WASHINGTON – An effective approach to suicide prevention engages the patient in a therapeutic relationship that starts with the patient’s narrative, Katherine A. Comtois, PhD, said at the American Association of Suicidality annual conference.

“The narrative should be the first touch” with the patient, advised Dr. Comtois, professor of psychiatry at the University of Washington, Seattle. “Start the narrative and form a connection, and then get to the other stuff.” She also recommended that therapists place themselves next to the patient, “court” the patient, be persistent, give positive reinforcement, and “give it all you’ve got.”

Mitchel L. Zoler/MDedge News

[email protected]

WASHINGTON – An effective approach to suicide prevention engages the patient in a therapeutic relationship that starts with the patient’s narrative, Katherine A. Comtois, PhD, said at the American Association of Suicidality annual conference.

“The narrative should be the first touch” with the patient, advised Dr. Comtois, professor of psychiatry at the University of Washington, Seattle. “Start the narrative and form a connection, and then get to the other stuff.” She also recommended that therapists place themselves next to the patient, “court” the patient, be persistent, give positive reinforcement, and “give it all you’ve got.”

Mitchel L. Zoler/MDedge News

[email protected]

WASHINGTON – An effective approach to suicide prevention engages the patient in a therapeutic relationship that starts with the patient’s narrative, Katherine A. Comtois, PhD, said at the American Association of Suicidality annual conference.

“The narrative should be the first touch” with the patient, advised Dr. Comtois, professor of psychiatry at the University of Washington, Seattle. “Start the narrative and form a connection, and then get to the other stuff.” She also recommended that therapists place themselves next to the patient, “court” the patient, be persistent, give positive reinforcement, and “give it all you’ve got.”

Mitchel L. Zoler/MDedge News

[email protected]

PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.

“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”

In one of the most recent developments, the multikinase inhibitor cabozantinib significantly improved the primary endpoint of overall survival versus placebo in HCC patients in the randomized phase 3 CELESTIAL trial.

Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.

“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.

For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).

In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).

Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.

“In essence, you have an approximate 2-year survival,” he said.

More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.

Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.

Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.

Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.

Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.

Global Academy for Medical Education and this news organization are owned by the same company.

PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.

“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”

In one of the most recent developments, the multikinase inhibitor cabozantinib significantly improved the primary endpoint of overall survival versus placebo in HCC patients in the randomized phase 3 CELESTIAL trial.

Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.

“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.

For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).

In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).

Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.

“In essence, you have an approximate 2-year survival,” he said.

More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.

Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.

Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.

Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.

Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.

Global Academy for Medical Education and this news organization are owned by the same company.

PHILADELPHIA – Recent approvals and investigations of targeted and immune treatments for advanced hepatocellular carcinoma (HCC) are encouraging, Nikolaos Pyrsopoulos, MD, MBA, said at Digestive Diseases: New Advances, jointly provided by Rutgers and Global Academy for Medical Education.

“I am excited, because a few years ago, there was only one [Food and Drug Administration] approved medication,” Dr. Pyrsopoulos, division director for gastroenterology and hepatology at Rutgers New Jersey Medical School, Newark, said in an interview. “We are on the cusp where new compounds not only are being tested, but they are being approved.”

In one of the most recent developments, the multikinase inhibitor cabozantinib significantly improved the primary endpoint of overall survival versus placebo in HCC patients in the randomized phase 3 CELESTIAL trial.

Median overall survival in CELESTIAL was 10.2 months for cabozantinib versus 8.0 for placebo (P = .0049), according to the published report, and investigators also reported significant improvements in progression-free survival and response versus placebo.

“It is very encouraging,” Dr. Pyrsopoulos said of the cabozantinib results in a presentation on advances in HCC that he gave at the conference.

For years, the only FDA-approved treatment for advanced HCC was sorafenib. In the randomized phase 3 SHARP trial, published in the New England Journal of Medicine in 2008, patients receiving the multikinase inhibitor had a median survival of 10.7 months, versus 7.9 months for placebo (P less than .001).

In April 2017, the FDA approved regorafenib for patients with HCC previously treated with sorafenib. In the randomized phase 3 RESORCE trial, published in The Lancet in 2017, median overall survival was 10.6 months for regorafenib-treated patients versus 7.8 months in the placebo group. Investigators reported that regorafenib improved overall survival with a hazard ratio of 0.63 (P less than .0001).

Dr. Pyrsopoulos noted that a strategy of sorafenib followed by regorafenib would combine two treatments, each of which in clinical trials had a median overall survival approaching 11 months.

“In essence, you have an approximate 2-year survival,” he said.

More agents are under investigation, including lenvatinib, another multikinase inhibitor. In results of a phase 3 randomized trial presented at the 2017 meeting of the American Society of Clinical Oncology, lenvatinib was noninferior to sorafenib in overall survival, with treatment-related adverse effects such as hypertension and diarrhea that were expected based on previous experience with the drug, investigators said.

Cancer immunotherapy is making inroads into HCC. Just a few months after approving regorafenib, the FDA granted approval to nivolumab, a PD-1 inhibitor, for patients with HCC previously treated with sorafenib. The September 2017 approval of this checkpoint inhibitor was based in part on data from the CheckMate-040 trial that included a 14.3% response rate in the 154-patient subgroup of patients who had progressive disease on sorafenib or were intolerant of the treatment.

Dr. Pyrsopoulos highlighted another checkpoint inhibitor, known as BGB-A317, or tislelizumab. In January, BeiGene announced the initiation of a global phase 3 trial of this anti-PD-1 antibody versus sorafenib as first-line treatment of patients with unresectable HCC.

Although cancer immunotherapy holds great promise for HCC and other cancers, the treatments are associated with unique immune-related adverse events (irAEs) including immune-related hepatitis that may require corticosteroid treatment, according to Dr. Pyrsopoulos.

Dr. Pyrsopoulos reported disclosures related to AbbVie, Bayer, Genfit, Gilead Sciences, Hologic, Merck, Prometheus, Shire, and Vital Therapies.

Global Academy for Medical Education and this news organization are owned by the same company.

