Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Lab rat

Photo by Janet Stevens

Human neural stem cell treatments are showing promise for reversing learning and memory deficits after chemotherapy, according to an article in Cancer Research.

Investigators found that transplanting stem cells in rats a week after they completed a series of chemotherapy sessions restored a range of cognitive functions, as

measured a month later via behavioral testing.

In contrast, animals that did not receive stem cells showed significant learning and memory impairment.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said study author Charles Limoli, PhD, of the University of California, Irvine.

For this study, Dr Limoli and his colleagues transplanted adult neural stem cells into the brains of rats that had received cyclophosphamide.

The cells migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

The investigators also found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Dr Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

Fitness class

Middle-aged women who are physically active a few times a week have a lower risk of vascular events than inactive women, according to research published in Circulation.

Women who engaged in physical activity 2 to 3 times per week were about 20% less likely to develop heart disease, stroke, or venous thromboembolism (VTE) than women who reported little or no activity.

However, more frequent activity was associated with an increased risk of vascular events.

“Inactive middle-aged women should try to do some activity regularly,” said study author Miranda Armstrong, PhD, of the University of Oxford in the UK.

“However, to prevent heart disease, stroke, and blood clots, women don’t need to do very frequent activity, as this seems to provide little additional benefit above that of moderately frequent activity.”

Dr Armstrong and her colleagues analyzed 1.1 million women in the UK with no history of cancer, heart disease, stroke, VTE, or diabetes who joined the Million Women Study from 1996 to 2001. Their average age at study entry was 56.

The women reported their level of physical activity—hours spent walking, cycling, gardening, and doing housework—at the beginning of the study and 3 years later. The researchers then examined hospital admissions and deaths in relation to participants’ responses.

During an average follow-up of 9 years, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first VTE.

Women who reportedly engaged in moderate physical activity had a significantly lower risk of each event compared to inactive women (P<0.001 for all).

On the other hand, the risk of cerebrovascular disease and VTE were significantly higher in women who engaged in physical activity daily, when compared to women who reported physical activity 2 to 3 times a week (P<0.001).

For coronary heart disease, women who reported daily activity had a significantly higher risk only if that activity was strenuous (P=0.002)—not for any physical activity (P=0.8).

Fitness class

Middle-aged women who are physically active a few times a week have a lower risk of vascular events than inactive women, according to research published in Circulation.

Women who engaged in physical activity 2 to 3 times per week were about 20% less likely to develop heart disease, stroke, or venous thromboembolism (VTE) than women who reported little or no activity.

However, more frequent activity was associated with an increased risk of vascular events.

“Inactive middle-aged women should try to do some activity regularly,” said study author Miranda Armstrong, PhD, of the University of Oxford in the UK.

“However, to prevent heart disease, stroke, and blood clots, women don’t need to do very frequent activity, as this seems to provide little additional benefit above that of moderately frequent activity.”

Dr Armstrong and her colleagues analyzed 1.1 million women in the UK with no history of cancer, heart disease, stroke, VTE, or diabetes who joined the Million Women Study from 1996 to 2001. Their average age at study entry was 56.

The women reported their level of physical activity—hours spent walking, cycling, gardening, and doing housework—at the beginning of the study and 3 years later. The researchers then examined hospital admissions and deaths in relation to participants’ responses.

During an average follow-up of 9 years, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first VTE.

Women who reportedly engaged in moderate physical activity had a significantly lower risk of each event compared to inactive women (P<0.001 for all).

On the other hand, the risk of cerebrovascular disease and VTE were significantly higher in women who engaged in physical activity daily, when compared to women who reported physical activity 2 to 3 times a week (P<0.001).

For coronary heart disease, women who reported daily activity had a significantly higher risk only if that activity was strenuous (P=0.002)—not for any physical activity (P=0.8).

Fitness class

Middle-aged women who are physically active a few times a week have a lower risk of vascular events than inactive women, according to research published in Circulation.

Women who engaged in physical activity 2 to 3 times per week were about 20% less likely to develop heart disease, stroke, or venous thromboembolism (VTE) than women who reported little or no activity.

However, more frequent activity was associated with an increased risk of vascular events.

“Inactive middle-aged women should try to do some activity regularly,” said study author Miranda Armstrong, PhD, of the University of Oxford in the UK.

“However, to prevent heart disease, stroke, and blood clots, women don’t need to do very frequent activity, as this seems to provide little additional benefit above that of moderately frequent activity.”

Dr Armstrong and her colleagues analyzed 1.1 million women in the UK with no history of cancer, heart disease, stroke, VTE, or diabetes who joined the Million Women Study from 1996 to 2001. Their average age at study entry was 56.

The women reported their level of physical activity—hours spent walking, cycling, gardening, and doing housework—at the beginning of the study and 3 years later. The researchers then examined hospital admissions and deaths in relation to participants’ responses.

During an average follow-up of 9 years, 49,113 women had a first coronary heart disease event, 17,822 had a first cerebrovascular event, and 14,550 had a first VTE.

Women who reportedly engaged in moderate physical activity had a significantly lower risk of each event compared to inactive women (P<0.001 for all).

On the other hand, the risk of cerebrovascular disease and VTE were significantly higher in women who engaged in physical activity daily, when compared to women who reported physical activity 2 to 3 times a week (P<0.001).

For coronary heart disease, women who reported daily activity had a significantly higher risk only if that activity was strenuous (P=0.002)—not for any physical activity (P=0.8).

Age is the most important risk factor for stroke in patients with atrial fibrillation, and not all stroke risk factors in the CHA2DS2-VASc score carry equal risk, a retrospective, population-based study showed.

Analysis of data from 186,570 Taiwanese patients with atrial fibrillation (AF) found that the risk of ischemic stroke ranged from 1.96% per year for men with vascular diseases to 3.5% per year for those aged 65-74 years. In women, the risk increased from 1.91% per year for women with hypertension to 3.34% per year for those aged 65-74 years, wrote Dr. Tze-Fan Chao of Taipei (Taiwan) Veterans General Hospital and coauthors (J. Am. Coll. Cardiol. 2015;65:635-42 [doi: 10.1016/j.jacc.2014.11.046]).

The study results showed that male AF patients with a CHA2DS2-VASc score of 1 had an annual stroke rate of 2.75%; women with a CHA2DS2-VASc score of 2 had a greater than two-fold increase in stroke risk, compared with women with a score of 1.

“Our study is the first population-based investigation analyzing the risk of ischemic stroke in nonanticoagulated AF male patients with a CHA2DS2-VASc score of 1 and female patients with a CHA2DS2-VASc score of 2, according to the specific covariates composing the CHA2DS2-VASc score,” Dr. Chao wrote.

The investigators cited several limitations. One is that they were unable to determine whether the cause of ischemic stroke was tied to AF-related thromboembolism or atherosclerosis and thrombosis of the cerebral artery. This limitation, however, was common among previous randomized trials, they noted.

The study was partly supported by grants from the National Science Council and Taipei (Taiwan) Veterans General Hospital. One author declared consultancies and speakers fees from private industry. No other conflicts of interest were declared.

Age is the most important risk factor for stroke in patients with atrial fibrillation, and not all stroke risk factors in the CHA2DS2-VASc score carry equal risk, a retrospective, population-based study showed.

Analysis of data from 186,570 Taiwanese patients with atrial fibrillation (AF) found that the risk of ischemic stroke ranged from 1.96% per year for men with vascular diseases to 3.5% per year for those aged 65-74 years. In women, the risk increased from 1.91% per year for women with hypertension to 3.34% per year for those aged 65-74 years, wrote Dr. Tze-Fan Chao of Taipei (Taiwan) Veterans General Hospital and coauthors (J. Am. Coll. Cardiol. 2015;65:635-42 [doi: 10.1016/j.jacc.2014.11.046]).

