Stephen K. Tyring, MD, PhD

The Diagnosis: Calciphylaxis

Calciphylaxis is a rare life-threatening condition that most often is seen in patients with end-stage renal disease at a rate of 35 per 10,000 chronic dialysis patients.¹ It less commonly has been described in nonuremic patients. The exact incidence of nonuremic calciphylaxis is unknown, but multiple risk factors have been identified, such as alcoholic liver disease, primary hyperparathyroidism, connective tissue diseases, and underlying malignancies. Other less common risk factors include type 2 diabetes mellitus, hypercoagulable disorders, obesity, hypoalbuminemia, and warfarin/ corticosteroid use.² However, most often no obvious triggers are identified.¹

Regardless of the etiology, calciphylaxis is characterized by the calcification of blood vessels and connective tissues, leading to vessel injury, intimal fibrosis, and thrombosis, followed by ischemic necrosis of the skin and soft tissue. It is postulated that microvascular calcification occurs as an active cell-mediated process that depends on the balance between the promoters and inhibitors of calcification.¹ In our patient, liver disease likely predisposed formation of calcification through the creation of an environment susceptible to vascular injury via decreased synthesis of proteins C and S.³ Synthesis of fetuin-A, a protein that acts as a circulating inhibitor of vascular ossification/calcification, also is decreased in calcification. Another inhibitor of calcification, matrix Gla protein, is unable to undergo activation through vitamin K–dependent carboxylation secondary to liver disease–induced vitamin K deficiency.³ Microvascular calcification without calciphylaxis may occur in other conditions such as type 2 diabetes mellitus. Therefore, clinicopathologic correlation is important in determining the diagnosis.

Calciphylaxis has a variety of clinical presentations depending on the stage of disease. It begins as a fixed, indurated, livedo reticularis–like plaque. The lesions become increasingly violaceous with intermixed areas of light blanched skin secondary to ischemia and then develop retiform pupura.⁴ Eventually, affected sites can become bullous and ulcerate or form a necrotic eschar. Severe pain is a cardinal feature throughout all stages.⁴ Lesions in nonuremic calciphylaxis most commonly are located in the central and/or proximal areas of the body.²

Clinical suspicion is essential for diagnosis. Skin biopsy is the standard method for confirmation in unclear cases. The classic histologic features include intravascular and extravascular calcification, microthrombosis, and fibrointimal hyperplasia of the small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.¹ Von Kossa immunostaining is used to increase the detection of calcium deposits (Figure 1).¹ In addition to the classic changes, our case demonstrated a rare histologic variant with pseudoxanthoma elasticum (PXE)–like changes (Figure 2), which are thought to occur secondary to pathologic elastin fibrogenesis or increased proteolytic activity resulting in abnormal remodeling of the extracellular matrix in the setting of increased calcification of elastin fibers.⁵ Detection of PXE-like changes may be a helpful clue when specimens lack other characteristic signs.

Wound care, pain control, and addressing underlying causes are mainstays of therapy. Sodium thiosulfate, an antioxidant with vasodilatory properties that also inhibits adipocyte calcification and blocks the ability of adipocytes to induce calcification of vascular smooth-muscle cells, also is useful. Antibiotic prophylaxis is not indicated.¹

Even with treatment, both uremic and nonuremic calciphylaxis have a dismal prognosis; 1-year mortality is approximately 50% to 60% and rises to 80% at 2 years.⁴ Lesion location affects prognosis, and more proximal lesions portend worse outcomes. In patients with both proximal and distal lesions, there is a 90% mortality rate within 1 year. Ulceration also portends worse outcomes, as the wounds often are resistant to healing and act as nidi for infection.⁴ Septicemia is the most common cause of death.¹

Ecthyma gangrenosum is a cutaneous manifestation secondary to an infection most commonly associated with Pseudomonas aeruginosa.⁶ It often presents in immunocompromised patients with an underlying gramnegative septicemia.⁷ The clinical presentation initially begins with painless macules that rapidly progress into necrotic ulcers, usually accompanied by associated systemic symptoms such as fever, chills, and hypotension. Histopathology reveals numerous gram-negative rods around necrotic vessels.⁷

Idiopathic purpura fulminans is the rarest form of purpura fulminans. It is caused by autoantibody formation against protein S, resulting in protein S depletion and subsequent hypercoagulability.⁸ It usually occurs 7 to 10 days after the onset of a precipitating infection. Lesions begin as erythematous macules that progress within hours to painful, sharply defined areas of purpura and hemorrhagic cutaneous necrosis that may extend to deeper tissues.⁸ Secondary infection of gangrenous tissue may occur. Distribution usually is diffuse and signs of septic shock and disseminated intravascular coagulation usually are present.

