The adipokine hormones leptin, adiponectin, and resistin are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. Researchers examined the association between adipokine levels and peripheral artery disease (PAD) in a cross-sectional sample of 179 vascular surgery outpatients (97% of whom were men) with PAD recruited from the San Francisco Veterans Affairs Medical Center.

copyright/pixologicstudio/Thinkstock

In an analysis adjusting for body mass index and atherosclerotic risk factors, higher serum leptin was associated with PAD (odds ratio, 2.54; P = .03), whereas high molecular weight adiponectin and resistin were not significantly associated with PAD (J Surg Res. 2019;238:48-56). “Our results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes,” wrote Greg J. Zahner, MSc, University of California, San Francisco, and colleagues.

They reported that they had no relevant disclosures.

[email protected]

The adipokine hormones leptin, adiponectin, and resistin are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. Researchers examined the association between adipokine levels and peripheral artery disease (PAD) in a cross-sectional sample of 179 vascular surgery outpatients (97% of whom were men) with PAD recruited from the San Francisco Veterans Affairs Medical Center.

copyright/pixologicstudio/Thinkstock

In an analysis adjusting for body mass index and atherosclerotic risk factors, higher serum leptin was associated with PAD (odds ratio, 2.54; P = .03), whereas high molecular weight adiponectin and resistin were not significantly associated with PAD (J Surg Res. 2019;238:48-56). “Our results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes,” wrote Greg J. Zahner, MSc, University of California, San Francisco, and colleagues.

They reported that they had no relevant disclosures.

[email protected]

The adipokine hormones leptin, adiponectin, and resistin are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. Researchers examined the association between adipokine levels and peripheral artery disease (PAD) in a cross-sectional sample of 179 vascular surgery outpatients (97% of whom were men) with PAD recruited from the San Francisco Veterans Affairs Medical Center.

copyright/pixologicstudio/Thinkstock

In an analysis adjusting for body mass index and atherosclerotic risk factors, higher serum leptin was associated with PAD (odds ratio, 2.54; P = .03), whereas high molecular weight adiponectin and resistin were not significantly associated with PAD (J Surg Res. 2019;238:48-56). “Our results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes,” wrote Greg J. Zahner, MSc, University of California, San Francisco, and colleagues.

They reported that they had no relevant disclosures.

[email protected]

Achieving sustained virologic response to direct-acting antiviral therapy for chronic hepatitis C virus infection cuts lifetime hepatocellular carcinoma risk by approximately 70%, even when patients have baseline cirrhosis, experts wrote in Gastroenterology.

When used after curative-intent treatment for hepatocellular carcinoma, direct-acting antiviral (DAA) therapy also does not appear to make recurrent cancer more probable or more aggressive, wrote Amit G. Singal, MD, and associates in an American Gastroenterological Association clinical practice update. Studies that compared DAA therapy with either interferon-based therapy or no treatment have found “similar if not lower recurrence than the comparator groups,” they wrote. Rather, hepatocellular carcinoma is in itself highly recurrent: “While surgical resection and local ablative therapies are considered curative, [probability of] recurrence approaches 25%-35% within the first year, and 50%-60% within 2 years.”

Direct-acting antiviral therapy for chronic hepatitis C infection improves several aspects of liver health, but experts have debated whether and how these benefits affect the risk and behavior of hepatocellular carcinoma. To explore the issue, Dr. Singal, medical director of the liver tumor program and clinical chief of hepatology at UT Southwestern Medical Center in Dallas and associates reviewed published clinical trials, observational studies, and systematic reviews. Among 11 studies of more than 3,000 patients in five countries, sustained virologic response (SVR) to DAA therapy was associated with about a 70% reduction in the risk of liver cancer, even after adjustment for clinical and demographic variables. “The relative reduction is similar in patients with and without cirrhosis,” the experts wrote.

Since patients with fibrosis (F3) or cirrhosis are at highest risk for hepatocellular carcinoma, they should undergo baseline imaging and remain under indefinite post-SVR surveillance as long as they are eligible for potentially curative treatment, the practice update states. The experts recommended twice-yearly ultrasound, with or without serum alpha-fetoprotein, noting that current evidence supports neither shorter surveillance intervals nor alternative imaging modalities.

“The presence of active hepatocellular carcinoma is associated with a small but statistically significant decrease in SVR with DAA therapy,” the experts confirmed, based on the results of three studies. They recommended that, when possible, patients with hepatocellular carcinoma first receive curative-intent treatment, such as with liver resection or ablation. Direct-acting antiviral therapy can begin 4-6 months later, once there has been time to confirm response to hepatocellular carcinoma treatment.

For patients who are listed for liver transplantation, timing of DAA therapy “should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction,” they added. “For example, DAA therapy may be beneficial pretransplant for patients in regions with long wait times or limited hepatitis C virus–positive donor organ availability, whereas therapy may be delayed until posttransplant in regions with shorter wait times or a high proportion of hepatitis C virus–positive donor organs that would otherwise go unused.”

For patients with active intermediate or advanced liver cancer, it remains unclear whether DAA therapy is usually worth the costs and risks, they noted. This is because the likelihood of complete response is lower and the competing risk of death is higher than in patients with earlier-stage hepatocellular carcinoma. Pending further data, they recommend basing the decision on patients’ preferences, tumor burden, degree of liver dysfunction, and life expectancy. At their institutions, the researchers do not treat patients with DAA therapy unless their life expectancy exceeds 2 years.

The experts disclosed research funding from the National Cancer Institute, U.S. Veterans Administration, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singal reported personal fees or research funding from AbbVie, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Gilead, Glycotest, Roche, and Wako Diagnostics. His coauthors disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, Intercept, and Merck.

SOURCE: Singal AG et al. Gastroenterology. 2019 Mar 13. doi: 10.1053/j.gastro.2019.02.046.

Achieving sustained virologic response to direct-acting antiviral therapy for chronic hepatitis C virus infection cuts lifetime hepatocellular carcinoma risk by approximately 70%, even when patients have baseline cirrhosis, experts wrote in Gastroenterology.

When used after curative-intent treatment for hepatocellular carcinoma, direct-acting antiviral (DAA) therapy also does not appear to make recurrent cancer more probable or more aggressive, wrote Amit G. Singal, MD, and associates in an American Gastroenterological Association clinical practice update. Studies that compared DAA therapy with either interferon-based therapy or no treatment have found “similar if not lower recurrence than the comparator groups,” they wrote. Rather, hepatocellular carcinoma is in itself highly recurrent: “While surgical resection and local ablative therapies are considered curative, [probability of] recurrence approaches 25%-35% within the first year, and 50%-60% within 2 years.”

Direct-acting antiviral therapy for chronic hepatitis C infection improves several aspects of liver health, but experts have debated whether and how these benefits affect the risk and behavior of hepatocellular carcinoma. To explore the issue, Dr. Singal, medical director of the liver tumor program and clinical chief of hepatology at UT Southwestern Medical Center in Dallas and associates reviewed published clinical trials, observational studies, and systematic reviews. Among 11 studies of more than 3,000 patients in five countries, sustained virologic response (SVR) to DAA therapy was associated with about a 70% reduction in the risk of liver cancer, even after adjustment for clinical and demographic variables. “The relative reduction is similar in patients with and without cirrhosis,” the experts wrote.

Since patients with fibrosis (F3) or cirrhosis are at highest risk for hepatocellular carcinoma, they should undergo baseline imaging and remain under indefinite post-SVR surveillance as long as they are eligible for potentially curative treatment, the practice update states. The experts recommended twice-yearly ultrasound, with or without serum alpha-fetoprotein, noting that current evidence supports neither shorter surveillance intervals nor alternative imaging modalities.

“The presence of active hepatocellular carcinoma is associated with a small but statistically significant decrease in SVR with DAA therapy,” the experts confirmed, based on the results of three studies. They recommended that, when possible, patients with hepatocellular carcinoma first receive curative-intent treatment, such as with liver resection or ablation. Direct-acting antiviral therapy can begin 4-6 months later, once there has been time to confirm response to hepatocellular carcinoma treatment.

For patients who are listed for liver transplantation, timing of DAA therapy “should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction,” they added. “For example, DAA therapy may be beneficial pretransplant for patients in regions with long wait times or limited hepatitis C virus–positive donor organ availability, whereas therapy may be delayed until posttransplant in regions with shorter wait times or a high proportion of hepatitis C virus–positive donor organs that would otherwise go unused.”

For patients with active intermediate or advanced liver cancer, it remains unclear whether DAA therapy is usually worth the costs and risks, they noted. This is because the likelihood of complete response is lower and the competing risk of death is higher than in patients with earlier-stage hepatocellular carcinoma. Pending further data, they recommend basing the decision on patients’ preferences, tumor burden, degree of liver dysfunction, and life expectancy. At their institutions, the researchers do not treat patients with DAA therapy unless their life expectancy exceeds 2 years.

The experts disclosed research funding from the National Cancer Institute, U.S. Veterans Administration, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singal reported personal fees or research funding from AbbVie, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Gilead, Glycotest, Roche, and Wako Diagnostics. His coauthors disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, Intercept, and Merck.

SOURCE: Singal AG et al. Gastroenterology. 2019 Mar 13. doi: 10.1053/j.gastro.2019.02.046.

Achieving sustained virologic response to direct-acting antiviral therapy for chronic hepatitis C virus infection cuts lifetime hepatocellular carcinoma risk by approximately 70%, even when patients have baseline cirrhosis, experts wrote in Gastroenterology.

When used after curative-intent treatment for hepatocellular carcinoma, direct-acting antiviral (DAA) therapy also does not appear to make recurrent cancer more probable or more aggressive, wrote Amit G. Singal, MD, and associates in an American Gastroenterological Association clinical practice update. Studies that compared DAA therapy with either interferon-based therapy or no treatment have found “similar if not lower recurrence than the comparator groups,” they wrote. Rather, hepatocellular carcinoma is in itself highly recurrent: “While surgical resection and local ablative therapies are considered curative, [probability of] recurrence approaches 25%-35% within the first year, and 50%-60% within 2 years.”

Direct-acting antiviral therapy for chronic hepatitis C infection improves several aspects of liver health, but experts have debated whether and how these benefits affect the risk and behavior of hepatocellular carcinoma. To explore the issue, Dr. Singal, medical director of the liver tumor program and clinical chief of hepatology at UT Southwestern Medical Center in Dallas and associates reviewed published clinical trials, observational studies, and systematic reviews. Among 11 studies of more than 3,000 patients in five countries, sustained virologic response (SVR) to DAA therapy was associated with about a 70% reduction in the risk of liver cancer, even after adjustment for clinical and demographic variables. “The relative reduction is similar in patients with and without cirrhosis,” the experts wrote.

