Breast Cancer ICYMI

Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.^1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.¹ The most common form of cancer is papillary carcinoma followed by follicular carcinoma.² Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.³ Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.³

Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.^2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.³

Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.^3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.^7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.⁹

The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.

Methods

The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.

All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.^1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.

Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.

Results

A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 

Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 

When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 

Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.

There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.

Discussion

The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).

The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.¹¹ They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).¹⁰ This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.¹

Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.⁵ Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.

Limitations

This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.

Conclusion

This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.⁸ Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.⁸ Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.

Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.^1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.¹ The most common form of cancer is papillary carcinoma followed by follicular carcinoma.² Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.³ Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.³

Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.^2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.³

Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.^3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.^7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.⁹

The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.

Methods

The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.

All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.^1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.

Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.

Results

A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 

Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 

When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 

Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.

There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.

Discussion

The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).

The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.¹¹ They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).¹⁰ This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.¹

Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.⁵ Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.

Limitations

This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.

Conclusion

This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.⁸ Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.⁸ Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.

Thyroid nodules are identified incidentally in 4% to 10% of the general population in the US.^1,2 Clinicians and patients often are concerned about potential malignancy when thyroid nodules are identified because 5% to 15% of nodules will be cancerous.¹ The most common form of cancer is papillary carcinoma followed by follicular carcinoma.² Initially, serum thyroid-stimulating hormone (TSH) levels and thyroid ultrasound are used to evaluate a thyroid nodule because both tests can reveal vital information about malignancy potential.³ Ultrasound characteristics, such as macrocalcifications, hypoechogenicity, absence of halo, increased vascularity, and irregular nodular margins, increase suspicion for malignancy and warrant further investigation.³

Ultrasound-guided fine-needle aspiration (FNA) is the modality of choice for evaluation of thyroid nodules with sensitivity and specificity > 90%.^2,4 Most patients receive a definitive diagnosis with this test; however, about 25% of cases are indeterminate based on the Bethesda System and require surgical investigation.³

Currently, it is well accepted clinical practice to refer all nodules > 4 cm for surgical intervention regardless of malignancy risk factors or the mass effect of the nodule.^3-6 The preference for surgery—rather than FNA—is because of the notable false negative rate with FNA in larger nodules; studies have described false negative rates for FNA close to 10%.^7,8 In contrast, Megwalu recently reported a FNA false negative rate of 0%.⁹

The risk of malignancy associated with nodule size has been researched for many years, but studies have produced conflicting results. In this retrospective cohort study, the authors compared malignancy rates between patients with nodules ≥ 3 cm and those with nodules < 3 cm.

Methods

The authors performed a retrospective chart review of the medical records of 329 patients presenting for thyroid nodule evaluation found on physical exam or incidentally identified with imaging at the Dayton Veteran Affairs Medical Center from January 2000 to May 2016. Data collection included sex, age, race, personal history of neck radiation treatment, family history of thyroid cancer, personal history of thyroid cancer, hot nodules/Graves disease, abnormal neck lymph nodes, and serum TSH levels. The authors looked for an association between TSH level and cancer. Hot thyroid nodules are known to have low risk of malignancy.

All patients aged 18 to 99 years with a thyroid nodule evaluated with FNA were included in the study. Patients were divided into 2 groups, those with nodules ≥ 3 cm and those with nodules < 3 cm. For nodules requiring subsequent biopsies, only the initial nodule biopsy was included in our study. The 3-cm cutoff was selected based on previous studies.^1,5,10 Patients who did not undergo a FNA study were excluded. Indications for surgery were positive FNA results, suspicious imaging, size of nodule, or patient preference.

Means and standard deviations are reported for continuous variables and counts and percentages for categorical variables. We used the Mann-Whitney test for comparisons involving continuous variables with 2 groups and the Kruskal-Wallis test for 4 groups. The chi-square test—corrected for continuity if necessary—was used to compare 2 categorical variables. We used multiple logistic regression to adjust for demographic and clinical variables other than nodule size that were related to malignancy. Inferences were made at the 0.05 level of significance.

Results

A total of 329 patients with thyroid nodules were identified: 236 were < 3 cm and 93 were ≥ 3 cm. The 2 groups differed on race, with more white patients in the < 3-cm nodule group (78% vs 67%, P = .036) (Table 1). 

Prevalence of cancer based on FNA in nodules < 3 cm was 6.4% (95% CI, 3.6%–10.3%) and nodules ≥ 3 cm was 8.6% (95% CI, 3.8%–16.2%; P = .23) (Table 2). 

When divided into 4 subgroups, cancer using FNA was found in 35.1% of nodules < 2 cm, 21.1% of nodules 2 cm to < 3 cm, 42.1% of nodules 3 cm to 4 cm, and 18.2% of nodules > 4 cm (P = .32) (Table 3). 

Surgical pathology results showed 17 cases of papillary carcinoma in nodules < 3 cm, whereas there were 9 cases of papillary carcinoma and 1 case of follicular carcinoma in nodules > 3 cm. When correlated with the cytology results, 10 cases were reported as benign, 11 were malignant, and 6 samples were non-diagnostic.

There were 30 nondiagnostic FNA samples: 7 patients had surgery, 19 were monitored with serial imaging, 2 were lost to follow-up, and 2 expired for other reasons. Of the 19 patients who were monitored with serial imaging, the nodules were stable and did not require repeat sampling.

Discussion

The authors found no relationship between thyroid nodule size and malignancy over a 16-year period in a veteran population, either with FNA or surgical pathology. The lack of relationship persists when adjusted for the only nonthyroid variable on which the 2 groups differed (race).

The finding of no relationship between larger thyroid nodule size and cancer is consistent with other studies. In a 10-year chart review of 695 patients at Walter Reed Army Medical Center, Burch and colleagues found a malignancy rate of 18.6% but no association between thyroid nodule size and malignancy.¹¹ They concluded that nodules ≥ 4 cm did not increase malignancy risk. In a 3-year retrospective study of 326 patients, Mangister and colleagues reported that the malignancy rate was higher in nodules < 3 cm (48.4%) compared with nodules ≥ 3 cm (33.3%).¹⁰ This study concluded that the malignancy potential of thyroid nodules peaked at 2 cm and decreased at > 3 cm. Kamran and colleagues reported a nonlinear relationship between nodule size and malignancy with a threshold of 2 cm, beyond which there was no increased risk of malignancy.¹

Conversely, in a prospective study Kuru and colleagues followed 571 patients who had undergone thyroidectomy and found that nodules ≥ 4 cm were associated with increased malignancy risk compared with nodules < 4 cm. However, with a cutoff of 3 cm there was no relationship.⁵ Discrepancies among studies might be because of variability in patient demographics and the prevalence of thyroid cancer in a specific institution. Although the majority of thyroid nodules are seen in females, the current study’s population was predominantly male and entirely veteran. Consequently, interpretation of these studies highlight the need to individualize clinical decision-making for each patient.

Limitations

This study has several limitations. It was conducted at a single institution with a group of veterans, which limits the ability to generalize its results to the general population. Second, data omissions are likely in retrospective chart reviews, and ensuring accuracy of data collection could be challenging. Third, all thyroid nodules found to be benign with cytology did not undergo surgical intervention to confirm the diagnosis; therefore, only 93 of 329 nodules were evaluated with the definitive diagnostic test. Therefore, selection bias was introduced into the nodule size comparisons when surgical intervention was used to measure the outcome. However, because false negative rates for FNA is low, likely few malignant nodules were missed. In addition, all patients with thyroid nodules are not referred for surgery because of potential complications.

Conclusion

This study strongly suggests there is no increased or decreased cancer risk for thyroid nodules ≥ 3 cm compared with those < 3 cm. Current clinical practice is to refer patients with larger nodules for surgical evaluation. In a large systemic review, Shin and colleagues reported higher pretest probability of malignancy in larger nodules and recommended consideration of surgical intervention for nodules > 3 cm because of false negatives and concerns for diagnostic inaccuracy with FNA.⁸ Although data were mixed, Shin and colleagues reported higher incidence of false negative FNA results in larger nodules.⁸ Given the authors’ findings and earlier conflicting results, the decision for surgical intervention cannot be made solely on nodule size and requires consideration of additional factors including FNA results, nodule characteristics, patient risk factors, and patient preference.

Central nervous system (CNS) lymphoma can be classified into 2 categories: primary CNS lymphoma (PCNSL), which includes disease limited to brain, eyes, spinal cord; and leptomeninges without coexisting or previous systemic lymphoma. Secondary CNS lymphoma (SCNSL) is essentially metastatic disease from a systemic primary site.¹ The focus of this case presentation is PCNSL, with an emphasis on imaging characteristics and differential diagnosis.

The median age at diagnosis for PCNSL is 65 years, and the overall incidence has been decreasing since the mid-1990s, likely related to the increased use of highly-active antiretroviral therapy (HAART) in patients with AIDS.^2,3 Although overall incidence has decreased, incidence in the elderly population has increased.⁴ Historically, PCNSL has been considered an AIDS-defining illness.⁵ These patients, among other immunocompromised patients, such as those on chronic immunosuppressive therapy, are at a higher risk for developing the malignancy.⁶

Clinical presentation varies because of the location of CNS involvement and may present with headache, mood or personality disturbances, or focal neurologic deficits. Seizures are less likely due to the tendency of PCNSL to spare gray matter. Initial workup generally includes a head computed tomography (CT) scan, as well as a contrast-enhanced magnetic resonance image (MRI), which may help direct clinicians to the appropriate diagnosis. However, there is significant overlap between the imaging characteristics of PCNSL and numerous other disease processes, including glioblastoma and demyelination. The imaging characteristics of PCNSL are considerably different depending on the patient’s immune status.⁷

This case illustrates a rare presentation of PCNSL in an immunocompetent patient whose MRI characteristics were seemingly more consistent with those seen in patients with immunodeficiency. The main differential diagnoses and key imaging characteristics, which may help obtain accurate diagnosis, will be discussed.

Case Presentation

A 72-year-old male veteran presented with a 2-month history of subjective weakness in his upper and lower extremities progressing to multiple falls at home. He had no significant medical history other than a thymectomy at age 15 for an enlarged thymus, which per patient report, was benign. An initial laboratory test that included vitamin B₁₂, folate, thyroid-stimulating hormone, complete blood cell count, and comprehensive metabolic panel, were unremarkable, with a white blood cell count of 8.5 K/uL. The initial neurologic evaluation did not show any focal neurologic deficits; however, during the initial hospital stay, the patient developed increasing lower extremity weakness on examination. A noncontrast CT head scan showed extensive nonspecific hypodensities within the periventricular white matter (Figure 1). A contrast-enhanced MRI showed enhancing lesions involving the corpus callosum, left cerebral peduncle, and right temporal lobe (Figures 2, 3, and 4). These lesions also exhibited significant restricted diffusion and a mild amount of surrounding vasogenic edema. The working diagnosis after the MRI included primary CNS lymphoma, multifocal glioblastoma, and tumefactive demyelinating disease. The patient was started on IV steroids and transferred for neurosurgical evaluation and biopsy at an outside hospital. The frontal lesion was biopsied, and the initial frozen section was consistent with lymphoma; a bone marrow biopsy was negative. The workup for immunodeficiency was unremarkable. Pathology revealed high-grade B-cell lymphoma, and the patient began a chemotherapy regimen.

Discussion

The workup of altered mental status, focal neurologic deficits, headaches, or other neurologic conditions often begins with a noncontrast CT scan. On CT, PCNSL generally appears isodense to hyperdense to gray matter, but appearance is variable. The often hyperdense appearance is attributable to the hypercellular nature of lymphoma. Many times, as in this case, CT may show only vague hypodensities, some of which may be associated with surrounding edema. This presentation is nonspecific and may be seen with advancing age due to changes of chronic microvascular ischemia as well as demyelination, other malignancies, and several other disease processes, both benign and malignant. After the initial CT scan, further workup requires evaluation with MRI. PCNSL exhibits restricted diffusion and variable signal intensity on T2-weighted imaging.

PCNSL is frequently centrally located within the periventricular white matter, often within the frontal lobe but can involve other lobes, the basal ganglia, brainstem, cerebellum, or less likely, the spinal canal.⁷ Contrary to primary CNS disease, secondary lymphoma within the CNS has been described classically as affecting a leptomeningeal (pia and arachnoid mater) distribution two-thirds of the time, with parenchymal involvement occurring in the other one-third of patients. A recent study by Malikova and colleagues found parenchymal involvement may be much more common than previously thought.¹ Leptomeningeal spread of disease often involves the cranial nerves, subependymal regions, spinal cord, or spinal nerve roots. Dural involvement in primary or secondary lymphoma is rare.

PCNSL nearly always shows enhancement. Linear enhancement along perivascular spaces is highly characteristic of PCNSL. The typical appearance of PCNSL associated with immunodeficiency varies from that seen in an otherwise immunocompetent patient. Patients with immunodeficiency usually have multifocal involvement, central necrosis leading to a ring enhancement appearance, and have more propensity for spontaneous hemorrhage.⁷ Immunocompetent patients are less likely to present with multifocal disease and rarely show ring enhancement. Also, spontaneous hemorrhage is rare in immunocompetent patients. In our case, extensive multifocal involvement was present, whereas typically immunocompetent patients will present with a solitary homogeneously enhancing parenchymal mass.

The primary differential for PCNSL includes malignant glioma, tumefactive multiple sclerosis, metastatic disease, and in an immunocompromised patient, toxoplasmosis. The degree of associated vasogenic edema and mass effect is generally lower in PCNSL than that of malignant gliomas and metastasis. Also, PCNSL tends to spare the cerebral cortex.⁸

Classically, PCNSL, malignant gliomas, and demyelinating disease have been considered the main differential for lesions that cross midline and involve both cerebral hemispheres. Lymphoma generally exhibits more restricted diffusion than malignant gliomas and metastasis, attributable to the highly cellular nature of lymphoma.⁷ Tumefactive multiple sclerosis is associated with relatively minimal mass effect for lesion size and exhibits less restricted diffusion values when compared to high grade gliomas and PCNSL. One fairly specific finding for tumefactive demyelinating lesions is incomplete rim enhancement.⁹ Unfortunately, an MRI is not reliable in differentiating these entities, and biopsy is required for definitive diagnosis. Many advancing imaging modalities may help provide the correct diagnosis of PCNSL, including diffusion-weighted and apparent diffusion coefficient imaging, diffusion tensor imaging, MR spectroscopy and PET imaging.⁷

Conclusion

With the increasing use of HAART, the paradigm of PCNSL is shifting toward one predominantly affecting immunocompetent patients. PCNSL should be considered in any patient with multiple enhancing CNS lesions, regardless of immune status. Several key imaging characteristics may help differentiate PCNSL and other disease processes; however, at this time, biopsy is recommended for definitive diagnosis.