Hughes syndrome, also known as antiphospholipid syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent arterial or venous thrombosis.⁹ Cutaneous manifestations consist of livedo reticularis, arterial and venous ulcers, and superficial thrombophlebitis.¹⁰ Laboratory testing for antiphospholipid antibodies and obtaining a detailed history of the patient’s cardiovascular health are crucial for diagnosis.⁹

Necrotizing fasciitis typically begins as an inconspicuous superficial cutaneous infection that rapidly is transmitted to the fascia. Infection can spread along fascial planes for several days without affecting the overlying skin, leading to delayed diagnosis.¹¹ The first signs to appear are disproportionate pain and a change in skin color to reddish-purple or bluish-gray. Next, the skin will become indurated, swollen, shiny, and more painful.¹¹ Skin breakdown will begin in 3 to 5 days and is accompanied by bullae and cutaneous gangrene. The involved area becomes painless due to thrombosis of the small vessels that supply the superficial nerves.¹² Septic shock ultimately will develop if untreated.

We present a rare case of nonuremic calciphylaxis. We encourage dermatologists to include calciphylaxis in the differential when evaluating any patient with a painful retiform rash or ulcerated eschar, even in the absence of renal disease.

The Diagnosis: Calciphylaxis

Calciphylaxis is a rare life-threatening condition that most often is seen in patients with end-stage renal disease at a rate of 35 per 10,000 chronic dialysis patients.¹ It less commonly has been described in nonuremic patients. The exact incidence of nonuremic calciphylaxis is unknown, but multiple risk factors have been identified, such as alcoholic liver disease, primary hyperparathyroidism, connective tissue diseases, and underlying malignancies. Other less common risk factors include type 2 diabetes mellitus, hypercoagulable disorders, obesity, hypoalbuminemia, and warfarin/ corticosteroid use.² However, most often no obvious triggers are identified.¹

Regardless of the etiology, calciphylaxis is characterized by the calcification of blood vessels and connective tissues, leading to vessel injury, intimal fibrosis, and thrombosis, followed by ischemic necrosis of the skin and soft tissue. It is postulated that microvascular calcification occurs as an active cell-mediated process that depends on the balance between the promoters and inhibitors of calcification.¹ In our patient, liver disease likely predisposed formation of calcification through the creation of an environment susceptible to vascular injury via decreased synthesis of proteins C and S.³ Synthesis of fetuin-A, a protein that acts as a circulating inhibitor of vascular ossification/calcification, also is decreased in calcification. Another inhibitor of calcification, matrix Gla protein, is unable to undergo activation through vitamin K–dependent carboxylation secondary to liver disease–induced vitamin K deficiency.³ Microvascular calcification without calciphylaxis may occur in other conditions such as type 2 diabetes mellitus. Therefore, clinicopathologic correlation is important in determining the diagnosis.

Calciphylaxis has a variety of clinical presentations depending on the stage of disease. It begins as a fixed, indurated, livedo reticularis–like plaque. The lesions become increasingly violaceous with intermixed areas of light blanched skin secondary to ischemia and then develop retiform pupura.⁴ Eventually, affected sites can become bullous and ulcerate or form a necrotic eschar. Severe pain is a cardinal feature throughout all stages.⁴ Lesions in nonuremic calciphylaxis most commonly are located in the central and/or proximal areas of the body.²

Clinical suspicion is essential for diagnosis. Skin biopsy is the standard method for confirmation in unclear cases. The classic histologic features include intravascular and extravascular calcification, microthrombosis, and fibrointimal hyperplasia of the small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.¹ Von Kossa immunostaining is used to increase the detection of calcium deposits (Figure 1).¹ In addition to the classic changes, our case demonstrated a rare histologic variant with pseudoxanthoma elasticum (PXE)–like changes (Figure 2), which are thought to occur secondary to pathologic elastin fibrogenesis or increased proteolytic activity resulting in abnormal remodeling of the extracellular matrix in the setting of increased calcification of elastin fibers.⁵ Detection of PXE-like changes may be a helpful clue when specimens lack other characteristic signs.