Since patients with fibrosis (F3) or cirrhosis are at highest risk for hepatocellular carcinoma, they should undergo baseline imaging and remain under indefinite post-SVR surveillance as long as they are eligible for potentially curative treatment, the practice update states. The experts recommended twice-yearly ultrasound, with or without serum alpha-fetoprotein, noting that current evidence supports neither shorter surveillance intervals nor alternative imaging modalities.

“The presence of active hepatocellular carcinoma is associated with a small but statistically significant decrease in SVR with DAA therapy,” the experts confirmed, based on the results of three studies. They recommended that, when possible, patients with hepatocellular carcinoma first receive curative-intent treatment, such as with liver resection or ablation. Direct-acting antiviral therapy can begin 4-6 months later, once there has been time to confirm response to hepatocellular carcinoma treatment.

For patients who are listed for liver transplantation, timing of DAA therapy “should be determined on a case-by-case basis with consideration of median wait times for the region, availability of HCV-positive organs, and degree of liver dysfunction,” they added. “For example, DAA therapy may be beneficial pretransplant for patients in regions with long wait times or limited hepatitis C virus–positive donor organ availability, whereas therapy may be delayed until posttransplant in regions with shorter wait times or a high proportion of hepatitis C virus–positive donor organs that would otherwise go unused.”

For patients with active intermediate or advanced liver cancer, it remains unclear whether DAA therapy is usually worth the costs and risks, they noted. This is because the likelihood of complete response is lower and the competing risk of death is higher than in patients with earlier-stage hepatocellular carcinoma. Pending further data, they recommend basing the decision on patients’ preferences, tumor burden, degree of liver dysfunction, and life expectancy. At their institutions, the researchers do not treat patients with DAA therapy unless their life expectancy exceeds 2 years.

The experts disclosed research funding from the National Cancer Institute, U.S. Veterans Administration, and the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Singal reported personal fees or research funding from AbbVie, Bayer, Bristol-Myers Squibb, Eisai, Exact Sciences, Exelixis, Gilead, Glycotest, Roche, and Wako Diagnostics. His coauthors disclosed ties to AbbVie, Allergan, Bristol-Myers Squibb, Conatus, Genfit, Gilead, Intercept, and Merck.

SOURCE: Singal AG et al. Gastroenterology. 2019 Mar 13. doi: 10.1053/j.gastro.2019.02.046.

The Diagnosis: Metastatic Adenocarcinoma of the Colon 

Cutaneous adenocarcinomas are uncommon, whether they present as a primary lesion or metastatic disease. In our patient, the histologic findings and immunohistochemical staining pattern were consistent with metastatic adenocarcinoma of the colon, an uncommon clinical presentation.  

Colonic adenocarcinoma can cause cutaneous metastasis in 3% of cases. The most common sites of metastases include the abdomen, chest, and back.¹ On histologic examination, hematoxylin and eosin (H&E)-stained sections of cutaneous metastatic adenocarcinoma illustrate a malignant gland-forming neoplasm in the dermis with luminal mucin and necrotic debris (quiz image). The glands are lined by tall columnar epithelial cells with hyperchromatic nuclei. Alternatively, poorly differentiated morphology can be seen with fewer glands and more infiltrating nests of tumor cells.² Immunohistochemically, colonic adenocarcinoma typically is negative for cytokeratin (CK) 7 and positive for CK20 and caudal type homeobox transcription factor 2 (CDX-2).³  

Primary cutaneous mucinous carcinoma is characterized by islands of neoplastic cells floating in pools of mucin (Figure 1). It may be indistinguishable from metastatic mucinous carcinomas of the colon or breast. Immunohistochemistry can be helpful in differentiating metastatic breast vs colon carcinoma. Cytokeratin 7, GATA binding protein 3, gross cystic disease fluid protein 15, and estrogen receptor will be positive in carcinomas of the breast and will be negative in colonic adenocarcinomas.^4-6 Furthermore, lesional cells in metastatic adenocarcinoma of the colon are positive for CDX-2 and CK20, while those in metastatic carcinoma of the breast are negative.² Immunohistochemistry also can differentiate primary cutaneous carcinoma from metastatic adenocarcinoma. When used in combination, p63 and podoplanin (D2-40) offer a highly sensitive and specific indicator of a primary cutaneous neoplasm, as both demonstrate either focal or diffuse positivity in this setting. In contrast, these stains typically are negative in metastatic adenocarcinomas of the skin.⁷ 

Endometriosis affects 1% to 2% of all reproductive-age females, of which extrapelvic manifestations account for only 0.5% to 1.0% of cases.⁸ Histologically, extrapelvic endometriosis is characterized by the triad of endometrial-type glands, endometrial stroma, and hemorrhage or hemosiderin deposition (Figure 2). The glands can enlarge and demonstrate architectural distortion with partial lack of polarity. These features initially can be concerning for adenocarcinoma, but on closer examination, nuclear morphology is regular and mitoses are absent.^8,9 The diagnosis usually can be rendered with H&E alone; however, immunohistochemical stains for CD10 and estrogen receptor can highlight the endometrial stroma.¹⁰ Furthermore, endometrial glands will stain positive for paired box gene 8 (PAX8), a marker that is not expressed within the gastrointestinal tract and associated malignancies.¹¹  

Primary cutaneous angiosarcoma may mimic adenocarcinoma, as the endothelial-lined vessels can be confused as malignant glands (Figure 3). Angiosarcoma often is seen in 1 of 3 clinical presentations: the head and neck of elderly patients, postradiation treatment, and chronic lymphedema.^12,13 Regardless of the location, the disease carries a poor prognosis, with a 5-year survival rate of 12% following initial diagnosis.¹³ Angiosarcoma is characterized by malignant endothelial cells dissecting through the dermis. Although the histology can be deceptively bland in some cases, the neoplasm most commonly demonstrates notable atypia with a multilayered endothelium and occasional intravascular atypical cells ("fish in the creek appearance").^13,14 There can be frequent mitoses, and the atypical cells may show intracytoplasmic lumina containing red blood cells. The lesional cells are positive for endothelial markers such as erythroblast transformation specific related gene (ERG), CD31, CD34, and friend leukemia integration factor 1 (FLI-1).^15,16  

Breast cancer also can cause cutaneous metastases in approximately 20% of cases, with the most common presenting site being the anterior chest wall.¹⁷ Macroscopically, these lesions appear most commonly as painless nodules but also as telangiectatic, erysipeloid, fibrotic, and alopecic lesions.^17-19 The histologic findings from H&E-stained sections of a cutaneous metastasis of breast cancer are variable and depend on the specific tumor subtype (eg, ductal, lobular, mucinous). However, the classic histologic presentation is that of nests and cords of malignant epithelial cells with variable gland formation. Often, tumor cells infiltrate in a single-file fashion (Figure 4).¹⁷ Although inflammatory breast carcinoma is a strictly clinical diagnosis, the presence of tumor cells in the lymphovascular spaces is a histologic clue to this diagnosis. Immunohistochemically, GATA binding protein 3 is helpful in identifying both hormone receptor-positive and -negative breast cancer subtypes that have metastasized.²⁰ 

Within the histologic differential diagnoses, the most useful tool to diagnose metastatic adenocarcinoma of the colon often is a thorough clinical history. In the absence of a clinical history of adenocarcinoma, immunohistochemistry can be a useful adjunct to aid in the correct characterization and classification of a malignant gland-forming tumor.^2,3,6 

The Diagnosis: Metastatic Adenocarcinoma of the Colon 

Cutaneous adenocarcinomas are uncommon, whether they present as a primary lesion or metastatic disease. In our patient, the histologic findings and immunohistochemical staining pattern were consistent with metastatic adenocarcinoma of the colon, an uncommon clinical presentation.  

Colonic adenocarcinoma can cause cutaneous metastasis in 3% of cases. The most common sites of metastases include the abdomen, chest, and back.¹ On histologic examination, hematoxylin and eosin (H&E)-stained sections of cutaneous metastatic adenocarcinoma illustrate a malignant gland-forming neoplasm in the dermis with luminal mucin and necrotic debris (quiz image). The glands are lined by tall columnar epithelial cells with hyperchromatic nuclei. Alternatively, poorly differentiated morphology can be seen with fewer glands and more infiltrating nests of tumor cells.² Immunohistochemically, colonic adenocarcinoma typically is negative for cytokeratin (CK) 7 and positive for CK20 and caudal type homeobox transcription factor 2 (CDX-2).³  

Primary cutaneous mucinous carcinoma is characterized by islands of neoplastic cells floating in pools of mucin (Figure 1). It may be indistinguishable from metastatic mucinous carcinomas of the colon or breast. Immunohistochemistry can be helpful in differentiating metastatic breast vs colon carcinoma. Cytokeratin 7, GATA binding protein 3, gross cystic disease fluid protein 15, and estrogen receptor will be positive in carcinomas of the breast and will be negative in colonic adenocarcinomas.^4-6 Furthermore, lesional cells in metastatic adenocarcinoma of the colon are positive for CDX-2 and CK20, while those in metastatic carcinoma of the breast are negative.² Immunohistochemistry also can differentiate primary cutaneous carcinoma from metastatic adenocarcinoma. When used in combination, p63 and podoplanin (D2-40) offer a highly sensitive and specific indicator of a primary cutaneous neoplasm, as both demonstrate either focal or diffuse positivity in this setting. In contrast, these stains typically are negative in metastatic adenocarcinomas of the skin.⁷ 

Endometriosis affects 1% to 2% of all reproductive-age females, of which extrapelvic manifestations account for only 0.5% to 1.0% of cases.⁸ Histologically, extrapelvic endometriosis is characterized by the triad of endometrial-type glands, endometrial stroma, and hemorrhage or hemosiderin deposition (Figure 2). The glands can enlarge and demonstrate architectural distortion with partial lack of polarity. These features initially can be concerning for adenocarcinoma, but on closer examination, nuclear morphology is regular and mitoses are absent.^8,9 The diagnosis usually can be rendered with H&E alone; however, immunohistochemical stains for CD10 and estrogen receptor can highlight the endometrial stroma.¹⁰ Furthermore, endometrial glands will stain positive for paired box gene 8 (PAX8), a marker that is not expressed within the gastrointestinal tract and associated malignancies.¹¹  

