interest. The study received funding from the National Institutes of Health.
Source: Peterson et al. ASCO 2018, Abstract 6063.
Novel Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1 (FULL)
Neuroendocrine tumors (NETs) are uncommon and can occur in the context of genetic conditions. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder of the tumor suppressor gene of the same name—MEN1, which encodes for the protein menin. Multiple endocrine neoplasia type 1 is characterized clinically by the presence of 2 or more of the following NETs: parathyroid, pituitary, and pancreaticoduodenal.1 Pancreaticoduodenal NETs occur in 30% to 80% of patients with MEN1 and have malignant potential. Although the majority of pancreaticoduodenal NETs are nonfunctioning, patients may present with symptoms secondary to mass effect.
Genetic testing exists for MEN1, but not all genetic mutations that cause MEN1 have been discovered. Therefore, because negative genetic testing does not rule out MEN1, a diagnosis is based on tumor type and location. Neuroendocrine tumors of the biliary tree are rare, and there
are no well-accepted guidelines on how to stage them.2-4 The following case demonstrates an unusual initial presentation of a NET in the context of MEN1.
Case Report
A 29-year-old, active-duty African-American man deployed in Kuwait presented with icterus, flank pain, and hematuria. His past medical history was significant for nephrolithiasis, and his family history was notable for hyperparathyroidism. Laboratory results showed primary hyperparathyroidism and evidence of biliary obstruction.
A sestamibi scan demonstrated uptake in a location corresponding with the right inferior parathyroid gland. A computed tomography (CT) scan showed nephrolithiasis and hepatic biliary ductal dilatation. Magnetic resonance cholangiopancreatography (MRCP) revealed both intra- and extrahepatic ductal dilatation, focal narrowing of the proximal common bile duct, and possible adenopathy that was concerning for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 1 cm to 2 cm focal stricture within the mid-common bile duct with intra- and extrahepatic ductal dilatation (Figure 1). An endoscopy showed no masses in the duodenum, and anendoscopic ultrasound showed no masses in the pancreas. Endoscopic brushings and endoscopic, ultrasound-guided, fine-needle aspiration
cytology were nondiagnostic. Exploratory laparotomy revealed a dilated hepatic bile duct, an inflamed porta hepatis, and a mass involving the distal hepatic bile duct. 
The patient underwent cholecystectomy, radical extra hepatic bile duct resection to the level of the hepatic bifurcation, and hepaticojejunostomy. Gross examination of the specimen showed a nodule centered in the distal common hepatic duct with an adjacent, 2-cm lymph node. The histologic examination revealed a neoplastic proliferation consisting of epithelioid cells with round nuclei and granular chromatin with amphophilic cytoplasm in a trabecular and nested architecture.
The tumor was centered in the submucosa, which is typical of gastrointestinal NETs (Figure 2). There was no evidence of direct tumor extension elsewhere. About 40% of the tumor cells contained eosinophilic, intracytoplasmic inclusions (Figure 3). The tumor did not involve the margins or lymph node. 
Positive staining with the neuroendocrine markers synaptophysin and chromagranin A confirmed a well-differentiated NET. The intracytoplasmic inclusions stained strongly positive for cytokeratin CAM 5.2. The tumor had higher-grade features, including tumor cell necrosis, a Ki-67 labeling index of 3%, and perineural invasion. The 2010 World Health Organization (WHO) criteria for NET of the digestive system classified this tumor as a grade 2, well-differentiated NET and as stage 1a (limited to the bile duct).4
Postoperatively, octreotide scan with single-photon emission computed tomography (SPECT)-CT did not show additional masses or lesions. Serum pancreatic polypeptide was elevated, with the remaining serum and plasma NET markers—including gastrin, glucagon, insulin, chromogranin A, and vasoactive intestinal polypeptide (VIP)—being within reference ranges. Genetic testing (GeneDx, Inc, Gaithersburg, MD) showed an E563X nonsense mutation in the MEN1 gene, confirming a MEN1 disorder. The patient then underwent a 4-gland parathyroidectomy with reimplantation; the parathyroid glands demonstrated hyperplasia in all 4 glands.
Biochemical follow-up at 14 months showed that the serum pancreatic polypeptide had normalized. There was no evidence of pituitary orpancreatic hypersecretion. The patient developed hypoparathyroidism, requiring calcium and calcitriol supplementation. Radiographic follow-up using abdominal magnetic resonance imaging at 16 months showed no evidence of disease.
Discussion
This case illustrates a genetic disease with an unusual initial presentation. Primary extrahepatic bile duct NETs are rare and have been reported previously in patients without MEN1.5-9 Neuroendocrine tumors in the hepatic bile duct in patients with MEN1 also have been reported but only after these tumors first appeared in the pancreas or duodenum.10 An extensive literature search revealed no prior reports extrahepatic bile duct NETs with MEN1 as the primary site or with biliary obstruction, which is why this patient’s presentation is particularly interesting.5,6,10-13 The table summarizes select reports of NETs. 
Tumor location in this patient was atypical, and genetic testing guided the management. Serum MEN1 genetic testing is indicated in patients with ≥ 2 tumors that are atypical but possibly associated with MEN1 (such as adrenal tumors, gastrinomas, and carcinoids) and in patients aged < 45 years with primary hyperparathyroidism.14,15 The patient in this study was aged 29 years and had hyperparathyroidism and an NET of the hepatic bile duct. This condition was sufficient to warrant genetic testing, the results of which affected the patient’s subsequent parathyroid surgery.15 Despite the suggestion of unifocal localization on the sestamibi scan, the patient underwent the more appropriate subtotal parathyroidectomy.14 The patient’s tumor most likely originated from a germline mutation of the MEN1 gene.
As a result of the patient’s genetic test results, his daughter also was tested. She was found to have the same mutation as her father and will undergo proper tumor surveillance for MEN1. There was no personal or family history of hemangioblastomas, renal cell carcinomas, or cystadenomas, which would have prompted testing for von Hippel-Lindau disease. Likewise, there was no personal or family history of café-au-lait macules and neurofibromas, which would have prompted testing for neurofibromatosis type 1.
Due to the paucity of cases, there are currently no well-accepted guidelines on how to stage extrahepatic biliary NETs.3-5,16 The WHO recommends staging according to adenocarcinomas of the gallbladder and bile duct.3 As such, the pathologic stage of this tumor would be stage 1a.
The significance of the intracytoplasmic inclusion in this case is unknown. Pancreatic NETs and neuroendocrine carcinomas have demonstrated intracytoplasmic inclusions that stain positively for keratin and may indicate more aggressive tumor behavior.17-19 In 1 report, electron microscopic examination demonstrated intermediate filaments with entrapped neurosecretory granules.18 In a series of 84 cases of pancreatic endocrine tumors, 14 had intracytoplasmic inclusions; of these, 5 had MEN1.17 In the present case, the patient continues to show no evidence of tumor recurrence at 16 months after resection.
Conclusion
Extrahepatic biliary neuroendocrine tumors are rare. Further investigation into biliary tree NET staging and future studies to determine the significance of intracytoplasmic inclusions may be beneficial. This case highlights the appropriate use of genetic testing and supports expanding the clinical diagnosis of MEN1 to include NETs of the extrahepatic bile duct.
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1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: WB Saunders; 2011.
2. American Joint Committee on Cancer. Neuroendocrine Tumors. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Handbook. 7th ed. From the AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2010:227-236.
3. Komminoth P, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:274-276.
4. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13.
5. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature. Endocr Pract. 2009;15(7):737-749.
6. Bhandarwar AH, Shaikh TA, Borisa AD, et al. Primary neuroendocrine tumor of the left hepatic duct: a case report with review of the literature. Case Rep Surg. 2012:786432.
7. Bhalla P, Powle V, Shah RC, Jagannath P. Neuroendocrine tumor of common hepatic duct. Indian J Gastroenterol. 2012;31(3):144-146.
8. Khan FA, Stevens-Chase A, Chaudhry R, Hashmi A, Edelman D, Weaver D. Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct. Int J Surg Case Rep. 2017;30:46-49.
9. Hong N, Kim HJ, Byun JH, et al. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40(1):181-191.
10. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome. World J Gastroenterol. 2013;19(45):8312-8320.
11. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43-83.
12. Pieterman CRC, Conemans EB, Dreijerink KMA, et al. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer. 2014;21(3):R121-R142.
13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med. 1990;322(11):723-727.
14. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
15. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
16. Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20(4):765-775.
17. Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called “rhabdoid” phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17(1):75-81.
18. Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the “rhabdoid” inclusions seen in pancreatic endocrine
neoplasms. Am J Surg Pathol. 2004;28(2):271-273.
19. Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with ‘Rhabdoid’ features. Am J Surg Pathol. 2003;27(5):642-649.
Neuroendocrine tumors (NETs) are uncommon and can occur in the context of genetic conditions. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder of the tumor suppressor gene of the same name—MEN1, which encodes for the protein menin. Multiple endocrine neoplasia type 1 is characterized clinically by the presence of 2 or more of the following NETs: parathyroid, pituitary, and pancreaticoduodenal.1 Pancreaticoduodenal NETs occur in 30% to 80% of patients with MEN1 and have malignant potential. Although the majority of pancreaticoduodenal NETs are nonfunctioning, patients may present with symptoms secondary to mass effect.
Genetic testing exists for MEN1, but not all genetic mutations that cause MEN1 have been discovered. Therefore, because negative genetic testing does not rule out MEN1, a diagnosis is based on tumor type and location. Neuroendocrine tumors of the biliary tree are rare, and there
are no well-accepted guidelines on how to stage them.2-4 The following case demonstrates an unusual initial presentation of a NET in the context of MEN1.
Case Report
A 29-year-old, active-duty African-American man deployed in Kuwait presented with icterus, flank pain, and hematuria. His past medical history was significant for nephrolithiasis, and his family history was notable for hyperparathyroidism. Laboratory results showed primary hyperparathyroidism and evidence of biliary obstruction.
A sestamibi scan demonstrated uptake in a location corresponding with the right inferior parathyroid gland. A computed tomography (CT) scan showed nephrolithiasis and hepatic biliary ductal dilatation. Magnetic resonance cholangiopancreatography (MRCP) revealed both intra- and extrahepatic ductal dilatation, focal narrowing of the proximal common bile duct, and possible adenopathy that was concerning for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 1 cm to 2 cm focal stricture within the mid-common bile duct with intra- and extrahepatic ductal dilatation (Figure 1). An endoscopy showed no masses in the duodenum, and anendoscopic ultrasound showed no masses in the pancreas. Endoscopic brushings and endoscopic, ultrasound-guided, fine-needle aspiration
cytology were nondiagnostic. Exploratory laparotomy revealed a dilated hepatic bile duct, an inflamed porta hepatis, and a mass involving the distal hepatic bile duct.
The patient underwent cholecystectomy, radical extra hepatic bile duct resection to the level of the hepatic bifurcation, and hepaticojejunostomy. Gross examination of the specimen showed a nodule centered in the distal common hepatic duct with an adjacent, 2-cm lymph node. The histologic examination revealed a neoplastic proliferation consisting of epithelioid cells with round nuclei and granular chromatin with amphophilic cytoplasm in a trabecular and nested architecture.
The tumor was centered in the submucosa, which is typical of gastrointestinal NETs (Figure 2). There was no evidence of direct tumor extension elsewhere. About 40% of the tumor cells contained eosinophilic, intracytoplasmic inclusions (Figure 3). The tumor did not involve the margins or lymph node.
Positive staining with the neuroendocrine markers synaptophysin and chromagranin A confirmed a well-differentiated NET. The intracytoplasmic inclusions stained strongly positive for cytokeratin CAM 5.2. The tumor had higher-grade features, including tumor cell necrosis, a Ki-67 labeling index of 3%, and perineural invasion. The 2010 World Health Organization (WHO) criteria for NET of the digestive system classified this tumor as a grade 2, well-differentiated NET and as stage 1a (limited to the bile duct).4
Postoperatively, octreotide scan with single-photon emission computed tomography (SPECT)-CT did not show additional masses or lesions. Serum pancreatic polypeptide was elevated, with the remaining serum and plasma NET markers—including gastrin, glucagon, insulin, chromogranin A, and vasoactive intestinal polypeptide (VIP)—being within reference ranges. Genetic testing (GeneDx, Inc, Gaithersburg, MD) showed an E563X nonsense mutation in the MEN1 gene, confirming a MEN1 disorder. The patient then underwent a 4-gland parathyroidectomy with reimplantation; the parathyroid glands demonstrated hyperplasia in all 4 glands.
Biochemical follow-up at 14 months showed that the serum pancreatic polypeptide had normalized. There was no evidence of pituitary orpancreatic hypersecretion. The patient developed hypoparathyroidism, requiring calcium and calcitriol supplementation. Radiographic follow-up using abdominal magnetic resonance imaging at 16 months showed no evidence of disease.
Discussion
This case illustrates a genetic disease with an unusual initial presentation. Primary extrahepatic bile duct NETs are rare and have been reported previously in patients without MEN1.5-9 Neuroendocrine tumors in the hepatic bile duct in patients with MEN1 also have been reported but only after these tumors first appeared in the pancreas or duodenum.10 An extensive literature search revealed no prior reports extrahepatic bile duct NETs with MEN1 as the primary site or with biliary obstruction, which is why this patient’s presentation is particularly interesting.5,6,10-13 The table summarizes select reports of NETs.
Tumor location in this patient was atypical, and genetic testing guided the management. Serum MEN1 genetic testing is indicated in patients with ≥ 2 tumors that are atypical but possibly associated with MEN1 (such as adrenal tumors, gastrinomas, and carcinoids) and in patients aged < 45 years with primary hyperparathyroidism.14,15 The patient in this study was aged 29 years and had hyperparathyroidism and an NET of the hepatic bile duct. This condition was sufficient to warrant genetic testing, the results of which affected the patient’s subsequent parathyroid surgery.15 Despite the suggestion of unifocal localization on the sestamibi scan, the patient underwent the more appropriate subtotal parathyroidectomy.14 The patient’s tumor most likely originated from a germline mutation of the MEN1 gene.
As a result of the patient’s genetic test results, his daughter also was tested. She was found to have the same mutation as her father and will undergo proper tumor surveillance for MEN1. There was no personal or family history of hemangioblastomas, renal cell carcinomas, or cystadenomas, which would have prompted testing for von Hippel-Lindau disease. Likewise, there was no personal or family history of café-au-lait macules and neurofibromas, which would have prompted testing for neurofibromatosis type 1.
Due to the paucity of cases, there are currently no well-accepted guidelines on how to stage extrahepatic biliary NETs.3-5,16 The WHO recommends staging according to adenocarcinomas of the gallbladder and bile duct.3 As such, the pathologic stage of this tumor would be stage 1a.
The significance of the intracytoplasmic inclusion in this case is unknown. Pancreatic NETs and neuroendocrine carcinomas have demonstrated intracytoplasmic inclusions that stain positively for keratin and may indicate more aggressive tumor behavior.17-19 In 1 report, electron microscopic examination demonstrated intermediate filaments with entrapped neurosecretory granules.18 In a series of 84 cases of pancreatic endocrine tumors, 14 had intracytoplasmic inclusions; of these, 5 had MEN1.17 In the present case, the patient continues to show no evidence of tumor recurrence at 16 months after resection.
Conclusion
Extrahepatic biliary neuroendocrine tumors are rare. Further investigation into biliary tree NET staging and future studies to determine the significance of intracytoplasmic inclusions may be beneficial. This case highlights the appropriate use of genetic testing and supports expanding the clinical diagnosis of MEN1 to include NETs of the extrahepatic bile duct.
Click here to read the digital edition.
Neuroendocrine tumors (NETs) are uncommon and can occur in the context of genetic conditions. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder of the tumor suppressor gene of the same name—MEN1, which encodes for the protein menin. Multiple endocrine neoplasia type 1 is characterized clinically by the presence of 2 or more of the following NETs: parathyroid, pituitary, and pancreaticoduodenal.1 Pancreaticoduodenal NETs occur in 30% to 80% of patients with MEN1 and have malignant potential. Although the majority of pancreaticoduodenal NETs are nonfunctioning, patients may present with symptoms secondary to mass effect.
Genetic testing exists for MEN1, but not all genetic mutations that cause MEN1 have been discovered. Therefore, because negative genetic testing does not rule out MEN1, a diagnosis is based on tumor type and location. Neuroendocrine tumors of the biliary tree are rare, and there
are no well-accepted guidelines on how to stage them.2-4 The following case demonstrates an unusual initial presentation of a NET in the context of MEN1.
Case Report
A 29-year-old, active-duty African-American man deployed in Kuwait presented with icterus, flank pain, and hematuria. His past medical history was significant for nephrolithiasis, and his family history was notable for hyperparathyroidism. Laboratory results showed primary hyperparathyroidism and evidence of biliary obstruction.