Central nervous system (CNS) lymphoma can be classified into 2 categories: primary CNS lymphoma (PCNSL), which includes disease limited to brain, eyes, spinal cord; and leptomeninges without coexisting or previous systemic lymphoma. Secondary CNS lymphoma (SCNSL) is essentially metastatic disease from a systemic primary site.¹ The focus of this case presentation is PCNSL, with an emphasis on imaging characteristics and differential diagnosis.

The median age at diagnosis for PCNSL is 65 years, and the overall incidence has been decreasing since the mid-1990s, likely related to the increased use of highly-active antiretroviral therapy (HAART) in patients with AIDS.^2,3 Although overall incidence has decreased, incidence in the elderly population has increased.⁴ Historically, PCNSL has been considered an AIDS-defining illness.⁵ These patients, among other immunocompromised patients, such as those on chronic immunosuppressive therapy, are at a higher risk for developing the malignancy.⁶

Clinical presentation varies because of the location of CNS involvement and may present with headache, mood or personality disturbances, or focal neurologic deficits. Seizures are less likely due to the tendency of PCNSL to spare gray matter. Initial workup generally includes a head computed tomography (CT) scan, as well as a contrast-enhanced magnetic resonance image (MRI), which may help direct clinicians to the appropriate diagnosis. However, there is significant overlap between the imaging characteristics of PCNSL and numerous other disease processes, including glioblastoma and demyelination. The imaging characteristics of PCNSL are considerably different depending on the patient’s immune status.⁷

This case illustrates a rare presentation of PCNSL in an immunocompetent patient whose MRI characteristics were seemingly more consistent with those seen in patients with immunodeficiency. The main differential diagnoses and key imaging characteristics, which may help obtain accurate diagnosis, will be discussed.

Case Presentation

A 72-year-old male veteran presented with a 2-month history of subjective weakness in his upper and lower extremities progressing to multiple falls at home. He had no significant medical history other than a thymectomy at age 15 for an enlarged thymus, which per patient report, was benign. An initial laboratory test that included vitamin B₁₂, folate, thyroid-stimulating hormone, complete blood cell count, and comprehensive metabolic panel, were unremarkable, with a white blood cell count of 8.5 K/uL. The initial neurologic evaluation did not show any focal neurologic deficits; however, during the initial hospital stay, the patient developed increasing lower extremity weakness on examination. A noncontrast CT head scan showed extensive nonspecific hypodensities within the periventricular white matter (Figure 1). A contrast-enhanced MRI showed enhancing lesions involving the corpus callosum, left cerebral peduncle, and right temporal lobe (Figures 2, 3, and 4). These lesions also exhibited significant restricted diffusion and a mild amount of surrounding vasogenic edema. The working diagnosis after the MRI included primary CNS lymphoma, multifocal glioblastoma, and tumefactive demyelinating disease. The patient was started on IV steroids and transferred for neurosurgical evaluation and biopsy at an outside hospital. The frontal lesion was biopsied, and the initial frozen section was consistent with lymphoma; a bone marrow biopsy was negative. The workup for immunodeficiency was unremarkable. Pathology revealed high-grade B-cell lymphoma, and the patient began a chemotherapy regimen.

Discussion

The workup of altered mental status, focal neurologic deficits, headaches, or other neurologic conditions often begins with a noncontrast CT scan. On CT, PCNSL generally appears isodense to hyperdense to gray matter, but appearance is variable. The often hyperdense appearance is attributable to the hypercellular nature of lymphoma. Many times, as in this case, CT may show only vague hypodensities, some of which may be associated with surrounding edema. This presentation is nonspecific and may be seen with advancing age due to changes of chronic microvascular ischemia as well as demyelination, other malignancies, and several other disease processes, both benign and malignant. After the initial CT scan, further workup requires evaluation with MRI. PCNSL exhibits restricted diffusion and variable signal intensity on T2-weighted imaging.

PCNSL is frequently centrally located within the periventricular white matter, often within the frontal lobe but can involve other lobes, the basal ganglia, brainstem, cerebellum, or less likely, the spinal canal.⁷ Contrary to primary CNS disease, secondary lymphoma within the CNS has been described classically as affecting a leptomeningeal (pia and arachnoid mater) distribution two-thirds of the time, with parenchymal involvement occurring in the other one-third of patients. A recent study by Malikova and colleagues found parenchymal involvement may be much more common than previously thought.¹ Leptomeningeal spread of disease often involves the cranial nerves, subependymal regions, spinal cord, or spinal nerve roots. Dural involvement in primary or secondary lymphoma is rare.

PCNSL nearly always shows enhancement. Linear enhancement along perivascular spaces is highly characteristic of PCNSL. The typical appearance of PCNSL associated with immunodeficiency varies from that seen in an otherwise immunocompetent patient. Patients with immunodeficiency usually have multifocal involvement, central necrosis leading to a ring enhancement appearance, and have more propensity for spontaneous hemorrhage.⁷ Immunocompetent patients are less likely to present with multifocal disease and rarely show ring enhancement. Also, spontaneous hemorrhage is rare in immunocompetent patients. In our case, extensive multifocal involvement was present, whereas typically immunocompetent patients will present with a solitary homogeneously enhancing parenchymal mass.

The primary differential for PCNSL includes malignant glioma, tumefactive multiple sclerosis, metastatic disease, and in an immunocompromised patient, toxoplasmosis. The degree of associated vasogenic edema and mass effect is generally lower in PCNSL than that of malignant gliomas and metastasis. Also, PCNSL tends to spare the cerebral cortex.⁸

Classically, PCNSL, malignant gliomas, and demyelinating disease have been considered the main differential for lesions that cross midline and involve both cerebral hemispheres. Lymphoma generally exhibits more restricted diffusion than malignant gliomas and metastasis, attributable to the highly cellular nature of lymphoma.⁷ Tumefactive multiple sclerosis is associated with relatively minimal mass effect for lesion size and exhibits less restricted diffusion values when compared to high grade gliomas and PCNSL. One fairly specific finding for tumefactive demyelinating lesions is incomplete rim enhancement.⁹ Unfortunately, an MRI is not reliable in differentiating these entities, and biopsy is required for definitive diagnosis. Many advancing imaging modalities may help provide the correct diagnosis of PCNSL, including diffusion-weighted and apparent diffusion coefficient imaging, diffusion tensor imaging, MR spectroscopy and PET imaging.⁷

Conclusion

With the increasing use of HAART, the paradigm of PCNSL is shifting toward one predominantly affecting immunocompetent patients. PCNSL should be considered in any patient with multiple enhancing CNS lesions, regardless of immune status. Several key imaging characteristics may help differentiate PCNSL and other disease processes; however, at this time, biopsy is recommended for definitive diagnosis.

Central nervous system (CNS) lymphoma can be classified into 2 categories: primary CNS lymphoma (PCNSL), which includes disease limited to brain, eyes, spinal cord; and leptomeninges without coexisting or previous systemic lymphoma. Secondary CNS lymphoma (SCNSL) is essentially metastatic disease from a systemic primary site.¹ The focus of this case presentation is PCNSL, with an emphasis on imaging characteristics and differential diagnosis.

The median age at diagnosis for PCNSL is 65 years, and the overall incidence has been decreasing since the mid-1990s, likely related to the increased use of highly-active antiretroviral therapy (HAART) in patients with AIDS.^2,3 Although overall incidence has decreased, incidence in the elderly population has increased.⁴ Historically, PCNSL has been considered an AIDS-defining illness.⁵ These patients, among other immunocompromised patients, such as those on chronic immunosuppressive therapy, are at a higher risk for developing the malignancy.⁶

Clinical presentation varies because of the location of CNS involvement and may present with headache, mood or personality disturbances, or focal neurologic deficits. Seizures are less likely due to the tendency of PCNSL to spare gray matter. Initial workup generally includes a head computed tomography (CT) scan, as well as a contrast-enhanced magnetic resonance image (MRI), which may help direct clinicians to the appropriate diagnosis. However, there is significant overlap between the imaging characteristics of PCNSL and numerous other disease processes, including glioblastoma and demyelination. The imaging characteristics of PCNSL are considerably different depending on the patient’s immune status.⁷

This case illustrates a rare presentation of PCNSL in an immunocompetent patient whose MRI characteristics were seemingly more consistent with those seen in patients with immunodeficiency. The main differential diagnoses and key imaging characteristics, which may help obtain accurate diagnosis, will be discussed.

Case Presentation

A 72-year-old male veteran presented with a 2-month history of subjective weakness in his upper and lower extremities progressing to multiple falls at home. He had no significant medical history other than a thymectomy at age 15 for an enlarged thymus, which per patient report, was benign. An initial laboratory test that included vitamin B₁₂, folate, thyroid-stimulating hormone, complete blood cell count, and comprehensive metabolic panel, were unremarkable, with a white blood cell count of 8.5 K/uL. The initial neurologic evaluation did not show any focal neurologic deficits; however, during the initial hospital stay, the patient developed increasing lower extremity weakness on examination. A noncontrast CT head scan showed extensive nonspecific hypodensities within the periventricular white matter (Figure 1). A contrast-enhanced MRI showed enhancing lesions involving the corpus callosum, left cerebral peduncle, and right temporal lobe (Figures 2, 3, and 4). These lesions also exhibited significant restricted diffusion and a mild amount of surrounding vasogenic edema. The working diagnosis after the MRI included primary CNS lymphoma, multifocal glioblastoma, and tumefactive demyelinating disease. The patient was started on IV steroids and transferred for neurosurgical evaluation and biopsy at an outside hospital. The frontal lesion was biopsied, and the initial frozen section was consistent with lymphoma; a bone marrow biopsy was negative. The workup for immunodeficiency was unremarkable. Pathology revealed high-grade B-cell lymphoma, and the patient began a chemotherapy regimen.

Discussion

The workup of altered mental status, focal neurologic deficits, headaches, or other neurologic conditions often begins with a noncontrast CT scan. On CT, PCNSL generally appears isodense to hyperdense to gray matter, but appearance is variable. The often hyperdense appearance is attributable to the hypercellular nature of lymphoma. Many times, as in this case, CT may show only vague hypodensities, some of which may be associated with surrounding edema. This presentation is nonspecific and may be seen with advancing age due to changes of chronic microvascular ischemia as well as demyelination, other malignancies, and several other disease processes, both benign and malignant. After the initial CT scan, further workup requires evaluation with MRI. PCNSL exhibits restricted diffusion and variable signal intensity on T2-weighted imaging.

PCNSL is frequently centrally located within the periventricular white matter, often within the frontal lobe but can involve other lobes, the basal ganglia, brainstem, cerebellum, or less likely, the spinal canal.⁷ Contrary to primary CNS disease, secondary lymphoma within the CNS has been described classically as affecting a leptomeningeal (pia and arachnoid mater) distribution two-thirds of the time, with parenchymal involvement occurring in the other one-third of patients. A recent study by Malikova and colleagues found parenchymal involvement may be much more common than previously thought.¹ Leptomeningeal spread of disease often involves the cranial nerves, subependymal regions, spinal cord, or spinal nerve roots. Dural involvement in primary or secondary lymphoma is rare.

PCNSL nearly always shows enhancement. Linear enhancement along perivascular spaces is highly characteristic of PCNSL. The typical appearance of PCNSL associated with immunodeficiency varies from that seen in an otherwise immunocompetent patient. Patients with immunodeficiency usually have multifocal involvement, central necrosis leading to a ring enhancement appearance, and have more propensity for spontaneous hemorrhage.⁷ Immunocompetent patients are less likely to present with multifocal disease and rarely show ring enhancement. Also, spontaneous hemorrhage is rare in immunocompetent patients. In our case, extensive multifocal involvement was present, whereas typically immunocompetent patients will present with a solitary homogeneously enhancing parenchymal mass.

The primary differential for PCNSL includes malignant glioma, tumefactive multiple sclerosis, metastatic disease, and in an immunocompromised patient, toxoplasmosis. The degree of associated vasogenic edema and mass effect is generally lower in PCNSL than that of malignant gliomas and metastasis. Also, PCNSL tends to spare the cerebral cortex.⁸

Classically, PCNSL, malignant gliomas, and demyelinating disease have been considered the main differential for lesions that cross midline and involve both cerebral hemispheres. Lymphoma generally exhibits more restricted diffusion than malignant gliomas and metastasis, attributable to the highly cellular nature of lymphoma.⁷ Tumefactive multiple sclerosis is associated with relatively minimal mass effect for lesion size and exhibits less restricted diffusion values when compared to high grade gliomas and PCNSL. One fairly specific finding for tumefactive demyelinating lesions is incomplete rim enhancement.⁹ Unfortunately, an MRI is not reliable in differentiating these entities, and biopsy is required for definitive diagnosis. Many advancing imaging modalities may help provide the correct diagnosis of PCNSL, including diffusion-weighted and apparent diffusion coefficient imaging, diffusion tensor imaging, MR spectroscopy and PET imaging.⁷

Conclusion

With the increasing use of HAART, the paradigm of PCNSL is shifting toward one predominantly affecting immunocompetent patients. PCNSL should be considered in any patient with multiple enhancing CNS lesions, regardless of immune status. Several key imaging characteristics may help differentiate PCNSL and other disease processes; however, at this time, biopsy is recommended for definitive diagnosis.

Colorectal cancer is the second most common cause of cancer death in the US, with one-third of all colorectal cancers occurring within the rectum. Each year, an estimated 40000 Americans are diagnosed with rectal cancer (RC).^1,2 The prognosis and treatment of RC depends on both T and N stage at the time of diagnosis.^3-5 According to the most recent National Comprehensive Cancer Network guidelines from May 2019, patients with T1 to T2N0 tumors should undergo transanal or transabdominal surgery upfront, whereas patients with T3 to T4N0 or any TN1 to 2 should start with neoadjuvant therapy for better locoregional control, followed by surgery.⁶ Therefore, the appropriate management of RC requires adequate staging.

Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) are the imaging techniques currently used to stage RC. In a meta-analysis of 90 articles published between 1985 and 2002 that compared the 3 radiologic modalities, Bipat and colleagues found that MRI and EUS had a similar sensitivity of 94%, whereas the specificity of EUS (86%) was significantly higher than that of MRI (69%) for muscularis propria invasion.⁷ CT was performed only in a limited number of trials because CT was considered inadequate to assess early T stage. For perirectal tissue invasion, the sensitivity of EUS was statistically higher than that of CT and MRI imaging: 90% compared with 79% and 82%, respectively. The specificity estimates for EUS, CT, and MRI were comparable: 75%, 78%, and 76%, respectively. The respective sensitivity and specificity of the 3 imaging modalities to evaluate lymph nodes were also comparable: EUS, 67% and 78%; CT, 55% and 74%; and MRI, 66% and 76%.

The role of EUS in the diagnosis and treatment of RC has long been validated.^1,2-5 A meta-analysis of 42 studies involving 5039 patients found EUS to be highly accurate for differentiating various T stages.⁸ However, EUS cannot assess iliac and mesenteric lymph nodes or posterior tumor extension beyond endopelvic fascia in advanced RC. Notable heterogeneity was found among the studies in the meta-analyses with regard to the type of equipment used for staging, as well as the criteria used to assess the depth of penetration and nodal status. The recent introduction of phased-array coils and the development of T2-weighted fast spin sequences have improved the resolution of MRI. The MERCURY trial showed that extension of tumor to within 1 mm of the circumferential margin on high-resolution MRI correctly predicted margin involvement at the time of surgery in 92% of the patients.⁹ In the retrospective study by Balyasnikova and colleagues, MRI was found to correctly identify partial submucosal invasion and suitability for local excision in 89% of the cases.¹⁰

Therefore, both EUS and MRI are useful, more so than CT, in assessment of the depth of tumor invasion, nodal staging, and predicting the circumferential resection margin. The use of EUS, however, does not preclude the use of MRI, or vice versa. Rather, the 2 modalities can complement each other in staging and proper patient selection for treatment.¹¹

Despite data supporting the value of EUS in staging RC, its use is limited by a high degree of operator dependence and a substantial learning curve,^12-17 which may explain the low EUS accuracy observed in some reports.^7,13,15 Given the presence of recognized alternatives such as MRI, we decided to reevaluate EUS accuracy for the staging of RC outside high-volume specialized centers and prospective clinical trials.

Methods

A retrospective chart review was performed that included all consecutive patients undergoing rectal ultrasound from January 2011 to August 2015 at the US Department of Veterans Affairs Medical Center (VAMC) in Memphis, Tennessee. Sixty-five patients with short-stocked or sessile lesions < 15 cm from anal margin staged T2N0M0 or lower by endorectal ultrasound (ERUS) were included. The patients with neoplasms staged in excess of T2 or N0 were excluded from the study because treatment protocol dictates immediate neoadjuvant treatment, the administration of which would affect subsequent histopathology.

For the 37 patients included in the final analysis, ERUS results were compared with surgical pathology to ascertain accuracy. The resections were performed endoscopically or surgically with a goal of obtaining clear margins. The choice of procedure depended on size, shape, location, and depth of invasion. All patients underwent clinical and endoscopic surveillance with flexible sigmoidoscopy/EUS every 3 to 6 months for the first 2 years. We used 2 different gold standards for surveillance depending on the type of procedure performed to remove the lesion. A pathology report was the gold standard used for patients who underwent surgery. In patients who underwent endoscopic resection, we used the lack of recurrent disease, determined by normal endoscopic and endoscopic ultrasound examination, to signify complete endoscopic resection and therefore adequate staging as an early neoplasm.

Results

From January 2011 to August 2015, 65 rectal ultrasounds were performed. All EUS procedures were performed by 1 physician (C Ruben Tombazzi). All patients had previous endoscopic evaluation and tissue diagnoses. Twenty-eight patients were excluded: 18 had T3 or N1 disease, 2 had T2N0 but refused surgery, 2 had anal cancer, 3 patients with suspected cancer had benign nonneoplastic disease (2 radiation proctitis, 1 normal rectal wall), and 3 underwent EUS for benign tumors (1 ganglioneuroma and 2 lipomas).

Thirty-seven patients were included in the study, 3 of whom were staged as T2N0 and 34 as T1N0 or lower by EUS. All patients were men ranging in age from 43 to 73 years (mean, 59 years). All 37 patients underwent endoscopic or surgical resection of their early rectal neoplasm. The final pathologic evaluation of the specimens demonstrated 14 carcinoid tumors, 11 adenocarcinomas, 6 tubular adenomas with high-grade dysplasia, and 6 benign adenomas. The preoperative EUS staging was confirmed for all patients, with 100% sensitivity, specificity, and accuracy. None of the patients who underwent endoscopic or surgical transanal resection had recurrence, determined by normal endoscopic and endoscopic ultrasound appearance, during a mean of 32.6 months surveillance.

Discussion

EUS has long been a recognized method for T and N staging of RC.^1,3-5,7,8 Our data confirm that, in experienced hands, EUS is highly accurate in the staging of early rectal cancers.

The impact of EUS on the management of RC was demonstrated in a Mayo Clinic prospective blinded study.¹ In that cohort of 80 consecutive patients who had previously had a CT for staging, EUS altered patient management in about 30% of cases. The most common change precipatated by EUS was the indication for additional neoadjuvant treatment.

However, the results have not been as encouraging when ERUS is performed outside of strict research protocol. A multicenter, prospective, country-wide quality assurance study from > 300 German hospitals was designed to assess the diagnostic accuracy of EUS in RC.¹³ Of 29206 patients, 7096 underwent surgery, without neoadjuvant treatment, and were included in the final analysis. The correspondence of tumor invasion with histopathology was 64.7%, with understaging of 18% and overstaging of 17.3%.¹³ These numbers were better in hospitals with greater experience performing ERUS: 73% accuracy in the centers with a case load of > 30 cases per year compared with 63.2% accuracy for the centers with < 10 cases a year. Marusch and colleagues had previously demonstrated an EUS accuracy of 63.3% in a study of 1463 patients with RC in Germany.¹⁴ Another study based out of the UK had similar findings. Ashraf and colleagues performed a database analyses from 20 UK centers and identified 165 patients with RC who underwent ERUS and endoscopic microsurgery.¹⁵ Compared with histopathology, EUS had 57.1% sensitivity, 73% specificity, and 42.9% accuracy for T1 cancers; EUS accuracy was 50% for T2 and 58% for T3 tumors. The authors concluded that the general accuracy of EUS in determining stage was around 50%, the statistical equivalent of flipping a coin.

The low accuracy of EUS observed by German and British multicenter studies^13-15 was attributed to the difference that may exist in clinical trials at specialized centers compared with wider use of EUS in a community setting. As seen by our data, the Memphis VAMC is not a high-volume center for the treatment of RC. However, all our EUS procedures were performed and interpreted by a single operator (C. Ruben Tombazzi) with 18 years of EUS experience. We cannot conclude that no patient was overstaged, as patients receiving a stage of T3N0 or T > N0 received neoadjuvant treatment and were not included. However, we can conclude that no patient was understaged. All patients deemed to be T1 to T2N0 included in our study received accurate staging. Our results are consistent with the high accuracy of EUS reported from other centers with experience in diagnosis and treatment of RC.^1,3-5,17,18

Although EUS is accurate in differentiating T1 from T2 tumors, it cannot reliably differentiate T1 from T0 lesions. In one study, 57.6% of adenomas and 30.7% of carcinomas in situ were staged as T1 on EUS, while almost half of T1 cancers were interpreted as T0.¹⁷ This drawback is a well-known limitation of EUS; although, the misinterpretation does not affect treatment, as both T0 and T1 lesions can be treated successfully by local excision alone, which was the algorithm used for our patients. The choice of the specific procedure for local excision was left to the clinicians and included transanal endoscopic or surgical resections. At a mean follow-up of 32.6 months, none of the 37 patients who underwent endoscopic or surgical transanal resection had evidence of recurrent disease.

A limitation of EUS, or any other imaging modality, is differentiating tumor invasion from peritumoral inflammation. The inflammation can render images of tumor borders ill-defined and irregular, which hinders precise staging. However, the accurate identification of tumors with deep involvement of the submucosa (T1sm3) is of importance, because these tumors are more advanced than the superficial and intermediate T1 lesions (T1sm1 and T1sm2, respectively).

Patients with RC whose lesions are considered T1sm3 are at higher risk of harboring lymph node metastases.¹⁸ Nascimbeni and colleagues had shown that the invasion into the lower third of the submucosa (sm3) was an independent risk factor for lower cancer-free survival among patients with T1 RC.¹⁹We did not measure the distance of the tumor to muscular layer in our study, but we relied on EUS to predict the circumferential tumor margins and guide the surgical resection. Of the 11 patients with T1 rectal adenocarcinomas and the 6 patients with tubular adenoma with high-grade dysplasia, all treated by local excision, none developed a local or distant recurrence during follow-up.

Unlike rectal adenocarcinomas, the prognosis for carcinoid tumors correlates not only with the depth of invasion but also with the size of the tumor. The other adverse prognostic features include poor differentiation, high mitosis index, and lymphovascular invasion.²⁰

EUS had been shown to be highly accurate in determining the precise carcinoid tumor size, depth of invasion, and lymph node metastases.^20,21 In a study of 66 resected rectal carcinoid tumors by Ishii and colleagues, 57 lesions had a diameter of ≤ 10 mm and 9 lesions had a diameter of > 10 mm.²¹ All of the 57 carcinoid tumors with a diameter of ≤ 10 mm were confined to the submucosa. In contrast, 5 of the 9 lesions > 10 mm invaded the muscularis propria, 6 had a lymphovascular invasion, 4 were lymph node metastases, and 1 was a liver metastasis.

In our series, 4 of the 14 carcinoid tumors were > 10 mm but none were > 20 mm. None of the carcinoids with a diameter ≤ 10 mm invaded the muscularis propria. Of the 4 carcinoids > 10 mm, 1 was T2N0 and 3 were T1N0. All carcinoid tumors in our series were low grade and with low proliferation indexes, and all were treated successfully by local excision.

Conclusion

We believe our study shows that EUS can be highly accurate in staging rectal lesions, specifically lesions that are T1-T2N0, be they adenocarcinoma or carcinoid. Although we could not assess overstaging for lesions that were staged > T2 or > N0, we were able to determine no understaging for all of our patients. In experienced hands, EUS remains a highly accurate staging tool for early rectal carcinoma.

Colorectal cancer is the second most common cause of cancer death in the US, with one-third of all colorectal cancers occurring within the rectum. Each year, an estimated 40000 Americans are diagnosed with rectal cancer (RC).^1,2 The prognosis and treatment of RC depends on both T and N stage at the time of diagnosis.^3-5 According to the most recent National Comprehensive Cancer Network guidelines from May 2019, patients with T1 to T2N0 tumors should undergo transanal or transabdominal surgery upfront, whereas patients with T3 to T4N0 or any TN1 to 2 should start with neoadjuvant therapy for better locoregional control, followed by surgery.⁶ Therefore, the appropriate management of RC requires adequate staging.

Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) are the imaging techniques currently used to stage RC. In a meta-analysis of 90 articles published between 1985 and 2002 that compared the 3 radiologic modalities, Bipat and colleagues found that MRI and EUS had a similar sensitivity of 94%, whereas the specificity of EUS (86%) was significantly higher than that of MRI (69%) for muscularis propria invasion.⁷ CT was performed only in a limited number of trials because CT was considered inadequate to assess early T stage. For perirectal tissue invasion, the sensitivity of EUS was statistically higher than that of CT and MRI imaging: 90% compared with 79% and 82%, respectively. The specificity estimates for EUS, CT, and MRI were comparable: 75%, 78%, and 76%, respectively. The respective sensitivity and specificity of the 3 imaging modalities to evaluate lymph nodes were also comparable: EUS, 67% and 78%; CT, 55% and 74%; and MRI, 66% and 76%.

The role of EUS in the diagnosis and treatment of RC has long been validated.^1,2-5 A meta-analysis of 42 studies involving 5039 patients found EUS to be highly accurate for differentiating various T stages.⁸ However, EUS cannot assess iliac and mesenteric lymph nodes or posterior tumor extension beyond endopelvic fascia in advanced RC. Notable heterogeneity was found among the studies in the meta-analyses with regard to the type of equipment used for staging, as well as the criteria used to assess the depth of penetration and nodal status. The recent introduction of phased-array coils and the development of T2-weighted fast spin sequences have improved the resolution of MRI. The MERCURY trial showed that extension of tumor to within 1 mm of the circumferential margin on high-resolution MRI correctly predicted margin involvement at the time of surgery in 92% of the patients.⁹ In the retrospective study by Balyasnikova and colleagues, MRI was found to correctly identify partial submucosal invasion and suitability for local excision in 89% of the cases.¹⁰

Therefore, both EUS and MRI are useful, more so than CT, in assessment of the depth of tumor invasion, nodal staging, and predicting the circumferential resection margin. The use of EUS, however, does not preclude the use of MRI, or vice versa. Rather, the 2 modalities can complement each other in staging and proper patient selection for treatment.¹¹

Despite data supporting the value of EUS in staging RC, its use is limited by a high degree of operator dependence and a substantial learning curve,^12-17 which may explain the low EUS accuracy observed in some reports.^7,13,15 Given the presence of recognized alternatives such as MRI, we decided to reevaluate EUS accuracy for the staging of RC outside high-volume specialized centers and prospective clinical trials.

Methods

A retrospective chart review was performed that included all consecutive patients undergoing rectal ultrasound from January 2011 to August 2015 at the US Department of Veterans Affairs Medical Center (VAMC) in Memphis, Tennessee. Sixty-five patients with short-stocked or sessile lesions < 15 cm from anal margin staged T2N0M0 or lower by endorectal ultrasound (ERUS) were included. The patients with neoplasms staged in excess of T2 or N0 were excluded from the study because treatment protocol dictates immediate neoadjuvant treatment, the administration of which would affect subsequent histopathology.