Wound care, pain control, and addressing underlying causes are mainstays of therapy. Sodium thiosulfate, an antioxidant with vasodilatory properties that also inhibits adipocyte calcification and blocks the ability of adipocytes to induce calcification of vascular smooth-muscle cells, also is useful. Antibiotic prophylaxis is not indicated.¹

Even with treatment, both uremic and nonuremic calciphylaxis have a dismal prognosis; 1-year mortality is approximately 50% to 60% and rises to 80% at 2 years.⁴ Lesion location affects prognosis, and more proximal lesions portend worse outcomes. In patients with both proximal and distal lesions, there is a 90% mortality rate within 1 year. Ulceration also portends worse outcomes, as the wounds often are resistant to healing and act as nidi for infection.⁴ Septicemia is the most common cause of death.¹

Ecthyma gangrenosum is a cutaneous manifestation secondary to an infection most commonly associated with Pseudomonas aeruginosa.⁶ It often presents in immunocompromised patients with an underlying gramnegative septicemia.⁷ The clinical presentation initially begins with painless macules that rapidly progress into necrotic ulcers, usually accompanied by associated systemic symptoms such as fever, chills, and hypotension. Histopathology reveals numerous gram-negative rods around necrotic vessels.⁷

Idiopathic purpura fulminans is the rarest form of purpura fulminans. It is caused by autoantibody formation against protein S, resulting in protein S depletion and subsequent hypercoagulability.⁸ It usually occurs 7 to 10 days after the onset of a precipitating infection. Lesions begin as erythematous macules that progress within hours to painful, sharply defined areas of purpura and hemorrhagic cutaneous necrosis that may extend to deeper tissues.⁸ Secondary infection of gangrenous tissue may occur. Distribution usually is diffuse and signs of septic shock and disseminated intravascular coagulation usually are present.

Hughes syndrome, also known as antiphospholipid syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent arterial or venous thrombosis.⁹ Cutaneous manifestations consist of livedo reticularis, arterial and venous ulcers, and superficial thrombophlebitis.¹⁰ Laboratory testing for antiphospholipid antibodies and obtaining a detailed history of the patient’s cardiovascular health are crucial for diagnosis.⁹

Necrotizing fasciitis typically begins as an inconspicuous superficial cutaneous infection that rapidly is transmitted to the fascia. Infection can spread along fascial planes for several days without affecting the overlying skin, leading to delayed diagnosis.¹¹ The first signs to appear are disproportionate pain and a change in skin color to reddish-purple or bluish-gray. Next, the skin will become indurated, swollen, shiny, and more painful.¹¹ Skin breakdown will begin in 3 to 5 days and is accompanied by bullae and cutaneous gangrene. The involved area becomes painless due to thrombosis of the small vessels that supply the superficial nerves.¹² Septic shock ultimately will develop if untreated.

We present a rare case of nonuremic calciphylaxis. We encourage dermatologists to include calciphylaxis in the differential when evaluating any patient with a painful retiform rash or ulcerated eschar, even in the absence of renal disease.

The Diagnosis: Calciphylaxis

Calciphylaxis is a rare life-threatening condition that most often is seen in patients with end-stage renal disease at a rate of 35 per 10,000 chronic dialysis patients.¹ It less commonly has been described in nonuremic patients. The exact incidence of nonuremic calciphylaxis is unknown, but multiple risk factors have been identified, such as alcoholic liver disease, primary hyperparathyroidism, connective tissue diseases, and underlying malignancies. Other less common risk factors include type 2 diabetes mellitus, hypercoagulable disorders, obesity, hypoalbuminemia, and warfarin/ corticosteroid use.² However, most often no obvious triggers are identified.¹

Regardless of the etiology, calciphylaxis is characterized by the calcification of blood vessels and connective tissues, leading to vessel injury, intimal fibrosis, and thrombosis, followed by ischemic necrosis of the skin and soft tissue. It is postulated that microvascular calcification occurs as an active cell-mediated process that depends on the balance between the promoters and inhibitors of calcification.¹ In our patient, liver disease likely predisposed formation of calcification through the creation of an environment susceptible to vascular injury via decreased synthesis of proteins C and S.³ Synthesis of fetuin-A, a protein that acts as a circulating inhibitor of vascular ossification/calcification, also is decreased in calcification. Another inhibitor of calcification, matrix Gla protein, is unable to undergo activation through vitamin K–dependent carboxylation secondary to liver disease–induced vitamin K deficiency.³ Microvascular calcification without calciphylaxis may occur in other conditions such as type 2 diabetes mellitus. Therefore, clinicopathologic correlation is important in determining the diagnosis.