A sestamibi scan demonstrated uptake in a location corresponding with the right inferior parathyroid gland. A computed tomography (CT) scan showed nephrolithiasis and hepatic biliary ductal dilatation. Magnetic resonance cholangiopancreatography (MRCP) revealed both intra- and extrahepatic ductal dilatation, focal narrowing of the proximal common bile duct, and possible adenopathy that was concerning for cholangiocarcinoma. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a 1 cm to 2 cm focal stricture within the mid-common bile duct with intra- and extrahepatic ductal dilatation (Figure 1). An endoscopy showed no masses in the duodenum, and anendoscopic ultrasound showed no masses in the pancreas. Endoscopic brushings and endoscopic, ultrasound-guided, fine-needle aspiration
cytology were nondiagnostic. Exploratory laparotomy revealed a dilated hepatic bile duct, an inflamed porta hepatis, and a mass involving the distal hepatic bile duct.
The patient underwent cholecystectomy, radical extra hepatic bile duct resection to the level of the hepatic bifurcation, and hepaticojejunostomy. Gross examination of the specimen showed a nodule centered in the distal common hepatic duct with an adjacent, 2-cm lymph node. The histologic examination revealed a neoplastic proliferation consisting of epithelioid cells with round nuclei and granular chromatin with amphophilic cytoplasm in a trabecular and nested architecture.
The tumor was centered in the submucosa, which is typical of gastrointestinal NETs (Figure 2). There was no evidence of direct tumor extension elsewhere. About 40% of the tumor cells contained eosinophilic, intracytoplasmic inclusions (Figure 3). The tumor did not involve the margins or lymph node.
Positive staining with the neuroendocrine markers synaptophysin and chromagranin A confirmed a well-differentiated NET. The intracytoplasmic inclusions stained strongly positive for cytokeratin CAM 5.2. The tumor had higher-grade features, including tumor cell necrosis, a Ki-67 labeling index of 3%, and perineural invasion. The 2010 World Health Organization (WHO) criteria for NET of the digestive system classified this tumor as a grade 2, well-differentiated NET and as stage 1a (limited to the bile duct).4
Postoperatively, octreotide scan with single-photon emission computed tomography (SPECT)-CT did not show additional masses or lesions. Serum pancreatic polypeptide was elevated, with the remaining serum and plasma NET markers—including gastrin, glucagon, insulin, chromogranin A, and vasoactive intestinal polypeptide (VIP)—being within reference ranges. Genetic testing (GeneDx, Inc, Gaithersburg, MD) showed an E563X nonsense mutation in the MEN1 gene, confirming a MEN1 disorder. The patient then underwent a 4-gland parathyroidectomy with reimplantation; the parathyroid glands demonstrated hyperplasia in all 4 glands.
Biochemical follow-up at 14 months showed that the serum pancreatic polypeptide had normalized. There was no evidence of pituitary orpancreatic hypersecretion. The patient developed hypoparathyroidism, requiring calcium and calcitriol supplementation. Radiographic follow-up using abdominal magnetic resonance imaging at 16 months showed no evidence of disease.
Discussion
This case illustrates a genetic disease with an unusual initial presentation. Primary extrahepatic bile duct NETs are rare and have been reported previously in patients without MEN1.5-9 Neuroendocrine tumors in the hepatic bile duct in patients with MEN1 also have been reported but only after these tumors first appeared in the pancreas or duodenum.10 An extensive literature search revealed no prior reports extrahepatic bile duct NETs with MEN1 as the primary site or with biliary obstruction, which is why this patient’s presentation is particularly interesting.5,6,10-13 The table summarizes select reports of NETs.
Tumor location in this patient was atypical, and genetic testing guided the management. Serum MEN1 genetic testing is indicated in patients with ≥ 2 tumors that are atypical but possibly associated with MEN1 (such as adrenal tumors, gastrinomas, and carcinoids) and in patients aged < 45 years with primary hyperparathyroidism.14,15 The patient in this study was aged 29 years and had hyperparathyroidism and an NET of the hepatic bile duct. This condition was sufficient to warrant genetic testing, the results of which affected the patient’s subsequent parathyroid surgery.15 Despite the suggestion of unifocal localization on the sestamibi scan, the patient underwent the more appropriate subtotal parathyroidectomy.14 The patient’s tumor most likely originated from a germline mutation of the MEN1 gene.
As a result of the patient’s genetic test results, his daughter also was tested. She was found to have the same mutation as her father and will undergo proper tumor surveillance for MEN1. There was no personal or family history of hemangioblastomas, renal cell carcinomas, or cystadenomas, which would have prompted testing for von Hippel-Lindau disease. Likewise, there was no personal or family history of café-au-lait macules and neurofibromas, which would have prompted testing for neurofibromatosis type 1.
Due to the paucity of cases, there are currently no well-accepted guidelines on how to stage extrahepatic biliary NETs.3-5,16 The WHO recommends staging according to adenocarcinomas of the gallbladder and bile duct.3 As such, the pathologic stage of this tumor would be stage 1a.
The significance of the intracytoplasmic inclusion in this case is unknown. Pancreatic NETs and neuroendocrine carcinomas have demonstrated intracytoplasmic inclusions that stain positively for keratin and may indicate more aggressive tumor behavior.17-19 In 1 report, electron microscopic examination demonstrated intermediate filaments with entrapped neurosecretory granules.18 In a series of 84 cases of pancreatic endocrine tumors, 14 had intracytoplasmic inclusions; of these, 5 had MEN1.17 In the present case, the patient continues to show no evidence of tumor recurrence at 16 months after resection.
Conclusion
Extrahepatic biliary neuroendocrine tumors are rare. Further investigation into biliary tree NET staging and future studies to determine the significance of intracytoplasmic inclusions may be beneficial. This case highlights the appropriate use of genetic testing and supports expanding the clinical diagnosis of MEN1 to include NETs of the extrahepatic bile duct.
Click here to read the digital edition.
1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: WB Saunders; 2011.
2. American Joint Committee on Cancer. Neuroendocrine Tumors. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Handbook. 7th ed. From the AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2010:227-236.
3. Komminoth P, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:274-276.
4. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13.
5. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature. Endocr Pract. 2009;15(7):737-749.
6. Bhandarwar AH, Shaikh TA, Borisa AD, et al. Primary neuroendocrine tumor of the left hepatic duct: a case report with review of the literature. Case Rep Surg. 2012:786432.
7. Bhalla P, Powle V, Shah RC, Jagannath P. Neuroendocrine tumor of common hepatic duct. Indian J Gastroenterol. 2012;31(3):144-146.
8. Khan FA, Stevens-Chase A, Chaudhry R, Hashmi A, Edelman D, Weaver D. Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct. Int J Surg Case Rep. 2017;30:46-49.
9. Hong N, Kim HJ, Byun JH, et al. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40(1):181-191.
10. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome. World J Gastroenterol. 2013;19(45):8312-8320.
11. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43-83.
12. Pieterman CRC, Conemans EB, Dreijerink KMA, et al. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer. 2014;21(3):R121-R142.
13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med. 1990;322(11):723-727.
14. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
15. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
16. Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20(4):765-775.
17. Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called “rhabdoid” phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17(1):75-81.
18. Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the “rhabdoid” inclusions seen in pancreatic endocrine
neoplasms. Am J Surg Pathol. 2004;28(2):271-273.
19. Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with ‘Rhabdoid’ features. Am J Surg Pathol. 2003;27(5):642-649.
1. Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: WB Saunders; 2011.
2. American Joint Committee on Cancer. Neuroendocrine Tumors. In: Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer Staging Handbook. 7th ed. From the AJCC Cancer Staging Manual. New York, NY: Springer-Verlag; 2010:227-236.
3. Komminoth P, Arnold R, Capella C, et al. Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:274-276.
4. Rindi G, Arnold R, Bosman FT. Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, et al, eds. WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, France: IARC Press; 2010:13.
5. Price TN, Thompson GB, Lewis JT, Lloyd RV, Young WF. Zollinger-Ellison syndrome due to primary gastrinoma of the extrahepatic biliary tree: three case reports and review of literature. Endocr Pract. 2009;15(7):737-749.
6. Bhandarwar AH, Shaikh TA, Borisa AD, et al. Primary neuroendocrine tumor of the left hepatic duct: a case report with review of the literature. Case Rep Surg. 2012:786432.
7. Bhalla P, Powle V, Shah RC, Jagannath P. Neuroendocrine tumor of common hepatic duct. Indian J Gastroenterol. 2012;31(3):144-146.