For the 37 patients included in the final analysis, ERUS results were compared with surgical pathology to ascertain accuracy. The resections were performed endoscopically or surgically with a goal of obtaining clear margins. The choice of procedure depended on size, shape, location, and depth of invasion. All patients underwent clinical and endoscopic surveillance with flexible sigmoidoscopy/EUS every 3 to 6 months for the first 2 years. We used 2 different gold standards for surveillance depending on the type of procedure performed to remove the lesion. A pathology report was the gold standard used for patients who underwent surgery. In patients who underwent endoscopic resection, we used the lack of recurrent disease, determined by normal endoscopic and endoscopic ultrasound examination, to signify complete endoscopic resection and therefore adequate staging as an early neoplasm.

Results

From January 2011 to August 2015, 65 rectal ultrasounds were performed. All EUS procedures were performed by 1 physician (C Ruben Tombazzi). All patients had previous endoscopic evaluation and tissue diagnoses. Twenty-eight patients were excluded: 18 had T3 or N1 disease, 2 had T2N0 but refused surgery, 2 had anal cancer, 3 patients with suspected cancer had benign nonneoplastic disease (2 radiation proctitis, 1 normal rectal wall), and 3 underwent EUS for benign tumors (1 ganglioneuroma and 2 lipomas).

Thirty-seven patients were included in the study, 3 of whom were staged as T2N0 and 34 as T1N0 or lower by EUS. All patients were men ranging in age from 43 to 73 years (mean, 59 years). All 37 patients underwent endoscopic or surgical resection of their early rectal neoplasm. The final pathologic evaluation of the specimens demonstrated 14 carcinoid tumors, 11 adenocarcinomas, 6 tubular adenomas with high-grade dysplasia, and 6 benign adenomas. The preoperative EUS staging was confirmed for all patients, with 100% sensitivity, specificity, and accuracy. None of the patients who underwent endoscopic or surgical transanal resection had recurrence, determined by normal endoscopic and endoscopic ultrasound appearance, during a mean of 32.6 months surveillance.

Discussion

EUS has long been a recognized method for T and N staging of RC.^1,3-5,7,8 Our data confirm that, in experienced hands, EUS is highly accurate in the staging of early rectal cancers.

The impact of EUS on the management of RC was demonstrated in a Mayo Clinic prospective blinded study.¹ In that cohort of 80 consecutive patients who had previously had a CT for staging, EUS altered patient management in about 30% of cases. The most common change precipatated by EUS was the indication for additional neoadjuvant treatment.

However, the results have not been as encouraging when ERUS is performed outside of strict research protocol. A multicenter, prospective, country-wide quality assurance study from > 300 German hospitals was designed to assess the diagnostic accuracy of EUS in RC.¹³ Of 29206 patients, 7096 underwent surgery, without neoadjuvant treatment, and were included in the final analysis. The correspondence of tumor invasion with histopathology was 64.7%, with understaging of 18% and overstaging of 17.3%.¹³ These numbers were better in hospitals with greater experience performing ERUS: 73% accuracy in the centers with a case load of > 30 cases per year compared with 63.2% accuracy for the centers with < 10 cases a year. Marusch and colleagues had previously demonstrated an EUS accuracy of 63.3% in a study of 1463 patients with RC in Germany.¹⁴ Another study based out of the UK had similar findings. Ashraf and colleagues performed a database analyses from 20 UK centers and identified 165 patients with RC who underwent ERUS and endoscopic microsurgery.¹⁵ Compared with histopathology, EUS had 57.1% sensitivity, 73% specificity, and 42.9% accuracy for T1 cancers; EUS accuracy was 50% for T2 and 58% for T3 tumors. The authors concluded that the general accuracy of EUS in determining stage was around 50%, the statistical equivalent of flipping a coin.

The low accuracy of EUS observed by German and British multicenter studies^13-15 was attributed to the difference that may exist in clinical trials at specialized centers compared with wider use of EUS in a community setting. As seen by our data, the Memphis VAMC is not a high-volume center for the treatment of RC. However, all our EUS procedures were performed and interpreted by a single operator (C. Ruben Tombazzi) with 18 years of EUS experience. We cannot conclude that no patient was overstaged, as patients receiving a stage of T3N0 or T > N0 received neoadjuvant treatment and were not included. However, we can conclude that no patient was understaged. All patients deemed to be T1 to T2N0 included in our study received accurate staging. Our results are consistent with the high accuracy of EUS reported from other centers with experience in diagnosis and treatment of RC.^1,3-5,17,18

Although EUS is accurate in differentiating T1 from T2 tumors, it cannot reliably differentiate T1 from T0 lesions. In one study, 57.6% of adenomas and 30.7% of carcinomas in situ were staged as T1 on EUS, while almost half of T1 cancers were interpreted as T0.¹⁷ This drawback is a well-known limitation of EUS; although, the misinterpretation does not affect treatment, as both T0 and T1 lesions can be treated successfully by local excision alone, which was the algorithm used for our patients. The choice of the specific procedure for local excision was left to the clinicians and included transanal endoscopic or surgical resections. At a mean follow-up of 32.6 months, none of the 37 patients who underwent endoscopic or surgical transanal resection had evidence of recurrent disease.

A limitation of EUS, or any other imaging modality, is differentiating tumor invasion from peritumoral inflammation. The inflammation can render images of tumor borders ill-defined and irregular, which hinders precise staging. However, the accurate identification of tumors with deep involvement of the submucosa (T1sm3) is of importance, because these tumors are more advanced than the superficial and intermediate T1 lesions (T1sm1 and T1sm2, respectively).

Patients with RC whose lesions are considered T1sm3 are at higher risk of harboring lymph node metastases.¹⁸ Nascimbeni and colleagues had shown that the invasion into the lower third of the submucosa (sm3) was an independent risk factor for lower cancer-free survival among patients with T1 RC.¹⁹We did not measure the distance of the tumor to muscular layer in our study, but we relied on EUS to predict the circumferential tumor margins and guide the surgical resection. Of the 11 patients with T1 rectal adenocarcinomas and the 6 patients with tubular adenoma with high-grade dysplasia, all treated by local excision, none developed a local or distant recurrence during follow-up.

Unlike rectal adenocarcinomas, the prognosis for carcinoid tumors correlates not only with the depth of invasion but also with the size of the tumor. The other adverse prognostic features include poor differentiation, high mitosis index, and lymphovascular invasion.²⁰

EUS had been shown to be highly accurate in determining the precise carcinoid tumor size, depth of invasion, and lymph node metastases.^20,21 In a study of 66 resected rectal carcinoid tumors by Ishii and colleagues, 57 lesions had a diameter of ≤ 10 mm and 9 lesions had a diameter of > 10 mm.²¹ All of the 57 carcinoid tumors with a diameter of ≤ 10 mm were confined to the submucosa. In contrast, 5 of the 9 lesions > 10 mm invaded the muscularis propria, 6 had a lymphovascular invasion, 4 were lymph node metastases, and 1 was a liver metastasis.

In our series, 4 of the 14 carcinoid tumors were > 10 mm but none were > 20 mm. None of the carcinoids with a diameter ≤ 10 mm invaded the muscularis propria. Of the 4 carcinoids > 10 mm, 1 was T2N0 and 3 were T1N0. All carcinoid tumors in our series were low grade and with low proliferation indexes, and all were treated successfully by local excision.

Conclusion

We believe our study shows that EUS can be highly accurate in staging rectal lesions, specifically lesions that are T1-T2N0, be they adenocarcinoma or carcinoid. Although we could not assess overstaging for lesions that were staged > T2 or > N0, we were able to determine no understaging for all of our patients. In experienced hands, EUS remains a highly accurate staging tool for early rectal carcinoma.

Colorectal cancer is the second most common cause of cancer death in the US, with one-third of all colorectal cancers occurring within the rectum. Each year, an estimated 40000 Americans are diagnosed with rectal cancer (RC).^1,2 The prognosis and treatment of RC depends on both T and N stage at the time of diagnosis.^3-5 According to the most recent National Comprehensive Cancer Network guidelines from May 2019, patients with T1 to T2N0 tumors should undergo transanal or transabdominal surgery upfront, whereas patients with T3 to T4N0 or any TN1 to 2 should start with neoadjuvant therapy for better locoregional control, followed by surgery.⁶ Therefore, the appropriate management of RC requires adequate staging.

Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and computed tomography (CT) are the imaging techniques currently used to stage RC. In a meta-analysis of 90 articles published between 1985 and 2002 that compared the 3 radiologic modalities, Bipat and colleagues found that MRI and EUS had a similar sensitivity of 94%, whereas the specificity of EUS (86%) was significantly higher than that of MRI (69%) for muscularis propria invasion.⁷ CT was performed only in a limited number of trials because CT was considered inadequate to assess early T stage. For perirectal tissue invasion, the sensitivity of EUS was statistically higher than that of CT and MRI imaging: 90% compared with 79% and 82%, respectively. The specificity estimates for EUS, CT, and MRI were comparable: 75%, 78%, and 76%, respectively. The respective sensitivity and specificity of the 3 imaging modalities to evaluate lymph nodes were also comparable: EUS, 67% and 78%; CT, 55% and 74%; and MRI, 66% and 76%.

The role of EUS in the diagnosis and treatment of RC has long been validated.^1,2-5 A meta-analysis of 42 studies involving 5039 patients found EUS to be highly accurate for differentiating various T stages.⁸ However, EUS cannot assess iliac and mesenteric lymph nodes or posterior tumor extension beyond endopelvic fascia in advanced RC. Notable heterogeneity was found among the studies in the meta-analyses with regard to the type of equipment used for staging, as well as the criteria used to assess the depth of penetration and nodal status. The recent introduction of phased-array coils and the development of T2-weighted fast spin sequences have improved the resolution of MRI. The MERCURY trial showed that extension of tumor to within 1 mm of the circumferential margin on high-resolution MRI correctly predicted margin involvement at the time of surgery in 92% of the patients.⁹ In the retrospective study by Balyasnikova and colleagues, MRI was found to correctly identify partial submucosal invasion and suitability for local excision in 89% of the cases.¹⁰

Therefore, both EUS and MRI are useful, more so than CT, in assessment of the depth of tumor invasion, nodal staging, and predicting the circumferential resection margin. The use of EUS, however, does not preclude the use of MRI, or vice versa. Rather, the 2 modalities can complement each other in staging and proper patient selection for treatment.¹¹

Despite data supporting the value of EUS in staging RC, its use is limited by a high degree of operator dependence and a substantial learning curve,^12-17 which may explain the low EUS accuracy observed in some reports.^7,13,15 Given the presence of recognized alternatives such as MRI, we decided to reevaluate EUS accuracy for the staging of RC outside high-volume specialized centers and prospective clinical trials.

Methods

A retrospective chart review was performed that included all consecutive patients undergoing rectal ultrasound from January 2011 to August 2015 at the US Department of Veterans Affairs Medical Center (VAMC) in Memphis, Tennessee. Sixty-five patients with short-stocked or sessile lesions < 15 cm from anal margin staged T2N0M0 or lower by endorectal ultrasound (ERUS) were included. The patients with neoplasms staged in excess of T2 or N0 were excluded from the study because treatment protocol dictates immediate neoadjuvant treatment, the administration of which would affect subsequent histopathology.

For the 37 patients included in the final analysis, ERUS results were compared with surgical pathology to ascertain accuracy. The resections were performed endoscopically or surgically with a goal of obtaining clear margins. The choice of procedure depended on size, shape, location, and depth of invasion. All patients underwent clinical and endoscopic surveillance with flexible sigmoidoscopy/EUS every 3 to 6 months for the first 2 years. We used 2 different gold standards for surveillance depending on the type of procedure performed to remove the lesion. A pathology report was the gold standard used for patients who underwent surgery. In patients who underwent endoscopic resection, we used the lack of recurrent disease, determined by normal endoscopic and endoscopic ultrasound examination, to signify complete endoscopic resection and therefore adequate staging as an early neoplasm.

Results

From January 2011 to August 2015, 65 rectal ultrasounds were performed. All EUS procedures were performed by 1 physician (C Ruben Tombazzi). All patients had previous endoscopic evaluation and tissue diagnoses. Twenty-eight patients were excluded: 18 had T3 or N1 disease, 2 had T2N0 but refused surgery, 2 had anal cancer, 3 patients with suspected cancer had benign nonneoplastic disease (2 radiation proctitis, 1 normal rectal wall), and 3 underwent EUS for benign tumors (1 ganglioneuroma and 2 lipomas).

Thirty-seven patients were included in the study, 3 of whom were staged as T2N0 and 34 as T1N0 or lower by EUS. All patients were men ranging in age from 43 to 73 years (mean, 59 years). All 37 patients underwent endoscopic or surgical resection of their early rectal neoplasm. The final pathologic evaluation of the specimens demonstrated 14 carcinoid tumors, 11 adenocarcinomas, 6 tubular adenomas with high-grade dysplasia, and 6 benign adenomas. The preoperative EUS staging was confirmed for all patients, with 100% sensitivity, specificity, and accuracy. None of the patients who underwent endoscopic or surgical transanal resection had recurrence, determined by normal endoscopic and endoscopic ultrasound appearance, during a mean of 32.6 months surveillance.

Discussion

EUS has long been a recognized method for T and N staging of RC.^1,3-5,7,8 Our data confirm that, in experienced hands, EUS is highly accurate in the staging of early rectal cancers.

The impact of EUS on the management of RC was demonstrated in a Mayo Clinic prospective blinded study.¹ In that cohort of 80 consecutive patients who had previously had a CT for staging, EUS altered patient management in about 30% of cases. The most common change precipatated by EUS was the indication for additional neoadjuvant treatment.

However, the results have not been as encouraging when ERUS is performed outside of strict research protocol. A multicenter, prospective, country-wide quality assurance study from > 300 German hospitals was designed to assess the diagnostic accuracy of EUS in RC.¹³ Of 29206 patients, 7096 underwent surgery, without neoadjuvant treatment, and were included in the final analysis. The correspondence of tumor invasion with histopathology was 64.7%, with understaging of 18% and overstaging of 17.3%.¹³ These numbers were better in hospitals with greater experience performing ERUS: 73% accuracy in the centers with a case load of > 30 cases per year compared with 63.2% accuracy for the centers with < 10 cases a year. Marusch and colleagues had previously demonstrated an EUS accuracy of 63.3% in a study of 1463 patients with RC in Germany.¹⁴ Another study based out of the UK had similar findings. Ashraf and colleagues performed a database analyses from 20 UK centers and identified 165 patients with RC who underwent ERUS and endoscopic microsurgery.¹⁵ Compared with histopathology, EUS had 57.1% sensitivity, 73% specificity, and 42.9% accuracy for T1 cancers; EUS accuracy was 50% for T2 and 58% for T3 tumors. The authors concluded that the general accuracy of EUS in determining stage was around 50%, the statistical equivalent of flipping a coin.