Primary cutaneous angiosarcoma may mimic adenocarcinoma, as the endothelial-lined vessels can be confused as malignant glands (Figure 3). Angiosarcoma often is seen in 1 of 3 clinical presentations: the head and neck of elderly patients, postradiation treatment, and chronic lymphedema.^12,13 Regardless of the location, the disease carries a poor prognosis, with a 5-year survival rate of 12% following initial diagnosis.¹³ Angiosarcoma is characterized by malignant endothelial cells dissecting through the dermis. Although the histology can be deceptively bland in some cases, the neoplasm most commonly demonstrates notable atypia with a multilayered endothelium and occasional intravascular atypical cells ("fish in the creek appearance").^13,14 There can be frequent mitoses, and the atypical cells may show intracytoplasmic lumina containing red blood cells. The lesional cells are positive for endothelial markers such as erythroblast transformation specific related gene (ERG), CD31, CD34, and friend leukemia integration factor 1 (FLI-1).^15,16  

Breast cancer also can cause cutaneous metastases in approximately 20% of cases, with the most common presenting site being the anterior chest wall.¹⁷ Macroscopically, these lesions appear most commonly as painless nodules but also as telangiectatic, erysipeloid, fibrotic, and alopecic lesions.^17-19 The histologic findings from H&E-stained sections of a cutaneous metastasis of breast cancer are variable and depend on the specific tumor subtype (eg, ductal, lobular, mucinous). However, the classic histologic presentation is that of nests and cords of malignant epithelial cells with variable gland formation. Often, tumor cells infiltrate in a single-file fashion (Figure 4).¹⁷ Although inflammatory breast carcinoma is a strictly clinical diagnosis, the presence of tumor cells in the lymphovascular spaces is a histologic clue to this diagnosis. Immunohistochemically, GATA binding protein 3 is helpful in identifying both hormone receptor-positive and -negative breast cancer subtypes that have metastasized.²⁰ 

Within the histologic differential diagnoses, the most useful tool to diagnose metastatic adenocarcinoma of the colon often is a thorough clinical history. In the absence of a clinical history of adenocarcinoma, immunohistochemistry can be a useful adjunct to aid in the correct characterization and classification of a malignant gland-forming tumor.^2,3,6 

The Diagnosis: Metastatic Adenocarcinoma of the Colon 

Cutaneous adenocarcinomas are uncommon, whether they present as a primary lesion or metastatic disease. In our patient, the histologic findings and immunohistochemical staining pattern were consistent with metastatic adenocarcinoma of the colon, an uncommon clinical presentation.  

Colonic adenocarcinoma can cause cutaneous metastasis in 3% of cases. The most common sites of metastases include the abdomen, chest, and back.¹ On histologic examination, hematoxylin and eosin (H&E)-stained sections of cutaneous metastatic adenocarcinoma illustrate a malignant gland-forming neoplasm in the dermis with luminal mucin and necrotic debris (quiz image). The glands are lined by tall columnar epithelial cells with hyperchromatic nuclei. Alternatively, poorly differentiated morphology can be seen with fewer glands and more infiltrating nests of tumor cells.² Immunohistochemically, colonic adenocarcinoma typically is negative for cytokeratin (CK) 7 and positive for CK20 and caudal type homeobox transcription factor 2 (CDX-2).³  

Primary cutaneous mucinous carcinoma is characterized by islands of neoplastic cells floating in pools of mucin (Figure 1). It may be indistinguishable from metastatic mucinous carcinomas of the colon or breast. Immunohistochemistry can be helpful in differentiating metastatic breast vs colon carcinoma. Cytokeratin 7, GATA binding protein 3, gross cystic disease fluid protein 15, and estrogen receptor will be positive in carcinomas of the breast and will be negative in colonic adenocarcinomas.^4-6 Furthermore, lesional cells in metastatic adenocarcinoma of the colon are positive for CDX-2 and CK20, while those in metastatic carcinoma of the breast are negative.² Immunohistochemistry also can differentiate primary cutaneous carcinoma from metastatic adenocarcinoma. When used in combination, p63 and podoplanin (D2-40) offer a highly sensitive and specific indicator of a primary cutaneous neoplasm, as both demonstrate either focal or diffuse positivity in this setting. In contrast, these stains typically are negative in metastatic adenocarcinomas of the skin.⁷ 

Endometriosis affects 1% to 2% of all reproductive-age females, of which extrapelvic manifestations account for only 0.5% to 1.0% of cases.⁸ Histologically, extrapelvic endometriosis is characterized by the triad of endometrial-type glands, endometrial stroma, and hemorrhage or hemosiderin deposition (Figure 2). The glands can enlarge and demonstrate architectural distortion with partial lack of polarity. These features initially can be concerning for adenocarcinoma, but on closer examination, nuclear morphology is regular and mitoses are absent.^8,9 The diagnosis usually can be rendered with H&E alone; however, immunohistochemical stains for CD10 and estrogen receptor can highlight the endometrial stroma.¹⁰ Furthermore, endometrial glands will stain positive for paired box gene 8 (PAX8), a marker that is not expressed within the gastrointestinal tract and associated malignancies.¹¹  

Primary cutaneous angiosarcoma may mimic adenocarcinoma, as the endothelial-lined vessels can be confused as malignant glands (Figure 3). Angiosarcoma often is seen in 1 of 3 clinical presentations: the head and neck of elderly patients, postradiation treatment, and chronic lymphedema.^12,13 Regardless of the location, the disease carries a poor prognosis, with a 5-year survival rate of 12% following initial diagnosis.¹³ Angiosarcoma is characterized by malignant endothelial cells dissecting through the dermis. Although the histology can be deceptively bland in some cases, the neoplasm most commonly demonstrates notable atypia with a multilayered endothelium and occasional intravascular atypical cells ("fish in the creek appearance").^13,14 There can be frequent mitoses, and the atypical cells may show intracytoplasmic lumina containing red blood cells. The lesional cells are positive for endothelial markers such as erythroblast transformation specific related gene (ERG), CD31, CD34, and friend leukemia integration factor 1 (FLI-1).^15,16  

Breast cancer also can cause cutaneous metastases in approximately 20% of cases, with the most common presenting site being the anterior chest wall.¹⁷ Macroscopically, these lesions appear most commonly as painless nodules but also as telangiectatic, erysipeloid, fibrotic, and alopecic lesions.^17-19 The histologic findings from H&E-stained sections of a cutaneous metastasis of breast cancer are variable and depend on the specific tumor subtype (eg, ductal, lobular, mucinous). However, the classic histologic presentation is that of nests and cords of malignant epithelial cells with variable gland formation. Often, tumor cells infiltrate in a single-file fashion (Figure 4).¹⁷ Although inflammatory breast carcinoma is a strictly clinical diagnosis, the presence of tumor cells in the lymphovascular spaces is a histologic clue to this diagnosis. Immunohistochemically, GATA binding protein 3 is helpful in identifying both hormone receptor-positive and -negative breast cancer subtypes that have metastasized.²⁰ 

Within the histologic differential diagnoses, the most useful tool to diagnose metastatic adenocarcinoma of the colon often is a thorough clinical history. In the absence of a clinical history of adenocarcinoma, immunohistochemistry can be a useful adjunct to aid in the correct characterization and classification of a malignant gland-forming tumor.^2,3,6 

While reviewing some epidemiology data for a lecture recently, I couldn’t believe my eyes: The numbers indicated an increase in sexually transmitted infections (STIs) among older Americans. Filled with doubt about the accuracy, I decided to research further. My first stop was a PA colleague who works with a mobile urgent care company that specializes in retirement communities—and she confirmed that she has witnessed this “trend”!

The fundamental public health concern for older Americans is, of course, long-term illness, disability, and dependency on others. However, experts on aging agree that since the last century, disability rates among those older than 65 have declined, as have the number of seniors living in nursing homes. Suffice it to say, the good news is that Americans are living longer—the bad news, they are doing so with an increased risk for cardiovascular disease and malignant neoplasms. The other downside is that seniors have increased risk for infectious diseases.¹

Healthy People 2020 continues to recognize HIV and other STIs as problems in the United States and to promote efforts to reduce them. Unfortunately, prevention strategies for older adults in primary care settings are often not aimed at these diseases. More broadly, sexual behaviors tend to be discussed less with this population.²

The disturbing climb in STIs among older Americans is part of a more momentous national trend that the CDC says must be tackled. Overall rates of STIs in 2016 were the highest ever recorded in a single year.³ And although STI rates are highest among people ages 15 to 24, the upsurge among older Americans is larger than it is for the rest of the US population. According to the CDC, in 2016, there were 82,938 cases of gonorrhea, syphilis, and chlamydia reported among Americans ages 45 and older—about a 20% percent increase from 2015 and continuing a trend of annual increases since at least 2012.³ The infographic shows the rates for individual STIs.

The CDC notes that STIs put people “at risk for severe, lifelong health outcomes like chronic pain, severe reproductive health complications, and HIV" particularly if left untreated.⁴ Jonathan Mermin, MD, Director of the CDC National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention has described STIs as “a persistent enemy, growing in number and outpacing our ability to respond.”⁵

Over the next 3 weeks, we will explore this public health issue—starting next week with the big question: Why is this trend occurring? In the meantime, feel free to share your thoughts with me at [email protected]. See you next Thursday!

While reviewing some epidemiology data for a lecture recently, I couldn’t believe my eyes: The numbers indicated an increase in sexually transmitted infections (STIs) among older Americans. Filled with doubt about the accuracy, I decided to research further. My first stop was a PA colleague who works with a mobile urgent care company that specializes in retirement communities—and she confirmed that she has witnessed this “trend”!

The fundamental public health concern for older Americans is, of course, long-term illness, disability, and dependency on others. However, experts on aging agree that since the last century, disability rates among those older than 65 have declined, as have the number of seniors living in nursing homes. Suffice it to say, the good news is that Americans are living longer—the bad news, they are doing so with an increased risk for cardiovascular disease and malignant neoplasms. The other downside is that seniors have increased risk for infectious diseases.¹

Healthy People 2020 continues to recognize HIV and other STIs as problems in the United States and to promote efforts to reduce them. Unfortunately, prevention strategies for older adults in primary care settings are often not aimed at these diseases. More broadly, sexual behaviors tend to be discussed less with this population.²

The disturbing climb in STIs among older Americans is part of a more momentous national trend that the CDC says must be tackled. Overall rates of STIs in 2016 were the highest ever recorded in a single year.³ And although STI rates are highest among people ages 15 to 24, the upsurge among older Americans is larger than it is for the rest of the US population. According to the CDC, in 2016, there were 82,938 cases of gonorrhea, syphilis, and chlamydia reported among Americans ages 45 and older—about a 20% percent increase from 2015 and continuing a trend of annual increases since at least 2012.³ The infographic shows the rates for individual STIs.