8. Khan FA, Stevens-Chase A, Chaudhry R, Hashmi A, Edelman D, Weaver D. Extrahepatic biliary obstrution secondary to neuroendocrine tumor of the common hepatic duct. Int J Surg Case Rep. 2017;30:46-49.
9. Hong N, Kim HJ, Byun JH, et al. Neuroendocrine neoplasms of the extrahepatic bile duct: radiologic and clinical characteristics. Abdom Imaging. 2015;40(1):181-191.
10. Tonelli F, Giudici F, Nesi G, Batignani G, Brandi ML. Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome. World J Gastroenterol. 2013;19(45):8312-8320.
11. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. Medicine (Baltimore). 2004;83(1):43-83.
12. Pieterman CRC, Conemans EB, Dreijerink KMA, et al. Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis. Endocr Relat Cancer. 2014;21(3):R121-R142.
13. Pipeleers-Marichal M, Somers G, Willems G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type 1 and the Zollinger-Ellison syndrome. N Engl J Med. 1990;322(11):723-727.
14. Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011.
15. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
16. Michalopoulos N, Papavramidis TS, Karayannopoulou G, Pliakos I, Papavramidis ST, Kanellos I. Neuroendocrine tumors of extrahepatic biliary tract. Pathol Oncol Res. 2014;20(4):765-775.
17. Serra S, Asa SL, Chetty R. Intracytoplasmic inclusions (including the so-called “rhabdoid” phenotype) in pancreatic endocrine tumors. Endocr Pathol. 2006;17(1):75-81.
18. Shia J, Erlandson RA, Klimstra DS. Whorls of intermediate filaments with entrapped neurosecretory granules correspond to the “rhabdoid” inclusions seen in pancreatic endocrine
neoplasms. Am J Surg Pathol. 2004;28(2):271-273.
19. Perez-Montiel MD, Frankel WL, Suster S. Neuroendocrine carcinomas of the pancreas with ‘Rhabdoid’ features. Am J Surg Pathol. 2003;27(5):642-649.
FDA approves dabrafenib/trametinib for BRAF-positive anaplastic thyroid cancer
FDA approval was based on results from an open-label clinical trial of patients with various rare, BRAF V600E–positive cancers. In a group of 23 patients, 57% experienced a partial response and 4% experienced a full response. In the response group, nine patients had no significant tumor growth for a period of at least 6 months.
The most common side effects of dabrafenib/trametinib are fever, rash, chills, headache, joint pain, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, high blood pressure, and difficulty breathing. Both drugs can cause damage to developing fetuses, and women should be advised to use proper contraception.
“This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in the press release.
Find the full press release on the FDA website.
FDA approval was based on results from an open-label clinical trial of patients with various rare, BRAF V600E–positive cancers. In a group of 23 patients, 57% experienced a partial response and 4% experienced a full response. In the response group, nine patients had no significant tumor growth for a period of at least 6 months.
The most common side effects of dabrafenib/trametinib are fever, rash, chills, headache, joint pain, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, high blood pressure, and difficulty breathing. Both drugs can cause damage to developing fetuses, and women should be advised to use proper contraception.
“This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in the press release.
Find the full press release on the FDA website.
FDA approval was based on results from an open-label clinical trial of patients with various rare, BRAF V600E–positive cancers. In a group of 23 patients, 57% experienced a partial response and 4% experienced a full response. In the response group, nine patients had no significant tumor growth for a period of at least 6 months.
The most common side effects of dabrafenib/trametinib are fever, rash, chills, headache, joint pain, cough, fatigue, nausea, vomiting, diarrhea, myalgia, dry skin, decreased appetite, edema, hemorrhage, high blood pressure, and difficulty breathing. Both drugs can cause damage to developing fetuses, and women should be advised to use proper contraception.
“This approval demonstrates that targeting the same molecular pathway in diverse diseases is an effective way to expedite the development of treatments that may help more patients,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, said in the press release.
Find the full press release on the FDA website.
Resolution of refractory pruritus with aprepitant in a patient with microcystic adnexal carcinoma
Substance P is an important neurotransmitter implicated in itch pathways.1 After binding to its receptor, neurokinin-1 (NK-1), substance P induces release of factors including histamine, which may cause pruritus.2 Recent literature has reported successful use of aprepitant, an NK-1 antagonist that has been approved by the US Food and Drug Administration for the treatment of chemotherapy-induced nausea and vomiting, for treatment of pruritus. We report here the case of a patient with microcystic adnexal carcinoma (MAC) who presented with refractory pruritus and who had rapid and complete resolution of itch after administration of aprepitant.
Case presentation and summary
A 73-year-old man presented with a 12-year history of a small nodule on his philtrum, which had been increasing in size. He subsequently developed upper-lip numbness and nasal induration. He complained of 2.5 months of severe, debilitating, full-body pruritus. His symptoms were refractory to treatment with prednisone, gabapentin, doxycycline, doxepin, antihistamines, and topical steroids. At the time of consultation, he was being treated with hydroxyzine and topical pramocaine lotion with minimal relief.
At initial dermatologic evaluation, his tumor involved the lower two-thirds of the nose and entire upper cutaneous lip. There was a 4-mm rolled ulcer on the nasal tip and a 1-cm exophytic, smooth nodule on the left upper lip with palpable 4-cm submandibular adenopathy (Figure). Skin examination otherwise revealed linear excoriations on the upper back with no additional primary lesions. The nodule was biopsied, and the patient was diagnosed with MAC with gross nodal involvement. Laboratory findings including serum chemistries, blood urea nitrogen, complete blood cell count, thyroid, and liver function were normal. Positron emission tomography-computed tomography (PET-CT) imaging was negative for distant metastases.
Treatment was initiated with oral aprepitant – 125 mg on day 1, 80 mg on day 2, and 80 mg on day 3 –with concomitant weekly carboplatin (AUC 1.5) and paclitaxel (30 mg/m2) as well as radiation. Within hours after the first dose of aprepitant, the patient reported a notable cessation in his pruritus. He reported that after 5 hours, his skin “finally turned off” and over the hour that followed, he had complete resolution of symptoms. He completed chemoradiation with a significant disease response. Despite persistent MAC confined to the philtrum, he has been followed for over 2 years without recurrence of itch.
Discussion
MAC is an uncommon cutaneous malignancy of sweat and eccrine gland differentiation. In all, 700 cases of MAC have been described in the literature; a 2008 review estimated the incidence of metastasis at around 2.1%.3 Though metastasis is exceedingly rare, the tumor is locally aggressive and there are reports of invasion into the muscle, perichondrium, periosteum, bone marrow, as well as perineural spaces and vascular adventitia.4
The clinical presentation of MAC includes smooth, flesh-colored or yellow papules, nodules, or plaques.3 Patients often present with numbness, paresthesia, and burning in the area of involvement because of neural infiltration with tumor. Despite the rarity of MAC, pruritus has been reported as a presenting symptom in 1 other case in the literature.4 Our case represents the first report of MAC presenting with a grossly enlarging centrofacial mass, lymph node involvement, and severe full-body pruritus. Our patient responded completely, and within hours, to treatment with aprepitant after experiencing months of failure with conventional antipruritus treatments and without recurrence in symptoms in more than 2 years of follow-up.
Aprepitant blocks the binding of substance P to its receptor NK-1 and has been approved as an anti-emetic for chemotherapy patients. Substance P has been shown to be important in both nausea and itch pathways. The largest prospective study to date on aprepitant for the indication of pruritus in 45 patients with metastatic solid tumors demonstrated a 91% response rate, defined by >50% reduction in pruritus intensity, and 13% recurrence rate that occurred at a median of 7 weeks after initial treatment.5 Aprepitant treatment has been used with success for pruritus associated with both malignant and nonmalignant conditions in at least 74 patients,6 among whom the malignant conditions included cutaneous T-cell lymphoma, Hodgkin lymphoma, and metastatic solid tumors.5-7 Aprepitant has also been used for erlotinib- and nivolumab-induced pruritus in non–small cell lung cancer, which suggests a possible future role for aprepitant in the treatment of pruritus secondary to novel cancer therapies, perhaps including immune checkpoint inhibitors.8-10
However, despite those reports, and likely owing to the multifactorial nature of pruritus, aprepitant is not unviversally effective. Mechanisms of malignancy-associated itch are yet to be elucidated, and optimal patient selection for aprepitant use needs to be determined. However, our patient’s notable response supports the increasing evidence that substance P is a key mediator of pruritus and that disruption of binding to its receptor may result in significant improvement in symptoms in certain patients. It remains to be seen whether the cell type or the tendency toward neural invasion plays a role. Large, randomized studies are needed to guide patient selection and confirm the findings reported here and in the literature, with careful documentation of and close attention paid to timing of pruritus relief and improvement in patient quality of life. Aprepitant might be an important therapeutic tool for refractory, malignancy-associated pruritus, in which patient quality of life is especially critical.