The low accuracy of EUS observed by German and British multicenter studies^13-15 was attributed to the difference that may exist in clinical trials at specialized centers compared with wider use of EUS in a community setting. As seen by our data, the Memphis VAMC is not a high-volume center for the treatment of RC. However, all our EUS procedures were performed and interpreted by a single operator (C. Ruben Tombazzi) with 18 years of EUS experience. We cannot conclude that no patient was overstaged, as patients receiving a stage of T3N0 or T > N0 received neoadjuvant treatment and were not included. However, we can conclude that no patient was understaged. All patients deemed to be T1 to T2N0 included in our study received accurate staging. Our results are consistent with the high accuracy of EUS reported from other centers with experience in diagnosis and treatment of RC.^1,3-5,17,18

Although EUS is accurate in differentiating T1 from T2 tumors, it cannot reliably differentiate T1 from T0 lesions. In one study, 57.6% of adenomas and 30.7% of carcinomas in situ were staged as T1 on EUS, while almost half of T1 cancers were interpreted as T0.¹⁷ This drawback is a well-known limitation of EUS; although, the misinterpretation does not affect treatment, as both T0 and T1 lesions can be treated successfully by local excision alone, which was the algorithm used for our patients. The choice of the specific procedure for local excision was left to the clinicians and included transanal endoscopic or surgical resections. At a mean follow-up of 32.6 months, none of the 37 patients who underwent endoscopic or surgical transanal resection had evidence of recurrent disease.

A limitation of EUS, or any other imaging modality, is differentiating tumor invasion from peritumoral inflammation. The inflammation can render images of tumor borders ill-defined and irregular, which hinders precise staging. However, the accurate identification of tumors with deep involvement of the submucosa (T1sm3) is of importance, because these tumors are more advanced than the superficial and intermediate T1 lesions (T1sm1 and T1sm2, respectively).

Patients with RC whose lesions are considered T1sm3 are at higher risk of harboring lymph node metastases.¹⁸ Nascimbeni and colleagues had shown that the invasion into the lower third of the submucosa (sm3) was an independent risk factor for lower cancer-free survival among patients with T1 RC.¹⁹We did not measure the distance of the tumor to muscular layer in our study, but we relied on EUS to predict the circumferential tumor margins and guide the surgical resection. Of the 11 patients with T1 rectal adenocarcinomas and the 6 patients with tubular adenoma with high-grade dysplasia, all treated by local excision, none developed a local or distant recurrence during follow-up.

Unlike rectal adenocarcinomas, the prognosis for carcinoid tumors correlates not only with the depth of invasion but also with the size of the tumor. The other adverse prognostic features include poor differentiation, high mitosis index, and lymphovascular invasion.²⁰

EUS had been shown to be highly accurate in determining the precise carcinoid tumor size, depth of invasion, and lymph node metastases.^20,21 In a study of 66 resected rectal carcinoid tumors by Ishii and colleagues, 57 lesions had a diameter of ≤ 10 mm and 9 lesions had a diameter of > 10 mm.²¹ All of the 57 carcinoid tumors with a diameter of ≤ 10 mm were confined to the submucosa. In contrast, 5 of the 9 lesions > 10 mm invaded the muscularis propria, 6 had a lymphovascular invasion, 4 were lymph node metastases, and 1 was a liver metastasis.

In our series, 4 of the 14 carcinoid tumors were > 10 mm but none were > 20 mm. None of the carcinoids with a diameter ≤ 10 mm invaded the muscularis propria. Of the 4 carcinoids > 10 mm, 1 was T2N0 and 3 were T1N0. All carcinoid tumors in our series were low grade and with low proliferation indexes, and all were treated successfully by local excision.

Conclusion

We believe our study shows that EUS can be highly accurate in staging rectal lesions, specifically lesions that are T1-T2N0, be they adenocarcinoma or carcinoid. Although we could not assess overstaging for lesions that were staged > T2 or > N0, we were able to determine no understaging for all of our patients. In experienced hands, EUS remains a highly accurate staging tool for early rectal carcinoma.

A study modeling outcomes for women with estrogen receptor–positive, HER2-negative breast cancer indicates that those with the highest score on a clinicomolecular test would be most likely to benefit from chemotherapy to reduce the risk of distant recurrence.

The model, created by William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues, uses validated 10-year risk of distant breast recurrences as a function of the EndoPredict (EPclin) 12-gene clinicomolecular assay score.

The model suggests that for patients with a low EPclin score, chemotherapy would offer no additional benefit over endocrine therapy, whereas those with high scores would have an increase in recurrence-free survival with chemotherapy.

“Overall, this demonstrates that EndoPredict provides guidance on the expected absolute benefit from adjuvant chemotherapy in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer. Therefore, EndoPredict can identify patients likely to benefit sufficiently from adjuvant chemotherapy to justify associated toxicities,” Dr. Gradishar and associates wrote in Precision Oncology.

The assay has previously been shown to accurately predict the risk of distant metastases in patients with estrogen receptor–positive, human epidermal growth factor receptor–2 negative (ER+/HER2–) breast cancer, but the ability to predict absolute benefit of chemotherapy is less clear, and it would be unethical to conduct a randomized trial with a no-chemotherapy arm, the investigators noted.

Instead, the investigators created a mathematical model to try to answer the question. They determined the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.

They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit, and 1.5% for maximal interaction, suggesting no significant added benefit from chemotherapy.

In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.

“Overall, these data demonstrate that high EPclin scores are associated with maximal predicted chemotherapy benefit, and low EPclin scores are associated with no clinically meaningful benefit. This association is irrespective of interaction strength between EPclin and predicted chemotherapy benefit, and the impact of any interaction on absolute benefit is much smaller than the ability to accurately estimate absolute risk,” they wrote.

The study was supported by Myriad Genetics. Dr. Gradishar disclosed consulting or advisory roles with Genentech and Roche. Five of the coauthors are employees of Myriad Genetics or Myriad International.

SOURCE: Gradishar W et al. Precision Oncology. 2016 Aug. 6. doi: 10.1200/PO.18.00361.

A study modeling outcomes for women with estrogen receptor–positive, HER2-negative breast cancer indicates that those with the highest score on a clinicomolecular test would be most likely to benefit from chemotherapy to reduce the risk of distant recurrence.

The model, created by William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues, uses validated 10-year risk of distant breast recurrences as a function of the EndoPredict (EPclin) 12-gene clinicomolecular assay score.

The model suggests that for patients with a low EPclin score, chemotherapy would offer no additional benefit over endocrine therapy, whereas those with high scores would have an increase in recurrence-free survival with chemotherapy.

“Overall, this demonstrates that EndoPredict provides guidance on the expected absolute benefit from adjuvant chemotherapy in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer. Therefore, EndoPredict can identify patients likely to benefit sufficiently from adjuvant chemotherapy to justify associated toxicities,” Dr. Gradishar and associates wrote in Precision Oncology.

The assay has previously been shown to accurately predict the risk of distant metastases in patients with estrogen receptor–positive, human epidermal growth factor receptor–2 negative (ER+/HER2–) breast cancer, but the ability to predict absolute benefit of chemotherapy is less clear, and it would be unethical to conduct a randomized trial with a no-chemotherapy arm, the investigators noted.

Instead, the investigators created a mathematical model to try to answer the question. They determined the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.

They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit, and 1.5% for maximal interaction, suggesting no significant added benefit from chemotherapy.

In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.

“Overall, these data demonstrate that high EPclin scores are associated with maximal predicted chemotherapy benefit, and low EPclin scores are associated with no clinically meaningful benefit. This association is irrespective of interaction strength between EPclin and predicted chemotherapy benefit, and the impact of any interaction on absolute benefit is much smaller than the ability to accurately estimate absolute risk,” they wrote.

The study was supported by Myriad Genetics. Dr. Gradishar disclosed consulting or advisory roles with Genentech and Roche. Five of the coauthors are employees of Myriad Genetics or Myriad International.

SOURCE: Gradishar W et al. Precision Oncology. 2016 Aug. 6. doi: 10.1200/PO.18.00361.

A study modeling outcomes for women with estrogen receptor–positive, HER2-negative breast cancer indicates that those with the highest score on a clinicomolecular test would be most likely to benefit from chemotherapy to reduce the risk of distant recurrence.

The model, created by William Gradishar, MD, from the Robert H. Lurie Comprehensive Cancer Center in Chicago, and colleagues, uses validated 10-year risk of distant breast recurrences as a function of the EndoPredict (EPclin) 12-gene clinicomolecular assay score.

The model suggests that for patients with a low EPclin score, chemotherapy would offer no additional benefit over endocrine therapy, whereas those with high scores would have an increase in recurrence-free survival with chemotherapy.

“Overall, this demonstrates that EndoPredict provides guidance on the expected absolute benefit from adjuvant chemotherapy in addition to prognostic information for patients with ER-positive, HER2-negative early-stage breast cancer. Therefore, EndoPredict can identify patients likely to benefit sufficiently from adjuvant chemotherapy to justify associated toxicities,” Dr. Gradishar and associates wrote in Precision Oncology.

The assay has previously been shown to accurately predict the risk of distant metastases in patients with estrogen receptor–positive, human epidermal growth factor receptor–2 negative (ER+/HER2–) breast cancer, but the ability to predict absolute benefit of chemotherapy is less clear, and it would be unethical to conduct a randomized trial with a no-chemotherapy arm, the investigators noted.

Instead, the investigators created a mathematical model to try to answer the question. They determined the average relative benefit of chemotherapy for reducing distant recurrence using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group, and they estimated absolute chemotherapy benefit differences across a range of interaction strengths between relative chemotherapy benefit and the EPclin score. Finally, they calculated average absolute benefit for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics, maker of the assay.

They found that the average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% assuming no interaction between prognostic factors and chemotherapy benefit, and 1.5% for maximal interaction, suggesting no significant added benefit from chemotherapy.

In contrast, for patients with a high EPclin score, the absolute benefit assuming no interaction was 5.3% and the benefit assuming maximal interaction was 7.3%.

“Overall, these data demonstrate that high EPclin scores are associated with maximal predicted chemotherapy benefit, and low EPclin scores are associated with no clinically meaningful benefit. This association is irrespective of interaction strength between EPclin and predicted chemotherapy benefit, and the impact of any interaction on absolute benefit is much smaller than the ability to accurately estimate absolute risk,” they wrote.

The study was supported by Myriad Genetics. Dr. Gradishar disclosed consulting or advisory roles with Genentech and Roche. Five of the coauthors are employees of Myriad Genetics or Myriad International.

SOURCE: Gradishar W et al. Precision Oncology. 2016 Aug. 6. doi: 10.1200/PO.18.00361.

Vaccination is not a risk factor for multiple sclerosis (MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
 

Technical University of Munich

In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.

To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.

Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.

The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.

The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.

The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.

A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.

[email protected]

SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.

Vaccination is not a risk factor for multiple sclerosis (MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
 

Technical University of Munich

In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.

To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.

Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.

The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.

The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.

The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.

A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.

[email protected]

SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.

Vaccination is not a risk factor for multiple sclerosis (MS), according to an analysis published July 30 in Neurology. Although the results suggest that vaccination is associated with a lower likelihood of incident MS within the following 5 years, “these data alone do not allow for any conclusion regarding a possible protective effect of vaccinations regarding the development of MS,” wrote Alexander Hapfelmeier, PhD, of the Technical University of Munich and colleagues.
 

Technical University of Munich

In recent years, researchers have proposed and investigated various potential environmental risk factors for the development of MS. Vaccination is one proposed environmental risk factor, but case reports and small studies have yielded conflicting results about its association with incident MS.

To examine this question more closely, Dr. Hapfelmeier and colleagues performed a systematic retrospective analysis of ambulatory claims data held by the Bavarian Association of Statutory Health Insurance Physicians. They reviewed the data to identify patients with new-onset MS and at least two ICD-10 diagnoses of the disorder. They next identified two control cohorts of participants diagnosed with other autoimmune diseases: Crohn’s disease and psoriasis. Finally, they randomly selected a third control cohort of patients without any of these diagnoses and matched them by age, sex, and district to patients with MS in a 5:1 ratio. Eligible participants were younger than 70 years.

Dr. Hapfelmeier and colleagues reviewed the incidence and frequency of vaccinations (such as those targeting tick-borne encephalitis, human papillomavirus, and influenza virus) in all cohorts. They created unconditional logistic regression models to assess the association between vaccination and MS. They also created separate models to contrast the MS cohort with each of the control cohorts.

The researchers included 12,262 patients with MS, 19,296 patients with Crohn’s disease, 112,292 patients with psoriasis, and 79,185 participants without these autoimmune diseases in their analysis. They found 456 participants with Crohn’s disease and psoriasis, 216 participants with MS and psoriasis, 48 participants with Crohn’s disease and MS, and 2 participants with Crohn’s disease, psoriasis, and MS. Dr. Hapfelmeier and colleagues allocated these participants to each of the respective cohorts and did not analyze them differently because of the comparatively small sample sizes.

The investigators analyzed the occurrence of vaccination in all participants during the 5 years before first diagnosis. Among patients who received vaccination, the odds ratio of MS was 0.870 in participants without autoimmune disease, 0.919 in participants with Crohn’s disease, and 0.973 in participants with psoriasis. Decreased risk of MS was most notable for vaccinations against influenza and tick-borne encephalitis. The results were consistent regardless of time frame, control cohort, and definition of MS.

The subjective definition of the MS cohort was a limitation of the study, but the authors addressed it by also using several strict definitions of that cohort. Another limitation is that the source data may reflect entry errors and incorrect coding.

A grant from the German Federal Ministry of Education and Research Competence Network MS supported the study. The authors had no conflicts that were relevant to the topic of the study.

[email protected]

SOURCE: Hapfelmeier A et al. Neurology. 2019 Jul 30. doi: 10.1212/WNL.0000000000008012.

When it comes to cardiovascular disease (CVD) risk after a breast cancer diagnosis, it’s not so much a matter of the amount of body fat carried but rather where it is located, results of a retrospective cohort study of nearly 3,000 survivors suggest.