The study results showed that male AF patients with a CHA2DS2-VASc score of 1 had an annual stroke rate of 2.75%; women with a CHA2DS2-VASc score of 2 had a greater than two-fold increase in stroke risk, compared with women with a score of 1.

“Our study is the first population-based investigation analyzing the risk of ischemic stroke in nonanticoagulated AF male patients with a CHA2DS2-VASc score of 1 and female patients with a CHA2DS2-VASc score of 2, according to the specific covariates composing the CHA2DS2-VASc score,” Dr. Chao wrote.

The investigators cited several limitations. One is that they were unable to determine whether the cause of ischemic stroke was tied to AF-related thromboembolism or atherosclerosis and thrombosis of the cerebral artery. This limitation, however, was common among previous randomized trials, they noted.

The study was partly supported by grants from the National Science Council and Taipei (Taiwan) Veterans General Hospital. One author declared consultancies and speakers fees from private industry. No other conflicts of interest were declared.

Age is the most important risk factor for stroke in patients with atrial fibrillation, and not all stroke risk factors in the CHA2DS2-VASc score carry equal risk, a retrospective, population-based study showed.

Analysis of data from 186,570 Taiwanese patients with atrial fibrillation (AF) found that the risk of ischemic stroke ranged from 1.96% per year for men with vascular diseases to 3.5% per year for those aged 65-74 years. In women, the risk increased from 1.91% per year for women with hypertension to 3.34% per year for those aged 65-74 years, wrote Dr. Tze-Fan Chao of Taipei (Taiwan) Veterans General Hospital and coauthors (J. Am. Coll. Cardiol. 2015;65:635-42 [doi: 10.1016/j.jacc.2014.11.046]).

The study results showed that male AF patients with a CHA2DS2-VASc score of 1 had an annual stroke rate of 2.75%; women with a CHA2DS2-VASc score of 2 had a greater than two-fold increase in stroke risk, compared with women with a score of 1.

“Our study is the first population-based investigation analyzing the risk of ischemic stroke in nonanticoagulated AF male patients with a CHA2DS2-VASc score of 1 and female patients with a CHA2DS2-VASc score of 2, according to the specific covariates composing the CHA2DS2-VASc score,” Dr. Chao wrote.

The investigators cited several limitations. One is that they were unable to determine whether the cause of ischemic stroke was tied to AF-related thromboembolism or atherosclerosis and thrombosis of the cerebral artery. This limitation, however, was common among previous randomized trials, they noted.

The study was partly supported by grants from the National Science Council and Taipei (Taiwan) Veterans General Hospital. One author declared consultancies and speakers fees from private industry. No other conflicts of interest were declared.

Strenuous daily exercise actually increased the risk of coronary heart disease, venous thromboembolism, and cerebrovascular disease, compared with moderate physical activity, according to new data from the Million Women Study.

At baseline, the 1.1 million women who participated in the study were 55.9 years old on average, with a mean body mass index of 26 kg/m². Over the next 9 years, those reporting moderate activity had significantly lower risks of all three conditions than did inactive women, according to a study published online Feb. 16 in Circulation [doi:10.1161/CIRCULATIONAHA.114.010296].

©Monkey Business Images/thinkstockphotos.com

However, women who undertook daily strenuous activity had a 15% increase in their risk of coronary heart disease, a 25% increase in cerebrovascular disease risk, and a 29% increase in venous thromboembolism (VTE) risk, compared with those who exercised strenuously two to three times a week, judging from the findings of Cox regression models that controlled for BMI, smoking, and alcohol consumption.

“Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and even an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group,” wrote Dr. Miranda E. G. Armstrong of the University of Oxford, England, and colleagues.

The study was supported by the UK Medical Research Council, Cancer Research UK, and the BHF Centre of Research Excellence. There were no other conflicts of interest declared.

Strenuous daily exercise actually increased the risk of coronary heart disease, venous thromboembolism, and cerebrovascular disease, compared with moderate physical activity, according to new data from the Million Women Study.

At baseline, the 1.1 million women who participated in the study were 55.9 years old on average, with a mean body mass index of 26 kg/m². Over the next 9 years, those reporting moderate activity had significantly lower risks of all three conditions than did inactive women, according to a study published online Feb. 16 in Circulation [doi:10.1161/CIRCULATIONAHA.114.010296].

©Monkey Business Images/thinkstockphotos.com

However, women who undertook daily strenuous activity had a 15% increase in their risk of coronary heart disease, a 25% increase in cerebrovascular disease risk, and a 29% increase in venous thromboembolism (VTE) risk, compared with those who exercised strenuously two to three times a week, judging from the findings of Cox regression models that controlled for BMI, smoking, and alcohol consumption.

“Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and even an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group,” wrote Dr. Miranda E. G. Armstrong of the University of Oxford, England, and colleagues.

The study was supported by the UK Medical Research Council, Cancer Research UK, and the BHF Centre of Research Excellence. There were no other conflicts of interest declared.

Strenuous daily exercise actually increased the risk of coronary heart disease, venous thromboembolism, and cerebrovascular disease, compared with moderate physical activity, according to new data from the Million Women Study.

At baseline, the 1.1 million women who participated in the study were 55.9 years old on average, with a mean body mass index of 26 kg/m². Over the next 9 years, those reporting moderate activity had significantly lower risks of all three conditions than did inactive women, according to a study published online Feb. 16 in Circulation [doi:10.1161/CIRCULATIONAHA.114.010296].

©Monkey Business Images/thinkstockphotos.com

However, women who undertook daily strenuous activity had a 15% increase in their risk of coronary heart disease, a 25% increase in cerebrovascular disease risk, and a 29% increase in venous thromboembolism (VTE) risk, compared with those who exercised strenuously two to three times a week, judging from the findings of Cox regression models that controlled for BMI, smoking, and alcohol consumption.

“Among active women, there was little evidence of progressive reductions in risk with more frequent activity, and even an increase in risk for CHD, cerebrovascular disease, and VTE in the most active group,” wrote Dr. Miranda E. G. Armstrong of the University of Oxford, England, and colleagues.

The study was supported by the UK Medical Research Council, Cancer Research UK, and the BHF Centre of Research Excellence. There were no other conflicts of interest declared.

Hematopoietic stem cells

in the bone marrow

Scientists have reported a method for equipping mouse hematopoietic stem cells (HSCs) with a fluorescent marker that can be switched on from the outside.

Using this tool, they were able to observe how HSCs mature into blood cells under normal conditions, and they developed a mathematical model of the dynamics of hematopoiesis.

The research suggests the normal process of hematopoiesis differs from what scientists previously assumed when using data from stem cell transplants.

“[A] problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice,” said study author Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism.”

The researchers described this model in Nature.

The team genetically modified mice by introducing a protein into their HSCs that sends out a yellow fluorescent signal. This marker can be turned on by administering a reagent. All daughter cells that arise from a cell containing the marker also send out a light signal.

When they turned on the marker in adult mice, the researchers observed that at least a third of a mouse’s HSCs (approximately 5000 cells) produce differentiated progenitor cells.

“This was the first surprise,” said study author Katrin Busch, also of DKFZ. “Until now, scientists had believed that, in the normal state, very few stem cells—only about 10—are actively involved in blood formation.”

The researchers performed a mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. They were surprised to find that, under normal conditions, HSCs do not replenish blood cells.

Instead, blood cells are supplied by the first progenitor cells that develop during the differentiation step. These cells are able to regenerate themselves for a long time, though not quite as long as HSCs.

To ensure that the population of this cell type never runs out, HSCs must occasionally produce a couple of new first progenitors.

During murine embryonic development, however, the situation is different. To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from HSCs.

The researchers were also able to accelerate this process in adult mice by artificially depleting their white blood cells. Under these conditions, HSCs increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells.

During this process, several hundred times more myeloid cells (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells).

“When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost,” Dr Rodewald noted.

“Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism.”

The researchers now plan to use their model to investigate the impact of pathogenic challenges to blood formation; for example, in cancer, cachexia, or infection. This method would also allow them to follow potential aging processes in HSCs as they occur naturally in a living organism.

Hematopoietic stem cells

in the bone marrow

Scientists have reported a method for equipping mouse hematopoietic stem cells (HSCs) with a fluorescent marker that can be switched on from the outside.

Using this tool, they were able to observe how HSCs mature into blood cells under normal conditions, and they developed a mathematical model of the dynamics of hematopoiesis.

The research suggests the normal process of hematopoiesis differs from what scientists previously assumed when using data from stem cell transplants.

“[A] problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice,” said study author Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism.”

The researchers described this model in Nature.

The team genetically modified mice by introducing a protein into their HSCs that sends out a yellow fluorescent signal. This marker can be turned on by administering a reagent. All daughter cells that arise from a cell containing the marker also send out a light signal.

When they turned on the marker in adult mice, the researchers observed that at least a third of a mouse’s HSCs (approximately 5000 cells) produce differentiated progenitor cells.

“This was the first surprise,” said study author Katrin Busch, also of DKFZ. “Until now, scientists had believed that, in the normal state, very few stem cells—only about 10—are actively involved in blood formation.”

The researchers performed a mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. They were surprised to find that, under normal conditions, HSCs do not replenish blood cells.

Instead, blood cells are supplied by the first progenitor cells that develop during the differentiation step. These cells are able to regenerate themselves for a long time, though not quite as long as HSCs.

To ensure that the population of this cell type never runs out, HSCs must occasionally produce a couple of new first progenitors.

During murine embryonic development, however, the situation is different. To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from HSCs.

The researchers were also able to accelerate this process in adult mice by artificially depleting their white blood cells. Under these conditions, HSCs increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells.

During this process, several hundred times more myeloid cells (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells).

“When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost,” Dr Rodewald noted.

“Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism.”

The researchers now plan to use their model to investigate the impact of pathogenic challenges to blood formation; for example, in cancer, cachexia, or infection. This method would also allow them to follow potential aging processes in HSCs as they occur naturally in a living organism.

Hematopoietic stem cells

in the bone marrow

Scientists have reported a method for equipping mouse hematopoietic stem cells (HSCs) with a fluorescent marker that can be switched on from the outside.

Using this tool, they were able to observe how HSCs mature into blood cells under normal conditions, and they developed a mathematical model of the dynamics of hematopoiesis.

The research suggests the normal process of hematopoiesis differs from what scientists previously assumed when using data from stem cell transplants.

“[A] problem with almost all research on hematopoiesis in past decades is that it has been restricted to experiments in culture or using transplantation into mice,” said study author Hans-Reimer Rodewald, PhD, of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg.

“We have now developed the first model where we can observe the development of a stem cell into a mature blood cell in a living organism.”

The researchers described this model in Nature.

The team genetically modified mice by introducing a protein into their HSCs that sends out a yellow fluorescent signal. This marker can be turned on by administering a reagent. All daughter cells that arise from a cell containing the marker also send out a light signal.

When they turned on the marker in adult mice, the researchers observed that at least a third of a mouse’s HSCs (approximately 5000 cells) produce differentiated progenitor cells.

“This was the first surprise,” said study author Katrin Busch, also of DKFZ. “Until now, scientists had believed that, in the normal state, very few stem cells—only about 10—are actively involved in blood formation.”

The researchers performed a mathematical analysis of these experimental data to provide additional insight into blood stem cell dynamics. They were surprised to find that, under normal conditions, HSCs do not replenish blood cells.

Instead, blood cells are supplied by the first progenitor cells that develop during the differentiation step. These cells are able to regenerate themselves for a long time, though not quite as long as HSCs.

To ensure that the population of this cell type never runs out, HSCs must occasionally produce a couple of new first progenitors.

During murine embryonic development, however, the situation is different. To build up the system, all mature blood and immune cells develop much more rapidly and almost completely from HSCs.

The researchers were also able to accelerate this process in adult mice by artificially depleting their white blood cells. Under these conditions, HSCs increase the formation of first progenitor cells, which then immediately start supplying new, mature blood cells.

During this process, several hundred times more myeloid cells (thrombocytes, erythrocytes, granulocytes, monocytes) form than long-lived lymphocytes (T cells, B cells, natural killer cells).

“When we transplanted our labeled blood stem cells from the bone marrow into other mice, only a few stem cells were active in the recipients, and many stem cells were lost,” Dr Rodewald noted.

“Our new data therefore show that the findings obtained up until now using transplanted stem cells can surely not be reflective of normal hematopoiesis. On the contrary, transplantation is an exception. This shows how important it is that we actually follow hematopoiesis under normal conditions in a living organism.”

The researchers now plan to use their model to investigate the impact of pathogenic challenges to blood formation; for example, in cancer, cachexia, or infection. This method would also allow them to follow potential aging processes in HSCs as they occur naturally in a living organism.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Leukemia patient

Photo by Bill Branson

New research indicates that patients who undergo cranial radiotherapy (CRT) for pediatric cancer may have an increased risk of anterior pituitary deficits decades after they receive treatment.

The study also suggests these deficiencies often go undiagnosed, although they can impact health and quality of life.

These discoveries, reported in the Journal of Clinical Oncology, highlight the need for lifelong health screenings of pediatric cancer survivors, researchers say.

They studied 748 survivors of leukemia, brain, and other cancers, assessing the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulating hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after CRT.

The researchers observed survivors for a mean of 27.3 years (range, 10.8 to 47.7 years).

GHD was the most common deficiency, with an estimated point prevalence of 46.5%. The estimated point prevalence was 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD. The cumulative incidence of the deficiencies increased with follow-up.

Higher doses of CRT were associated with an increased risk of deficiencies. Doses of 22 to 29.9 Gy were significantly associated with GHD, doses of 22 Gy or higher were associated with LH/FSHD, and doses of 30 Gy or greater were associated with TSHD and ACTHD.

The researchers also found that male sex and obesity were significantly associated with LH/FSHD, and white race was significantly associated with LH/FSHD and TSHD.

GHD and LH/FSHD were the deficiencies that were most likely to be undiagnosed. GHD was not treated in 99.7% of affected survivors, and LH/FSHD was not treated in 78.5%.

There was an association between untreated GHD and reduced strength and muscle size, low energy, poor fitness, and abdominal obesity. Untreated LH/FSHD was associated with low bone mineral density, reduced fitness, high blood pressure, abdominal obesity, and elevated cholesterol and other blood lipids.

“This study provides much needed long-term follow-up data and shows that the risk of pituitary problems follows these survivors into adulthood,” said study author Wassim Chemaitilly, MD, of St Jude Children’s Research Center in Memphis, Tennessee.

“The findings also underscore the need for the nation’s growing population of childhood cancer survivors to get recommended health screenings, and the challenges they face in trying to navigate the healthcare system and follow that advice.”

Guidelines developed by the Children’s Oncology Group call for childhood cancer survivors treated with CRT to have their pituitary function checked annually. Dr Chemaitilly said the high percentage of survivors with previously undiagnosed hormone deficiencies in this study highlights the need for new strategies to ensure survivors receive recommended health checks.

He also said additional research is needed to help guide the management of adults with growth hormone deficiency. Treatment is expensive, and the long-term benefits in adults are uncertain.

Micrograph showing MM

In a final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend pomalidomide (Imnovid) for the treatment of multiple myeloma (MM).

NICE recommends thalidomide for most MM patients as a first-line treatment and bortezomib for patients who are unable to receive thalidomide and those who fail first-line treatment.

For patients who have received 2 prior therapies, the agency recommends lenalidomide.

NICE considered pomalidomide for use in MM patients after their third or subsequent relapse.