The CDC notes that STIs put people “at risk for severe, lifelong health outcomes like chronic pain, severe reproductive health complications, and HIV" particularly if left untreated.⁴ Jonathan Mermin, MD, Director of the CDC National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention has described STIs as “a persistent enemy, growing in number and outpacing our ability to respond.”⁵

Over the next 3 weeks, we will explore this public health issue—starting next week with the big question: Why is this trend occurring? In the meantime, feel free to share your thoughts with me at [email protected]. See you next Thursday!

While reviewing some epidemiology data for a lecture recently, I couldn’t believe my eyes: The numbers indicated an increase in sexually transmitted infections (STIs) among older Americans. Filled with doubt about the accuracy, I decided to research further. My first stop was a PA colleague who works with a mobile urgent care company that specializes in retirement communities—and she confirmed that she has witnessed this “trend”!

The fundamental public health concern for older Americans is, of course, long-term illness, disability, and dependency on others. However, experts on aging agree that since the last century, disability rates among those older than 65 have declined, as have the number of seniors living in nursing homes. Suffice it to say, the good news is that Americans are living longer—the bad news, they are doing so with an increased risk for cardiovascular disease and malignant neoplasms. The other downside is that seniors have increased risk for infectious diseases.¹

Healthy People 2020 continues to recognize HIV and other STIs as problems in the United States and to promote efforts to reduce them. Unfortunately, prevention strategies for older adults in primary care settings are often not aimed at these diseases. More broadly, sexual behaviors tend to be discussed less with this population.²

The disturbing climb in STIs among older Americans is part of a more momentous national trend that the CDC says must be tackled. Overall rates of STIs in 2016 were the highest ever recorded in a single year.³ And although STI rates are highest among people ages 15 to 24, the upsurge among older Americans is larger than it is for the rest of the US population. According to the CDC, in 2016, there were 82,938 cases of gonorrhea, syphilis, and chlamydia reported among Americans ages 45 and older—about a 20% percent increase from 2015 and continuing a trend of annual increases since at least 2012.³ The infographic shows the rates for individual STIs.

The CDC notes that STIs put people “at risk for severe, lifelong health outcomes like chronic pain, severe reproductive health complications, and HIV" particularly if left untreated.⁴ Jonathan Mermin, MD, Director of the CDC National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention has described STIs as “a persistent enemy, growing in number and outpacing our ability to respond.”⁵

Over the next 3 weeks, we will explore this public health issue—starting next week with the big question: Why is this trend occurring? In the meantime, feel free to share your thoughts with me at [email protected]. See you next Thursday!

Since the measles outbreak in the Pacific Northwest (where I did my training and remain in touch with colleagues and patients), parents with infants ages 6 to 11 months are requesting vaccinations before 12 months—the standard age to start immunizations.¹ But physicians decline to provide inoculation, citing institutional policy on the risks of early vaccination. What are these risks, and how should we respond when parents ask about early vaccination?

The safety and efficacy of early vaccination are well documented. Early vaccination is a technique employed to curb outbreaks both in the United States and worldwide. Guidelines from the Centers for Disease Control and Prevention (CDC) recommend vaccinating infants at 6 months of age if they will be traveling,² and the World Health Organization (WHO) recommends vaccinations during a measles outbreak as part of intensified service delivery or in settings, such as daycare facilities, in which there is an increased risk for disease exposure during an outbreak.³ Any dose given before 12 months is considered supplemental, and the child must still complete the regular 2-dose vaccine schedule. Studies on the adverse effect profiles of vaccines show that the younger the infant, the fewer adverse events occur—because adverse events reflect the increasingly robust immune response that comes with age.⁴

Many physicians are concerned about adequate immune response. In vaccine research, this is gauged by the proportion of patients with seroconversion after vaccination. This is also reflected in vaccine efficacy (VE), which gradually increases with age and maturity of the immune system. For example, measles VE is 60% to 70% in 6-to-8-month cohorts⁵ and 70% to 80% in 9-to-11-month cohorts.⁶ VE at 12 months is in the 90% range, and completion of the 2-dose series yields a VE of ≥ 95%.⁷ Thus, while the vaccine is more effective at later ages, it still provides protection to younger cohorts.

Early vaccination has few risks and significant benefit. Therefore, relaxing the lower boundary for the measles vaccine is appropriate.

“Blunting” (ie, a reduced immune response to the second dose of vaccine³) is another concern with early measles vaccination, but a WHO meta-analysis proved this concern to be unfounded.^1,3 Twelve papers examining seropositivity in children who received a second measles vaccine after early primary vaccination found a pooled proportion of seropositivity of 97%.^1,8,9 Furthermore, evidence shows that children have sustained measles-specific T-cell responses after early primary measles immunization.¹⁰

Early vaccination has few risks and significant benefit. Therefore, in light of the recent measles outbreak, relaxing the lower boundary for the measles vaccine is appropriate. In addition to physically protecting the patient and general population, honoring parents’ requests for vaccination respects their autonomy and fosters trust. Synthesis of good science with a trusting doctor–patient relationship is key to ending the measles outbreak.

Rachel Roth, MD
Tel Aviv, Israel

Since the measles outbreak in the Pacific Northwest (where I did my training and remain in touch with colleagues and patients), parents with infants ages 6 to 11 months are requesting vaccinations before 12 months—the standard age to start immunizations.¹ But physicians decline to provide inoculation, citing institutional policy on the risks of early vaccination. What are these risks, and how should we respond when parents ask about early vaccination?

The safety and efficacy of early vaccination are well documented. Early vaccination is a technique employed to curb outbreaks both in the United States and worldwide. Guidelines from the Centers for Disease Control and Prevention (CDC) recommend vaccinating infants at 6 months of age if they will be traveling,² and the World Health Organization (WHO) recommends vaccinations during a measles outbreak as part of intensified service delivery or in settings, such as daycare facilities, in which there is an increased risk for disease exposure during an outbreak.³ Any dose given before 12 months is considered supplemental, and the child must still complete the regular 2-dose vaccine schedule. Studies on the adverse effect profiles of vaccines show that the younger the infant, the fewer adverse events occur—because adverse events reflect the increasingly robust immune response that comes with age.⁴

Many physicians are concerned about adequate immune response. In vaccine research, this is gauged by the proportion of patients with seroconversion after vaccination. This is also reflected in vaccine efficacy (VE), which gradually increases with age and maturity of the immune system. For example, measles VE is 60% to 70% in 6-to-8-month cohorts⁵ and 70% to 80% in 9-to-11-month cohorts.⁶ VE at 12 months is in the 90% range, and completion of the 2-dose series yields a VE of ≥ 95%.⁷ Thus, while the vaccine is more effective at later ages, it still provides protection to younger cohorts.

Early vaccination has few risks and significant benefit. Therefore, relaxing the lower boundary for the measles vaccine is appropriate.

“Blunting” (ie, a reduced immune response to the second dose of vaccine³) is another concern with early measles vaccination, but a WHO meta-analysis proved this concern to be unfounded.^1,3 Twelve papers examining seropositivity in children who received a second measles vaccine after early primary vaccination found a pooled proportion of seropositivity of 97%.^1,8,9 Furthermore, evidence shows that children have sustained measles-specific T-cell responses after early primary measles immunization.¹⁰

Early vaccination has few risks and significant benefit. Therefore, in light of the recent measles outbreak, relaxing the lower boundary for the measles vaccine is appropriate. In addition to physically protecting the patient and general population, honoring parents’ requests for vaccination respects their autonomy and fosters trust. Synthesis of good science with a trusting doctor–patient relationship is key to ending the measles outbreak.

Rachel Roth, MD
Tel Aviv, Israel

Since the measles outbreak in the Pacific Northwest (where I did my training and remain in touch with colleagues and patients), parents with infants ages 6 to 11 months are requesting vaccinations before 12 months—the standard age to start immunizations.¹ But physicians decline to provide inoculation, citing institutional policy on the risks of early vaccination. What are these risks, and how should we respond when parents ask about early vaccination?

The safety and efficacy of early vaccination are well documented. Early vaccination is a technique employed to curb outbreaks both in the United States and worldwide. Guidelines from the Centers for Disease Control and Prevention (CDC) recommend vaccinating infants at 6 months of age if they will be traveling,² and the World Health Organization (WHO) recommends vaccinations during a measles outbreak as part of intensified service delivery or in settings, such as daycare facilities, in which there is an increased risk for disease exposure during an outbreak.³ Any dose given before 12 months is considered supplemental, and the child must still complete the regular 2-dose vaccine schedule. Studies on the adverse effect profiles of vaccines show that the younger the infant, the fewer adverse events occur—because adverse events reflect the increasingly robust immune response that comes with age.⁴

Many physicians are concerned about adequate immune response. In vaccine research, this is gauged by the proportion of patients with seroconversion after vaccination. This is also reflected in vaccine efficacy (VE), which gradually increases with age and maturity of the immune system. For example, measles VE is 60% to 70% in 6-to-8-month cohorts⁵ and 70% to 80% in 9-to-11-month cohorts.⁶ VE at 12 months is in the 90% range, and completion of the 2-dose series yields a VE of ≥ 95%.⁷ Thus, while the vaccine is more effective at later ages, it still provides protection to younger cohorts.

Early vaccination has few risks and significant benefit. Therefore, relaxing the lower boundary for the measles vaccine is appropriate.

“Blunting” (ie, a reduced immune response to the second dose of vaccine³) is another concern with early measles vaccination, but a WHO meta-analysis proved this concern to be unfounded.^1,3 Twelve papers examining seropositivity in children who received a second measles vaccine after early primary vaccination found a pooled proportion of seropositivity of 97%.^1,8,9 Furthermore, evidence shows that children have sustained measles-specific T-cell responses after early primary measles immunization.¹⁰

Early vaccination has few risks and significant benefit. Therefore, in light of the recent measles outbreak, relaxing the lower boundary for the measles vaccine is appropriate. In addition to physically protecting the patient and general population, honoring parents’ requests for vaccination respects their autonomy and fosters trust. Synthesis of good science with a trusting doctor–patient relationship is key to ending the measles outbreak.

Rachel Roth, MD
Tel Aviv, Israel

The average life expectancy in the United States declined from 78.9 years in 2014 to 78.6 years in 2017.¹ The 2017 figure—78.6 years—means life expectancy is shorter in the United States than in other countries.¹ The decline is due, in part, to the drug overdose epidemic in the United States.² In 2017, 70,237 people died by drug overdose²—with prescription drugs, heroin, and opioids (especially fentanyl) being the major threats.³ From 2016 to 2017, overdoses from synthetic opioids, such as fentanyl, fentanyl analogs, and tramadol, increased from 6.2 to 9 per 100,000 people.²

The decline in life expectancy is due, in part, to the drug overdose epidemic in the United States.