Calciphylaxis has a variety of clinical presentations depending on the stage of disease. It begins as a fixed, indurated, livedo reticularis–like plaque. The lesions become increasingly violaceous with intermixed areas of light blanched skin secondary to ischemia and then develop retiform pupura.⁴ Eventually, affected sites can become bullous and ulcerate or form a necrotic eschar. Severe pain is a cardinal feature throughout all stages.⁴ Lesions in nonuremic calciphylaxis most commonly are located in the central and/or proximal areas of the body.²

Clinical suspicion is essential for diagnosis. Skin biopsy is the standard method for confirmation in unclear cases. The classic histologic features include intravascular and extravascular calcification, microthrombosis, and fibrointimal hyperplasia of the small dermal and subcutaneous arteries and arterioles, leading to ischemia and intense septal panniculitis.¹ Von Kossa immunostaining is used to increase the detection of calcium deposits (Figure 1).¹ In addition to the classic changes, our case demonstrated a rare histologic variant with pseudoxanthoma elasticum (PXE)–like changes (Figure 2), which are thought to occur secondary to pathologic elastin fibrogenesis or increased proteolytic activity resulting in abnormal remodeling of the extracellular matrix in the setting of increased calcification of elastin fibers.⁵ Detection of PXE-like changes may be a helpful clue when specimens lack other characteristic signs.

Wound care, pain control, and addressing underlying causes are mainstays of therapy. Sodium thiosulfate, an antioxidant with vasodilatory properties that also inhibits adipocyte calcification and blocks the ability of adipocytes to induce calcification of vascular smooth-muscle cells, also is useful. Antibiotic prophylaxis is not indicated.¹

Even with treatment, both uremic and nonuremic calciphylaxis have a dismal prognosis; 1-year mortality is approximately 50% to 60% and rises to 80% at 2 years.⁴ Lesion location affects prognosis, and more proximal lesions portend worse outcomes. In patients with both proximal and distal lesions, there is a 90% mortality rate within 1 year. Ulceration also portends worse outcomes, as the wounds often are resistant to healing and act as nidi for infection.⁴ Septicemia is the most common cause of death.¹

Ecthyma gangrenosum is a cutaneous manifestation secondary to an infection most commonly associated with Pseudomonas aeruginosa.⁶ It often presents in immunocompromised patients with an underlying gramnegative septicemia.⁷ The clinical presentation initially begins with painless macules that rapidly progress into necrotic ulcers, usually accompanied by associated systemic symptoms such as fever, chills, and hypotension. Histopathology reveals numerous gram-negative rods around necrotic vessels.⁷

Idiopathic purpura fulminans is the rarest form of purpura fulminans. It is caused by autoantibody formation against protein S, resulting in protein S depletion and subsequent hypercoagulability.⁸ It usually occurs 7 to 10 days after the onset of a precipitating infection. Lesions begin as erythematous macules that progress within hours to painful, sharply defined areas of purpura and hemorrhagic cutaneous necrosis that may extend to deeper tissues.⁸ Secondary infection of gangrenous tissue may occur. Distribution usually is diffuse and signs of septic shock and disseminated intravascular coagulation usually are present.

Hughes syndrome, also known as antiphospholipid syndrome, is an acquired autoimmune disorder that manifests clinically as recurrent arterial or venous thrombosis.⁹ Cutaneous manifestations consist of livedo reticularis, arterial and venous ulcers, and superficial thrombophlebitis.¹⁰ Laboratory testing for antiphospholipid antibodies and obtaining a detailed history of the patient’s cardiovascular health are crucial for diagnosis.⁹

Necrotizing fasciitis typically begins as an inconspicuous superficial cutaneous infection that rapidly is transmitted to the fascia. Infection can spread along fascial planes for several days without affecting the overlying skin, leading to delayed diagnosis.¹¹ The first signs to appear are disproportionate pain and a change in skin color to reddish-purple or bluish-gray. Next, the skin will become indurated, swollen, shiny, and more painful.¹¹ Skin breakdown will begin in 3 to 5 days and is accompanied by bullae and cutaneous gangrene. The involved area becomes painless due to thrombosis of the small vessels that supply the superficial nerves.¹² Septic shock ultimately will develop if untreated.