Acknowledgments
This work was presented at the Multinational Association of Supportive Care and Cancer Meeting, in Miami Florida, June 26-28, 2014. The authors are indebted to Saajar Jadeja for his assistance preparing the manuscript.
1. Wallengren J. Neuroanatomy and neurophysiology of itch. Dermatol Ther. 2005;18(4):292-303.
2. Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123(3):398-410.
3. Wetter R, Goldstein GD. Microcystic adnexal carcinoma: a diagnostic and therapeutic challenge. Dermatol Ther. 2008;21(6):452-458.
4. Adamson T. Microcystic adnexal carcinoma. Dermatol Nurs. 2004;16(4):365.
5. Santini D, Vincenzi B, Guida FM, et al. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol. 2012;13(10):1020-1024.
6. Song JS, Tawa M, Chau NG, Kupper TS, LeBoeuf NR. Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature. BMC Cancer. 2017;17.
7. Villafranca JJA, Siles MG, Casanova M, Goitia BT, Domínguez AR. Paraneoplastic pruritus presenting with Hodgkin’s lymphoma: a case report. J Med Case Reports. 2014;8:300.
8. Ito J, Fujimoto D, Nakamura A, et al. Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer Amst Neth. 2017;109:58-61.
9. Levêque D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363(17):1680-1681; author reply 1681.
10. Gerber PA, Buhren BA, Homey B. More on aprepitant for erlotinib-induced pruritus. N Engl J Med. 2011;364(5):486-487.
Substance P is an important neurotransmitter implicated in itch pathways.1 After binding to its receptor, neurokinin-1 (NK-1), substance P induces release of factors including histamine, which may cause pruritus.2 Recent literature has reported successful use of aprepitant, an NK-1 antagonist that has been approved by the US Food and Drug Administration for the treatment of chemotherapy-induced nausea and vomiting, for treatment of pruritus. We report here the case of a patient with microcystic adnexal carcinoma (MAC) who presented with refractory pruritus and who had rapid and complete resolution of itch after administration of aprepitant.
Case presentation and summary
A 73-year-old man presented with a 12-year history of a small nodule on his philtrum, which had been increasing in size. He subsequently developed upper-lip numbness and nasal induration. He complained of 2.5 months of severe, debilitating, full-body pruritus. His symptoms were refractory to treatment with prednisone, gabapentin, doxycycline, doxepin, antihistamines, and topical steroids. At the time of consultation, he was being treated with hydroxyzine and topical pramocaine lotion with minimal relief.
At initial dermatologic evaluation, his tumor involved the lower two-thirds of the nose and entire upper cutaneous lip. There was a 4-mm rolled ulcer on the nasal tip and a 1-cm exophytic, smooth nodule on the left upper lip with palpable 4-cm submandibular adenopathy (Figure). Skin examination otherwise revealed linear excoriations on the upper back with no additional primary lesions. The nodule was biopsied, and the patient was diagnosed with MAC with gross nodal involvement. Laboratory findings including serum chemistries, blood urea nitrogen, complete blood cell count, thyroid, and liver function were normal. Positron emission tomography-computed tomography (PET-CT) imaging was negative for distant metastases.
Treatment was initiated with oral aprepitant – 125 mg on day 1, 80 mg on day 2, and 80 mg on day 3 –with concomitant weekly carboplatin (AUC 1.5) and paclitaxel (30 mg/m2) as well as radiation. Within hours after the first dose of aprepitant, the patient reported a notable cessation in his pruritus. He reported that after 5 hours, his skin “finally turned off” and over the hour that followed, he had complete resolution of symptoms. He completed chemoradiation with a significant disease response. Despite persistent MAC confined to the philtrum, he has been followed for over 2 years without recurrence of itch.
Discussion
MAC is an uncommon cutaneous malignancy of sweat and eccrine gland differentiation. In all, 700 cases of MAC have been described in the literature; a 2008 review estimated the incidence of metastasis at around 2.1%.3 Though metastasis is exceedingly rare, the tumor is locally aggressive and there are reports of invasion into the muscle, perichondrium, periosteum, bone marrow, as well as perineural spaces and vascular adventitia.4
The clinical presentation of MAC includes smooth, flesh-colored or yellow papules, nodules, or plaques.3 Patients often present with numbness, paresthesia, and burning in the area of involvement because of neural infiltration with tumor. Despite the rarity of MAC, pruritus has been reported as a presenting symptom in 1 other case in the literature.4 Our case represents the first report of MAC presenting with a grossly enlarging centrofacial mass, lymph node involvement, and severe full-body pruritus. Our patient responded completely, and within hours, to treatment with aprepitant after experiencing months of failure with conventional antipruritus treatments and without recurrence in symptoms in more than 2 years of follow-up.
Aprepitant blocks the binding of substance P to its receptor NK-1 and has been approved as an anti-emetic for chemotherapy patients. Substance P has been shown to be important in both nausea and itch pathways. The largest prospective study to date on aprepitant for the indication of pruritus in 45 patients with metastatic solid tumors demonstrated a 91% response rate, defined by >50% reduction in pruritus intensity, and 13% recurrence rate that occurred at a median of 7 weeks after initial treatment.5 Aprepitant treatment has been used with success for pruritus associated with both malignant and nonmalignant conditions in at least 74 patients,6 among whom the malignant conditions included cutaneous T-cell lymphoma, Hodgkin lymphoma, and metastatic solid tumors.5-7 Aprepitant has also been used for erlotinib- and nivolumab-induced pruritus in non–small cell lung cancer, which suggests a possible future role for aprepitant in the treatment of pruritus secondary to novel cancer therapies, perhaps including immune checkpoint inhibitors.8-10
However, despite those reports, and likely owing to the multifactorial nature of pruritus, aprepitant is not unviversally effective. Mechanisms of malignancy-associated itch are yet to be elucidated, and optimal patient selection for aprepitant use needs to be determined. However, our patient’s notable response supports the increasing evidence that substance P is a key mediator of pruritus and that disruption of binding to its receptor may result in significant improvement in symptoms in certain patients. It remains to be seen whether the cell type or the tendency toward neural invasion plays a role. Large, randomized studies are needed to guide patient selection and confirm the findings reported here and in the literature, with careful documentation of and close attention paid to timing of pruritus relief and improvement in patient quality of life. Aprepitant might be an important therapeutic tool for refractory, malignancy-associated pruritus, in which patient quality of life is especially critical.
Acknowledgments
This work was presented at the Multinational Association of Supportive Care and Cancer Meeting, in Miami Florida, June 26-28, 2014. The authors are indebted to Saajar Jadeja for his assistance preparing the manuscript.
Substance P is an important neurotransmitter implicated in itch pathways.1 After binding to its receptor, neurokinin-1 (NK-1), substance P induces release of factors including histamine, which may cause pruritus.2 Recent literature has reported successful use of aprepitant, an NK-1 antagonist that has been approved by the US Food and Drug Administration for the treatment of chemotherapy-induced nausea and vomiting, for treatment of pruritus. We report here the case of a patient with microcystic adnexal carcinoma (MAC) who presented with refractory pruritus and who had rapid and complete resolution of itch after administration of aprepitant.
Case presentation and summary
A 73-year-old man presented with a 12-year history of a small nodule on his philtrum, which had been increasing in size. He subsequently developed upper-lip numbness and nasal induration. He complained of 2.5 months of severe, debilitating, full-body pruritus. His symptoms were refractory to treatment with prednisone, gabapentin, doxycycline, doxepin, antihistamines, and topical steroids. At the time of consultation, he was being treated with hydroxyzine and topical pramocaine lotion with minimal relief.
At initial dermatologic evaluation, his tumor involved the lower two-thirds of the nose and entire upper cutaneous lip. There was a 4-mm rolled ulcer on the nasal tip and a 1-cm exophytic, smooth nodule on the left upper lip with palpable 4-cm submandibular adenopathy (Figure). Skin examination otherwise revealed linear excoriations on the upper back with no additional primary lesions. The nodule was biopsied, and the patient was diagnosed with MAC with gross nodal involvement. Laboratory findings including serum chemistries, blood urea nitrogen, complete blood cell count, thyroid, and liver function were normal. Positron emission tomography-computed tomography (PET-CT) imaging was negative for distant metastases.