These statistics should motivate all health care professionals to improve the general public’s health metrics, especially when treating patients with substance use disorders. But to best do so, we need a collaborative effort across many professions—not just health care providers, but also public health officials, elected government leaders, and law enforcement. To better define what this would entail, we suggest ways in which these groups could expand their roles to help reduce overdose deaths.

Health care professionals:

• implement safer opioid prescribing for patients who have chronic pain;
• educate patients about the risks of opioid use;
• consider alternative therapies for pain management; and
• utilize electronic databases to monitor controlled substance prescribing.

Public health officials:

• expand naloxone distribution; and
• enhance harm reduction (eg, syringe exchange programs, substance abuse treatment options).

Government leaders:

• draft legislation that allows the use of better interventions for treating individuals with drug dependence or those who overdose; and
• improve criminal justice approaches so that laws are less punitive and more therapeutic for individuals who suffer from drug dependence.

Law enforcement:

• supply naltrexone kits to first responders and provide appropriate training.

Kuldeep Ghosh, MD, MS
Rajashekhar Yeruva, MD
Steven Lippmann, MD
Louisville, Ky

The average life expectancy in the United States declined from 78.9 years in 2014 to 78.6 years in 2017.¹ The 2017 figure—78.6 years—means life expectancy is shorter in the United States than in other countries.¹ The decline is due, in part, to the drug overdose epidemic in the United States.² In 2017, 70,237 people died by drug overdose²—with prescription drugs, heroin, and opioids (especially fentanyl) being the major threats.³ From 2016 to 2017, overdoses from synthetic opioids, such as fentanyl, fentanyl analogs, and tramadol, increased from 6.2 to 9 per 100,000 people.²

The decline in life expectancy is due, in part, to the drug overdose epidemic in the United States.

These statistics should motivate all health care professionals to improve the general public’s health metrics, especially when treating patients with substance use disorders. But to best do so, we need a collaborative effort across many professions—not just health care providers, but also public health officials, elected government leaders, and law enforcement. To better define what this would entail, we suggest ways in which these groups could expand their roles to help reduce overdose deaths.

Health care professionals:

• implement safer opioid prescribing for patients who have chronic pain;
• educate patients about the risks of opioid use;
• consider alternative therapies for pain management; and
• utilize electronic databases to monitor controlled substance prescribing.

Public health officials:

• expand naloxone distribution; and
• enhance harm reduction (eg, syringe exchange programs, substance abuse treatment options).

Government leaders:

• draft legislation that allows the use of better interventions for treating individuals with drug dependence or those who overdose; and
• improve criminal justice approaches so that laws are less punitive and more therapeutic for individuals who suffer from drug dependence.

Law enforcement:

• supply naltrexone kits to first responders and provide appropriate training.

Kuldeep Ghosh, MD, MS
Rajashekhar Yeruva, MD
Steven Lippmann, MD
Louisville, Ky

The average life expectancy in the United States declined from 78.9 years in 2014 to 78.6 years in 2017.¹ The 2017 figure—78.6 years—means life expectancy is shorter in the United States than in other countries.¹ The decline is due, in part, to the drug overdose epidemic in the United States.² In 2017, 70,237 people died by drug overdose²—with prescription drugs, heroin, and opioids (especially fentanyl) being the major threats.³ From 2016 to 2017, overdoses from synthetic opioids, such as fentanyl, fentanyl analogs, and tramadol, increased from 6.2 to 9 per 100,000 people.²

The decline in life expectancy is due, in part, to the drug overdose epidemic in the United States.

These statistics should motivate all health care professionals to improve the general public’s health metrics, especially when treating patients with substance use disorders. But to best do so, we need a collaborative effort across many professions—not just health care providers, but also public health officials, elected government leaders, and law enforcement. To better define what this would entail, we suggest ways in which these groups could expand their roles to help reduce overdose deaths.

Health care professionals:

• implement safer opioid prescribing for patients who have chronic pain;
• educate patients about the risks of opioid use;
• consider alternative therapies for pain management; and
• utilize electronic databases to monitor controlled substance prescribing.

Public health officials:

• expand naloxone distribution; and
• enhance harm reduction (eg, syringe exchange programs, substance abuse treatment options).

Government leaders:

• draft legislation that allows the use of better interventions for treating individuals with drug dependence or those who overdose; and
• improve criminal justice approaches so that laws are less punitive and more therapeutic for individuals who suffer from drug dependence.

Law enforcement:

• supply naltrexone kits to first responders and provide appropriate training.

Kuldeep Ghosh, MD, MS
Rajashekhar Yeruva, MD
Steven Lippmann, MD
Louisville, Ky

A recent letter, “Hypoglycemia in the elderly: Watch for atypical symptoms” (J Fam Pract. 2019;68:116) provided an incomplete list of the letter’s authors. The list should have read: Jan Brož, MD, Jana Urbanová, MD, PhD, Prague, Czech Republic; Brian M. Frier, MD, BSc, Edinburgh, United Kingdom.

A recent letter, “Hypoglycemia in the elderly: Watch for atypical symptoms” (J Fam Pract. 2019;68:116) provided an incomplete list of the letter’s authors. The list should have read: Jan Brož, MD, Jana Urbanová, MD, PhD, Prague, Czech Republic; Brian M. Frier, MD, BSc, Edinburgh, United Kingdom.

A recent letter, “Hypoglycemia in the elderly: Watch for atypical symptoms” (J Fam Pract. 2019;68:116) provided an incomplete list of the letter’s authors. The list should have read: Jan Brož, MD, Jana Urbanová, MD, PhD, Prague, Czech Republic; Brian M. Frier, MD, BSc, Edinburgh, United Kingdom.

EVIDENCE SUMMARY

An international prospective cohort study analyzed data from 14,687 patients, 4802 of whom were on an ACEI or ARB, to study the effect on 30-day morbidity and mortality of withholding the medications 24 hours before a noncardiac surgery.¹ Of the ACEI or ARB users, 26% (1245) withheld their medication and 3557 continued it 24 hours before surgery.

Large study shows benefit in withholding meds

Patients who withheld the ACEI or ARB were less likely to experience the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1245 [12%] vs 459/3557 [12.9%]; adjusted relative risk [RR] = 0.82; 95% confidence interval [CI], 0.70-0.96; P = .01; number needed to treat [NNT] = 116) and intraoperative hypotension (adjusted RR = 0.80; 95% CI, 0.72-0.93; P < .001; NNT = 18). For the NNT calculation, which the investigators didn’t perform, the treatment is the number needed to withhold an ACEI or ARB to show benefit.

Smaller, weaker studies yield different results

A retrospective cohort analysis of propensity-matched ACEI users with ACEI nonusers (9028 in each group) undergoing noncardiac surgery compared intra- and postoperative respiratory complications or mortality.² The study found no association with either 30-day mortality (odds ratio [OR] = 0.93; 95% CI, 0.73-1.19) or the composite of in-hospital morbidity and mortality (OR = 1.06; 95% CI, 0.97-1.15). Limitations included comparison of users with nonusers as opposed to an intention-to-withhold study, the retrospective nature of the study, and the fact that outcomes were gathered from ICD-9 billing codes rather than obtained prospectively.

A Cochrane review assessed the benefits and harms of perioperative ACEIs or ARBs on mortality and morbidity in adults undergoing any type of surgery.³ Seven RCTs with a total of 571 participants were included in the review. Overall, the review didn’t find evidence to support prevention of mortality, morbidity, and complications by perioperative ACEIs or ARBs because the included studies were of low and very low methodological quality, had a high risk for bias, and lacked power. Moreover, the review didn’t assess the effect of withholding ACEIs or ARBs before surgery.

A random-effects meta-analysis of 5 studies (3 randomized trials and 2 observational studies) totaling 434 patients suggested that patients receiving ACEIs or ARBs immediately before surgery were more likely to develop hypotension requiring vasopressors (RR = 1.50; 95% CI, 1.15-1.96).⁴ Sufficient data weren’t available to assess other outcomes, and the included studies were relatively small and generally not powered to observe clinically significant consequences nor designed to measure the incidence of patient-important outcomes.

Continue to: RECOMMENDATIONS

RECOMMENDATIONS

The 2014 American College of Cardiology/American Heart Association Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery states that continuing ACEIs or ARBs perioperatively is reasonable (class IIa recommendation [moderate benefit of treatment relative to risk]; level of evidence [LOE], B [data from limited populations and single randomized or nonrandomized trials]). ⁵

The guideline also recommends that if ACEIs or ARBs are held before surgery, it is reasonable to restart them as soon as clinically feasible postoperatively (class IIa recommendation; LOE, C [data from very limited populations and consensus opinion or case studies]).

Editor’s Takeaway

The results of the large prospective cohort contradict those of previous smaller, methodologically weaker studies, and the new findings should be taken seriously.¹ Nevertheless, selection bias (why did investigators stop the ACEI?) remains. Until we have a large RCT, the preop question to ask may be why not stop the ACEI?

EVIDENCE SUMMARY

An international prospective cohort study analyzed data from 14,687 patients, 4802 of whom were on an ACEI or ARB, to study the effect on 30-day morbidity and mortality of withholding the medications 24 hours before a noncardiac surgery.¹ Of the ACEI or ARB users, 26% (1245) withheld their medication and 3557 continued it 24 hours before surgery.

Large study shows benefit in withholding meds

Patients who withheld the ACEI or ARB were less likely to experience the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1245 [12%] vs 459/3557 [12.9%]; adjusted relative risk [RR] = 0.82; 95% confidence interval [CI], 0.70-0.96; P = .01; number needed to treat [NNT] = 116) and intraoperative hypotension (adjusted RR = 0.80; 95% CI, 0.72-0.93; P < .001; NNT = 18). For the NNT calculation, which the investigators didn’t perform, the treatment is the number needed to withhold an ACEI or ARB to show benefit.

Smaller, weaker studies yield different results

A retrospective cohort analysis of propensity-matched ACEI users with ACEI nonusers (9028 in each group) undergoing noncardiac surgery compared intra- and postoperative respiratory complications or mortality.² The study found no association with either 30-day mortality (odds ratio [OR] = 0.93; 95% CI, 0.73-1.19) or the composite of in-hospital morbidity and mortality (OR = 1.06; 95% CI, 0.97-1.15). Limitations included comparison of users with nonusers as opposed to an intention-to-withhold study, the retrospective nature of the study, and the fact that outcomes were gathered from ICD-9 billing codes rather than obtained prospectively.