We present a rare case of nonuremic calciphylaxis. We encourage dermatologists to include calciphylaxis in the differential when evaluating any patient with a painful retiform rash or ulcerated eschar, even in the absence of renal disease.

Despite overwhelming evidence indicating vaccines are safe and effective at preventing diseases,¹ physicians are still faced with the dilemma of convincing patients to receive their recommended vaccinations. The topic comes up regularly on television talk shows; presidential debates; or in new documentary films, such as “Vaxxed: From Cover-up to Catastrophe,” which was pulled from the Tribeca Film Festival in March 2016.² The central debate over vaccines traces back almost 20 years to the study published in The Lancet regarding the measles-mumps-rubella vaccine and the link to autism. Although the article was retracted in 2010 and no evidence has been found linking vaccines with autism,^1,3 vaccination coverage gaps still exist. These gaps can leave communities vulnerable to vaccine-preventable diseases.⁴ This lack of protection is especially glaring for the human papillomavirus (HPV) vaccine, putting health care professionals including dermatologists in the position of educating parents and guardians to have their children immunized.

More than 10 years after the federal government approved the first vaccines to fight the cancer-causing HPV, less than half of adolescent girls and only a fifth of adolescent boys are getting immunized. The reasons for the low vaccination rates are particularly complicated because they play not only into fears over vaccines but also over a perceived risk the vaccine may encourage sexual activity in adolescents, which has not been proven.⁵ Another factor is reluctance on the part of physicians to discuss the vaccine with patients and to fully embrace its lifesaving potential. A recent study showed how physicians are contributing to the low rate.⁶ “The single biggest barrier to increasing HPV vaccination is not receiving a health care provider’s recommendation,” said Harvard University researcher Melissa Gilkey.⁷

According to the Centers for Disease Control and Prevention (CDC), as of 2014, only 40% of adolescent girls aged 13 to 17 years had completed the 3-dose course of the HPV vaccine and just 22% of adolescent boys,⁸ which is short of the 80% public health goal set in 2010 by the federal government.⁹ Vexingly, HPV vaccination rates lag behind the other 2 vaccines recommended in the same age group: the tetanus-diphtheria-acellular pertussis booster (88%) and the vaccine to prevent meningococcal disease (79%).⁸

Malo et al⁶ surveyed 776 primary care physicians and reported that more than a quarter of primary care respondents (27%) do not strongly endorse the HPV vaccine when talking with their patients’ families. Nearly 2 in 5 physicians (39%) did not recommend on-time HPV vaccination for their male patients compared to 26% for female patients.⁶

The starkest findings, however, related to how the physicians approached their discussions with parents and guardians. Only half recommended the vaccine the same day they discussed it, and 59% said they approached discussions by assessing the child’s risk for contracting the disease rather than consistently recommending it to all children as a routine immunization.⁶

Despite physician hesitancy, when looking at the facts there should be no debate. In December 2014, the US Food and Drug Administration approved the 9-valent HPV (9vHPV) vaccine for males and females aged 9 to 26 years. The vaccine covers HPV types 6, 11, 16, and 18, which are part of the quadrivalent HPV (qHPV) vaccine, along with HPV types 31, 33, 45, 52, and 58. The 9vHPV vaccine has the potential to offer protection against 30% to 35% more high-grade cervical lesions and to increase cervical cancer prevention from approximately 70% to 90%.¹⁰ It also will protect against 90% of the virus strains responsible for causing anogenital warts. According to CDC estimates, for every year that coverage does not increase, an additional 4400 women will develop cervical cancer. If providers can push the HPV vaccination rate up to the goal rate of 80%, the CDC estimates that 53,000 cases of cervical cancer could be prevented during the lifetime of patients younger than 12 years.¹¹

In a clinical trial of 14,215 women, Joura et al¹² reported that the 9vHPV vaccine had an efficacy of 96.7% to prevent high-grade cervical, vulvar, or vaginal dysplasia related to HPV types 31, 33, 45, 52, and 58 in women. Antibody responses to HPV-6, 11, 16, and 18 among participants who received the 9vHPV vaccine were noninferior to those who received the qHPV vaccine. The incidence of disease related to HPV-6, 11, 16, and 18 was similar in the 2 vaccine groups. The introduction of 9vHPV vaccination in both males and females was cost saving compared to the qHPV vaccine in cost-effectiveness analyses. Injection-site reactions were slightly more common with the 9vHPV vaccine compared to the qHPV vaccine but were generally mild with less than 0.1% of study participants discontinuing due to vaccine-related adverse events.¹²

Additionally, the vaccine has the potential to offer protection against penile, anal, vulvar, vaginal, and oropharyngeal cancers (OPCs). Data from Joura et al¹² demonstrate that 55% of anal and penile cancers biopsied in the study carried the 5 HPV types that are included only in the 9vHPV vaccine.