The agency said it could not recommend pomalidomide, in combination with dexamethasone, within its marketing authorization, which is to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on their last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets pomalidomide, showed that the drug does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE’s final draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues its final guidance, National Health Service (NHS) bodies should make decisions locally on the funding of specific treatments.

This draft guidance does not mean that patients currently taking pomalidomide will stop receiving it. They have the option to continue treatment until they and their clinicians consider it appropriate to stop.

And pomalidomide is recommended for use within NHS Scotland.

Insufficient evidence

The committee advising NICE was not able to judge with any confidence how much more effective pomalidomide was compared with current treatment options based on the evidence provided by Celgene before and after consultation.

However, bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial, and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months, on average, when compared with standard NHS care.

Nevertheless, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years (QALYs) gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

Also, the committee concluded that the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on the QALYs gained.

All cost-per-QALY figures presented by Celgene were over £50,000 compared with bortezomib and over £70,000 compared with bendamustine plus thalidomide and dexamethasone. And the figures would further increase when a number of more realistic assumptions were included in the model, the committee said.

A pack of pomalidomide (21 tablets of 1 mg, 2 mg, 3 mg, or 4 mg) costs £8884. The recommended dosage of the drug is 4 mg once daily, taken on days 1 to 21 of repeated 28 day cycles. Treatment should continue until disease progression.

Micrograph showing MM

In a final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend pomalidomide (Imnovid) for the treatment of multiple myeloma (MM).

NICE recommends thalidomide for most MM patients as a first-line treatment and bortezomib for patients who are unable to receive thalidomide and those who fail first-line treatment.

For patients who have received 2 prior therapies, the agency recommends lenalidomide.

NICE considered pomalidomide for use in MM patients after their third or subsequent relapse.

The agency said it could not recommend pomalidomide, in combination with dexamethasone, within its marketing authorization, which is to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on their last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets pomalidomide, showed that the drug does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE’s final draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues its final guidance, National Health Service (NHS) bodies should make decisions locally on the funding of specific treatments.

This draft guidance does not mean that patients currently taking pomalidomide will stop receiving it. They have the option to continue treatment until they and their clinicians consider it appropriate to stop.

And pomalidomide is recommended for use within NHS Scotland.

Insufficient evidence

The committee advising NICE was not able to judge with any confidence how much more effective pomalidomide was compared with current treatment options based on the evidence provided by Celgene before and after consultation.

However, bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial, and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months, on average, when compared with standard NHS care.

Nevertheless, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years (QALYs) gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

Also, the committee concluded that the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on the QALYs gained.

All cost-per-QALY figures presented by Celgene were over £50,000 compared with bortezomib and over £70,000 compared with bendamustine plus thalidomide and dexamethasone. And the figures would further increase when a number of more realistic assumptions were included in the model, the committee said.

A pack of pomalidomide (21 tablets of 1 mg, 2 mg, 3 mg, or 4 mg) costs £8884. The recommended dosage of the drug is 4 mg once daily, taken on days 1 to 21 of repeated 28 day cycles. Treatment should continue until disease progression.

Micrograph showing MM

In a final draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend pomalidomide (Imnovid) for the treatment of multiple myeloma (MM).

NICE recommends thalidomide for most MM patients as a first-line treatment and bortezomib for patients who are unable to receive thalidomide and those who fail first-line treatment.

For patients who have received 2 prior therapies, the agency recommends lenalidomide.

NICE considered pomalidomide for use in MM patients after their third or subsequent relapse.

The agency said it could not recommend pomalidomide, in combination with dexamethasone, within its marketing authorization, which is to treat adults with relapsed and refractory MM who have had at least 2 prior treatments, including lenalidomide and bortezomib, and whose disease has progressed on their last therapy.

“Unfortunately, we cannot recommend pomalidomide, as the analyses from Celgene, the company that markets pomalidomide, showed that the drug does not offer enough benefit to justify its high price,” said Sir Andrew Dillon, NICE chief executive.

NICE’s final draft guidance is now with consultees, who have the opportunity to appeal against it. Until NICE issues its final guidance, National Health Service (NHS) bodies should make decisions locally on the funding of specific treatments.

This draft guidance does not mean that patients currently taking pomalidomide will stop receiving it. They have the option to continue treatment until they and their clinicians consider it appropriate to stop.

And pomalidomide is recommended for use within NHS Scotland.

Insufficient evidence

The committee advising NICE was not able to judge with any confidence how much more effective pomalidomide was compared with current treatment options based on the evidence provided by Celgene before and after consultation.

However, bearing in mind the magnitude of the differences in the overall survival estimates between pomalidomide and high-dose dexamethasone in the phase 3 MM-003 trial, and all data presented to the committee for comparators, the committee was persuaded that pomalidomide extends life for at least 3 months, on average, when compared with standard NHS care.

Nevertheless, considering the incremental cost-effectiveness ratios, the committee concluded that, even with the end-of-life criteria met, the weighting that would have to be placed on the quality-adjusted life-years (QALYs) gained would be too high to consider pomalidomide a cost-effective use of NHS resources.

Also, the committee concluded that the uncertainty in the relative effectiveness of pomalidomide compared with established NHS practice would affect any weighting that could be placed on the QALYs gained.

All cost-per-QALY figures presented by Celgene were over £50,000 compared with bortezomib and over £70,000 compared with bendamustine plus thalidomide and dexamethasone. And the figures would further increase when a number of more realistic assumptions were included in the model, the committee said.

A pack of pomalidomide (21 tablets of 1 mg, 2 mg, 3 mg, or 4 mg) costs £8884. The recommended dosage of the drug is 4 mg once daily, taken on days 1 to 21 of repeated 28 day cycles. Treatment should continue until disease progression.

CT scan showing PE

Photo courtesy of Medical

College of Georgia

Pulmonary embolectomy, a procedure that was virtually abandoned in the 1950s because it resulted in high mortality rates, may actually prevent more deaths in severely ill patients with pulmonary embolism (PE) than current drug therapies alone, according to research published in the Texas Heart Institute Journal.

More than 2 dozen studies conducted between 1961 and 1984 suggest the death rate associated with pulmonary embolectomy is 32%.

But safer techniques have led to better outcomes, and surgeons continue to take their most seriously ill PE patients into the operating room.

Still, Alan R. Hartman, MD, of North Shore-LIJ Health System in Great Neck, New York, and his colleagues wanted to determine just how successful the surgery is and which patients are the best candidates for surgery.

To find out, the team went back into the surgical archives and identified 96 patients who underwent surgery during a 9-year period (from 2003 to 2011). The researchers assessed how many patients survived in the month following surgery and compared the results to historical mortality data from patients who did not undergo surgery.

All of the patients who had undergone surgery had acute, centrally located PE and severe global hyperkinetic right ventricular dysfunction.

All patients had either a large clot burden in the main pulmonary arteries or a saddle embolism. None of the patients had a history of chronic pulmonary thrombolytic disease or evidence of chronic disease on a computed-tomographic-angiography scan.

They all made it to surgery within an hour of the embolism. The surgery was performed through cardiopulmonary bypass, at normal body temperature, and without aortic cross-clamping, thus avoiding myocardial ischemia.

A pulmonary arteriotomy and clot extraction were performed under direct vision, according to Dr Hartman, which he believes is critical to the success of the procedure.

The mortality rate was 4.2%, which is lower than any other published reports. In addition, 68 patients (73.9%) were discharged home or to rehabilitation facilities.

Those patients with low blood pressure had a higher 30-day mortality rate—12.5% compared to 1.4% in those with normal blood pressure. Patients with low blood pressure also spent a longer time in the hospital—13.4 days compared to 9.1 days in patients with normal blood pressure.

Based on these results, the researchers concluded that acute pulmonary embolectomy can be a viable procedure for patients with severe, globally hypokinetic right ventricular dysfunction, with or without hemodynamic compromise.