A Cochrane review assessed the benefits and harms of perioperative ACEIs or ARBs on mortality and morbidity in adults undergoing any type of surgery.³ Seven RCTs with a total of 571 participants were included in the review. Overall, the review didn’t find evidence to support prevention of mortality, morbidity, and complications by perioperative ACEIs or ARBs because the included studies were of low and very low methodological quality, had a high risk for bias, and lacked power. Moreover, the review didn’t assess the effect of withholding ACEIs or ARBs before surgery.

A random-effects meta-analysis of 5 studies (3 randomized trials and 2 observational studies) totaling 434 patients suggested that patients receiving ACEIs or ARBs immediately before surgery were more likely to develop hypotension requiring vasopressors (RR = 1.50; 95% CI, 1.15-1.96).⁴ Sufficient data weren’t available to assess other outcomes, and the included studies were relatively small and generally not powered to observe clinically significant consequences nor designed to measure the incidence of patient-important outcomes.

Continue to: RECOMMENDATIONS

RECOMMENDATIONS

The 2014 American College of Cardiology/American Heart Association Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery states that continuing ACEIs or ARBs perioperatively is reasonable (class IIa recommendation [moderate benefit of treatment relative to risk]; level of evidence [LOE], B [data from limited populations and single randomized or nonrandomized trials]). ⁵

The guideline also recommends that if ACEIs or ARBs are held before surgery, it is reasonable to restart them as soon as clinically feasible postoperatively (class IIa recommendation; LOE, C [data from very limited populations and consensus opinion or case studies]).

Editor’s Takeaway

The results of the large prospective cohort contradict those of previous smaller, methodologically weaker studies, and the new findings should be taken seriously.¹ Nevertheless, selection bias (why did investigators stop the ACEI?) remains. Until we have a large RCT, the preop question to ask may be why not stop the ACEI?

EVIDENCE SUMMARY

An international prospective cohort study analyzed data from 14,687 patients, 4802 of whom were on an ACEI or ARB, to study the effect on 30-day morbidity and mortality of withholding the medications 24 hours before a noncardiac surgery.¹ Of the ACEI or ARB users, 26% (1245) withheld their medication and 3557 continued it 24 hours before surgery.

Large study shows benefit in withholding meds

Patients who withheld the ACEI or ARB were less likely to experience the primary composite outcome of all-cause death, stroke, or myocardial injury (150/1245 [12%] vs 459/3557 [12.9%]; adjusted relative risk [RR] = 0.82; 95% confidence interval [CI], 0.70-0.96; P = .01; number needed to treat [NNT] = 116) and intraoperative hypotension (adjusted RR = 0.80; 95% CI, 0.72-0.93; P < .001; NNT = 18). For the NNT calculation, which the investigators didn’t perform, the treatment is the number needed to withhold an ACEI or ARB to show benefit.

Smaller, weaker studies yield different results

A retrospective cohort analysis of propensity-matched ACEI users with ACEI nonusers (9028 in each group) undergoing noncardiac surgery compared intra- and postoperative respiratory complications or mortality.² The study found no association with either 30-day mortality (odds ratio [OR] = 0.93; 95% CI, 0.73-1.19) or the composite of in-hospital morbidity and mortality (OR = 1.06; 95% CI, 0.97-1.15). Limitations included comparison of users with nonusers as opposed to an intention-to-withhold study, the retrospective nature of the study, and the fact that outcomes were gathered from ICD-9 billing codes rather than obtained prospectively.

A Cochrane review assessed the benefits and harms of perioperative ACEIs or ARBs on mortality and morbidity in adults undergoing any type of surgery.³ Seven RCTs with a total of 571 participants were included in the review. Overall, the review didn’t find evidence to support prevention of mortality, morbidity, and complications by perioperative ACEIs or ARBs because the included studies were of low and very low methodological quality, had a high risk for bias, and lacked power. Moreover, the review didn’t assess the effect of withholding ACEIs or ARBs before surgery.

A random-effects meta-analysis of 5 studies (3 randomized trials and 2 observational studies) totaling 434 patients suggested that patients receiving ACEIs or ARBs immediately before surgery were more likely to develop hypotension requiring vasopressors (RR = 1.50; 95% CI, 1.15-1.96).⁴ Sufficient data weren’t available to assess other outcomes, and the included studies were relatively small and generally not powered to observe clinically significant consequences nor designed to measure the incidence of patient-important outcomes.

Continue to: RECOMMENDATIONS

RECOMMENDATIONS

The 2014 American College of Cardiology/American Heart Association Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery states that continuing ACEIs or ARBs perioperatively is reasonable (class IIa recommendation [moderate benefit of treatment relative to risk]; level of evidence [LOE], B [data from limited populations and single randomized or nonrandomized trials]). ⁵

The guideline also recommends that if ACEIs or ARBs are held before surgery, it is reasonable to restart them as soon as clinically feasible postoperatively (class IIa recommendation; LOE, C [data from very limited populations and consensus opinion or case studies]).

Editor’s Takeaway

The results of the large prospective cohort contradict those of previous smaller, methodologically weaker studies, and the new findings should be taken seriously.¹ Nevertheless, selection bias (why did investigators stop the ACEI?) remains. Until we have a large RCT, the preop question to ask may be why not stop the ACEI?

Just like the 2018 hypertension treatment guidelines, the 2018 Guidelines on the Management of Blood Cholesterol developed by the American College of Cardiology and the American Heart Association (ACC/AHA) have made treatment decisions much more complicated. In this issue of JFP, Wójcik and Shapiro summarize the 70-page document to help family physicians and other primary health care professionals use these complex guidelines in everyday practice.

The good news is that not much has changed from the 2013 ACC/AHA cholesterol guidelines regarding the treatment of patients with established cardiovascular disease and diabetes mellitus, and those with familial hyperlipidemia—the groups at highest risk for major cardiovascular events. Most of these patients should be treated aggressively, and a target low-density lipoprotein of 70 mg/dL is recommended.

I find the recommendations for adults ages 75 and older and for children and teens to be problematic.

The new guidelines recommend using ezetimibe or a PCSK9 inhibitor if the goal of 70 mg/dL cannot be achieved with a statin alone. There is randomized trial evidence to support the benefit of this aggressive approach. Generic ezetimibe costs about $20 per month,¹ but the PCSK9 inhibitors are about $500 per month,^2,3 so cost may be a treatment barrier for the 2 monoclonal antibodies approved for cardiovascular prevention: evolocumab and alirocumab.

For primary prevention, the new guidelines are much more complicated. They divide cardiovascular risk into 4 tiers depending on the 10-year risk for atherosclerotic cardiovascular disease calculated using the “pooled cohort equation.” Treatment recommendations are more aggressive for those at higher risk. Although it intuitively makes sense to treat those at higher risk more aggressively, there is no clinical trial evidence to support this approach’s superiority over the simpler approach recommended in the 2013 guidelines.

I find the recommendations for screening and primary prevention in adults ages 75 and older and for children and teens to be problematic. A meta-analysis of 28 studies found no statin treatment benefit for primary prevention in those older than 70.⁴ And there are no randomized trials showing benefit of screening and treating children and teens for hyperlipidemia.

On a positive note, most patients do not need to fast prior to having their lipids measured.

Read the 2018 cholesterol treatment guideline summary in this issue of JFP. But as you do so, remember that guidelines are guidelines; they are not mandates for treatment. You may need to customize these guidelines for your practice and your patients. In my opinion, the simpler 2013 cholesterol guidelines remain good guidelines.

Just like the 2018 hypertension treatment guidelines, the 2018 Guidelines on the Management of Blood Cholesterol developed by the American College of Cardiology and the American Heart Association (ACC/AHA) have made treatment decisions much more complicated. In this issue of JFP, Wójcik and Shapiro summarize the 70-page document to help family physicians and other primary health care professionals use these complex guidelines in everyday practice.

The good news is that not much has changed from the 2013 ACC/AHA cholesterol guidelines regarding the treatment of patients with established cardiovascular disease and diabetes mellitus, and those with familial hyperlipidemia—the groups at highest risk for major cardiovascular events. Most of these patients should be treated aggressively, and a target low-density lipoprotein of 70 mg/dL is recommended.

I find the recommendations for adults ages 75 and older and for children and teens to be problematic.

The new guidelines recommend using ezetimibe or a PCSK9 inhibitor if the goal of 70 mg/dL cannot be achieved with a statin alone. There is randomized trial evidence to support the benefit of this aggressive approach. Generic ezetimibe costs about $20 per month,¹ but the PCSK9 inhibitors are about $500 per month,^2,3 so cost may be a treatment barrier for the 2 monoclonal antibodies approved for cardiovascular prevention: evolocumab and alirocumab.

For primary prevention, the new guidelines are much more complicated. They divide cardiovascular risk into 4 tiers depending on the 10-year risk for atherosclerotic cardiovascular disease calculated using the “pooled cohort equation.” Treatment recommendations are more aggressive for those at higher risk. Although it intuitively makes sense to treat those at higher risk more aggressively, there is no clinical trial evidence to support this approach’s superiority over the simpler approach recommended in the 2013 guidelines.

I find the recommendations for screening and primary prevention in adults ages 75 and older and for children and teens to be problematic. A meta-analysis of 28 studies found no statin treatment benefit for primary prevention in those older than 70.⁴ And there are no randomized trials showing benefit of screening and treating children and teens for hyperlipidemia.

On a positive note, most patients do not need to fast prior to having their lipids measured.

Read the 2018 cholesterol treatment guideline summary in this issue of JFP. But as you do so, remember that guidelines are guidelines; they are not mandates for treatment. You may need to customize these guidelines for your practice and your patients. In my opinion, the simpler 2013 cholesterol guidelines remain good guidelines.

Just like the 2018 hypertension treatment guidelines, the 2018 Guidelines on the Management of Blood Cholesterol developed by the American College of Cardiology and the American Heart Association (ACC/AHA) have made treatment decisions much more complicated. In this issue of JFP, Wójcik and Shapiro summarize the 70-page document to help family physicians and other primary health care professionals use these complex guidelines in everyday practice.

The good news is that not much has changed from the 2013 ACC/AHA cholesterol guidelines regarding the treatment of patients with established cardiovascular disease and diabetes mellitus, and those with familial hyperlipidemia—the groups at highest risk for major cardiovascular events. Most of these patients should be treated aggressively, and a target low-density lipoprotein of 70 mg/dL is recommended.

I find the recommendations for adults ages 75 and older and for children and teens to be problematic.