A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.

The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.

Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.

Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.

This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia.

Refining Research Cohorts

“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”

One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.

For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.

“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”

A Reflection of Evolving Science

The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease diagnostic criteria in 2011. Those criteria divided the disease continuum into three phases—preclinical Alzheimer’s disease, mild cognitive impairment (MCI), and Alzheimer’s dementia—largely based on cognitive symptoms, but were the first to recognize a presymptomatic Alzheimer’s disease phase marked by brain changes, including amyloid buildup, without evidence of significant clinical symptoms. In the MCI stage, which may or may not progress to Alzheimer’s dementia, memory or other thinking problems are greater than normal for a patient’s age and education, but do not interfere with his or her independence. Alzheimer’s dementia is the final stage of the disease in which the symptoms of Alzheimer’s disease, such as memory loss, word-finding difficulties, and visual or spatial problems, are significant enough to impair a person’s ability to function independently.

Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.

These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.

“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”

It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.

The Three-Part Key: AT(N)

The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).

“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”

The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”

The biomarker profiles are:

• A−T−(N)−: Normal Alzheimer’s disease biomarkers
• A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
• A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
• A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
• A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
• A−T+(N)−: Non-Alzheimer’s disease pathologic change
• A−T−(N)+: Non-Alzheimer’s disease pathologic change
• A−T+(N)+: Non-Alzheimer’s disease pathologic change.

A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.

Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.

Biomarker Grouping and Cognitive Status Interactions

“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”

The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.

The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.

“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”

The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.

This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.

“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”

Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.

IDEAS on the Horizon

Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.

An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.

IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.

“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.

In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.

“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”

Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.

—Michele G. Sullivan

Suggested Reading

Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer’s disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement. 2018;14(4):532-534.

Silverberg N, Elliott C, Ryan L, et al. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):576-578.

A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.

The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.

Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.

Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.

This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia.

Refining Research Cohorts

“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”

One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.

For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.

“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”

A Reflection of Evolving Science

The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease diagnostic criteria in 2011. Those criteria divided the disease continuum into three phases—preclinical Alzheimer’s disease, mild cognitive impairment (MCI), and Alzheimer’s dementia—largely based on cognitive symptoms, but were the first to recognize a presymptomatic Alzheimer’s disease phase marked by brain changes, including amyloid buildup, without evidence of significant clinical symptoms. In the MCI stage, which may or may not progress to Alzheimer’s dementia, memory or other thinking problems are greater than normal for a patient’s age and education, but do not interfere with his or her independence. Alzheimer’s dementia is the final stage of the disease in which the symptoms of Alzheimer’s disease, such as memory loss, word-finding difficulties, and visual or spatial problems, are significant enough to impair a person’s ability to function independently.

Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.

These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.

“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”

It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.

The Three-Part Key: AT(N)

The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).

“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”

The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”

The biomarker profiles are:

• A−T−(N)−: Normal Alzheimer’s disease biomarkers
• A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
• A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
• A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
• A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
• A−T+(N)−: Non-Alzheimer’s disease pathologic change
• A−T−(N)+: Non-Alzheimer’s disease pathologic change
• A−T+(N)+: Non-Alzheimer’s disease pathologic change.

A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.

Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.

Biomarker Grouping and Cognitive Status Interactions

“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”

The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.

The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.

“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”

The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.

This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.

“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”

Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.

IDEAS on the Horizon

Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.

An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.

IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.

“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.

In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.

“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”

Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.

—Michele G. Sullivan

Suggested Reading

Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer’s disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement. 2018;14(4):532-534.

Silverberg N, Elliott C, Ryan L, et al. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):576-578.

A new definition of Alzheimer’s disease based solely on biomarkers has the potential to strengthen clinical trials and change the way physicians talk to patients.

The paradigm recasts Alzheimer’s disease from a symptomatic syndrome validated by biomarkers to a strictly biologic construct defined by the presence of amyloid beta, tau, and neuronal damage.

Amyloid beta is the key to this classification paradigm—any patient with it is on the Alzheimer’s continuum. But only those with both amyloid and tau in the brain are classified as having Alzheimer’s disease. A third biomarker, neurodegeneration, may be either present or absent for an Alzheimer’s disease profile. Cognitive staging adds important details, but remains secondary to the biomarker classification.

Jointly created by the National Institute on Aging (NIA) and the Alzheimer’s Association (AA), the system—dubbed the NIA-AA Research Framework—represents a common language that researchers around the world may now use to generate and test Alzheimer’s hypotheses and to optimize epidemiologic studies and interventional trials. It will be especially important as Alzheimer’s disease prevention trials seek to target patients who are cognitively normal, yet harbor the neuropathologic hallmarks of the disease.

This recasting adds Alzheimer’s disease to the list of biomarker-defined disorders such as hypertension, diabetes, and hyperlipidemia. It is a timely and necessary reframing, said Clifford R. Jack Jr, MD, chair of the 20-member committee that created the paradigm, which was published in the April issue of Alzheimer’s & Dementia.

Refining Research Cohorts

“This is a fundamental change in the definition of Alzheimer’s disease,” Dr. Jack said in an interview. “We are advocating that the disease be defined by its neuropathology [of plaques and tangles], which is specific to Alzheimer’s, and no longer by clinical symptoms which are not specific for any disease.”

One of the primary intents is to refine Alzheimer’s disease research cohorts, allowing pure stratification of patients who actually have the intended therapeutic targets of amyloid beta or tau. Without biomarker screening, as much as 30% of subjects who enroll in Alzheimer’s disease drug trials do not have the target pathologies—a situation that researchers say contributes to the long string of failed Alzheimer’s drug studies.

For now, the system is intended only for research settings, said Dr. Jack, an Alzheimer’s disease investigator at the Mayo Clinic in Rochester, Minnesota. But as biomarker testing comes of age and less expensive tests are discovered, the paradigm will likely be incorporated into clinical practice. The process can begin even now with a simple change in the way doctors talk to patients about Alzheimer’s disease, he said.