However, they cautioned that rates of success are dependent upon experience, surgical ability, and careful patient selection.

CT scan showing PE

Photo courtesy of Medical

College of Georgia

Pulmonary embolectomy, a procedure that was virtually abandoned in the 1950s because it resulted in high mortality rates, may actually prevent more deaths in severely ill patients with pulmonary embolism (PE) than current drug therapies alone, according to research published in the Texas Heart Institute Journal.

More than 2 dozen studies conducted between 1961 and 1984 suggest the death rate associated with pulmonary embolectomy is 32%.

But safer techniques have led to better outcomes, and surgeons continue to take their most seriously ill PE patients into the operating room.

Still, Alan R. Hartman, MD, of North Shore-LIJ Health System in Great Neck, New York, and his colleagues wanted to determine just how successful the surgery is and which patients are the best candidates for surgery.

To find out, the team went back into the surgical archives and identified 96 patients who underwent surgery during a 9-year period (from 2003 to 2011). The researchers assessed how many patients survived in the month following surgery and compared the results to historical mortality data from patients who did not undergo surgery.

All of the patients who had undergone surgery had acute, centrally located PE and severe global hyperkinetic right ventricular dysfunction.

All patients had either a large clot burden in the main pulmonary arteries or a saddle embolism. None of the patients had a history of chronic pulmonary thrombolytic disease or evidence of chronic disease on a computed-tomographic-angiography scan.

They all made it to surgery within an hour of the embolism. The surgery was performed through cardiopulmonary bypass, at normal body temperature, and without aortic cross-clamping, thus avoiding myocardial ischemia.

A pulmonary arteriotomy and clot extraction were performed under direct vision, according to Dr Hartman, which he believes is critical to the success of the procedure.

The mortality rate was 4.2%, which is lower than any other published reports. In addition, 68 patients (73.9%) were discharged home or to rehabilitation facilities.

Those patients with low blood pressure had a higher 30-day mortality rate—12.5% compared to 1.4% in those with normal blood pressure. Patients with low blood pressure also spent a longer time in the hospital—13.4 days compared to 9.1 days in patients with normal blood pressure.

Based on these results, the researchers concluded that acute pulmonary embolectomy can be a viable procedure for patients with severe, globally hypokinetic right ventricular dysfunction, with or without hemodynamic compromise.

However, they cautioned that rates of success are dependent upon experience, surgical ability, and careful patient selection.

CT scan showing PE

Photo courtesy of Medical

College of Georgia

Pulmonary embolectomy, a procedure that was virtually abandoned in the 1950s because it resulted in high mortality rates, may actually prevent more deaths in severely ill patients with pulmonary embolism (PE) than current drug therapies alone, according to research published in the Texas Heart Institute Journal.

More than 2 dozen studies conducted between 1961 and 1984 suggest the death rate associated with pulmonary embolectomy is 32%.

But safer techniques have led to better outcomes, and surgeons continue to take their most seriously ill PE patients into the operating room.

Still, Alan R. Hartman, MD, of North Shore-LIJ Health System in Great Neck, New York, and his colleagues wanted to determine just how successful the surgery is and which patients are the best candidates for surgery.

To find out, the team went back into the surgical archives and identified 96 patients who underwent surgery during a 9-year period (from 2003 to 2011). The researchers assessed how many patients survived in the month following surgery and compared the results to historical mortality data from patients who did not undergo surgery.

All of the patients who had undergone surgery had acute, centrally located PE and severe global hyperkinetic right ventricular dysfunction.

All patients had either a large clot burden in the main pulmonary arteries or a saddle embolism. None of the patients had a history of chronic pulmonary thrombolytic disease or evidence of chronic disease on a computed-tomographic-angiography scan.

They all made it to surgery within an hour of the embolism. The surgery was performed through cardiopulmonary bypass, at normal body temperature, and without aortic cross-clamping, thus avoiding myocardial ischemia.

A pulmonary arteriotomy and clot extraction were performed under direct vision, according to Dr Hartman, which he believes is critical to the success of the procedure.

The mortality rate was 4.2%, which is lower than any other published reports. In addition, 68 patients (73.9%) were discharged home or to rehabilitation facilities.

Those patients with low blood pressure had a higher 30-day mortality rate—12.5% compared to 1.4% in those with normal blood pressure. Patients with low blood pressure also spent a longer time in the hospital—13.4 days compared to 9.1 days in patients with normal blood pressure.

Based on these results, the researchers concluded that acute pulmonary embolectomy can be a viable procedure for patients with severe, globally hypokinetic right ventricular dysfunction, with or without hemodynamic compromise.

However, they cautioned that rates of success are dependent upon experience, surgical ability, and careful patient selection.

According to Current Procedural Terminology (CPT), modifier -25 is to be used to identify “significant, separately identifiable evaluation and management service by the same physician or other qualified health care professional on the same day of the procedure or other service.”¹ Modifier -25 frequently is integral to the description of patient visits in dermatology. Dermatologists use modifier -25 more than physicians of any other specialty, and in recent years, more than 50% of dermatology evaluation and management (E/M) visits have been appended with this modifier.

When patients present for assessment and management of various skin findings, a dermatologist may deem it appropriate to proceed with a diagnostic or therapeutic procedure at the same visit after obtaining the patient’s medical history, completing a review of systems, and conducting a clinical examination. Most commonly, a skin biopsy or destruction of a benign or malignant lesion may be performed, but other simple procedures also may be appropriate. The ability to assess and intervene during the same visit is optimal for patients who subsequently may require fewer follow-up visits and experience more immediate relief from their symptoms.

When E/M Cannot Be Billed Separately

Regulatory guidance from the National Correct Coding Initiative (NCCI) dated January 2013 indicates that procedures with a global period of 90 days are major surgical procedures, and if an E/M service is performed on the same day as such a procedure to decide whether or not to perform that procedure, then the E/M service should be reported with modifier -57.² On the other hand, CPT defines procedures with a 0- or 10-day global period as minor surgical procedures, and E/M services provided on the same day of service as these procedures are included in the procedure code and cannot be billed separately. For review, common dermatologic procedures with 0-day global periods include biopsies (CPT code 11000), shave removals (11300–11313), debridements (11000, 11011–11042), and Mohs micrographic surgery (17311–17315); procedures with 10-day global periods include destructions (17000–17286), excisions (11400–11646), and repairs (12001–13153). If an E/M service is performed on the same day as one of these procedures to decide whether to proceed with the minor surgical procedure, this E/M service cannot be reported separately. Additionally, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M with such a minor procedure.

When E/M Can Be Billed Separately

However, a “significant and separately identifiable E/M service unrelated to the decision to perform the minor procedure” is separately reportable with modifier -25. According to the NCCI, the minor procedure and the E/M do not require different diagnoses, but the E/M service must be above and beyond what is usually required for the minor surgical procedure.² Because a certain amount of so-called preservice time is built into minor procedure codes, the implication is that substantially more E/M was needed than envisioned in this preservice time, necessitating inclusion of an E/M in addition to a minor procedure when there is a single diagnosis.

When there is a single diagnosis, the physician has to decide when such a significant and separately identifiable service exists. If the physician determines that it is appropriate to code for E/M in addition to the minor procedure, clear documentation of the additional E/M service provided will reduce the likelihood of this choice being questioned. Specifically, it may be helpful to describe the additional history, examination results, medical knowledge, professional skill, and work time above and beyond what is usually required for the minor surgical procedure.