Treatment was initiated with oral aprepitant – 125 mg on day 1, 80 mg on day 2, and 80 mg on day 3 –with concomitant weekly carboplatin (AUC 1.5) and paclitaxel (30 mg/m2) as well as radiation. Within hours after the first dose of aprepitant, the patient reported a notable cessation in his pruritus. He reported that after 5 hours, his skin “finally turned off” and over the hour that followed, he had complete resolution of symptoms. He completed chemoradiation with a significant disease response. Despite persistent MAC confined to the philtrum, he has been followed for over 2 years without recurrence of itch.
Discussion
MAC is an uncommon cutaneous malignancy of sweat and eccrine gland differentiation. In all, 700 cases of MAC have been described in the literature; a 2008 review estimated the incidence of metastasis at around 2.1%.3 Though metastasis is exceedingly rare, the tumor is locally aggressive and there are reports of invasion into the muscle, perichondrium, periosteum, bone marrow, as well as perineural spaces and vascular adventitia.4
The clinical presentation of MAC includes smooth, flesh-colored or yellow papules, nodules, or plaques.3 Patients often present with numbness, paresthesia, and burning in the area of involvement because of neural infiltration with tumor. Despite the rarity of MAC, pruritus has been reported as a presenting symptom in 1 other case in the literature.4 Our case represents the first report of MAC presenting with a grossly enlarging centrofacial mass, lymph node involvement, and severe full-body pruritus. Our patient responded completely, and within hours, to treatment with aprepitant after experiencing months of failure with conventional antipruritus treatments and without recurrence in symptoms in more than 2 years of follow-up.
Aprepitant blocks the binding of substance P to its receptor NK-1 and has been approved as an anti-emetic for chemotherapy patients. Substance P has been shown to be important in both nausea and itch pathways. The largest prospective study to date on aprepitant for the indication of pruritus in 45 patients with metastatic solid tumors demonstrated a 91% response rate, defined by >50% reduction in pruritus intensity, and 13% recurrence rate that occurred at a median of 7 weeks after initial treatment.5 Aprepitant treatment has been used with success for pruritus associated with both malignant and nonmalignant conditions in at least 74 patients,6 among whom the malignant conditions included cutaneous T-cell lymphoma, Hodgkin lymphoma, and metastatic solid tumors.5-7 Aprepitant has also been used for erlotinib- and nivolumab-induced pruritus in non–small cell lung cancer, which suggests a possible future role for aprepitant in the treatment of pruritus secondary to novel cancer therapies, perhaps including immune checkpoint inhibitors.8-10
However, despite those reports, and likely owing to the multifactorial nature of pruritus, aprepitant is not unviversally effective. Mechanisms of malignancy-associated itch are yet to be elucidated, and optimal patient selection for aprepitant use needs to be determined. However, our patient’s notable response supports the increasing evidence that substance P is a key mediator of pruritus and that disruption of binding to its receptor may result in significant improvement in symptoms in certain patients. It remains to be seen whether the cell type or the tendency toward neural invasion plays a role. Large, randomized studies are needed to guide patient selection and confirm the findings reported here and in the literature, with careful documentation of and close attention paid to timing of pruritus relief and improvement in patient quality of life. Aprepitant might be an important therapeutic tool for refractory, malignancy-associated pruritus, in which patient quality of life is especially critical.
Acknowledgments
This work was presented at the Multinational Association of Supportive Care and Cancer Meeting, in Miami Florida, June 26-28, 2014. The authors are indebted to Saajar Jadeja for his assistance preparing the manuscript.
1. Wallengren J. Neuroanatomy and neurophysiology of itch. Dermatol Ther. 2005;18(4):292-303.
2. Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123(3):398-410.
3. Wetter R, Goldstein GD. Microcystic adnexal carcinoma: a diagnostic and therapeutic challenge. Dermatol Ther. 2008;21(6):452-458.
4. Adamson T. Microcystic adnexal carcinoma. Dermatol Nurs. 2004;16(4):365.
5. Santini D, Vincenzi B, Guida FM, et al. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol. 2012;13(10):1020-1024.
6. Song JS, Tawa M, Chau NG, Kupper TS, LeBoeuf NR. Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature. BMC Cancer. 2017;17.
7. Villafranca JJA, Siles MG, Casanova M, Goitia BT, Domínguez AR. Paraneoplastic pruritus presenting with Hodgkin’s lymphoma: a case report. J Med Case Reports. 2014;8:300.
8. Ito J, Fujimoto D, Nakamura A, et al. Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer Amst Neth. 2017;109:58-61.
9. Levêque D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363(17):1680-1681; author reply 1681.
10. Gerber PA, Buhren BA, Homey B. More on aprepitant for erlotinib-induced pruritus. N Engl J Med. 2011;364(5):486-487.
1. Wallengren J. Neuroanatomy and neurophysiology of itch. Dermatol Ther. 2005;18(4):292-303.
2. Kulka M, Sheen CH, Tancowny BP, Grammer LC, Schleimer RP. Neuropeptides activate human mast cell degranulation and chemokine production. Immunology. 2008;123(3):398-410.
3. Wetter R, Goldstein GD. Microcystic adnexal carcinoma: a diagnostic and therapeutic challenge. Dermatol Ther. 2008;21(6):452-458.
4. Adamson T. Microcystic adnexal carcinoma. Dermatol Nurs. 2004;16(4):365.
5. Santini D, Vincenzi B, Guida FM, et al. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol. 2012;13(10):1020-1024.
6. Song JS, Tawa M, Chau NG, Kupper TS, LeBoeuf NR. Aprepitant for refractory cutaneous T-cell lymphoma-associated pruritus: 4 cases and a review of the literature. BMC Cancer. 2017;17.
7. Villafranca JJA, Siles MG, Casanova M, Goitia BT, Domínguez AR. Paraneoplastic pruritus presenting with Hodgkin’s lymphoma: a case report. J Med Case Reports. 2014;8:300.
8. Ito J, Fujimoto D, Nakamura A, et al. Aprepitant for refractory nivolumab-induced pruritus. Lung Cancer Amst Neth. 2017;109:58-61.
9. Levêque D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363(17):1680-1681; author reply 1681.
10. Gerber PA, Buhren BA, Homey B. More on aprepitant for erlotinib-induced pruritus. N Engl J Med. 2011;364(5):486-487.
Probe linked to smartphone found effective in diagnosing oral cancer
DALLAS – A low-cost , in a clinical study of 92 people.
“Oral cancer is the sixth most common cancer in the world, but it’s the only major cancer whose outcome has not improved in the last 50 years,” study author Petra Wilder-Smith DDS, PhD, said in an interview following the annual conference of the American Society for Laser Medicine and Surgery Inc. “The main challenge is that over two-thirds of oral cancers are detected after they’ve metastasized. When you get spread like that, your survival is about 20% at 5 years, whereas if you detect it before spread, your survival is about 80% at 5 years.”
At the meeting, Vania Firmalino, an undergraduate student at the University of California, Irvine, discussed efforts by Dr. Wilder-Smith, Rongguang Liang, PhD, of the College of Optical Sciences at the University of Arizona, Tucson, and their colleagues to develop and evaluate the screening performance of a novel, low-cost smartphone-based mini probe for oral cancer screening and oral potentially premalignant lesions (OPMLs). The device provides high-resolution polarized white light images in combination with autofluorescence (AF) imaging capability.
The researchers found that inter-subject variation at each location was small, but inter-site differences were considerable. For example, optical data from OPMLs and oral cancer sites differed from normal with regard to white-light reflectance intensities, vascular homogeneity, and standard deviation. The AF signal in OPMLs and oral cancers shifted progressively to the red, together with a diminished green fluorescence signal. The cloud-based diagnostic algorithm based on these properties performed well, with an agreement with standard-of-care diagnosis of 80.6%.
“Artificial intelligence improves with data,” said Dr. Wilder-Smith, who is also a senior fellow at the university’s Chao Family Comprehensive Cancer Center. “We trained this system on about 200 images. When you’re up to 1,000 images per condition, that’s when you really start to get the benefits of artificial intelligence and machine learning. There’s huge potential here, especially when you think that 40% of the world’s risk for oral cancer is in India, which has good cell phone coverage. India also has a government-financed public health program whereby they already send health care workers to the remote areas of India to screen for basic diseases.”
The study won an award for best overall clinical abstract at the meeting. Dr. Wilder-Smith reported having no financial disclosures. The project was supported with funding from the National Institute of Biomedical Imaging and Bioengineering and the Beckman Foundation.