“We advocate that people stop using the terms ‘probable’ or ‘possible Alzheimer’s disease,’” Dr. Jack said. “A better term is ‘Alzheimer’s clinical syndrome.’ Without biomarkers, the clinical syndrome is the only thing you can know. What you can’t know is whether they do or do not have Alzheimer’s disease. When I am asked by physicians, ‘What do I tell my patients now?’ my very direct answer is ‘Tell them the truth.’ And the truth is that they have Alzheimer’s clinical syndrome and may or may not have Alzheimer’s disease.”

A Reflection of Evolving Science

The research framework reflects advances in Alzheimer’s disease science that have occurred since the NIA last updated its Alzheimer’s disease diagnostic criteria in 2011. Those criteria divided the disease continuum into three phases—preclinical Alzheimer’s disease, mild cognitive impairment (MCI), and Alzheimer’s dementia—largely based on cognitive symptoms, but were the first to recognize a presymptomatic Alzheimer’s disease phase marked by brain changes, including amyloid buildup, without evidence of significant clinical symptoms. In the MCI stage, which may or may not progress to Alzheimer’s dementia, memory or other thinking problems are greater than normal for a patient’s age and education, but do not interfere with his or her independence. Alzheimer’s dementia is the final stage of the disease in which the symptoms of Alzheimer’s disease, such as memory loss, word-finding difficulties, and visual or spatial problems, are significant enough to impair a person’s ability to function independently.

Since the 2011 diagnostic criteria emergered, advances in understanding the biology and pathology of Alzheimer’s disease, as well as technical advances in biomarker measurements, have made it possible not only to measure amyloid beta and tau in CSF, but also to see these proteins in living brains with specialized PET ligands. It also became obvious that about a third of subjects in any given Alzheimer’s disease study did not have the disease-defining brain plaques and tangles—the therapeutic targets of all the largest drug studies to date. And while it is clear that none of the interventions in those studies have exerted a significant benefit yet, “treating people for a disease they don’t have can’t possibly help the results,” Dr. Jack said.

These research observations and biomarker advances have reshaped the way researchers think about Alzheimer’s disease. To maximize research potential and create a global classification standard to unify studies, the NIA and the Alzheimer’s Association convened several meetings to redefine Alzheimer’s disease biologically by pathologic brain changes, as measured by biomarkers. In this paradigm, cognitive dysfunction is a symptom of Alzheimer’s disease, not its primary classification driver.

“The way Alzheimer’s disease has historically been defined is by clinical symptoms. A progressive amnestic dementia was Alzheimer’s, and if there was no progressive amnestic dementia, it was not,” Dr. Jack said. “Well, it turns out that both of those statements are wrong. About 30% of people with progressive amnestic dementia have other things causing it.”

It makes much more sense, he said, to define the disease based on its unique neuropathologic signature: amyloid beta plaques and tau neurofibrillary tangles in the brain.

The Three-Part Key: AT(N)

The NIA-AA Research Framework yields eight biomarker profiles with different combinations of amyloid (A), tau (T), and neurodegeneration or neuronal injury (N).

“Different measures have different roles,” Dr. Jack and his colleagues said. “Amyloid beta biomarkers determine whether or not an individual is in the Alzheimer’s continuum. Pathologic tau biomarkers determine if someone who is in the Alzheimer’s continuum has Alzheimer’s disease, because both amyloid beta and tau are required for a neuropathologic diagnosis of the disease. Neurodegenerative/neuronal injury biomarkers and cognitive symptoms, neither of which is specific for Alzheimer’s disease, are used only to stage severity, not to define the presence of the Alzheimer’s continuum.”

The “N” category is not as cut and dried at the other biomarkers, the paper noted. “Biomarkers in the (N) group are indicators of neurodegeneration or neuronal injury resulting from many causes; they are not specific for neurodegeneration due to Alzheimer’s disease. In any individual, the proportion of observed neurodegeneration/injury that can be attributed to Alzheimer’s disease versus other possible comorbid conditions (most of which have no extant biomarker) is unknown.”

The biomarker profiles are:

• A−T−(N)−: Normal Alzheimer’s disease biomarkers
• A+T−(N)−: Alzheimer’s pathologic change; Alzheimer’s continuum
• A+T+(N)−: Alzheimer’s disease; Alzheimer’s continuum
• A+T+(N)+: Alzheimer’s disease; Alzheimer’s continuum
• A+T−(N)+: Alzheimer’s with suspected non-Alzheimer’s pathologic change; Alzheimer’s continuum
• A−T+(N)−: Non-Alzheimer’s disease pathologic change
• A−T−(N)+: Non-Alzheimer’s disease pathologic change
• A−T+(N)+: Non-Alzheimer’s disease pathologic change.

A normal amyloid biomarker with abnormal tau or neurodegeneration “implies evidence of one or more neuropathologic processes other than Alzheimer’s disease and has been labeled ‘suspected non-Alzheimer’s pathophysiology’ (or SNAP),” according to the paper.

Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This staging scheme can be applied to anyone with a biomarker profile.

Biomarker Grouping and Cognitive Status Interactions

“This three-category division serves as the basis for cognitive categorization in many large, ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”

The second staging scheme, a six-stage numeric clinical staging scheme, will apply only to those who are amyloid-positive and on the Alzheimer’s continuum. Stages run from 1 (unimpaired) to 6 (severe dementia). The numeric staging does not concentrate solely on cognition, but also takes into account neurobehavioral and functional symptoms. It includes a transitional stage during which measures may be within population norms, but have declined relative to the individual’s past performance.

The numeric staging scheme is intended to mesh with FDA guidance for clinical trials outcomes, the committee noted.

“A useful application envisioned for this numeric cognitive staging scheme is interventional trials. Indeed, the NIA-AA numeric staging scheme is intentionally similar to the categorical system for staging Alzheimer’s disease outlined in recent FDA guidance for industry pertaining to developing drugs for treatment of early Alzheimer’s disease…. It was our belief that harmonizing this aspect of the framework with FDA guidance would enhance cross-fertilization between observational and interventional studies, which in turn would facilitate conduct of interventional clinical trials early in the disease process.”