Studies also show that the rate of OPC caused by HPV is rising rapidly and increasing more among men than women. Remarkably, OPC is projected to become more common than cervical cancer in 2020, with an estimated 70% of OPCs being caused by HPV in the United States.¹³ Theoretically, the 9vHPV vaccine has the potential to protect against even more cases of OPC because of its even broader coverage.¹⁴

Although optimal timing for the HPV vaccine would still be in preadolescence prior to sexual activity when exposure to HPV is less likely, CDC studies have shown benefit even in older patients who may have already been exposed to 1 or more HPV strains.¹⁵

Simply put, all the combined data highlight the overwhelming importance of HPV vaccination, with the 9vHPV vaccine representing a meaningful advantage over existing HPV vaccines. As physicians, we have a duty to our patients to emphasize the importance of this vaccine. It is a vaccine that has the potential to prevent multiple cancers, cancers for which we currently have no evidence-based prevention modalities, except in the case of cervical cancer. This responsibility falls on all providers, not just primary care providers. With a strong message from providers to vaccinate age-eligible males and females, we can move the United States from among the lowest rates of HPV vaccination to the highest, with subsequent reductions in the national cancer burden to follow.

Despite overwhelming evidence indicating vaccines are safe and effective at preventing diseases,¹ physicians are still faced with the dilemma of convincing patients to receive their recommended vaccinations. The topic comes up regularly on television talk shows; presidential debates; or in new documentary films, such as “Vaxxed: From Cover-up to Catastrophe,” which was pulled from the Tribeca Film Festival in March 2016.² The central debate over vaccines traces back almost 20 years to the study published in The Lancet regarding the measles-mumps-rubella vaccine and the link to autism. Although the article was retracted in 2010 and no evidence has been found linking vaccines with autism,^1,3 vaccination coverage gaps still exist. These gaps can leave communities vulnerable to vaccine-preventable diseases.⁴ This lack of protection is especially glaring for the human papillomavirus (HPV) vaccine, putting health care professionals including dermatologists in the position of educating parents and guardians to have their children immunized.

More than 10 years after the federal government approved the first vaccines to fight the cancer-causing HPV, less than half of adolescent girls and only a fifth of adolescent boys are getting immunized. The reasons for the low vaccination rates are particularly complicated because they play not only into fears over vaccines but also over a perceived risk the vaccine may encourage sexual activity in adolescents, which has not been proven.⁵ Another factor is reluctance on the part of physicians to discuss the vaccine with patients and to fully embrace its lifesaving potential. A recent study showed how physicians are contributing to the low rate.⁶ “The single biggest barrier to increasing HPV vaccination is not receiving a health care provider’s recommendation,” said Harvard University researcher Melissa Gilkey.⁷

According to the Centers for Disease Control and Prevention (CDC), as of 2014, only 40% of adolescent girls aged 13 to 17 years had completed the 3-dose course of the HPV vaccine and just 22% of adolescent boys,⁸ which is short of the 80% public health goal set in 2010 by the federal government.⁹ Vexingly, HPV vaccination rates lag behind the other 2 vaccines recommended in the same age group: the tetanus-diphtheria-acellular pertussis booster (88%) and the vaccine to prevent meningococcal disease (79%).⁸

Malo et al⁶ surveyed 776 primary care physicians and reported that more than a quarter of primary care respondents (27%) do not strongly endorse the HPV vaccine when talking with their patients’ families. Nearly 2 in 5 physicians (39%) did not recommend on-time HPV vaccination for their male patients compared to 26% for female patients.⁶

The starkest findings, however, related to how the physicians approached their discussions with parents and guardians. Only half recommended the vaccine the same day they discussed it, and 59% said they approached discussions by assessing the child’s risk for contracting the disease rather than consistently recommending it to all children as a routine immunization.⁶