DALLAS – A low-cost , in a clinical study of 92 people.
“Oral cancer is the sixth most common cancer in the world, but it’s the only major cancer whose outcome has not improved in the last 50 years,” study author Petra Wilder-Smith DDS, PhD, said in an interview following the annual conference of the American Society for Laser Medicine and Surgery Inc. “The main challenge is that over two-thirds of oral cancers are detected after they’ve metastasized. When you get spread like that, your survival is about 20% at 5 years, whereas if you detect it before spread, your survival is about 80% at 5 years.”
At the meeting, Vania Firmalino, an undergraduate student at the University of California, Irvine, discussed efforts by Dr. Wilder-Smith, Rongguang Liang, PhD, of the College of Optical Sciences at the University of Arizona, Tucson, and their colleagues to develop and evaluate the screening performance of a novel, low-cost smartphone-based mini probe for oral cancer screening and oral potentially premalignant lesions (OPMLs). The device provides high-resolution polarized white light images in combination with autofluorescence (AF) imaging capability.
The researchers found that inter-subject variation at each location was small, but inter-site differences were considerable. For example, optical data from OPMLs and oral cancer sites differed from normal with regard to white-light reflectance intensities, vascular homogeneity, and standard deviation. The AF signal in OPMLs and oral cancers shifted progressively to the red, together with a diminished green fluorescence signal. The cloud-based diagnostic algorithm based on these properties performed well, with an agreement with standard-of-care diagnosis of 80.6%.
“Artificial intelligence improves with data,” said Dr. Wilder-Smith, who is also a senior fellow at the university’s Chao Family Comprehensive Cancer Center. “We trained this system on about 200 images. When you’re up to 1,000 images per condition, that’s when you really start to get the benefits of artificial intelligence and machine learning. There’s huge potential here, especially when you think that 40% of the world’s risk for oral cancer is in India, which has good cell phone coverage. India also has a government-financed public health program whereby they already send health care workers to the remote areas of India to screen for basic diseases.”
The study won an award for best overall clinical abstract at the meeting. Dr. Wilder-Smith reported having no financial disclosures. The project was supported with funding from the National Institute of Biomedical Imaging and Bioengineering and the Beckman Foundation.
DALLAS – A low-cost , in a clinical study of 92 people.
“Oral cancer is the sixth most common cancer in the world, but it’s the only major cancer whose outcome has not improved in the last 50 years,” study author Petra Wilder-Smith DDS, PhD, said in an interview following the annual conference of the American Society for Laser Medicine and Surgery Inc. “The main challenge is that over two-thirds of oral cancers are detected after they’ve metastasized. When you get spread like that, your survival is about 20% at 5 years, whereas if you detect it before spread, your survival is about 80% at 5 years.”
At the meeting, Vania Firmalino, an undergraduate student at the University of California, Irvine, discussed efforts by Dr. Wilder-Smith, Rongguang Liang, PhD, of the College of Optical Sciences at the University of Arizona, Tucson, and their colleagues to develop and evaluate the screening performance of a novel, low-cost smartphone-based mini probe for oral cancer screening and oral potentially premalignant lesions (OPMLs). The device provides high-resolution polarized white light images in combination with autofluorescence (AF) imaging capability.
The researchers found that inter-subject variation at each location was small, but inter-site differences were considerable. For example, optical data from OPMLs and oral cancer sites differed from normal with regard to white-light reflectance intensities, vascular homogeneity, and standard deviation. The AF signal in OPMLs and oral cancers shifted progressively to the red, together with a diminished green fluorescence signal. The cloud-based diagnostic algorithm based on these properties performed well, with an agreement with standard-of-care diagnosis of 80.6%.
“Artificial intelligence improves with data,” said Dr. Wilder-Smith, who is also a senior fellow at the university’s Chao Family Comprehensive Cancer Center. “We trained this system on about 200 images. When you’re up to 1,000 images per condition, that’s when you really start to get the benefits of artificial intelligence and machine learning. There’s huge potential here, especially when you think that 40% of the world’s risk for oral cancer is in India, which has good cell phone coverage. India also has a government-financed public health program whereby they already send health care workers to the remote areas of India to screen for basic diseases.”
The study won an award for best overall clinical abstract at the meeting. Dr. Wilder-Smith reported having no financial disclosures. The project was supported with funding from the National Institute of Biomedical Imaging and Bioengineering and the Beckman Foundation.
REPORTING FROM ASLMS 2018
Key clinical point: A compact oral probe that links to a smartphone was able to detect oral cancer.
Major finding: The optical diagnostic probe had a high rate of agreement (80.6%) with standard-of-care diagnosis.
Study details: A clinical analysis of 92 people with visually healthy oral mucosa or oral leukoplakia, erythroplakia, or ulceration.
Disclosures: Dr. Wilder-Smith reported having no financial disclosures. The National Institute of Biomedical Imaging and Bioengineering and the Beckman Foundation funded the project.
Early Intervention Has Long-Term Benefits for Oral Cancer Survivors
Exercise and physical therapy in the first weeks after surgery can have a positive impact on health, physical function, and quality of life (QOL) in patients with oral cancer. The changes persist for months afterward, say researchers from Chang Gung Memorial Hospital in Taiwan.
The study involved 65 patients who had undergone reconstructive microsurgery for oral cavity squamous cell carcinoma. The time of intervention had 3 phases: early (8 days to within a month after surgery), middle (1- 3 months after surgery), and late (> 3 months after surgery). The program included pain management, temporomandibular joint exercise, and shoulder and neck exercises.
In the early phase, the main goal was to help participants deal with pain, edema, shoulder dysfunction, and other consequences of surgery. Transcutaneous electrical stimulation for 15 minutes in each treatment session was followed by gentle massage and exercise. During the middle phase, the intervention focused on impairment from surgery or radiation therapy and intensified exercise. The late phase goal was to recover residual function as much as possible.
At 1 month, 40% of patients were on a soft diet. By 6 months, all nasogastric tubes had been removed, and 53% of patients had returned to a normal diet. The researchers note that early intervention to exercise the temporomandibular joint exercise may improve mouth opening. In the advanced stage group, the maximum mouth opening reached its highest at 3 months.
Scapular muscle strength and shoulder range of motion improved progressively during the 6-month follow-up. At 1 month, the mean DASH (Disability of the Arms, Shoulder, and Hand) score showed significant improvement (dropping from 34 to 17). Health-related QOL also showed significant improvement. The predicted return-to-work rate was 80% at 1 year: Patients in skilled or semiskilled work and the self-employed had the highest rates (88% and 87%, respectively).
Source:
Chen YH, Liang WA, Hsu CY, et al. PeerJ. 2018;6e4419.
doi: 10.7717/peerj.4419.
Exercise and physical therapy in the first weeks after surgery can have a positive impact on health, physical function, and quality of life (QOL) in patients with oral cancer. The changes persist for months afterward, say researchers from Chang Gung Memorial Hospital in Taiwan.
The study involved 65 patients who had undergone reconstructive microsurgery for oral cavity squamous cell carcinoma. The time of intervention had 3 phases: early (8 days to within a month after surgery), middle (1- 3 months after surgery), and late (> 3 months after surgery). The program included pain management, temporomandibular joint exercise, and shoulder and neck exercises.
In the early phase, the main goal was to help participants deal with pain, edema, shoulder dysfunction, and other consequences of surgery. Transcutaneous electrical stimulation for 15 minutes in each treatment session was followed by gentle massage and exercise. During the middle phase, the intervention focused on impairment from surgery or radiation therapy and intensified exercise. The late phase goal was to recover residual function as much as possible.
At 1 month, 40% of patients were on a soft diet. By 6 months, all nasogastric tubes had been removed, and 53% of patients had returned to a normal diet. The researchers note that early intervention to exercise the temporomandibular joint exercise may improve mouth opening. In the advanced stage group, the maximum mouth opening reached its highest at 3 months.
Scapular muscle strength and shoulder range of motion improved progressively during the 6-month follow-up. At 1 month, the mean DASH (Disability of the Arms, Shoulder, and Hand) score showed significant improvement (dropping from 34 to 17). Health-related QOL also showed significant improvement. The predicted return-to-work rate was 80% at 1 year: Patients in skilled or semiskilled work and the self-employed had the highest rates (88% and 87%, respectively).
Source:
Chen YH, Liang WA, Hsu CY, et al. PeerJ. 2018;6e4419.
doi: 10.7717/peerj.4419.