When there are many diagnosis codes for a single visit and only a subset of them are associated with the minor procedure, as is common in dermatology, then the decision to include an E/M service is simpler. In this case, if E/M services were provided that pertained to a diagnosis or diagnoses other than the one(s) associated with the minor procedure(s), then these additional E/M services will clearly not be included in the preservice time for the procedure and an E/M can virtually always be coded separately. For instance, if a patient presents with a growing scaly bump (clinically apparent squamous cell carcinoma) on the leg that the dermatologist deems is appropriate for biopsy but concurrently notices nummular dermatitis of the legs, which the patient describes as itchy and uncomfortable, then the diagnosis and management of the dermatitis would clearly be a separate E/M service and would not be included in the workup for the biopsy. The E/M code that is applied should, of course, reflect the services provided exclusive of those integral to the minor procedure. To make it easier for regulators and auditors, it may be helpful to clearly itemize the additional diagnoses unrelated to the minor procedure and describe the specific E/M services provided for these diagnoses. Although it is certainly not necessary or required, it also may be helpful to physically separate the documentation for the minor procedure from the E/M services for the additional diagnoses within the medical chart.

Final Thoughts

It is clear that frequent use of modifier -25 is appropriate in routine, high-quality dermatologic practice. Simultaneous provision of E/M services and minor procedures often is in the patient’s best interest, as it minimizes unnecessary office visits and expedites treatment. When modifier -25 is appropriately appended, careful documentation by the dermatologist can help to clarify the precise basis for its use. Recent NCCI edits provide guidelines for use of this modifier that can be adapted by individual dermatologists for particular patient circumstances.²

According to Current Procedural Terminology (CPT), modifier -25 is to be used to identify “significant, separately identifiable evaluation and management service by the same physician or other qualified health care professional on the same day of the procedure or other service.”¹ Modifier -25 frequently is integral to the description of patient visits in dermatology. Dermatologists use modifier -25 more than physicians of any other specialty, and in recent years, more than 50% of dermatology evaluation and management (E/M) visits have been appended with this modifier.

When patients present for assessment and management of various skin findings, a dermatologist may deem it appropriate to proceed with a diagnostic or therapeutic procedure at the same visit after obtaining the patient’s medical history, completing a review of systems, and conducting a clinical examination. Most commonly, a skin biopsy or destruction of a benign or malignant lesion may be performed, but other simple procedures also may be appropriate. The ability to assess and intervene during the same visit is optimal for patients who subsequently may require fewer follow-up visits and experience more immediate relief from their symptoms.

When E/M Cannot Be Billed Separately

Regulatory guidance from the National Correct Coding Initiative (NCCI) dated January 2013 indicates that procedures with a global period of 90 days are major surgical procedures, and if an E/M service is performed on the same day as such a procedure to decide whether or not to perform that procedure, then the E/M service should be reported with modifier -57.² On the other hand, CPT defines procedures with a 0- or 10-day global period as minor surgical procedures, and E/M services provided on the same day of service as these procedures are included in the procedure code and cannot be billed separately. For review, common dermatologic procedures with 0-day global periods include biopsies (CPT code 11000), shave removals (11300–11313), debridements (11000, 11011–11042), and Mohs micrographic surgery (17311–17315); procedures with 10-day global periods include destructions (17000–17286), excisions (11400–11646), and repairs (12001–13153). If an E/M service is performed on the same day as one of these procedures to decide whether to proceed with the minor surgical procedure, this E/M service cannot be reported separately. Additionally, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M with such a minor procedure.

When E/M Can Be Billed Separately

However, a “significant and separately identifiable E/M service unrelated to the decision to perform the minor procedure” is separately reportable with modifier -25. According to the NCCI, the minor procedure and the E/M do not require different diagnoses, but the E/M service must be above and beyond what is usually required for the minor surgical procedure.² Because a certain amount of so-called preservice time is built into minor procedure codes, the implication is that substantially more E/M was needed than envisioned in this preservice time, necessitating inclusion of an E/M in addition to a minor procedure when there is a single diagnosis.

When there is a single diagnosis, the physician has to decide when such a significant and separately identifiable service exists. If the physician determines that it is appropriate to code for E/M in addition to the minor procedure, clear documentation of the additional E/M service provided will reduce the likelihood of this choice being questioned. Specifically, it may be helpful to describe the additional history, examination results, medical knowledge, professional skill, and work time above and beyond what is usually required for the minor surgical procedure.

When there are many diagnosis codes for a single visit and only a subset of them are associated with the minor procedure, as is common in dermatology, then the decision to include an E/M service is simpler. In this case, if E/M services were provided that pertained to a diagnosis or diagnoses other than the one(s) associated with the minor procedure(s), then these additional E/M services will clearly not be included in the preservice time for the procedure and an E/M can virtually always be coded separately. For instance, if a patient presents with a growing scaly bump (clinically apparent squamous cell carcinoma) on the leg that the dermatologist deems is appropriate for biopsy but concurrently notices nummular dermatitis of the legs, which the patient describes as itchy and uncomfortable, then the diagnosis and management of the dermatitis would clearly be a separate E/M service and would not be included in the workup for the biopsy. The E/M code that is applied should, of course, reflect the services provided exclusive of those integral to the minor procedure. To make it easier for regulators and auditors, it may be helpful to clearly itemize the additional diagnoses unrelated to the minor procedure and describe the specific E/M services provided for these diagnoses. Although it is certainly not necessary or required, it also may be helpful to physically separate the documentation for the minor procedure from the E/M services for the additional diagnoses within the medical chart.

Final Thoughts

It is clear that frequent use of modifier -25 is appropriate in routine, high-quality dermatologic practice. Simultaneous provision of E/M services and minor procedures often is in the patient’s best interest, as it minimizes unnecessary office visits and expedites treatment. When modifier -25 is appropriately appended, careful documentation by the dermatologist can help to clarify the precise basis for its use. Recent NCCI edits provide guidelines for use of this modifier that can be adapted by individual dermatologists for particular patient circumstances.²

According to Current Procedural Terminology (CPT), modifier -25 is to be used to identify “significant, separately identifiable evaluation and management service by the same physician or other qualified health care professional on the same day of the procedure or other service.”¹ Modifier -25 frequently is integral to the description of patient visits in dermatology. Dermatologists use modifier -25 more than physicians of any other specialty, and in recent years, more than 50% of dermatology evaluation and management (E/M) visits have been appended with this modifier.

When patients present for assessment and management of various skin findings, a dermatologist may deem it appropriate to proceed with a diagnostic or therapeutic procedure at the same visit after obtaining the patient’s medical history, completing a review of systems, and conducting a clinical examination. Most commonly, a skin biopsy or destruction of a benign or malignant lesion may be performed, but other simple procedures also may be appropriate. The ability to assess and intervene during the same visit is optimal for patients who subsequently may require fewer follow-up visits and experience more immediate relief from their symptoms.

When E/M Cannot Be Billed Separately

Regulatory guidance from the National Correct Coding Initiative (NCCI) dated January 2013 indicates that procedures with a global period of 90 days are major surgical procedures, and if an E/M service is performed on the same day as such a procedure to decide whether or not to perform that procedure, then the E/M service should be reported with modifier -57.² On the other hand, CPT defines procedures with a 0- or 10-day global period as minor surgical procedures, and E/M services provided on the same day of service as these procedures are included in the procedure code and cannot be billed separately. For review, common dermatologic procedures with 0-day global periods include biopsies (CPT code 11000), shave removals (11300–11313), debridements (11000, 11011–11042), and Mohs micrographic surgery (17311–17315); procedures with 10-day global periods include destructions (17000–17286), excisions (11400–11646), and repairs (12001–13153). If an E/M service is performed on the same day as one of these procedures to decide whether to proceed with the minor surgical procedure, this E/M service cannot be reported separately. Additionally, the fact that the patient is new to the physician is not sufficient to allow reporting of an E/M with such a minor procedure.

When E/M Can Be Billed Separately

However, a “significant and separately identifiable E/M service unrelated to the decision to perform the minor procedure” is separately reportable with modifier -25. According to the NCCI, the minor procedure and the E/M do not require different diagnoses, but the E/M service must be above and beyond what is usually required for the minor surgical procedure.² Because a certain amount of so-called preservice time is built into minor procedure codes, the implication is that substantially more E/M was needed than envisioned in this preservice time, necessitating inclusion of an E/M in addition to a minor procedure when there is a single diagnosis.