The entire system yields a shorthand biomarker profile for each subject. For example, an A+T−(N)+ MCI profile suggests that Alzheimer’s and non-Alzheimer’s pathologic change may be contributing to the cognitive impairment. A cognitive staging number could also be added.

This biomarker profile introduces the option of completely avoiding traditional Alzheimer’s disease nomenclature, the committee noted.

“Some investigators may prefer to not use the biomarker category terminology … but instead simply report biomarker profile (ie, A+T+(N)+ instead of Alzheimer’s disease),” the authors said. An alternative is to combine the biomarker profile with a descriptive term—for example, “A+T+(N)+ with dementia” instead of “Alzheimer’s disease with dementia.”

Dr. Jack cautioned that the paradigm is not currently intended for clinical use. It relies on biomarkers obtained by methods that are either invasive (lumbar puncture), unavailable outside research settings (tau scans), or expensive when privately obtained (amyloid scans). Until this situation changes, the biomarker profile paradigm has little clinical impact.

IDEAS on the Horizon

Change may be coming, however. The Alzheimer’s Association-sponsored Imaging Dementia–Evidence for Amyloid Scanning (IDEAS) study is assessing the clinical usefulness of amyloid PET scans and their impact on patient outcomes. The goal is to accumulate enough data to prove whether amyloid scans are a cost-effective addition to the management of dementia patients. If federal payers decide to cover amyloid scans, advocates hope that private insurers might follow suit.

An interim analysis of 4,000 scans presented at the 2017 Alzheimer’s Association International Conference found that scan results changed patient management in 68% of cases, including by refining dementia diagnoses; adding, stopping, or switching medications; and altering patient counseling.

IDEAS uses an FDA-approved amyloid imaging agent. Tau PET ligands are in development, but have not been approved. However, other less invasive and less costly options may soon be developed, the committee noted. The search continues for a validated blood-based biomarker, including neurofilament light protein, plasma amyloid beta, and plasma tau.

“In the future, … blood-based biomarker tests—along with genetics, clinical, and demographic information—will likely play an important screening role in selecting individuals for more expensive or more invasive biomarker testing. This has been the history in other biologically defined diseases such as cardiovascular disease,” Dr. Jack and his colleagues noted.

In any case, without an effective treatment, much of the information conveyed by the biomarker profile paradigm remains academic, Dr. Jack said.

“If [the biomarker profile] were easy to determine and inexpensive, I imagine a lot of people would ask for it,” Dr. Jack said. “Certainly, many people would want to know, especially if they have a cognitive problem. People who have a family history, who may have Alzheimer’s pathology without the symptoms, might want to know. But the reality is that until there is a treatment that alters the course of this disease, finding out that you actually have Alzheimer’s disease is not going to enable you to change anything.”

Alzheimer’s & Dementia is the official journal of the Alzheimer’s Association. Dr. Jack has served on scientific advisory boards for Elan/Janssen AI, Bristol-Meyers Squibb, Eli Lilly, GE Healthcare, Siemens, and Eisai; received research support from Baxter International and Allon Therapeutics; and holds stock in Johnson & Johnson.

—Michele G. Sullivan

Suggested Reading

Jack CR Jr., Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-562.

Khachaturian AS, Hayden KM, Mielke MM, et al. Future prospects and challenges for Alzheimer’s disease drug development in the era of the NIA-AA Research Framework. Alzheimers Dement. 2018;14(4):532-534.

Silverberg N, Elliott C, Ryan L, et al. NIA commentary on the NIA-AA Research Framework: towards a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):576-578.

In utero exposure to antiepileptic drugs (AEDs) in combination, or sodium valproate alone, significantly decreases educational attainment in children age 7, compared with both a matched control group and the all-Wales national average, according to a report published online ahead of print March 27 in the Journal of Neurology, Neurosurgery and Psychiatry. “These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy,” said lead author Arron S. Lacey, Prudent Healthcare Intelligence Unit Research Data Analyst at Swansea University in the UK, and colleagues.

Although valproate is considered the most effective drug for treating genetic generalized epilepsy, recent prospective psychometric studies revealed cognitive impairment and neurodevelopmental disorders in 30% to 40% of children exposed to valproate in utero, as well as a significant decrease in IQ. According to Mr. Lacey and colleagues, to adequately counsel women about the risks of uncontrolled seizures during pregnancy and cognitive outcomes for their children, “it is important to know whether the psychometric differences seen in research conditions translate to children in the community.”

To identify whether children exposed to AEDs in utero have poorer school performance, Mr. Lacey and colleagues used the Secure Anonymous Information Linkage databank to access routinely collected health care records and identify children born to mothers with epilepsy. They then linked the identified children to their national attainment Key Stage 1 (KS1) tests in mathematics, language, and science at age 7, and compared them with matched controls (children born to mothers without epilepsy), and with the national KS1 results. As outcome measures, the investigators used the core subject indicator (CSI), which is the proportion of children achieving a minimum standard in all subjects, and the results in individual subjects.

The researchers identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (−12.7% less than the control group), mathematics (−12.1%), language (−10.4%) and science (−12.2%). Even fewer children with mothers prescribed multiple AEDs during pregnancy achieved the national minimum standard in CSI (−20.7% less than the control group), mathematics (−21.9%), language (−19.3%), and science (−19.4%). Researchers did not observe significant differences in children whose mothers were prescribed carbamazepine or women taking an AED, when compared with the control group.

According to the researchers, the main strength of the study is the ability to select a large cohort of 440 children with national test results without major recruitment bias and compare it with a large control group. One main study limitation “was not being able to use the maternal IQ, as well as other maternal factors, such as maternal weight or alcohol consumption during pregnancy, as covariates,” said the authors. In addition, researchers were unable to account for how parental style, or ability, may have influenced educational attainment.

“Our results add to the growing evidence that in utero exposure to certain AEDs can cause developmental problems in children. Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” the researchers concluded.

—Erica Tricarico

Suggested Reading

Lacey AS, Pickrell WO, Thomas RH, et al. Educational attainment of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2018 March 27 [Epub ahead of print].