The new guidelines recommend using ezetimibe or a PCSK9 inhibitor if the goal of 70 mg/dL cannot be achieved with a statin alone. There is randomized trial evidence to support the benefit of this aggressive approach. Generic ezetimibe costs about $20 per month,¹ but the PCSK9 inhibitors are about $500 per month,^2,3 so cost may be a treatment barrier for the 2 monoclonal antibodies approved for cardiovascular prevention: evolocumab and alirocumab.

For primary prevention, the new guidelines are much more complicated. They divide cardiovascular risk into 4 tiers depending on the 10-year risk for atherosclerotic cardiovascular disease calculated using the “pooled cohort equation.” Treatment recommendations are more aggressive for those at higher risk. Although it intuitively makes sense to treat those at higher risk more aggressively, there is no clinical trial evidence to support this approach’s superiority over the simpler approach recommended in the 2013 guidelines.

I find the recommendations for screening and primary prevention in adults ages 75 and older and for children and teens to be problematic. A meta-analysis of 28 studies found no statin treatment benefit for primary prevention in those older than 70.⁴ And there are no randomized trials showing benefit of screening and treating children and teens for hyperlipidemia.

On a positive note, most patients do not need to fast prior to having their lipids measured.

Read the 2018 cholesterol treatment guideline summary in this issue of JFP. But as you do so, remember that guidelines are guidelines; they are not mandates for treatment. You may need to customize these guidelines for your practice and your patients. In my opinion, the simpler 2013 cholesterol guidelines remain good guidelines.

THE CASE

A 29-year-old G7P2315 woman gave birth to a girl at 37 weeks via spontaneous vaginal delivery. APGAR scores were 9 and 9. Birth weight was 2760 g. Cardiovascular and pulmonary examinations were normal (heart rate, 154 beats/min; respiratory rate, 52 breaths/min). Following delivery, the neonate appeared healthy, had a lusty cry, and had no visible craniofacial or cutaneous abnormalities; however, the bilateral knees were hyperextended to 90° to 110° (FIGURE 1A).

The mother had started prenatal care at 7 weeks with 10 total visits to her family physician (JD) throughout the pregnancy. Routine laboratory screening and prenatal ultrasounds (including an anatomy scan) were normal. She had a history of 3 preterm deliveries at 35 weeks, 36 weeks, and 36 weeks, respectively, and had been on progesterone shots once weekly starting at 18 weeks during the current pregnancy. She had no history of infections or recent travel. Her family history was remarkable for a sister who gave birth to a child with thrombocytopenia absent radius syndrome.

THE DIAGNOSIS

The neonate tolerated passive flexion of the knees to a neutral position. Hip examination demonstrated appropriate range of movement with negative Ortolani and Barlow tests. The infant’s feet aligned correctly, with toes in the front and heels in the back, and an x-ray of the bilateral knees showed no fractures or dislocation.

Based on the clinical examination and x-ray findings, we made a diagnosis of congenital genu recurvatum. A pediatric orthopedics consultation was obtained, and the knees were placed in short leg splints in comfortable flexion to neutral on Day 1 of life. She was discharged the next day.

DISCUSSION

Congenital genu recurvatum, also known as congenital dislocation of the knee, is a rare condition involving abnormal hyperextension of the unilateral or bilateral knees with limited flexion.¹ Reports in the literature are limited, but there seems to be a female predominance among known cases of congenital genu recurvatum.² The clinical presentation varies. Finding may be isolated to the knee(s) but also can present in association with other congenital abnormalities, such as developmental dysplasia of the hip, clubfoot, and hindfoot and forefoot deformities.^3,4

Diagnosis is made clinically with radiographic imaging

Diagnosis of congenital genu recurvatum is made clinically and can be confirmed via radiographic imaging of the knees.5 Clinical diagnosis requires assessment of the degree of hyperextension and palpation of the femoral condyles, which become more prominent as the severity of the hyperextension increases.⁶ X-rays help assess if a true dislocation or subluxation of the tibia on the femur has occurred. Based on the clinical and radiographic findings, congenital genu recurvatum typically is classified according to 3 levels of severity: grade 1 classification only involves hyperextension of the knees without dislocation or subluxation, grade 2 involves the same characteristic hyperextension along with  anterior subluxation of the tibia on the femur, and grade 3 includes hyperextension with true dislocation of the tibia on the femur.¹ Grades 1 and 2 on this spectrum technically are diagnosed as congenital genu recurvatum while grade 3 is diagnosed as a congenital dislocation of the knee,⁷ although the 2 terms are used interchangeably in the literature. We classified our case as a grade 1 congenital genu recurvatum based on the clinical and radiographic findings.

Congenital knee hyperextension has intrinsic and extrinsic causes

Hyperextension of the knees at birth may be caused by various intrinsic or extrinsic factors. Intrinsic causes may include breech position, lack of intrauterine space, trauma to the mother, quadriceps contracture or fibrosis, absence of the suprapatellar pouch, deficient or hypoplastic anterior cruciate ligament, pathological tissues, arthrogryposis, or genetic disorders such as Larsen syndrome or achondroplasia.⁶

Continue to: Extrinsic causes...

Extrinsic causes may include traumatic dislocation during the birthing process³ or intrauterine pressure leading to malposition of the joints. When intrauterine pressure is combined with reduced intrauterine space, this phenomenon is known as packaging disorder.⁶ Entanglement of the umbilical cord around the legs of the fetus during development may be another potential factor.¹Of note: Cases involving both extrinsic or intrinsic etiologies can present with associated abnormalities that include congenital dislocation of the hip, congenital hip dysplasia, spina bifida, and/or cleft palate—in addition to knee hyperextension.

The exact etiology in our patient was unknown, but we determined the cause was extrinsic based on the lack of other genetic abnormalities. We initially considered a possible connection between our patient’s diagnosis and her family history of thrombocytopenia absent radius syndrome, but it was later determined that both were isolated cases and the limb abnormalities were coincidental.

Treatment options and outcomes for extrinsic and intrinsic etiologies depend on the severity of the hyperextension and any associated abnormalities, as well as the time in which therapy is initiated.¹ Reduction of the hyperextension within 24 hours of birth has been associated with excellent outcomes.⁸ Regardless of the cause, all cases of congenital genu recurvatum should first be treated conservatively. Evidence has suggested that conservative therapy involving early gentle manipulation of the knee combined with serial splinting and casting should be the first line of treatment.⁶ If initial treatment attempts fail or in cases occurring later in life, surgical interventions (eg, quadriceps release procedures such as percutaneous quadriceps recession or V-Y quadricepsplasty, proximal tibial closing-wedge, anterior displacement osteotomy) likely is warranted.^6,9

Our patient. At 1 week of life, our patient’s short leg splints were replaced with long leg splints with a maximal flexion of 20° to 30° (FIGURE 1B). Weekly follow-ups with serial casting were initiated in the pediatric orthopedics clinic. At 3 weeks of life, the patient’s knee flexion had improved and the splints were removed (FIGURE 1C). Upon clinical examination, the bilateral knees were extended to a neutral position, and both could be actively and passively flexed to 90°. The patient was referred to Physical Therapy to perform range of movement exercises on the knees.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

At 8 weeks of life, the bilateral legs were in full extension, and knee flexion was up to 130°. Physical therapy for knee range of movement exercise was continued on a weekly basis until 6 months of life, then twice monthly until the patient was 1 year old. Ultimately, the hyperextension was corrected, and the patient started walking at around 16 months of age. Her prognosis is good, and she will be able to participate in low-impact sports, after consulting with her orthopedist.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

Continue to: THE TAKEAWAY

THE TAKEAWAY

Congenital genu recurvatum is a rare condition that presents with abnormal hyperextension of the knee(s) with limited flexion. Early diagnosis and assessment of the severity of the hyperextension is crucial in determining the type of intervention to pursue. Conservative management entails serial casting and splinting to increase knee flexion. If conservative management fails or if the diagnosis is made later in life, surgical options often are pursued.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 MetroHealth Medical Drive, Cleveland, OH 44109; [email protected]

THE CASE

A 29-year-old G7P2315 woman gave birth to a girl at 37 weeks via spontaneous vaginal delivery. APGAR scores were 9 and 9. Birth weight was 2760 g. Cardiovascular and pulmonary examinations were normal (heart rate, 154 beats/min; respiratory rate, 52 breaths/min). Following delivery, the neonate appeared healthy, had a lusty cry, and had no visible craniofacial or cutaneous abnormalities; however, the bilateral knees were hyperextended to 90° to 110° (FIGURE 1A).

The mother had started prenatal care at 7 weeks with 10 total visits to her family physician (JD) throughout the pregnancy. Routine laboratory screening and prenatal ultrasounds (including an anatomy scan) were normal. She had a history of 3 preterm deliveries at 35 weeks, 36 weeks, and 36 weeks, respectively, and had been on progesterone shots once weekly starting at 18 weeks during the current pregnancy. She had no history of infections or recent travel. Her family history was remarkable for a sister who gave birth to a child with thrombocytopenia absent radius syndrome.

THE DIAGNOSIS

The neonate tolerated passive flexion of the knees to a neutral position. Hip examination demonstrated appropriate range of movement with negative Ortolani and Barlow tests. The infant’s feet aligned correctly, with toes in the front and heels in the back, and an x-ray of the bilateral knees showed no fractures or dislocation.

Based on the clinical examination and x-ray findings, we made a diagnosis of congenital genu recurvatum. A pediatric orthopedics consultation was obtained, and the knees were placed in short leg splints in comfortable flexion to neutral on Day 1 of life. She was discharged the next day.

DISCUSSION

Congenital genu recurvatum, also known as congenital dislocation of the knee, is a rare condition involving abnormal hyperextension of the unilateral or bilateral knees with limited flexion.¹ Reports in the literature are limited, but there seems to be a female predominance among known cases of congenital genu recurvatum.² The clinical presentation varies. Finding may be isolated to the knee(s) but also can present in association with other congenital abnormalities, such as developmental dysplasia of the hip, clubfoot, and hindfoot and forefoot deformities.^3,4

Diagnosis is made clinically with radiographic imaging

Diagnosis of congenital genu recurvatum is made clinically and can be confirmed via radiographic imaging of the knees.5 Clinical diagnosis requires assessment of the degree of hyperextension and palpation of the femoral condyles, which become more prominent as the severity of the hyperextension increases.⁶ X-rays help assess if a true dislocation or subluxation of the tibia on the femur has occurred. Based on the clinical and radiographic findings, congenital genu recurvatum typically is classified according to 3 levels of severity: grade 1 classification only involves hyperextension of the knees without dislocation or subluxation, grade 2 involves the same characteristic hyperextension along with  anterior subluxation of the tibia on the femur, and grade 3 includes hyperextension with true dislocation of the tibia on the femur.¹ Grades 1 and 2 on this spectrum technically are diagnosed as congenital genu recurvatum while grade 3 is diagnosed as a congenital dislocation of the knee,⁷ although the 2 terms are used interchangeably in the literature. We classified our case as a grade 1 congenital genu recurvatum based on the clinical and radiographic findings.