When there is a single diagnosis, the physician has to decide when such a significant and separately identifiable service exists. If the physician determines that it is appropriate to code for E/M in addition to the minor procedure, clear documentation of the additional E/M service provided will reduce the likelihood of this choice being questioned. Specifically, it may be helpful to describe the additional history, examination results, medical knowledge, professional skill, and work time above and beyond what is usually required for the minor surgical procedure.

When there are many diagnosis codes for a single visit and only a subset of them are associated with the minor procedure, as is common in dermatology, then the decision to include an E/M service is simpler. In this case, if E/M services were provided that pertained to a diagnosis or diagnoses other than the one(s) associated with the minor procedure(s), then these additional E/M services will clearly not be included in the preservice time for the procedure and an E/M can virtually always be coded separately. For instance, if a patient presents with a growing scaly bump (clinically apparent squamous cell carcinoma) on the leg that the dermatologist deems is appropriate for biopsy but concurrently notices nummular dermatitis of the legs, which the patient describes as itchy and uncomfortable, then the diagnosis and management of the dermatitis would clearly be a separate E/M service and would not be included in the workup for the biopsy. The E/M code that is applied should, of course, reflect the services provided exclusive of those integral to the minor procedure. To make it easier for regulators and auditors, it may be helpful to clearly itemize the additional diagnoses unrelated to the minor procedure and describe the specific E/M services provided for these diagnoses. Although it is certainly not necessary or required, it also may be helpful to physically separate the documentation for the minor procedure from the E/M services for the additional diagnoses within the medical chart.

Final Thoughts

It is clear that frequent use of modifier -25 is appropriate in routine, high-quality dermatologic practice. Simultaneous provision of E/M services and minor procedures often is in the patient’s best interest, as it minimizes unnecessary office visits and expedites treatment. When modifier -25 is appropriately appended, careful documentation by the dermatologist can help to clarify the precise basis for its use. Recent NCCI edits provide guidelines for use of this modifier that can be adapted by individual dermatologists for particular patient circumstances.²

Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Pseudoglandular SCC, also known as adenoid SCC or acantholytic SCC, is an uncommon variant that was first described by Lever¹ in 1947 as an adenoacanthoma of the sweat glands. Of the many variants of SCC, pseudoglandular SCC generally is considered to behave aggressively with intermediate (3%–10%) risk for metastasis.² The metastatic potential of pseudoglandular SCC may be conferred in part by diminished expression of intercellular adhesion molecules, including desmoglein 3, epithelial cadherin, and syn-decan 1.^3,4 Pseudoglandular SCC presents most often on sun-damaged skin of elderly patients, especially the face and ears, as a pink or red nodule with central ulceration and a raised indurated border. It may be mistaken clinically for basal cell carcinoma (BCC) or keratoacanthoma.

On microscopic examination, the lesion is predominantly located in the dermis and may extend to the subcutis. There usually is connection to the overlying epidermis, which often shows hyperkeratosis and parakeratosis. Epidermal squamous dysplasia may be present. The dermis typically contains nests of squamous cells with a variable degree of central acantholysis. The morphology on low-power magnification consists of tubules of irregular size and shape, which are present either focally or throughout the lesion (Figure 1). The tubules are typically admixed with foci of keratinization. One or more layers of cohesive cells line the tubules. Partial keratinization may be found in the lining of tubules with more than 1 cell layer. The tumor cells are polygonal with eosinophilic cytoplasm, ovoid hyperchromatic or vesicular nuclei, and prominent nucleoli. Mitoses are common. The tubular lumina are filled with acantholytic cells, either singly or in small clusters, which may demonstrate residual bridging to tubular lining cells (Figure 2). The acantholytic cells show some variability in size and may be large, multinucleated, or keratinized. The tubules may contain material that is amorphous, basophilic, periodic acid–Schiff positive, diastase sensitive, and mucicarmine negative.⁵ Eccrine ducts at the periphery of the tumor may show reactive dilatation and proliferation. Tumor cells show positive immunostaining for epithelial membrane antigen, 34βE12, CK5/6, and tumor protein p63.^6-8 There is negative immunostaining for carcinoembryonic antigen, amylase, S-100 protein, and factor VIII.⁵

Figure 1. Glandlike tubular structures admixed with foci of keratinization (H&E, original magnification ×40). Figure 2. Pseudoglandular spaces containing acantholytic cells (H&E, original magnification ×100).

The differential diagnosis includes adenoid BCC, angiosarcoma, eccrine carcinoma, and metastatic adenocarcinoma of the skin. In adenoid BCC, excess stromal mucin imparts pseudoglandular architecture (Figure 3). However, features of conventional BCC, including peripheral nuclear palisading and retraction artifact often are present as well.

Figure 3. Thin strands of basaloid cells in a reticulate pattern with prominent stromal mucin in adenoid basal cell carcinoma. There also is palisading and retraction artifact of conventional basal cell carcinoma (H&amp;E, original magnification ×40).

Angiosarcoma shows slitlike vascular spaces lined by hyperchromatic endothelial cells (Figure 4). Further, there is positive immunostaining for vascular markers CD31 and CD34.

Figure 4. Slitlike vascular spaces lined by hyperchromatic endothelial cells in angiosarcoma (H&amp;E, original magnification ×100).

In eccrine carcinoma, there are invasive ductal structures lined by either a single or double layer of cells that may contain luminal material that is periodic acid–Schiff positive and diastase resistant (Figure 5).⁹ The tumor cells show positive immunostaining for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein.¹⁰

Figure 5. Invasive ductal structures of malignant eccrine carcinoma (H&amp;E, original magnification ×100).

Pseudoglandular SCC is susceptible to misdiagnosis as adenocarcinoma by sampling error if biopsies do not capture areas with typical features of SCC, including dysplastic squamous epithelium and keratinization. Metastatic adenocarcinoma of the skin is more likely to present with multiple nodules in older individuals. Lack of epidermal connection of the tumor and minimal to no acantholytic dyskeratosis further support cutaneous metastasis (Figure 6). Review of the patient’s clinical history might be helpful if adenocarcinoma was previously diagnosed. Immunohistochemical evaluation may aid in the prediction of the primary site in patients with metastatic adenocarcinoma of unknown origin.¹¹

Figure 6. The dermis is filled with malignant glandular epithelium that is CK7 positive, CK20 negative, and thyroid transcription factor 1 positive (immunohistochemistry not shown), consistent with metastatic adenocarcinoma of lung origin (H&amp;E, original magnification ×40).

Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Pseudoglandular SCC, also known as adenoid SCC or acantholytic SCC, is an uncommon variant that was first described by Lever¹ in 1947 as an adenoacanthoma of the sweat glands. Of the many variants of SCC, pseudoglandular SCC generally is considered to behave aggressively with intermediate (3%–10%) risk for metastasis.² The metastatic potential of pseudoglandular SCC may be conferred in part by diminished expression of intercellular adhesion molecules, including desmoglein 3, epithelial cadherin, and syn-decan 1.^3,4 Pseudoglandular SCC presents most often on sun-damaged skin of elderly patients, especially the face and ears, as a pink or red nodule with central ulceration and a raised indurated border. It may be mistaken clinically for basal cell carcinoma (BCC) or keratoacanthoma.