Exercise and physical therapy in the first weeks after surgery can have a positive impact on health, physical function, and quality of life (QOL) in patients with oral cancer. The changes persist for months afterward, say researchers from Chang Gung Memorial Hospital in Taiwan.
The study involved 65 patients who had undergone reconstructive microsurgery for oral cavity squamous cell carcinoma. The time of intervention had 3 phases: early (8 days to within a month after surgery), middle (1- 3 months after surgery), and late (> 3 months after surgery). The program included pain management, temporomandibular joint exercise, and shoulder and neck exercises.
In the early phase, the main goal was to help participants deal with pain, edema, shoulder dysfunction, and other consequences of surgery. Transcutaneous electrical stimulation for 15 minutes in each treatment session was followed by gentle massage and exercise. During the middle phase, the intervention focused on impairment from surgery or radiation therapy and intensified exercise. The late phase goal was to recover residual function as much as possible.
At 1 month, 40% of patients were on a soft diet. By 6 months, all nasogastric tubes had been removed, and 53% of patients had returned to a normal diet. The researchers note that early intervention to exercise the temporomandibular joint exercise may improve mouth opening. In the advanced stage group, the maximum mouth opening reached its highest at 3 months.
Scapular muscle strength and shoulder range of motion improved progressively during the 6-month follow-up. At 1 month, the mean DASH (Disability of the Arms, Shoulder, and Hand) score showed significant improvement (dropping from 34 to 17). Health-related QOL also showed significant improvement. The predicted return-to-work rate was 80% at 1 year: Patients in skilled or semiskilled work and the self-employed had the highest rates (88% and 87%, respectively).
Source:
Chen YH, Liang WA, Hsu CY, et al. PeerJ. 2018;6e4419.
doi: 10.7717/peerj.4419.
When it comes to thyroid cancer follow-up, serum microRNA profiles have earned new respect
CHICAGO –
The usual tool for trying to detect recurrence while following patients with papillary thyroid cancer after surgery has been the serum thyroglobulin assay. However, management of papillary thyroid cancer has become more conservative, involving lobectomy and isthmusectomy on the affected side rather than total gland resection. The benefit of the conservative approach is to avoid complications while maintaining an overall survival rate equivalent to the more extensive approach.
The investigators measured 754 miRNAs in serum samples of 11 patients with papillary thyroid cancer both before and 30 days after surgical thyroidectomy. They re-evaluated major candidate miRNAs using absolute quantitative polymerase chain reaction analysis in an independent cohort of 44 other patients with papillary thyroid cancer or benign nodules or 20 healthy controls, Dr. Rosignolo said at the annual meeting of the Endocrine Society.
The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days, and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy.
Serum levels of both miRNAs after 1 to 2 years of follow-up were consistent with ATA responses to therapy in all patients, including two patients who developed structural evidence of disease whose thyroglobulin assay results remained negative (less than 1 ng/mL) for cancer recurrence.
Fifteen of the 20 patients had excellent or indeterminate responses to therapy as defined by 2015 ATA guidelines. In these 15 cases, and in the single patient with a biochemical incomplete response, expression levels of miR-146a-5p and miR-221-3p decreased after surgery and remained low at the 1- to 2-year visit.
It was a very different story for the 4 patients with structural incomplete responses at 1 to 2 years. In this subgroup, initial postoperative declines in serum miR-146a-5p and miR-221-3p levels were followed by increases to levels at the 1- to 2-year visit that were similar to or higher than those found prior to surgery.
The study was funded by the Umberto Di Mario Foundation, Banca d’Italia, University of Rome Sapienza, the program of Biotechnologies and Clinical Medicine of the University of Rome Sapienza, the European Medical Writers Association, and the Umberto Di Mario Foundation.
SOURCE: Rosignolo F et al. J Endo Soc. 2017;1(1)3-13. ENDO 2018, Abstract OR17-1.
CHICAGO –
The usual tool for trying to detect recurrence while following patients with papillary thyroid cancer after surgery has been the serum thyroglobulin assay. However, management of papillary thyroid cancer has become more conservative, involving lobectomy and isthmusectomy on the affected side rather than total gland resection. The benefit of the conservative approach is to avoid complications while maintaining an overall survival rate equivalent to the more extensive approach.
The investigators measured 754 miRNAs in serum samples of 11 patients with papillary thyroid cancer both before and 30 days after surgical thyroidectomy. They re-evaluated major candidate miRNAs using absolute quantitative polymerase chain reaction analysis in an independent cohort of 44 other patients with papillary thyroid cancer or benign nodules or 20 healthy controls, Dr. Rosignolo said at the annual meeting of the Endocrine Society.
The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days, and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy.
Serum levels of both miRNAs after 1 to 2 years of follow-up were consistent with ATA responses to therapy in all patients, including two patients who developed structural evidence of disease whose thyroglobulin assay results remained negative (less than 1 ng/mL) for cancer recurrence.
Fifteen of the 20 patients had excellent or indeterminate responses to therapy as defined by 2015 ATA guidelines. In these 15 cases, and in the single patient with a biochemical incomplete response, expression levels of miR-146a-5p and miR-221-3p decreased after surgery and remained low at the 1- to 2-year visit.
It was a very different story for the 4 patients with structural incomplete responses at 1 to 2 years. In this subgroup, initial postoperative declines in serum miR-146a-5p and miR-221-3p levels were followed by increases to levels at the 1- to 2-year visit that were similar to or higher than those found prior to surgery.
The study was funded by the Umberto Di Mario Foundation, Banca d’Italia, University of Rome Sapienza, the program of Biotechnologies and Clinical Medicine of the University of Rome Sapienza, the European Medical Writers Association, and the Umberto Di Mario Foundation.
SOURCE: Rosignolo F et al. J Endo Soc. 2017;1(1)3-13. ENDO 2018, Abstract OR17-1.
CHICAGO –
The usual tool for trying to detect recurrence while following patients with papillary thyroid cancer after surgery has been the serum thyroglobulin assay. However, management of papillary thyroid cancer has become more conservative, involving lobectomy and isthmusectomy on the affected side rather than total gland resection. The benefit of the conservative approach is to avoid complications while maintaining an overall survival rate equivalent to the more extensive approach.
The investigators measured 754 miRNAs in serum samples of 11 patients with papillary thyroid cancer both before and 30 days after surgical thyroidectomy. They re-evaluated major candidate miRNAs using absolute quantitative polymerase chain reaction analysis in an independent cohort of 44 other patients with papillary thyroid cancer or benign nodules or 20 healthy controls, Dr. Rosignolo said at the annual meeting of the Endocrine Society.
The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days, and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy.
Serum levels of both miRNAs after 1 to 2 years of follow-up were consistent with ATA responses to therapy in all patients, including two patients who developed structural evidence of disease whose thyroglobulin assay results remained negative (less than 1 ng/mL) for cancer recurrence.
Fifteen of the 20 patients had excellent or indeterminate responses to therapy as defined by 2015 ATA guidelines. In these 15 cases, and in the single patient with a biochemical incomplete response, expression levels of miR-146a-5p and miR-221-3p decreased after surgery and remained low at the 1- to 2-year visit.
It was a very different story for the 4 patients with structural incomplete responses at 1 to 2 years. In this subgroup, initial postoperative declines in serum miR-146a-5p and miR-221-3p levels were followed by increases to levels at the 1- to 2-year visit that were similar to or higher than those found prior to surgery.
The study was funded by the Umberto Di Mario Foundation, Banca d’Italia, University of Rome Sapienza, the program of Biotechnologies and Clinical Medicine of the University of Rome Sapienza, the European Medical Writers Association, and the Umberto Di Mario Foundation.
SOURCE: Rosignolo F et al. J Endo Soc. 2017;1(1)3-13. ENDO 2018, Abstract OR17-1.
REPORTING FROM ENDO 2018
Key clinical point: Serum microRNA profiles hold promise for postsurgical monitoring of patients with papillary thyroid cancer.
Major finding: Of eight tested, two serum microRNA profiles – miR-146a-5p and miR-221-3p – were the most promising thyroid tumor biomarkers.
Study details: Prospective analysis of the blood of 31 patients with papillary thyroid cancer before and after surgery to assess which markers were most sensitive to cancer.
Disclosures: The study was funded by the Umberto Di Mario Foundation, Banca d’Italia, University of Rome Sapienza, the program of Biotechnologies and Clinical Medicine of the University of Rome Sapienza, the European Medical Writers Association, and the Umberto Di Mario Foundation.
Source: Rosignolo F et al. J Endo Soc. 2017;1(1):3-13. ENDO 2018, Abstract OR17-1.