Despite physician hesitancy, when looking at the facts there should be no debate. In December 2014, the US Food and Drug Administration approved the 9-valent HPV (9vHPV) vaccine for males and females aged 9 to 26 years. The vaccine covers HPV types 6, 11, 16, and 18, which are part of the quadrivalent HPV (qHPV) vaccine, along with HPV types 31, 33, 45, 52, and 58. The 9vHPV vaccine has the potential to offer protection against 30% to 35% more high-grade cervical lesions and to increase cervical cancer prevention from approximately 70% to 90%.¹⁰ It also will protect against 90% of the virus strains responsible for causing anogenital warts. According to CDC estimates, for every year that coverage does not increase, an additional 4400 women will develop cervical cancer. If providers can push the HPV vaccination rate up to the goal rate of 80%, the CDC estimates that 53,000 cases of cervical cancer could be prevented during the lifetime of patients younger than 12 years.¹¹

In a clinical trial of 14,215 women, Joura et al¹² reported that the 9vHPV vaccine had an efficacy of 96.7% to prevent high-grade cervical, vulvar, or vaginal dysplasia related to HPV types 31, 33, 45, 52, and 58 in women. Antibody responses to HPV-6, 11, 16, and 18 among participants who received the 9vHPV vaccine were noninferior to those who received the qHPV vaccine. The incidence of disease related to HPV-6, 11, 16, and 18 was similar in the 2 vaccine groups. The introduction of 9vHPV vaccination in both males and females was cost saving compared to the qHPV vaccine in cost-effectiveness analyses. Injection-site reactions were slightly more common with the 9vHPV vaccine compared to the qHPV vaccine but were generally mild with less than 0.1% of study participants discontinuing due to vaccine-related adverse events.¹²

Additionally, the vaccine has the potential to offer protection against penile, anal, vulvar, vaginal, and oropharyngeal cancers (OPCs). Data from Joura et al¹² demonstrate that 55% of anal and penile cancers biopsied in the study carried the 5 HPV types that are included only in the 9vHPV vaccine.

Studies also show that the rate of OPC caused by HPV is rising rapidly and increasing more among men than women. Remarkably, OPC is projected to become more common than cervical cancer in 2020, with an estimated 70% of OPCs being caused by HPV in the United States.¹³ Theoretically, the 9vHPV vaccine has the potential to protect against even more cases of OPC because of its even broader coverage.¹⁴

Although optimal timing for the HPV vaccine would still be in preadolescence prior to sexual activity when exposure to HPV is less likely, CDC studies have shown benefit even in older patients who may have already been exposed to 1 or more HPV strains.¹⁵

Simply put, all the combined data highlight the overwhelming importance of HPV vaccination, with the 9vHPV vaccine representing a meaningful advantage over existing HPV vaccines. As physicians, we have a duty to our patients to emphasize the importance of this vaccine. It is a vaccine that has the potential to prevent multiple cancers, cancers for which we currently have no evidence-based prevention modalities, except in the case of cervical cancer. This responsibility falls on all providers, not just primary care providers. With a strong message from providers to vaccinate age-eligible males and females, we can move the United States from among the lowest rates of HPV vaccination to the highest, with subsequent reductions in the national cancer burden to follow.

Despite overwhelming evidence indicating vaccines are safe and effective at preventing diseases,¹ physicians are still faced with the dilemma of convincing patients to receive their recommended vaccinations. The topic comes up regularly on television talk shows; presidential debates; or in new documentary films, such as “Vaxxed: From Cover-up to Catastrophe,” which was pulled from the Tribeca Film Festival in March 2016.² The central debate over vaccines traces back almost 20 years to the study published in The Lancet regarding the measles-mumps-rubella vaccine and the link to autism. Although the article was retracted in 2010 and no evidence has been found linking vaccines with autism,^1,3 vaccination coverage gaps still exist. These gaps can leave communities vulnerable to vaccine-preventable diseases.⁴ This lack of protection is especially glaring for the human papillomavirus (HPV) vaccine, putting health care professionals including dermatologists in the position of educating parents and guardians to have their children immunized.