On microscopic examination, the lesion is predominantly located in the dermis and may extend to the subcutis. There usually is connection to the overlying epidermis, which often shows hyperkeratosis and parakeratosis. Epidermal squamous dysplasia may be present. The dermis typically contains nests of squamous cells with a variable degree of central acantholysis. The morphology on low-power magnification consists of tubules of irregular size and shape, which are present either focally or throughout the lesion (Figure 1). The tubules are typically admixed with foci of keratinization. One or more layers of cohesive cells line the tubules. Partial keratinization may be found in the lining of tubules with more than 1 cell layer. The tumor cells are polygonal with eosinophilic cytoplasm, ovoid hyperchromatic or vesicular nuclei, and prominent nucleoli. Mitoses are common. The tubular lumina are filled with acantholytic cells, either singly or in small clusters, which may demonstrate residual bridging to tubular lining cells (Figure 2). The acantholytic cells show some variability in size and may be large, multinucleated, or keratinized. The tubules may contain material that is amorphous, basophilic, periodic acid–Schiff positive, diastase sensitive, and mucicarmine negative.⁵ Eccrine ducts at the periphery of the tumor may show reactive dilatation and proliferation. Tumor cells show positive immunostaining for epithelial membrane antigen, 34βE12, CK5/6, and tumor protein p63.^6-8 There is negative immunostaining for carcinoembryonic antigen, amylase, S-100 protein, and factor VIII.⁵

Figure 1. Glandlike tubular structures admixed with foci of keratinization (H&E, original magnification ×40). Figure 2. Pseudoglandular spaces containing acantholytic cells (H&E, original magnification ×100).

The differential diagnosis includes adenoid BCC, angiosarcoma, eccrine carcinoma, and metastatic adenocarcinoma of the skin. In adenoid BCC, excess stromal mucin imparts pseudoglandular architecture (Figure 3). However, features of conventional BCC, including peripheral nuclear palisading and retraction artifact often are present as well.

Figure 3. Thin strands of basaloid cells in a reticulate pattern with prominent stromal mucin in adenoid basal cell carcinoma. There also is palisading and retraction artifact of conventional basal cell carcinoma (H&amp;E, original magnification ×40).

Angiosarcoma shows slitlike vascular spaces lined by hyperchromatic endothelial cells (Figure 4). Further, there is positive immunostaining for vascular markers CD31 and CD34.

Figure 4. Slitlike vascular spaces lined by hyperchromatic endothelial cells in angiosarcoma (H&amp;E, original magnification ×100).

In eccrine carcinoma, there are invasive ductal structures lined by either a single or double layer of cells that may contain luminal material that is periodic acid–Schiff positive and diastase resistant (Figure 5).⁹ The tumor cells show positive immunostaining for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein.¹⁰

Figure 5. Invasive ductal structures of malignant eccrine carcinoma (H&amp;E, original magnification ×100).

Pseudoglandular SCC is susceptible to misdiagnosis as adenocarcinoma by sampling error if biopsies do not capture areas with typical features of SCC, including dysplastic squamous epithelium and keratinization. Metastatic adenocarcinoma of the skin is more likely to present with multiple nodules in older individuals. Lack of epidermal connection of the tumor and minimal to no acantholytic dyskeratosis further support cutaneous metastasis (Figure 6). Review of the patient’s clinical history might be helpful if adenocarcinoma was previously diagnosed. Immunohistochemical evaluation may aid in the prediction of the primary site in patients with metastatic adenocarcinoma of unknown origin.¹¹

Figure 6. The dermis is filled with malignant glandular epithelium that is CK7 positive, CK20 negative, and thyroid transcription factor 1 positive (immunohistochemistry not shown), consistent with metastatic adenocarcinoma of lung origin (H&amp;E, original magnification ×40).

Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Pseudoglandular SCC, also known as adenoid SCC or acantholytic SCC, is an uncommon variant that was first described by Lever¹ in 1947 as an adenoacanthoma of the sweat glands. Of the many variants of SCC, pseudoglandular SCC generally is considered to behave aggressively with intermediate (3%–10%) risk for metastasis.² The metastatic potential of pseudoglandular SCC may be conferred in part by diminished expression of intercellular adhesion molecules, including desmoglein 3, epithelial cadherin, and syn-decan 1.^3,4 Pseudoglandular SCC presents most often on sun-damaged skin of elderly patients, especially the face and ears, as a pink or red nodule with central ulceration and a raised indurated border. It may be mistaken clinically for basal cell carcinoma (BCC) or keratoacanthoma.

On microscopic examination, the lesion is predominantly located in the dermis and may extend to the subcutis. There usually is connection to the overlying epidermis, which often shows hyperkeratosis and parakeratosis. Epidermal squamous dysplasia may be present. The dermis typically contains nests of squamous cells with a variable degree of central acantholysis. The morphology on low-power magnification consists of tubules of irregular size and shape, which are present either focally or throughout the lesion (Figure 1). The tubules are typically admixed with foci of keratinization. One or more layers of cohesive cells line the tubules. Partial keratinization may be found in the lining of tubules with more than 1 cell layer. The tumor cells are polygonal with eosinophilic cytoplasm, ovoid hyperchromatic or vesicular nuclei, and prominent nucleoli. Mitoses are common. The tubular lumina are filled with acantholytic cells, either singly or in small clusters, which may demonstrate residual bridging to tubular lining cells (Figure 2). The acantholytic cells show some variability in size and may be large, multinucleated, or keratinized. The tubules may contain material that is amorphous, basophilic, periodic acid–Schiff positive, diastase sensitive, and mucicarmine negative.⁵ Eccrine ducts at the periphery of the tumor may show reactive dilatation and proliferation. Tumor cells show positive immunostaining for epithelial membrane antigen, 34βE12, CK5/6, and tumor protein p63.^6-8 There is negative immunostaining for carcinoembryonic antigen, amylase, S-100 protein, and factor VIII.⁵

Figure 1. Glandlike tubular structures admixed with foci of keratinization (H&E, original magnification ×40). Figure 2. Pseudoglandular spaces containing acantholytic cells (H&E, original magnification ×100).

The differential diagnosis includes adenoid BCC, angiosarcoma, eccrine carcinoma, and metastatic adenocarcinoma of the skin. In adenoid BCC, excess stromal mucin imparts pseudoglandular architecture (Figure 3). However, features of conventional BCC, including peripheral nuclear palisading and retraction artifact often are present as well.

Figure 3. Thin strands of basaloid cells in a reticulate pattern with prominent stromal mucin in adenoid basal cell carcinoma. There also is palisading and retraction artifact of conventional basal cell carcinoma (H&amp;E, original magnification ×40).

Angiosarcoma shows slitlike vascular spaces lined by hyperchromatic endothelial cells (Figure 4). Further, there is positive immunostaining for vascular markers CD31 and CD34.

Figure 4. Slitlike vascular spaces lined by hyperchromatic endothelial cells in angiosarcoma (H&amp;E, original magnification ×100).

In eccrine carcinoma, there are invasive ductal structures lined by either a single or double layer of cells that may contain luminal material that is periodic acid–Schiff positive and diastase resistant (Figure 5).⁹ The tumor cells show positive immunostaining for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein.¹⁰

Figure 5. Invasive ductal structures of malignant eccrine carcinoma (H&amp;E, original magnification ×100).

Pseudoglandular SCC is susceptible to misdiagnosis as adenocarcinoma by sampling error if biopsies do not capture areas with typical features of SCC, including dysplastic squamous epithelium and keratinization. Metastatic adenocarcinoma of the skin is more likely to present with multiple nodules in older individuals. Lack of epidermal connection of the tumor and minimal to no acantholytic dyskeratosis further support cutaneous metastasis (Figure 6). Review of the patient’s clinical history might be helpful if adenocarcinoma was previously diagnosed. Immunohistochemical evaluation may aid in the prediction of the primary site in patients with metastatic adenocarcinoma of unknown origin.¹¹

Figure 6. The dermis is filled with malignant glandular epithelium that is CK7 positive, CK20 negative, and thyroid transcription factor 1 positive (immunohistochemistry not shown), consistent with metastatic adenocarcinoma of lung origin (H&amp;E, original magnification ×40).