In utero exposure to antiepileptic drugs (AEDs) in combination, or sodium valproate alone, significantly decreases educational attainment in children age 7, compared with both a matched control group and the all-Wales national average, according to a report published online ahead of print March 27 in the Journal of Neurology, Neurosurgery and Psychiatry. “These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy,” said lead author Arron S. Lacey, Prudent Healthcare Intelligence Unit Research Data Analyst at Swansea University in the UK, and colleagues.

Although valproate is considered the most effective drug for treating genetic generalized epilepsy, recent prospective psychometric studies revealed cognitive impairment and neurodevelopmental disorders in 30% to 40% of children exposed to valproate in utero, as well as a significant decrease in IQ. According to Mr. Lacey and colleagues, to adequately counsel women about the risks of uncontrolled seizures during pregnancy and cognitive outcomes for their children, “it is important to know whether the psychometric differences seen in research conditions translate to children in the community.”

To identify whether children exposed to AEDs in utero have poorer school performance, Mr. Lacey and colleagues used the Secure Anonymous Information Linkage databank to access routinely collected health care records and identify children born to mothers with epilepsy. They then linked the identified children to their national attainment Key Stage 1 (KS1) tests in mathematics, language, and science at age 7, and compared them with matched controls (children born to mothers without epilepsy), and with the national KS1 results. As outcome measures, the investigators used the core subject indicator (CSI), which is the proportion of children achieving a minimum standard in all subjects, and the results in individual subjects.

The researchers identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (−12.7% less than the control group), mathematics (−12.1%), language (−10.4%) and science (−12.2%). Even fewer children with mothers prescribed multiple AEDs during pregnancy achieved the national minimum standard in CSI (−20.7% less than the control group), mathematics (−21.9%), language (−19.3%), and science (−19.4%). Researchers did not observe significant differences in children whose mothers were prescribed carbamazepine or women taking an AED, when compared with the control group.

According to the researchers, the main strength of the study is the ability to select a large cohort of 440 children with national test results without major recruitment bias and compare it with a large control group. One main study limitation “was not being able to use the maternal IQ, as well as other maternal factors, such as maternal weight or alcohol consumption during pregnancy, as covariates,” said the authors. In addition, researchers were unable to account for how parental style, or ability, may have influenced educational attainment.

“Our results add to the growing evidence that in utero exposure to certain AEDs can cause developmental problems in children. Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” the researchers concluded.

—Erica Tricarico

Suggested Reading

Lacey AS, Pickrell WO, Thomas RH, et al. Educational attainment of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2018 March 27 [Epub ahead of print].

In utero exposure to antiepileptic drugs (AEDs) in combination, or sodium valproate alone, significantly decreases educational attainment in children age 7, compared with both a matched control group and the all-Wales national average, according to a report published online ahead of print March 27 in the Journal of Neurology, Neurosurgery and Psychiatry. “These results give further support to the cognitive and developmental effects of in utero exposure to sodium valproate as well as multiple AEDs, which should be balanced against the need for effective seizure control for women during pregnancy,” said lead author Arron S. Lacey, Prudent Healthcare Intelligence Unit Research Data Analyst at Swansea University in the UK, and colleagues.

Although valproate is considered the most effective drug for treating genetic generalized epilepsy, recent prospective psychometric studies revealed cognitive impairment and neurodevelopmental disorders in 30% to 40% of children exposed to valproate in utero, as well as a significant decrease in IQ. According to Mr. Lacey and colleagues, to adequately counsel women about the risks of uncontrolled seizures during pregnancy and cognitive outcomes for their children, “it is important to know whether the psychometric differences seen in research conditions translate to children in the community.”

To identify whether children exposed to AEDs in utero have poorer school performance, Mr. Lacey and colleagues used the Secure Anonymous Information Linkage databank to access routinely collected health care records and identify children born to mothers with epilepsy. They then linked the identified children to their national attainment Key Stage 1 (KS1) tests in mathematics, language, and science at age 7, and compared them with matched controls (children born to mothers without epilepsy), and with the national KS1 results. As outcome measures, the investigators used the core subject indicator (CSI), which is the proportion of children achieving a minimum standard in all subjects, and the results in individual subjects.

The researchers identified 440 children born to mothers with epilepsy with available KS1 results. Compared with a matched control group, fewer children with mothers prescribed sodium valproate during pregnancy achieved the national minimum standard in CSI (−12.7% less than the control group), mathematics (−12.1%), language (−10.4%) and science (−12.2%). Even fewer children with mothers prescribed multiple AEDs during pregnancy achieved the national minimum standard in CSI (−20.7% less than the control group), mathematics (−21.9%), language (−19.3%), and science (−19.4%). Researchers did not observe significant differences in children whose mothers were prescribed carbamazepine or women taking an AED, when compared with the control group.

According to the researchers, the main strength of the study is the ability to select a large cohort of 440 children with national test results without major recruitment bias and compare it with a large control group. One main study limitation “was not being able to use the maternal IQ, as well as other maternal factors, such as maternal weight or alcohol consumption during pregnancy, as covariates,” said the authors. In addition, researchers were unable to account for how parental style, or ability, may have influenced educational attainment.

“Our results add to the growing evidence that in utero exposure to certain AEDs can cause developmental problems in children. Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” the researchers concluded.

—Erica Tricarico

Suggested Reading

Lacey AS, Pickrell WO, Thomas RH, et al. Educational attainment of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2018 March 27 [Epub ahead of print].

Allowing patients with a first episode to experience a second is unacceptable, Henry A. Nasrallah, MD, editor in chief of Current Psychiatry, said in his interview with Lorenzo Norris, MD, editor in chief of MDedge Psychiatry.

“It’s not too late to use injectables after the first episode, but my God, why are we letting them lose so much tissue and have so much suffering, so much PTSD, so much stigma, so much poverty, so much incarceration that comes from having repetitive psychotic episodes and deteriorating?” Dr. Nasrallah asked. “We can prevent all of that by utilizing, exploiting those agents.”