More than 10 years after the federal government approved the first vaccines to fight the cancer-causing HPV, less than half of adolescent girls and only a fifth of adolescent boys are getting immunized. The reasons for the low vaccination rates are particularly complicated because they play not only into fears over vaccines but also over a perceived risk the vaccine may encourage sexual activity in adolescents, which has not been proven.⁵ Another factor is reluctance on the part of physicians to discuss the vaccine with patients and to fully embrace its lifesaving potential. A recent study showed how physicians are contributing to the low rate.⁶ “The single biggest barrier to increasing HPV vaccination is not receiving a health care provider’s recommendation,” said Harvard University researcher Melissa Gilkey.⁷

According to the Centers for Disease Control and Prevention (CDC), as of 2014, only 40% of adolescent girls aged 13 to 17 years had completed the 3-dose course of the HPV vaccine and just 22% of adolescent boys,⁸ which is short of the 80% public health goal set in 2010 by the federal government.⁹ Vexingly, HPV vaccination rates lag behind the other 2 vaccines recommended in the same age group: the tetanus-diphtheria-acellular pertussis booster (88%) and the vaccine to prevent meningococcal disease (79%).⁸

Malo et al⁶ surveyed 776 primary care physicians and reported that more than a quarter of primary care respondents (27%) do not strongly endorse the HPV vaccine when talking with their patients’ families. Nearly 2 in 5 physicians (39%) did not recommend on-time HPV vaccination for their male patients compared to 26% for female patients.⁶

The starkest findings, however, related to how the physicians approached their discussions with parents and guardians. Only half recommended the vaccine the same day they discussed it, and 59% said they approached discussions by assessing the child’s risk for contracting the disease rather than consistently recommending it to all children as a routine immunization.⁶

Despite physician hesitancy, when looking at the facts there should be no debate. In December 2014, the US Food and Drug Administration approved the 9-valent HPV (9vHPV) vaccine for males and females aged 9 to 26 years. The vaccine covers HPV types 6, 11, 16, and 18, which are part of the quadrivalent HPV (qHPV) vaccine, along with HPV types 31, 33, 45, 52, and 58. The 9vHPV vaccine has the potential to offer protection against 30% to 35% more high-grade cervical lesions and to increase cervical cancer prevention from approximately 70% to 90%.¹⁰ It also will protect against 90% of the virus strains responsible for causing anogenital warts. According to CDC estimates, for every year that coverage does not increase, an additional 4400 women will develop cervical cancer. If providers can push the HPV vaccination rate up to the goal rate of 80%, the CDC estimates that 53,000 cases of cervical cancer could be prevented during the lifetime of patients younger than 12 years.¹¹

In a clinical trial of 14,215 women, Joura et al¹² reported that the 9vHPV vaccine had an efficacy of 96.7% to prevent high-grade cervical, vulvar, or vaginal dysplasia related to HPV types 31, 33, 45, 52, and 58 in women. Antibody responses to HPV-6, 11, 16, and 18 among participants who received the 9vHPV vaccine were noninferior to those who received the qHPV vaccine. The incidence of disease related to HPV-6, 11, 16, and 18 was similar in the 2 vaccine groups. The introduction of 9vHPV vaccination in both males and females was cost saving compared to the qHPV vaccine in cost-effectiveness analyses. Injection-site reactions were slightly more common with the 9vHPV vaccine compared to the qHPV vaccine but were generally mild with less than 0.1% of study participants discontinuing due to vaccine-related adverse events.¹²

Additionally, the vaccine has the potential to offer protection against penile, anal, vulvar, vaginal, and oropharyngeal cancers (OPCs). Data from Joura et al¹² demonstrate that 55% of anal and penile cancers biopsied in the study carried the 5 HPV types that are included only in the 9vHPV vaccine.

Studies also show that the rate of OPC caused by HPV is rising rapidly and increasing more among men than women. Remarkably, OPC is projected to become more common than cervical cancer in 2020, with an estimated 70% of OPCs being caused by HPV in the United States.¹³ Theoretically, the 9vHPV vaccine has the potential to protect against even more cases of OPC because of its even broader coverage.¹⁴

Although optimal timing for the HPV vaccine would still be in preadolescence prior to sexual activity when exposure to HPV is less likely, CDC studies have shown benefit even in older patients who may have already been exposed to 1 or more HPV strains.¹⁵

Simply put, all the combined data highlight the overwhelming importance of HPV vaccination, with the 9vHPV vaccine representing a meaningful advantage over existing HPV vaccines. As physicians, we have a duty to our patients to emphasize the importance of this vaccine. It is a vaccine that has the potential to prevent multiple cancers, cancers for which we currently have no evidence-based prevention modalities, except in the case of cervical cancer. This responsibility falls on all providers, not just primary care providers. With a strong message from providers to vaccinate age-eligible males and females, we can move the United States from among the lowest rates of HPV vaccination to the highest, with subsequent reductions in the national cancer burden to follow.