“It is well known that higher body mass index (BMI) is associated with CVD mortality in the general population. However, BMI is not always an accurate proxy for individual-level adiposity and does not describe adipose tissue distribution,” note lead investigator Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente Northern California, Oakland, Calif., and coinvestigators.

The investigators studied 2,943 survivors of nonmetastatic breast cancer having a mean age of 56 years who were initially CVD free, using clinically acquired CT scans obtained near diagnosis to measure adiposity in three compartments: visceral, subcutaneous, and intramuscular.

The cohort experienced 328 CVD events (nonfatal stroke, myocardial infarction, heart failure, or CVD death) during a median follow-up of 6 years, the investigators reported in Journal of Clinical Oncology. The 10-year cumulative incidence was 15%.

In analyses that were adjusted for potential confounders and took into account competing risks, survivors’ CVD risk increased significantly with each standard deviation (SD) increase in visceral adiposity (hazard ratio, 1.15; 95% confidence interval, 1.03-1.29) and each SD increase in intramuscular adiposity (HR, 1.21; 95% CI, 1.06-1.37). The association for subcutaneous adiposity was not significant.

Findings were similar across all BMI categories. Of particular note, among survivors having a normal BMI, risk of CVD events increased by 70% with each SD greater visceral adiposity (HR, 1.70; 95% CI, 1.10-2.62).

Risk also rose with BMI exceeding the normal range, but the association became significant only in survivors with a BMI placing them in obesity class II (35 kg/m² or greater) (HR, 1.70; 95% CI, 1.20-2.42).

“Although it has been assumed that excess adiposity increases the risk of CVD after breast cancer, this first-of-its-kind study demonstrates that adipose tissue distribution best identifies patients with breast cancer with higher CVD risk after diagnosis, including those with normal BMI,” Dr. Cespedes Feliciano and coinvestigators note.

“Software is now available that automatically measures body composition from clinically acquired CT scans, facilitating clinical integration,” they note. “Measures of adipose tissue distribution from CT or anthropometry (e.g., waist circumference) may help identify individuals with high CVD risk and tailor prevention efforts to patients’ body composition.”

Dr. Cespedes Feliciano disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Cespedes Feliciano EM et al. J Clin Oncol. 2019 Aug 1. doi: 10.1200/JCO.19.00286.

When it comes to cardiovascular disease (CVD) risk after a breast cancer diagnosis, it’s not so much a matter of the amount of body fat carried but rather where it is located, results of a retrospective cohort study of nearly 3,000 survivors suggest.

“It is well known that higher body mass index (BMI) is associated with CVD mortality in the general population. However, BMI is not always an accurate proxy for individual-level adiposity and does not describe adipose tissue distribution,” note lead investigator Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente Northern California, Oakland, Calif., and coinvestigators.

The investigators studied 2,943 survivors of nonmetastatic breast cancer having a mean age of 56 years who were initially CVD free, using clinically acquired CT scans obtained near diagnosis to measure adiposity in three compartments: visceral, subcutaneous, and intramuscular.

The cohort experienced 328 CVD events (nonfatal stroke, myocardial infarction, heart failure, or CVD death) during a median follow-up of 6 years, the investigators reported in Journal of Clinical Oncology. The 10-year cumulative incidence was 15%.

In analyses that were adjusted for potential confounders and took into account competing risks, survivors’ CVD risk increased significantly with each standard deviation (SD) increase in visceral adiposity (hazard ratio, 1.15; 95% confidence interval, 1.03-1.29) and each SD increase in intramuscular adiposity (HR, 1.21; 95% CI, 1.06-1.37). The association for subcutaneous adiposity was not significant.

Findings were similar across all BMI categories. Of particular note, among survivors having a normal BMI, risk of CVD events increased by 70% with each SD greater visceral adiposity (HR, 1.70; 95% CI, 1.10-2.62).

Risk also rose with BMI exceeding the normal range, but the association became significant only in survivors with a BMI placing them in obesity class II (35 kg/m² or greater) (HR, 1.70; 95% CI, 1.20-2.42).

“Although it has been assumed that excess adiposity increases the risk of CVD after breast cancer, this first-of-its-kind study demonstrates that adipose tissue distribution best identifies patients with breast cancer with higher CVD risk after diagnosis, including those with normal BMI,” Dr. Cespedes Feliciano and coinvestigators note.

“Software is now available that automatically measures body composition from clinically acquired CT scans, facilitating clinical integration,” they note. “Measures of adipose tissue distribution from CT or anthropometry (e.g., waist circumference) may help identify individuals with high CVD risk and tailor prevention efforts to patients’ body composition.”

Dr. Cespedes Feliciano disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Cespedes Feliciano EM et al. J Clin Oncol. 2019 Aug 1. doi: 10.1200/JCO.19.00286.

When it comes to cardiovascular disease (CVD) risk after a breast cancer diagnosis, it’s not so much a matter of the amount of body fat carried but rather where it is located, results of a retrospective cohort study of nearly 3,000 survivors suggest.

“It is well known that higher body mass index (BMI) is associated with CVD mortality in the general population. However, BMI is not always an accurate proxy for individual-level adiposity and does not describe adipose tissue distribution,” note lead investigator Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente Northern California, Oakland, Calif., and coinvestigators.

The investigators studied 2,943 survivors of nonmetastatic breast cancer having a mean age of 56 years who were initially CVD free, using clinically acquired CT scans obtained near diagnosis to measure adiposity in three compartments: visceral, subcutaneous, and intramuscular.

The cohort experienced 328 CVD events (nonfatal stroke, myocardial infarction, heart failure, or CVD death) during a median follow-up of 6 years, the investigators reported in Journal of Clinical Oncology. The 10-year cumulative incidence was 15%.

In analyses that were adjusted for potential confounders and took into account competing risks, survivors’ CVD risk increased significantly with each standard deviation (SD) increase in visceral adiposity (hazard ratio, 1.15; 95% confidence interval, 1.03-1.29) and each SD increase in intramuscular adiposity (HR, 1.21; 95% CI, 1.06-1.37). The association for subcutaneous adiposity was not significant.

Findings were similar across all BMI categories. Of particular note, among survivors having a normal BMI, risk of CVD events increased by 70% with each SD greater visceral adiposity (HR, 1.70; 95% CI, 1.10-2.62).

Risk also rose with BMI exceeding the normal range, but the association became significant only in survivors with a BMI placing them in obesity class II (35 kg/m² or greater) (HR, 1.70; 95% CI, 1.20-2.42).

“Although it has been assumed that excess adiposity increases the risk of CVD after breast cancer, this first-of-its-kind study demonstrates that adipose tissue distribution best identifies patients with breast cancer with higher CVD risk after diagnosis, including those with normal BMI,” Dr. Cespedes Feliciano and coinvestigators note.

“Software is now available that automatically measures body composition from clinically acquired CT scans, facilitating clinical integration,” they note. “Measures of adipose tissue distribution from CT or anthropometry (e.g., waist circumference) may help identify individuals with high CVD risk and tailor prevention efforts to patients’ body composition.”

Dr. Cespedes Feliciano disclosed no relevant conflicts of interest. The study did not receive any specific funding.

SOURCE: Cespedes Feliciano EM et al. J Clin Oncol. 2019 Aug 1. doi: 10.1200/JCO.19.00286.

Treatment costs are a significant factor in women’s decision making around breast cancer surgery, investigators reported.

With the health care costs of breast cancer estimated to reach $20 billion by 2020 in the United States, many of those costs are being shifted onto patients themselves, wrote Rachel A. Greenup, MD, from Duke University, Durham, N.C., and coauthors in the Journal of Oncology Practice.

“This financial hardship is now recognized as a major adverse effect of cancer care and has been associated with reduced quality of life, nonadherence, and an increased risk of early mortality,” they wrote.

Researchers surveyed 607 women with a history of breast cancer to examine the impact that cost had on their decisions about surgery and what financial harm they had experienced after breast cancer surgery.

Overall, 43% of women said they considered costs when making decisions about breast cancer treatment, 28% said cost influenced their decision making around breast cancer surgery, and 14% said costs were extremely important in that decision.

Women in the lowest income bracket – earning at or below $45,000 per year – identified cost as the most influential factor in their decision about breast cancer surgery, above loss of sensation, breast preservation or appearance, the need for long-term surveillance, or avoiding radiation.

However, more than three-quarters of women said they never discussed costs with their medical team.

Bilateral mastectomy, with and without reconstruction, was associated with higher patient-reported out-of-pocket costs, higher debt, higher rates of cancer-induced financial hardship, and higher rates of altered or reduced employment, compared with breast-conserving surgery.

More than one-third of participants reported significant to catastrophic financial burden because of their breast cancer care.

Even in the highest income brackets, two-thirds of women were financially unprepared for the cost of treatment, and 26% said their treatment costs were higher than expected.

The authors commented that “cost transparency” was uncommon between oncologically equivalent surgical treatments, “thus, patients with breast cancer may unknowingly be guiding therapeutic decisions that increase the risk of financial harm.”

“To date, patient out-of-pocket costs and subsequent risk of financial harm have not been routinely incorporated into shared decisions for breast cancer surgery, a process that has otherwise highly revered patient values,” they wrote.

The investigators suggested that revealing the greater risk for financial burden associated with treatments like bilateral mastectomy could help inform surgical treatment decisions.

The study was supported by the National Institutes of Health and the Duke Cancer Institute. Six authors reported honoraria, research funding, prior employment, and other support from the pharmaceutical sector.

SOURCE: Greenup RA et al. J Oncol Pract. 2019 Jul 29. doi: 10.1200/JOP.18.00796.

Treatment costs are a significant factor in women’s decision making around breast cancer surgery, investigators reported.

With the health care costs of breast cancer estimated to reach $20 billion by 2020 in the United States, many of those costs are being shifted onto patients themselves, wrote Rachel A. Greenup, MD, from Duke University, Durham, N.C., and coauthors in the Journal of Oncology Practice.

“This financial hardship is now recognized as a major adverse effect of cancer care and has been associated with reduced quality of life, nonadherence, and an increased risk of early mortality,” they wrote.

Researchers surveyed 607 women with a history of breast cancer to examine the impact that cost had on their decisions about surgery and what financial harm they had experienced after breast cancer surgery.

Overall, 43% of women said they considered costs when making decisions about breast cancer treatment, 28% said cost influenced their decision making around breast cancer surgery, and 14% said costs were extremely important in that decision.

Women in the lowest income bracket – earning at or below $45,000 per year – identified cost as the most influential factor in their decision about breast cancer surgery, above loss of sensation, breast preservation or appearance, the need for long-term surveillance, or avoiding radiation.

However, more than three-quarters of women said they never discussed costs with their medical team.

Bilateral mastectomy, with and without reconstruction, was associated with higher patient-reported out-of-pocket costs, higher debt, higher rates of cancer-induced financial hardship, and higher rates of altered or reduced employment, compared with breast-conserving surgery.

More than one-third of participants reported significant to catastrophic financial burden because of their breast cancer care.

Even in the highest income brackets, two-thirds of women were financially unprepared for the cost of treatment, and 26% said their treatment costs were higher than expected.

The authors commented that “cost transparency” was uncommon between oncologically equivalent surgical treatments, “thus, patients with breast cancer may unknowingly be guiding therapeutic decisions that increase the risk of financial harm.”

“To date, patient out-of-pocket costs and subsequent risk of financial harm have not been routinely incorporated into shared decisions for breast cancer surgery, a process that has otherwise highly revered patient values,” they wrote.

The investigators suggested that revealing the greater risk for financial burden associated with treatments like bilateral mastectomy could help inform surgical treatment decisions.

The study was supported by the National Institutes of Health and the Duke Cancer Institute. Six authors reported honoraria, research funding, prior employment, and other support from the pharmaceutical sector.

SOURCE: Greenup RA et al. J Oncol Pract. 2019 Jul 29. doi: 10.1200/JOP.18.00796.

Treatment costs are a significant factor in women’s decision making around breast cancer surgery, investigators reported.

With the health care costs of breast cancer estimated to reach $20 billion by 2020 in the United States, many of those costs are being shifted onto patients themselves, wrote Rachel A. Greenup, MD, from Duke University, Durham, N.C., and coauthors in the Journal of Oncology Practice.

“This financial hardship is now recognized as a major adverse effect of cancer care and has been associated with reduced quality of life, nonadherence, and an increased risk of early mortality,” they wrote.

Researchers surveyed 607 women with a history of breast cancer to examine the impact that cost had on their decisions about surgery and what financial harm they had experienced after breast cancer surgery.

Overall, 43% of women said they considered costs when making decisions about breast cancer treatment, 28% said cost influenced their decision making around breast cancer surgery, and 14% said costs were extremely important in that decision.

Women in the lowest income bracket – earning at or below $45,000 per year – identified cost as the most influential factor in their decision about breast cancer surgery, above loss of sensation, breast preservation or appearance, the need for long-term surveillance, or avoiding radiation.

However, more than three-quarters of women said they never discussed costs with their medical team.

Bilateral mastectomy, with and without reconstruction, was associated with higher patient-reported out-of-pocket costs, higher debt, higher rates of cancer-induced financial hardship, and higher rates of altered or reduced employment, compared with breast-conserving surgery.

More than one-third of participants reported significant to catastrophic financial burden because of their breast cancer care.

Even in the highest income brackets, two-thirds of women were financially unprepared for the cost of treatment, and 26% said their treatment costs were higher than expected.

The authors commented that “cost transparency” was uncommon between oncologically equivalent surgical treatments, “thus, patients with breast cancer may unknowingly be guiding therapeutic decisions that increase the risk of financial harm.”

“To date, patient out-of-pocket costs and subsequent risk of financial harm have not been routinely incorporated into shared decisions for breast cancer surgery, a process that has otherwise highly revered patient values,” they wrote.

The investigators suggested that revealing the greater risk for financial burden associated with treatments like bilateral mastectomy could help inform surgical treatment decisions.

The study was supported by the National Institutes of Health and the Duke Cancer Institute. Six authors reported honoraria, research funding, prior employment, and other support from the pharmaceutical sector.

SOURCE: Greenup RA et al. J Oncol Pract. 2019 Jul 29. doi: 10.1200/JOP.18.00796.

Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.¹ One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.

In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.

Purpose

In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.

This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.²

Scope of Problem

The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.³ Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.³ Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).

Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.