Dr. Nasrallah serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on the speakers bureaus of several companies. Dr. Norris has no disclosures.

Allowing patients with a first episode to experience a second is unacceptable, Henry A. Nasrallah, MD, editor in chief of Current Psychiatry, said in his interview with Lorenzo Norris, MD, editor in chief of MDedge Psychiatry.

“It’s not too late to use injectables after the first episode, but my God, why are we letting them lose so much tissue and have so much suffering, so much PTSD, so much stigma, so much poverty, so much incarceration that comes from having repetitive psychotic episodes and deteriorating?” Dr. Nasrallah asked. “We can prevent all of that by utilizing, exploiting those agents.”

Dr. Nasrallah serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on the speakers bureaus of several companies. Dr. Norris has no disclosures.

Allowing patients with a first episode to experience a second is unacceptable, Henry A. Nasrallah, MD, editor in chief of Current Psychiatry, said in his interview with Lorenzo Norris, MD, editor in chief of MDedge Psychiatry.

“It’s not too late to use injectables after the first episode, but my God, why are we letting them lose so much tissue and have so much suffering, so much PTSD, so much stigma, so much poverty, so much incarceration that comes from having repetitive psychotic episodes and deteriorating?” Dr. Nasrallah asked. “We can prevent all of that by utilizing, exploiting those agents.”

Dr. Nasrallah serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on the speakers bureaus of several companies. Dr. Norris has no disclosures.

LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.

The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.

Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.

Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 10³/mcL.

Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.

ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.

The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.

In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.

Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.

EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.

[email protected]

SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.

LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.

The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.

Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.

Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 10³/mcL.

Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.

ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.

The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.

In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.

Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.

EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.

[email protected]

SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.

LOS ANGELES – ALKS 8700, a novel prodrug of monomethyl fumarate, looks promising as an oral, disease-modifying treatment for relapsing forms of multiple sclerosis, according to interim findings from the phase 3 EVOLVE-MS-1 study.

The annualized relapse rate at a median follow-up of 0.93 patient-years (total, 497.1 patient-years) in 578 patients enrolled to date in the 2-year, open-label study was just 0.16, Robert T. Naismith, MD, reported during an emerging science session at the annual meeting of the American Academy of Neurology.

Further, a statistically significant 80% reduction from baseline was seen in the number of gadolinium-enhancing lesions in 374 patients who completed a 1-year MRI assessment (from a mean of 1.5 to 0.3), said Dr. Naismith of Washington University, St. Louis.

Patients enrolled in the ongoing study are adults aged 18-65 years (mean, 41 years) with confirmed relapsing-remitting MS (RRMS), Expanded Disability Status Scale score of 6.0 or less (mean, 2.7), and no evidence of relapse within 30 days prior to starting ALKS 8700. Those with progressive forms of MS are excluded, as are patients who are pregnant or breastfeeding, patients with a history of other clinically significant conditions, and those with clinically significant abnormal laboratory tests at screening or absolute lymphocyte counts less than 0.9 x 10³/mcL.

Of those enrolled so far, 72.5% received prior MS therapies, and their mean time since onset and diagnosis of MS was 9.7 and 7.6 years, respectively. The mean number of relapses in the prior year was 0.8.

ALKS 8700, also known as BIIB098, is given at a dose of 462 mg twice daily for up to 96 weeks; planned enrollment in EVOLVE-MS-1 is approximately 900 patients, Dr. Naismith said.

The preliminary findings from EVOLE-MS-1, which is limited by its single-arm, open-label design, “lend credence to ALKS 8700 as an oral treatment for patients with relapsing-remitting MS,” he said.

In addition to continued evaluation for long-term safety and tolerability in the current study, ALKS 8700 is also being evaluated in combination with 240 mg of twice daily dimethyl fumarate (DMF; Tecfidera) in the 5-week, randomized, double-blind EVOLVE-MS-2 study, which is looking at the gastrointestinal tolerability of the combination in patients with RRMS.

Oral DMF is approved for RRMS, and has been shown to significantly reduce clinical and MRI disease activity, but is commonly associated with GI events. Monomethyl fumarate is the active metabolite of DMF, and as a prodrug of monomethyl fumarate, ALKS 8700 is being developed to work in a manner similar to that of DMF, but with improved GI tolerability, Dr. Naismith explained.

EVOLE-MS-1 is funded by Alkermes. Dr. Naismith has served as a consultant and/or speaker for Alkermes, as well as for Acorda, Bayer, Biogen, Genentech, Genzyme, EMD Serono, Novartis, and Teva. He has received research support from the National Institutes of Health and the National Multiple Sclerosis Society.

[email protected]

SOURCE: Naismith R et al. AAN 2018 Emerging Science Abstract 006.

Meningiomas generally present as slow-growing, expanding intracranial lesions and are the most common benign intracranial tumor in adults.¹ Rarely, meningioma exhibits malignant potential and presents as an extracranial soft-tissue mass through extension or as a primary extracranial cutaneous neoplasm. The differential diagnosis of scalp neoplasms must be broadened to include uncommon tumors such as meningioma. We present a rare case of a 68-year-old woman with scalp metastasis of meningioma 11 years after initial resection of the primary tumor.

Case Report

A 68-year-old woman presented for evaluation of an asymptomatic nodule on the left parietal scalp of 2 years’ duration. She denied any headaches, difficulty with balance, vision changes, or changes in mentation. Her medical history was remarkable for a benign meningioma removed from the right parietal scalp 11 years prior without radiation therapy, as well as type 2 diabetes mellitus and arthritis. The patient’s son died from a brain tumor, but the exact tumor type and age at the time of death were unknown. Her current medications included metformin, insulin glargine, aspirin, and a daily multivitamin. She denied any allergies or history of smoking.

Physical examination of the scalp revealed 4 fixed, nontender, flesh-colored nodules: 2 on the left parietal scalp measuring 3.0 cm and 0.8 cm, respectively (Figure 1A); a 0.4-cm nodule on the right posterior occipital scalp; and a 1.6-cm sausage-shaped nodule on the right temple (Figure 1B). No positive lymph nodes were appreciated, and no additional lesions were noted. No additional atypical lesions were noted on full cutaneous examination.