Congenital knee hyperextension has intrinsic and extrinsic causes

Hyperextension of the knees at birth may be caused by various intrinsic or extrinsic factors. Intrinsic causes may include breech position, lack of intrauterine space, trauma to the mother, quadriceps contracture or fibrosis, absence of the suprapatellar pouch, deficient or hypoplastic anterior cruciate ligament, pathological tissues, arthrogryposis, or genetic disorders such as Larsen syndrome or achondroplasia.⁶

Continue to: Extrinsic causes...

Extrinsic causes may include traumatic dislocation during the birthing process³ or intrauterine pressure leading to malposition of the joints. When intrauterine pressure is combined with reduced intrauterine space, this phenomenon is known as packaging disorder.⁶ Entanglement of the umbilical cord around the legs of the fetus during development may be another potential factor.¹Of note: Cases involving both extrinsic or intrinsic etiologies can present with associated abnormalities that include congenital dislocation of the hip, congenital hip dysplasia, spina bifida, and/or cleft palate—in addition to knee hyperextension.

The exact etiology in our patient was unknown, but we determined the cause was extrinsic based on the lack of other genetic abnormalities. We initially considered a possible connection between our patient’s diagnosis and her family history of thrombocytopenia absent radius syndrome, but it was later determined that both were isolated cases and the limb abnormalities were coincidental.

Treatment options and outcomes for extrinsic and intrinsic etiologies depend on the severity of the hyperextension and any associated abnormalities, as well as the time in which therapy is initiated.¹ Reduction of the hyperextension within 24 hours of birth has been associated with excellent outcomes.⁸ Regardless of the cause, all cases of congenital genu recurvatum should first be treated conservatively. Evidence has suggested that conservative therapy involving early gentle manipulation of the knee combined with serial splinting and casting should be the first line of treatment.⁶ If initial treatment attempts fail or in cases occurring later in life, surgical interventions (eg, quadriceps release procedures such as percutaneous quadriceps recession or V-Y quadricepsplasty, proximal tibial closing-wedge, anterior displacement osteotomy) likely is warranted.^6,9

Our patient. At 1 week of life, our patient’s short leg splints were replaced with long leg splints with a maximal flexion of 20° to 30° (FIGURE 1B). Weekly follow-ups with serial casting were initiated in the pediatric orthopedics clinic. At 3 weeks of life, the patient’s knee flexion had improved and the splints were removed (FIGURE 1C). Upon clinical examination, the bilateral knees were extended to a neutral position, and both could be actively and passively flexed to 90°. The patient was referred to Physical Therapy to perform range of movement exercises on the knees.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

At 8 weeks of life, the bilateral legs were in full extension, and knee flexion was up to 130°. Physical therapy for knee range of movement exercise was continued on a weekly basis until 6 months of life, then twice monthly until the patient was 1 year old. Ultimately, the hyperextension was corrected, and the patient started walking at around 16 months of age. Her prognosis is good, and she will be able to participate in low-impact sports, after consulting with her orthopedist.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

Continue to: THE TAKEAWAY

THE TAKEAWAY

Congenital genu recurvatum is a rare condition that presents with abnormal hyperextension of the knee(s) with limited flexion. Early diagnosis and assessment of the severity of the hyperextension is crucial in determining the type of intervention to pursue. Conservative management entails serial casting and splinting to increase knee flexion. If conservative management fails or if the diagnosis is made later in life, surgical options often are pursued.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 MetroHealth Medical Drive, Cleveland, OH 44109; [email protected]

THE CASE

A 29-year-old G7P2315 woman gave birth to a girl at 37 weeks via spontaneous vaginal delivery. APGAR scores were 9 and 9. Birth weight was 2760 g. Cardiovascular and pulmonary examinations were normal (heart rate, 154 beats/min; respiratory rate, 52 breaths/min). Following delivery, the neonate appeared healthy, had a lusty cry, and had no visible craniofacial or cutaneous abnormalities; however, the bilateral knees were hyperextended to 90° to 110° (FIGURE 1A).

The mother had started prenatal care at 7 weeks with 10 total visits to her family physician (JD) throughout the pregnancy. Routine laboratory screening and prenatal ultrasounds (including an anatomy scan) were normal. She had a history of 3 preterm deliveries at 35 weeks, 36 weeks, and 36 weeks, respectively, and had been on progesterone shots once weekly starting at 18 weeks during the current pregnancy. She had no history of infections or recent travel. Her family history was remarkable for a sister who gave birth to a child with thrombocytopenia absent radius syndrome.

THE DIAGNOSIS

The neonate tolerated passive flexion of the knees to a neutral position. Hip examination demonstrated appropriate range of movement with negative Ortolani and Barlow tests. The infant’s feet aligned correctly, with toes in the front and heels in the back, and an x-ray of the bilateral knees showed no fractures or dislocation.

Based on the clinical examination and x-ray findings, we made a diagnosis of congenital genu recurvatum. A pediatric orthopedics consultation was obtained, and the knees were placed in short leg splints in comfortable flexion to neutral on Day 1 of life. She was discharged the next day.

DISCUSSION

Congenital genu recurvatum, also known as congenital dislocation of the knee, is a rare condition involving abnormal hyperextension of the unilateral or bilateral knees with limited flexion.¹ Reports in the literature are limited, but there seems to be a female predominance among known cases of congenital genu recurvatum.² The clinical presentation varies. Finding may be isolated to the knee(s) but also can present in association with other congenital abnormalities, such as developmental dysplasia of the hip, clubfoot, and hindfoot and forefoot deformities.^3,4

Diagnosis is made clinically with radiographic imaging

Diagnosis of congenital genu recurvatum is made clinically and can be confirmed via radiographic imaging of the knees.5 Clinical diagnosis requires assessment of the degree of hyperextension and palpation of the femoral condyles, which become more prominent as the severity of the hyperextension increases.⁶ X-rays help assess if a true dislocation or subluxation of the tibia on the femur has occurred. Based on the clinical and radiographic findings, congenital genu recurvatum typically is classified according to 3 levels of severity: grade 1 classification only involves hyperextension of the knees without dislocation or subluxation, grade 2 involves the same characteristic hyperextension along with  anterior subluxation of the tibia on the femur, and grade 3 includes hyperextension with true dislocation of the tibia on the femur.¹ Grades 1 and 2 on this spectrum technically are diagnosed as congenital genu recurvatum while grade 3 is diagnosed as a congenital dislocation of the knee,⁷ although the 2 terms are used interchangeably in the literature. We classified our case as a grade 1 congenital genu recurvatum based on the clinical and radiographic findings.

Congenital knee hyperextension has intrinsic and extrinsic causes

Hyperextension of the knees at birth may be caused by various intrinsic or extrinsic factors. Intrinsic causes may include breech position, lack of intrauterine space, trauma to the mother, quadriceps contracture or fibrosis, absence of the suprapatellar pouch, deficient or hypoplastic anterior cruciate ligament, pathological tissues, arthrogryposis, or genetic disorders such as Larsen syndrome or achondroplasia.⁶

Continue to: Extrinsic causes...

Extrinsic causes may include traumatic dislocation during the birthing process³ or intrauterine pressure leading to malposition of the joints. When intrauterine pressure is combined with reduced intrauterine space, this phenomenon is known as packaging disorder.⁶ Entanglement of the umbilical cord around the legs of the fetus during development may be another potential factor.¹Of note: Cases involving both extrinsic or intrinsic etiologies can present with associated abnormalities that include congenital dislocation of the hip, congenital hip dysplasia, spina bifida, and/or cleft palate—in addition to knee hyperextension.

The exact etiology in our patient was unknown, but we determined the cause was extrinsic based on the lack of other genetic abnormalities. We initially considered a possible connection between our patient’s diagnosis and her family history of thrombocytopenia absent radius syndrome, but it was later determined that both were isolated cases and the limb abnormalities were coincidental.

Treatment options and outcomes for extrinsic and intrinsic etiologies depend on the severity of the hyperextension and any associated abnormalities, as well as the time in which therapy is initiated.¹ Reduction of the hyperextension within 24 hours of birth has been associated with excellent outcomes.⁸ Regardless of the cause, all cases of congenital genu recurvatum should first be treated conservatively. Evidence has suggested that conservative therapy involving early gentle manipulation of the knee combined with serial splinting and casting should be the first line of treatment.⁶ If initial treatment attempts fail or in cases occurring later in life, surgical interventions (eg, quadriceps release procedures such as percutaneous quadriceps recession or V-Y quadricepsplasty, proximal tibial closing-wedge, anterior displacement osteotomy) likely is warranted.^6,9

Our patient. At 1 week of life, our patient’s short leg splints were replaced with long leg splints with a maximal flexion of 20° to 30° (FIGURE 1B). Weekly follow-ups with serial casting were initiated in the pediatric orthopedics clinic. At 3 weeks of life, the patient’s knee flexion had improved and the splints were removed (FIGURE 1C). Upon clinical examination, the bilateral knees were extended to a neutral position, and both could be actively and passively flexed to 90°. The patient was referred to Physical Therapy to perform range of movement exercises on the knees.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

At 8 weeks of life, the bilateral legs were in full extension, and knee flexion was up to 130°. Physical therapy for knee range of movement exercise was continued on a weekly basis until 6 months of life, then twice monthly until the patient was 1 year old. Ultimately, the hyperextension was corrected, and the patient started walking at around 16 months of age. Her prognosis is good, and she will be able to participate in low-impact sports, after consulting with her orthopedist.

IMAGE COURTESY OF: METROHEALTH MEDICAL CENTER, CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OHIO

Continue to: THE TAKEAWAY

THE TAKEAWAY

Congenital genu recurvatum is a rare condition that presents with abnormal hyperextension of the knee(s) with limited flexion. Early diagnosis and assessment of the severity of the hyperextension is crucial in determining the type of intervention to pursue. Conservative management entails serial casting and splinting to increase knee flexion. If conservative management fails or if the diagnosis is made later in life, surgical options often are pursued.

CORRESPONDENCE
Jaividhya Dasarathy, MD, FAAFP, 2500 MetroHealth Medical Drive, Cleveland, OH 44109; [email protected]