Case Presentations

Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 

Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).

Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.⁴ Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.

Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 

Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.

A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.^5,6

Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 

Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.^7-9

New Diffuse Glioma Classification

Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.¹⁰ The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.¹¹ Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.

As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.

Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 

Diagnostic Uses of Molecular Testing

While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.

Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.^15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.^18,19

Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.^20-26

Testing In the VA

The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 

The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.

Conclusion

In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).

Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 

Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Correspondence: Dr. Kulich ([email protected])

Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.¹ One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.

In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.

Purpose

In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.

This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.²

Scope of Problem

The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.³ Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.³ Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).

Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.

Case Presentations

Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 

Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).

Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.⁴ Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.

Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 

Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.

A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.^5,6

Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 

Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.^7-9

New Diffuse Glioma Classification

Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.¹⁰ The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.¹¹ Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.

As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.

Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 

Diagnostic Uses of Molecular Testing

While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.

Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.^15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.^18,19

Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.^20-26

Testing In the VA

The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 

The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.

Conclusion

In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).

Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 

Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Correspondence: Dr. Kulich ([email protected])

Over the past few decades, our understanding of the molecular underpinning of primary neoplasms of the central nervous system (CNS) has progressed substantially. Thanks in large part to this expansion in our knowledge base, the World Health Organization (WHO) has recently updated its classification of tumors of the CNS.¹ One of the key elements of this update was the inclusion of molecular diagnostic criteria for the classification of infiltrating gliomas. While the previous classification system was based upon histologic subtypes of the tumor (astrocytoma, oligodendroglioma, and oligoastrocytoma), the revised classification system incorporates molecular testing to establish the genetic characteristics of the tumor to reach a final integrated diagnosis.

In this article, we present 3 cases to highlight some of these recent changes in the WHO diagnostic categories of primary CNS tumors and to illustrate the role of specific molecular tests in reaching a final integrated diagnosis. We then propose a clinical practice guideline for the Veterans Health Administration (VHA) that recommends use of molecular testing for veterans as part of the diagnostic workup of primary CNS neoplasms.

Purpose

In 2013 the VHA National Director of Pathology & Laboratory Medicine Services (P&LMS) chartered a national molecular genetics pathology workgroup (MGPW) that was charged with 4 specific tasks: (1) Provide recommendations about the effective use of molecular genetic testing for veterans; (2) Promote increased quality and availability of molecular testing within the VHA; (3) Encourage internal referral testing; and (4) Create an organizational structure and policies for molecular genetic testing and laboratory developed tests. The workgroup is currently composed of 4 subcommittees: genetic medicine, hematopathology, pharmacogenomics, and molecular oncology. The molecular oncology subcommittee is focused upon molecular genetic testing for solid tumors.

This article is intended to be the first of several publications from the molecular oncology subcommittee of the MGPW that address some of the aforementioned tasks. Similar to the recent publication from the hematopathology subcommittee of the MGPW, this article focuses on CNS neoplasms.²

Scope of Problem

The incidence of tumors of the CNS in the US population varies among age groups. It is the most common solid tumor in children aged < 14 years and represents a significant cause of mortality across all age groups.³ Of CNS tumors, diffuse gliomas comprise about 20% of the tumors and more than 70% of the primary malignant CNS tumors.³ Analysis of the VA Central Cancer Registry data from 2010 to 2014 identified 1,186 veterans (about 237 veterans per year) who were diagnosed with diffuse gliomas. (Lynch, Kulich, Colman, unpublished data, February 2018). While the majority (nearly 80%) of these cases were glioblastomas (GBMs), unfortunately a majority of these cases did not undergo molecular testing (Lynch, Kulich, Colman, unpublished data, February 2018).

Although this low rate of testing may be in part reflective of the period from which these data were gleaned (ie, prior to the WHO release of their updated the classification of tumors of the CNS), it is important to raise VA practitioners’ awareness of these recent changes to ensure that veterans receive the proper diagnosis and treatment for their disease. Thus, while the number of veterans diagnosed with diffuse gliomas within the VHA is relatively small in comparison to other malignancies, such as prostatic adenocarcinomas and lung carcinomas, the majority of diffuse gliomas do not seem to be receiving the molecular testing that would be necessary for (1) appropriate classification under the recently revised WHO recommendations; and (2) making important treatment decisions.

Case Presentations

Case 1. A veteran of the Gulf War presented with a 3-month history of possible narcoleptic events associated with a motor vehicle accident. Magnetic resonance imaging (MRI) revealed a large left frontal mass lesion with minimal surrounding edema without appreciable contrast enhancement (Figures 1A, 1B, and 1C). 

Neither mitotic figures nor endothelial proliferation were identified. Immunohistochemical stains revealed a lack of R132H mutant IDH1 protein expression, a loss of nuclear staining for ATRX protein within a substantial number of cells, and a clonal pattern of p53 protein overexpression (Figures 1E, 1F, and 1G). The lesion demonstrated diffuse glial fibrillary acidic protein (GFAP) immunoreactivity and a low proliferation index (as determined by Ki-67 staining; estimated at less than 5%) (Figures 1H and 1I).

Based upon these results, an initial morphologic diagnosis of diffuse glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. While fluorescence in situ hybridization (FISH) studies were negative for 1p/19q codeletion, pyrosequencing analysis revealed the presence of a c.394C>T (R132C) mutation of the IDH1 gene (Figure 1J). The University of Pittsburgh Medical Center’s GlioSeq targeted next-generation sequence (NGS) analysis confirmed the presence of the c.394C > T mutation in IDH1 gene.⁴ Based upon this additional information, a final integrated morphologic and molecular diagnosis of diffuse astrocytoma, IDH-mutant was rendered.

Case 2. A Vietnam War veteran presented with a 6-week history of new onset falls with associated left lower extremity weakness. A MRI revealed a right frontoparietal mass lesion with surrounding edema without appreciable contrast enhancement (Figures 2A, 2B, and 2C). 

Immunohistochemical stains revealed R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, the lack of a clonal pattern of p53 protein overexpression, diffuse GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 20% (Figures 2E, 2F, 2G, 2H and 2I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were positive for 1p/19q codeletion, and pyrosequencing analysis confirmed the immunohistochemical findings of a c.395G>A (R132H) mutation of the IDH1 gene (Figure 2J). GlioSeq targeted NGS analysis confirmed the presence of the c.395G>A mutation in the IDH1 gene, a mutation in the telomerase reverse transcriptase (TERT) promoter, and possible decreased copy number of the CIC (chromosome 1p) and FUBP1 (chromosome 19q) genes.

A final integrated morphologic and molecular diagnosis of anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted was rendered based on the additional information. With this final diagnosis, methylation analysis of the MGMT gene promoter, which was performed for prognostic and predictive purposes, was identified in this case.^5,6

Case 3. A veteran of the Vietnam War presented with a new onset seizure. A MRI revealed a focally contrast-enhancing mass with surrounding edema within the left frontal lobe (Figures 3A, 3B, and 3C). 

Hematoxylin and eosin (H&E) stained sections following formalin fixation and paraffin embedding demonstrated similar findings (Figure 3D), and while mitotic figures were readily identified, areas of necrosis were not identified and endothelial proliferation was not a prominent feature. Immunohistochemical stains revealed no evidence of R132H mutant IDH1 protein expression, retention of nuclear staining for ATRX protein, a clonal pattern of p53 protein overexpression, patchy GFAP immunoreactivity, and a proliferation index (as determined by Ki-67 staining) focally approaching 50% (Figures 3E, 3F, 3G, 3H, and 3I).

Based upon these results, an initial morphologic diagnosis of diffuse (high grade) glioma was issued, and the tissue was subjected to a variety of nucleic acid-based tests. The FISH studies were negative for EGFR gene amplification and 1p/19q codeletion, although a gain of the long arm of chromosome 1 was detected. Pyrosequencing analysis for mutations in codon 132 of the IDH1 gene revealed no mutations (Figure 3J). GlioSeq targeted NGS analysis identified mutations within the NF1, TP53, and PIK3CA genes without evidence of mutations in the IDH1, IDH2, ATRX, H3F3A, or EGFR genes or the TERT promoter. Based upon this additional information, a final integrated morphologic and molecular diagnosis of GBM, IDH wild-type was issued. The MGMT gene promoter was negative for methylation, a finding that has prognostic and predictive impact with regard to treatment with temazolamide.^7-9

New Diffuse Glioma Classification

Since the issuance of the previous edition of the WHO classification of CNS tumors in 2007, several sentinel discoveries have been made that have advanced our understanding of the underlying biology of primary CNS neoplasms. Since a detailed review of these findings is beyond the scope and purpose of this manuscript and salient reviews on the topic can be found elsewhere, we will focus on the molecular findings that have been incorporated into the recently revised WHO classification.¹⁰ The importance of providing such information for proper patient management is illustrated by the recent acknowledgement by the American Academy of Neurology that molecular testing of brain tumors is a specific area in which there is a need for quality improvement.¹¹ Therefore, it is critical that these underlying molecular abnormalities are identified to allow for proper classification and treatment of diffuse gliomas in the veteran population.

As noted previously, based on VA cancer registry data, diffuse gliomas are the most commonly encountered primary CNS cancers in the veteran population. Several of the aforementioned seminal discoveries have been incorporated into the updated classification of diffuse gliomas. While the recently updated WHO classification allows for the assignment of “not otherwise specified (NOS)” diagnostic designation, this category must be limited to cases where there is insufficient data to allow for a more precise classification due to sample limitations and not simply due to a failure of VA pathology laboratories to pursue the appropriate diagnostic testing.

Figure 4 presents the recommended diagnostic workflow for the workup of diffuse gliomas. As illustrated in the above cases, a variety of different methodologies, including immunohistochemical, FISH, loss of heterozygosity analysis, traditional and NGS may be applied when elucidating the status of molecular events at critical diagnostic branch points. 

Diagnostic Uses of Molecular Testing

While the case studies in this article demonstrate the use of ancillary testing and provide a suggested strategy for properly subclassifying diffuse gliomas, inherent in this strategy is the assumption that, based upon the initial clinical and pathologic information available, one can accurately categorize the lesion as a diffuse glioma. In reality, such a distinction is not always a straightforward endeavor. It is well recognized that a proportion of low-grade, typically radiologically circumscribed, CNS neoplasms, such as pilocytic astrocytomas and glioneuronal tumors, may infiltrate the surrounding brain parenchyma. In addition, many of these low-grade CNS neoplasms also may have growth patterns that are shared with diffuse gliomas, a diagnostic challenge that often can be further hampered by the inherent limitations involved in obtaining adequate samples for diagnosis from the CNS.

Although there are limitations and caveats, molecular diagnostic testing may be invaluable in properly classifying CNS tumors in such situations. The finding of mutations in the IDH1 or IDH2 genes has been shown to be very valuable in distinguishing low-grade diffuse glioma from both nonneoplastic and low-grade circumscribed neuroepithelial neoplasms that may exhibit growth patterns that can mimic those of diffuse gliomas.^15-17 Conversely, finding abnormalities in the BRAF gene in a brain neoplasm that has a low-grade morphology suggests that the lesion may represent one of these low-grade lesions such as a pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or mixed neuronal-glial tumor as opposed to a diffuse glioma.^18,19

Depending upon the environment in which one practices, small biopsy specimens may be prevalent, and unfortunately, it is not uncommon to obtain a biopsy that exhibits a histologic growth pattern that is discordant from what one would predict based on the clinical context and imaging findings. Molecular testing may be useful in resolving discordances in such situations. If a biopsy of a ring-enhancing lesion demonstrates a diffuse glioma that doesn’t meet WHO grade IV criteria, applying methodologies that look for genetic features commonly encountered in high-grade astrocytomas may identify genetic abnormalities that suggest a more aggressive lesion than is indicated by the histologic findings. The presence of genetic abnormalities such as homozygous deletion of the CDKN2A gene, TERT promoter mutation, loss of heterozygosity of chromosome 10q and/or phosphatase and tensin homolog (PTEN) mutations, EGFR gene amplification or the presence of the EGFR variant III are a few findings that would suggest the aforementioned sample may represent an undersampling of a higher grade diffuse astrocytoma, which would be important information to convey to the treating clinicians.^20-26

Testing In the VA

The goals of the MPWG include promoting increased quality and availability of genetic testing within the VHA as well as encouraging internal referral testing. An informal survey of the chiefs of VA Pathology and Laboratory Medicine Services was conducted in November of 2017 in an attempt to identify internal VA pathology laboratories currently conducting testing that may be of use in the workup of diffuse gliomas (Table 1). 

The VA currently offers NGS panels for patients with advanced-stage malignancies under the auspices of the Precision Oncology Program, whose reports provide both (1) mutational analyses for genes such as TP53, ATRX, NF1, BRAF, PTEN, TERT IDH1, and IDH2 that may be useful in the proper classifying of high-grade diffuse gliomas; and (2) information regarding clinical trials for which the veteran may be eligible for based on their glioma’s mutational profile. Interested VA providers should visit tinyurl.com/precisiononcology/ for more information about this program. Finally, although internal testing within VA laboratories is recommended to allow for the development of more cost-effective testing, testing may be performed through many nationally contracted reference laboratories.

Conclusion

In light of the recent progress made in our understanding of the molecular events of gliomagenesis, the way we diagnose diffuse gliomas within the CNS has undergone a major paradigm shift. While histology still plays a critical role in the process, we believe that additional ancillary testing is a requirement for all diffuse gliomas diagnosed within VA pathology laboratories. In the context of recently encountered cases, we have provided a recommended workflow highlighting the testing that can be performed to allow for the proper diagnosis of our veterans with diffuse gliomas (Figure 4).

Unless limited by the amount of tissue available for such tests, ancillary testing must be performed on all diffuse gliomas diagnosed within the VA system to ensure proper diagnosis and treatment of our veterans with diffuse gliomas. 

Acknowledgments
The authors thank Dr. Craig M. Horbinski (Feinberg School of Medicine, Northwestern University) and Dr. Geoffrey H. Murdoch (University of Pittsburgh) for their constructive criticism of the manuscript. We also thank the following individuals for past service as members of the molecular oncology subcommittee of the MGPW: Dr. George Ansstas (Washington University School of Medicine), Dr. Osssama Hemadeh (Bay Pines VA Health Care System), Dr. James Herman (VA Pittsburgh Healthcare System), and Dr. Ryan Phan (formerly of the VA Greater Los Angeles Healthcare System) as well as the members of the Veterans Administration pathology and laboratory medicine service molecular genetics pathology workgroup.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies.