A diagnostic 6-mm punch biopsy of the largest nodule was performed. Intraoperatively, there was no apparent cyst wall, but coiled, loose, stringlike, pink-yellow tissue was removed from the base of the wound before closing with sutures.

The primary histologic finding was cells within fibrous tissue containing delicate round-oval nuclei, inconspicuous nucleoli, and lightly eosinophilic cytoplasm with an indistinct border (Figure 2). Immunohistochemical studies for S100 protein were focal and limited to the cytoplasm of a subset of neoplastic cells (Figure 3). Tumor cells stained positive for epithelial membrane antigen (EMA) and were focally positive for progesterone receptor (Figure 4). Tumor cells were negative for CD31 and CD34. Based on the clinical and histologic findings, a diagnosis of metastatic meningioma of the scalp was made.

Magnetic resonance imaging and positron emission tomography of the head, neck, and chest demonstrated 3 residual subcutaneous nodules on the scalp and an indeterminate subcentimeter nodule in the right lung. The 0.4-cm nodule on the right posterior occipital scalp was removed without complication, and no radiation therapy was administered. The rest of the lesions were monitored. She remained under the close observation of a neurosurgeon and underwent repeat imaging of the scalp nodules and lungs, initially at 3 months and then routinely at the patient’s comfort. The patient currently denies any neurologic symptoms.

Comment

Meningiomas are derived from meningothelial cells found in the leptomeninges and in the choroid plexus of the ventricles of the brain.² They are common intracranial neoplasms that generally are associated with a benign course and present during the fourth to sixth decades of life. Meningiomas constitute 13% to 30% of intracranial neoplasms and usually are female predominant (3:1).^3,4 Rarely, malignant transformation can lead to local and distant metastasis to the lungs,^5,6 liver,⁷ and skeletal system.⁸ In cases of metastatic spread, there is an increased incidence in males versus females.^9-11

Risk Factors
Although many meningiomas are sporadic, numerous risk factors have been associated with the disease development. One study showed a link between exposure to ionizing radiation and subsequent development of meningioma.¹² Another study found a population link between a higher incidence of meningioma and nuclear exposure in Hiroshima, Japan, after the atomic bomb blast in 1980.¹³ There is an increased incidence of meningioma in patients exposed to radiography from frequent dental imaging, particularly when older machines with higher levels of radiation exposure are used.¹⁴Another study demonstrated a correlation between meningioma and hormonal factors (eg, estrogen for hormone therapy) and exacerbation of symptoms during pregnancy.¹⁵ There also is an increased incidence of meningioma in breast cancer patients.⁴ Genetic alterations also have been implicated in the development of meningioma. It was found that 50% of patients with a mutation in the neurofibromatosis 2 gene (which codes for the merlin protein) had associated meningiomas.^16,17 Scalp nodules in patients with neurofibromatosis type 2 increases suspicion of a scalp meningioma and necessitates biopsy.

Clinical Presentation
Cutaneous meningiomas typically present as firm, subcutaneous nodules. Scalp nodules ranging from alopecia^18,19 to hypertrichosis²⁰ have been reported. These neoplasms can be painless or painful, depending on mass effect and location.

Classification
The primary clinical classification system of metastatic meningioma was first described in 1974.²¹ Type 1 meningioma refers to congenital lesions that tend to cluster closer to the midline. Type 2 refers to ectopic soft-tissue lesions that extend to the skin from likely remnants of arachnoid cells. These lesions are more likely to be found around the eyes, ears, nose, and mouth. Type 3 meningiomas extend from intracranial tumors that secondarily involve the skin through proliferation through bone or anatomic defects. Type 3 is the result of direct extension and the location of the cutaneous presentation depends on the location of the intracranial lesion.^4,22,23

Pathology
Meningiomas exhibit a range of morphologic appearances on histopathology. In almost all meningiomas, tumor cells are concentrically wrapped in tight whorls with round-oval nuclei and delicate chromatin, central clearing, and pale pseudonuclear inclusions. Lamellate calcifications known as psammoma bodies are a common finding. Immunohistochemical studies show that most meningiomas are positive for EMA, vimentin, and progesterone receptor. S100 protein expression, if present, usually is focal.

Differential Diagnosis
Asymptomatic nodules on the scalp may present a diagnostic challenge to physicians. Most common scalp lesions tend to be cystic or lipomatous. In children, a broad differential diagnosis should be considered, including dermoid and epidermoid tumors, dermal sinus tumors, hemangiomas, metastasis of another tumor, aplasia cutis congenita, pilomatricoma, and lipoma. In adults, the differential should focus on epidermoid cysts, lipomas, metastasis of other tumors, osteomas, arteriovenous fistulae, and heterotopic brain tissue. Often, microscopic examination is necessary, along with additional immunohistochemical staining (eg, EMA, vimentin).

Treatment
Treatment options for meningioma include observation, surgical resection, radiotherapy, and systemic therapy, as well as a combination of these modalities. The choice of therapy depends on such variables as patient age; performance status; comorbidities; presence or absence of symptoms (including focal neurologic deficits); and tumor location, size, and grade. It is important to note that there is limited knowledge looking at the results of various treatment modalities, and no consensus approach has been established.

Conclusion

Our patient’s medical history was remarkable for an intracranial meningioma 11 years prior to the current presentation, and she was found to have biopsy-proven metastatic meningioma without recurrence of the initial tumor. Patients presenting with a scalp nodule warrant a thorough medical history and consideration beyond common cysts and lipomas.

Meningiomas generally present as slow-growing, expanding intracranial lesions and are the most common benign intracranial tumor in adults.¹ Rarely, meningioma exhibits malignant potential and presents as an extracranial soft-tissue mass through extension or as a primary extracranial cutaneous neoplasm. The differential diagnosis of scalp neoplasms must be broadened to include uncommon tumors such as meningioma. We present a rare case of a 68-year-old woman with scalp metastasis of meningioma 11 years after initial resection of the primary tumor.