Dr. Kulich is the Acting Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System and member of the Division of Neuropathology at University of Pittsburgh Department of Pathology, Dr. Duvvuri is an Otolaryngologist at VA Pittsburgh Healthcare System, and Dr. Passero is the Section Chief of Hematology\Oncology at VA Pittsburgh Healthcare System in Pennsylvania. Dr. Becker is an Oncologist at VA-New York Harbor Healthcare System. Dr. Dacic is a Pathologist at University of Pittsburgh Department of Pathology in Pennsylvania. Dr. Ehsan is Chief of Pathology and Laboratory Medicine Services at the South Texas Veterans Healthcare System in San Antonio. Dr. Gutkin is the former Chief of Pathology and Laboratory Medicine Service at VA Pittsburgh Healthcare System. Dr. Hou is a Pathologist at St. Louis VA Medical Center in Missouri. Dr. Icardi is the VA National Director of Pathology and Laboratory Medicine Services. Dr. Lyle is a Pathologist at Bay Pine Health Care System in Florida. Dr. Lynch is an Investigator at VA Salt Lake Health Care System Informatics and Computing Infrastructure. Dr. Montgomery is an Oncologist at VA Puget Sound Health Care System, in Seattle, Washington. Dr. Przygodzki is the Director of Genomic Medicine Implementation and Associate Director of Genomic Medicine for the VA. Dr. Colman is a Neuro-Oncologist at George E. Wahlen VA Medical Center and the Director of Medical Neuro-Oncology at the Huntsman Cancer Institute, Salt Lake City, Utah.

Correspondence: Dr. Kulich ([email protected])

Following therapy with curative intent for early-stage primary breast care, the presence of circulating tumor DNA may identify those patients at high risk for relapse, investigators reported.

Among 101 women treated for early-stage breast cancer and followed for a median of nearly 3 years, detection of circulating tumor DNA (ctDNA) during follow-up was associated with a 2,400% increased risk for relapse, and detection of ctDNA at diagnosis but before treatment was associated with a nearly 500% risk, wrote Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research, London, and colleagues.

“Prospective clinical trials are now required to assess whether detection of ctDNA can improve outcomes in patients, and a phase 2 interventional trial in TNBC [triple-negative breast cancer] has been initiated. This trial may develop a new treatment paradigm for treating breast cancer, in which treatment is initiated at molecular relapse without waiting for symptomatic incurable metastatic disease to develop,” they wrote in JAMA Oncology.

The investigators conducted a prospective, multicenter validation study of samples collected from women with early-stage breast cancer irrespective of hormone-receptor or HER2 status. The patients were scheduled for neoadjuvant chemotherapy followed by surgery, or surgery followed by adjuvant therapy.

Of 170 women recruited, 101 had tumors with identified mutations and were included in the main cohort. The investigators also conducted secondary analyses with patients in this cohort plus an additional 43 women who had participated in a previous proof-of-principle study.

They first sequenced tumor DNA to identify somatic mutations in primary tumors that could then be tracked using a breast cancer driver gene panel. For each sample, a personalized digital polymerase chain reaction (dPCR) assay was created to identify the mutations in plasma samples.

The plasma samples were collected every 3 months for the first year of follow-up, then every 6 months thereafter.

In the main cohort, the median age was 54 years, and the median follow-up was 35.5 months. The investigators found that, for the primary endpoint of relapse-free survival, ctDNA was associated with a hazard ratio for relapse of 25.2 (P less than .001). Detection of ctDNA in samples taken at the time of diagnosis was also associated with worse relapse-free survival, with an HR of 5.8 (P = .01).

In a secondary analysis, ctDNA detection preceded clinical relapse by a median of 10.7 months, and was associated with relapse in all breast cancer subtypes.

Of 29 patients who experienced a relapse, 22 of 23 with extracranial distant metastatic relapse had prior ctDNA detection.

The remaining six patients experienced relapse without ctDNA detection either before or at the time of relapse. Each of these six patients had a relapse at a single site: in the brain in three patients (with no extracranial relapses), in the ovaries in one patient, and solitary locoregional relapses in two patients.

The investigators acknowledged that the results “demonstrate clinical validity for ctDNA mutation tracking with dPCR but do not demonstrate clinical utility. Without evidence that mutation tracking can improve patient outcome, our results should not be recommended yet for routine clinical practice.”

The study was funded by Breast Cancer Now, Le Cure, and National Institute for Health Research funding to the Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. Dr. Garcia-Murillas had no disclosures. Multiple coauthors reported grants and/or fees from various pharmaceutical companies.

SOURCE: Garcia-Murillias I et al. JAMA Oncol. 2019 Aug 1. doi: 10.1001/jamaoncol.2019.1838.

Following therapy with curative intent for early-stage primary breast care, the presence of circulating tumor DNA may identify those patients at high risk for relapse, investigators reported.

Among 101 women treated for early-stage breast cancer and followed for a median of nearly 3 years, detection of circulating tumor DNA (ctDNA) during follow-up was associated with a 2,400% increased risk for relapse, and detection of ctDNA at diagnosis but before treatment was associated with a nearly 500% risk, wrote Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research, London, and colleagues.

“Prospective clinical trials are now required to assess whether detection of ctDNA can improve outcomes in patients, and a phase 2 interventional trial in TNBC [triple-negative breast cancer] has been initiated. This trial may develop a new treatment paradigm for treating breast cancer, in which treatment is initiated at molecular relapse without waiting for symptomatic incurable metastatic disease to develop,” they wrote in JAMA Oncology.

The investigators conducted a prospective, multicenter validation study of samples collected from women with early-stage breast cancer irrespective of hormone-receptor or HER2 status. The patients were scheduled for neoadjuvant chemotherapy followed by surgery, or surgery followed by adjuvant therapy.

Of 170 women recruited, 101 had tumors with identified mutations and were included in the main cohort. The investigators also conducted secondary analyses with patients in this cohort plus an additional 43 women who had participated in a previous proof-of-principle study.

They first sequenced tumor DNA to identify somatic mutations in primary tumors that could then be tracked using a breast cancer driver gene panel. For each sample, a personalized digital polymerase chain reaction (dPCR) assay was created to identify the mutations in plasma samples.

The plasma samples were collected every 3 months for the first year of follow-up, then every 6 months thereafter.

In the main cohort, the median age was 54 years, and the median follow-up was 35.5 months. The investigators found that, for the primary endpoint of relapse-free survival, ctDNA was associated with a hazard ratio for relapse of 25.2 (P less than .001). Detection of ctDNA in samples taken at the time of diagnosis was also associated with worse relapse-free survival, with an HR of 5.8 (P = .01).

In a secondary analysis, ctDNA detection preceded clinical relapse by a median of 10.7 months, and was associated with relapse in all breast cancer subtypes.

Of 29 patients who experienced a relapse, 22 of 23 with extracranial distant metastatic relapse had prior ctDNA detection.

The remaining six patients experienced relapse without ctDNA detection either before or at the time of relapse. Each of these six patients had a relapse at a single site: in the brain in three patients (with no extracranial relapses), in the ovaries in one patient, and solitary locoregional relapses in two patients.

The investigators acknowledged that the results “demonstrate clinical validity for ctDNA mutation tracking with dPCR but do not demonstrate clinical utility. Without evidence that mutation tracking can improve patient outcome, our results should not be recommended yet for routine clinical practice.”

The study was funded by Breast Cancer Now, Le Cure, and National Institute for Health Research funding to the Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. Dr. Garcia-Murillas had no disclosures. Multiple coauthors reported grants and/or fees from various pharmaceutical companies.

SOURCE: Garcia-Murillias I et al. JAMA Oncol. 2019 Aug 1. doi: 10.1001/jamaoncol.2019.1838.

Following therapy with curative intent for early-stage primary breast care, the presence of circulating tumor DNA may identify those patients at high risk for relapse, investigators reported.

Among 101 women treated for early-stage breast cancer and followed for a median of nearly 3 years, detection of circulating tumor DNA (ctDNA) during follow-up was associated with a 2,400% increased risk for relapse, and detection of ctDNA at diagnosis but before treatment was associated with a nearly 500% risk, wrote Isaac Garcia-Murillas, PhD, of the Institute of Cancer Research, London, and colleagues.

“Prospective clinical trials are now required to assess whether detection of ctDNA can improve outcomes in patients, and a phase 2 interventional trial in TNBC [triple-negative breast cancer] has been initiated. This trial may develop a new treatment paradigm for treating breast cancer, in which treatment is initiated at molecular relapse without waiting for symptomatic incurable metastatic disease to develop,” they wrote in JAMA Oncology.

The investigators conducted a prospective, multicenter validation study of samples collected from women with early-stage breast cancer irrespective of hormone-receptor or HER2 status. The patients were scheduled for neoadjuvant chemotherapy followed by surgery, or surgery followed by adjuvant therapy.

Of 170 women recruited, 101 had tumors with identified mutations and were included in the main cohort. The investigators also conducted secondary analyses with patients in this cohort plus an additional 43 women who had participated in a previous proof-of-principle study.

They first sequenced tumor DNA to identify somatic mutations in primary tumors that could then be tracked using a breast cancer driver gene panel. For each sample, a personalized digital polymerase chain reaction (dPCR) assay was created to identify the mutations in plasma samples.

The plasma samples were collected every 3 months for the first year of follow-up, then every 6 months thereafter.

In the main cohort, the median age was 54 years, and the median follow-up was 35.5 months. The investigators found that, for the primary endpoint of relapse-free survival, ctDNA was associated with a hazard ratio for relapse of 25.2 (P less than .001). Detection of ctDNA in samples taken at the time of diagnosis was also associated with worse relapse-free survival, with an HR of 5.8 (P = .01).

In a secondary analysis, ctDNA detection preceded clinical relapse by a median of 10.7 months, and was associated with relapse in all breast cancer subtypes.

Of 29 patients who experienced a relapse, 22 of 23 with extracranial distant metastatic relapse had prior ctDNA detection.

The remaining six patients experienced relapse without ctDNA detection either before or at the time of relapse. Each of these six patients had a relapse at a single site: in the brain in three patients (with no extracranial relapses), in the ovaries in one patient, and solitary locoregional relapses in two patients.

The investigators acknowledged that the results “demonstrate clinical validity for ctDNA mutation tracking with dPCR but do not demonstrate clinical utility. Without evidence that mutation tracking can improve patient outcome, our results should not be recommended yet for routine clinical practice.”

The study was funded by Breast Cancer Now, Le Cure, and National Institute for Health Research funding to the Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research. Dr. Garcia-Murillas had no disclosures. Multiple coauthors reported grants and/or fees from various pharmaceutical companies.

SOURCE: Garcia-Murillias I et al. JAMA Oncol. 2019 Aug 1. doi: 10.1001/jamaoncol.2019.1838.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

[email protected]

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

[email protected]

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.

Adults with low levels of hemoglobin and adults with high levels of hemoglobin have an increased risk of developing dementia over 12 years of follow-up, compared with adults with midrange levels, according to a population-based study in the Netherlands.

This U-shaped association “may relate to differences in white matter integrity and cerebral perfusion,” the researchers wrote in Neurology.

Ton Everaers, Erasmus Medical Center

“With around 10% of people over age 65 having anemia in the Americas and Europe and up to 45% in African and southeast Asian countries, these results could have important implications for the burden of dementia,” said study author M. Arfan Ikram, MD, PhD, in a news release. Dr. Ikram is a professor of epidemiology at Erasmus Medical Center in Rotterdam, the Netherlands.

Prior studies have found that low hemoglobin levels are associated with adverse health outcomes, such as coronary heart disease, stroke, and mortality, but data about the relationship between hemoglobin levels and dementia risk have been limited.

A population-based cohort study

To examine the long-term association of hemoglobin levels and anemia with risk of dementia, Dr. Ikram and coauthors analyzed data from the Rotterdam Study, an ongoing population-based cohort study in the Netherlands that started in 1990. Their analysis included data from 12,305 participants without dementia who had serum hemoglobin measured at baseline (mean age, 64.6 years; 57.7% women).

During a mean follow-up of 12.1 years, 1,520 participants developed dementia, 1,194 of whom had Alzheimer’s disease.

“Both low and high hemoglobin levels were associated with increased dementia risk,” the authors wrote. Compared with participants in the middle quintile of hemoglobin levels (8.57-8.99 mmol/L), participants in the lowest quintile (less than 8.11 mmol/L) had a hazard ratio of dementia of 1.29, and participants in the highest quintile (greater than 9.40 mmol/L) had an HR of 1.20.

About 6% of the participants had anemia – that is, a hemoglobin level of less than 8.1 mmol/L for men and less than 7.5 mmol/L for women. Anemia was associated with a 34% increased risk of dementia and a 41% increased risk of Alzheimer’s disease.

Of the 745 people with anemia, 128 developed dementia, compared with 1,392 of the 11,560 people who did not have anemia (17% vs. 12%).

A U-shaped association

The researchers also examined hemoglobin in relation to vascular brain disease, structural connectivity, and global cerebral perfusion among 5,267 participants without dementia who had brain MRI. White matter hyperintensity volume and hemoglobin had a U-shaped association, similar to that for dementia and hemoglobin. In addition, hemoglobin inversely correlated to cerebral perfusion.

The results remained consistent after adjustment for factors such as smoking, high blood pressure, high cholesterol, and alcohol use.

A limitation of the study is that the participants lived in the Netherlands and were primarily of European descent, so the results may not apply to other populations, the authors wrote.

Dr. Ikram noted that the study does not prove that low or high hemoglobin levels cause dementia. “More research is needed to determine whether hemoglobin levels play a direct role in this increased risk or whether these associations can be explained by underlying issues or other vascular or metabolic changes.”

The study was supported by the Netherlands Cardiovascular Research Initiative; Erasmus Medical Centre; Erasmus University Rotterdam; Netherlands Organization for Scientific Research; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Netherlands Genomic Initiative; Dutch Ministry of Education, Culture, and Science; Dutch Ministry of Health, Welfare, and Sports; European Commission; Municipality of Rotterdam; Netherlands Consortium for Healthy Aging; and Dutch Heart Foundation. The authors reported no relevant disclosures.

[email protected]

SOURCE: Ikram MA et al. Neurology. 2019 Jul 31. doi: 10.1212/WNL.0000000000008003.