Case Report

A 68-year-old woman presented for evaluation of an asymptomatic nodule on the left parietal scalp of 2 years’ duration. She denied any headaches, difficulty with balance, vision changes, or changes in mentation. Her medical history was remarkable for a benign meningioma removed from the right parietal scalp 11 years prior without radiation therapy, as well as type 2 diabetes mellitus and arthritis. The patient’s son died from a brain tumor, but the exact tumor type and age at the time of death were unknown. Her current medications included metformin, insulin glargine, aspirin, and a daily multivitamin. She denied any allergies or history of smoking.

Physical examination of the scalp revealed 4 fixed, nontender, flesh-colored nodules: 2 on the left parietal scalp measuring 3.0 cm and 0.8 cm, respectively (Figure 1A); a 0.4-cm nodule on the right posterior occipital scalp; and a 1.6-cm sausage-shaped nodule on the right temple (Figure 1B). No positive lymph nodes were appreciated, and no additional lesions were noted. No additional atypical lesions were noted on full cutaneous examination.

A diagnostic 6-mm punch biopsy of the largest nodule was performed. Intraoperatively, there was no apparent cyst wall, but coiled, loose, stringlike, pink-yellow tissue was removed from the base of the wound before closing with sutures.

The primary histologic finding was cells within fibrous tissue containing delicate round-oval nuclei, inconspicuous nucleoli, and lightly eosinophilic cytoplasm with an indistinct border (Figure 2). Immunohistochemical studies for S100 protein were focal and limited to the cytoplasm of a subset of neoplastic cells (Figure 3). Tumor cells stained positive for epithelial membrane antigen (EMA) and were focally positive for progesterone receptor (Figure 4). Tumor cells were negative for CD31 and CD34. Based on the clinical and histologic findings, a diagnosis of metastatic meningioma of the scalp was made.

Magnetic resonance imaging and positron emission tomography of the head, neck, and chest demonstrated 3 residual subcutaneous nodules on the scalp and an indeterminate subcentimeter nodule in the right lung. The 0.4-cm nodule on the right posterior occipital scalp was removed without complication, and no radiation therapy was administered. The rest of the lesions were monitored. She remained under the close observation of a neurosurgeon and underwent repeat imaging of the scalp nodules and lungs, initially at 3 months and then routinely at the patient’s comfort. The patient currently denies any neurologic symptoms.

Comment

Meningiomas are derived from meningothelial cells found in the leptomeninges and in the choroid plexus of the ventricles of the brain.² They are common intracranial neoplasms that generally are associated with a benign course and present during the fourth to sixth decades of life. Meningiomas constitute 13% to 30% of intracranial neoplasms and usually are female predominant (3:1).^3,4 Rarely, malignant transformation can lead to local and distant metastasis to the lungs,^5,6 liver,⁷ and skeletal system.⁸ In cases of metastatic spread, there is an increased incidence in males versus females.^9-11

Risk Factors
Although many meningiomas are sporadic, numerous risk factors have been associated with the disease development. One study showed a link between exposure to ionizing radiation and subsequent development of meningioma.¹² Another study found a population link between a higher incidence of meningioma and nuclear exposure in Hiroshima, Japan, after the atomic bomb blast in 1980.¹³ There is an increased incidence of meningioma in patients exposed to radiography from frequent dental imaging, particularly when older machines with higher levels of radiation exposure are used.¹⁴Another study demonstrated a correlation between meningioma and hormonal factors (eg, estrogen for hormone therapy) and exacerbation of symptoms during pregnancy.¹⁵ There also is an increased incidence of meningioma in breast cancer patients.⁴ Genetic alterations also have been implicated in the development of meningioma. It was found that 50% of patients with a mutation in the neurofibromatosis 2 gene (which codes for the merlin protein) had associated meningiomas.^16,17 Scalp nodules in patients with neurofibromatosis type 2 increases suspicion of a scalp meningioma and necessitates biopsy.

Clinical Presentation
Cutaneous meningiomas typically present as firm, subcutaneous nodules. Scalp nodules ranging from alopecia^18,19 to hypertrichosis²⁰ have been reported. These neoplasms can be painless or painful, depending on mass effect and location.

Classification
The primary clinical classification system of metastatic meningioma was first described in 1974.²¹ Type 1 meningioma refers to congenital lesions that tend to cluster closer to the midline. Type 2 refers to ectopic soft-tissue lesions that extend to the skin from likely remnants of arachnoid cells. These lesions are more likely to be found around the eyes, ears, nose, and mouth. Type 3 meningiomas extend from intracranial tumors that secondarily involve the skin through proliferation through bone or anatomic defects. Type 3 is the result of direct extension and the location of the cutaneous presentation depends on the location of the intracranial lesion.^4,22,23

Pathology
Meningiomas exhibit a range of morphologic appearances on histopathology. In almost all meningiomas, tumor cells are concentrically wrapped in tight whorls with round-oval nuclei and delicate chromatin, central clearing, and pale pseudonuclear inclusions. Lamellate calcifications known as psammoma bodies are a common finding. Immunohistochemical studies show that most meningiomas are positive for EMA, vimentin, and progesterone receptor. S100 protein expression, if present, usually is focal.

Differential Diagnosis
Asymptomatic nodules on the scalp may present a diagnostic challenge to physicians. Most common scalp lesions tend to be cystic or lipomatous. In children, a broad differential diagnosis should be considered, including dermoid and epidermoid tumors, dermal sinus tumors, hemangiomas, metastasis of another tumor, aplasia cutis congenita, pilomatricoma, and lipoma. In adults, the differential should focus on epidermoid cysts, lipomas, metastasis of other tumors, osteomas, arteriovenous fistulae, and heterotopic brain tissue. Often, microscopic examination is necessary, along with additional immunohistochemical staining (eg, EMA, vimentin).

Treatment
Treatment options for meningioma include observation, surgical resection, radiotherapy, and systemic therapy, as well as a combination of these modalities. The choice of therapy depends on such variables as patient age; performance status; comorbidities; presence or absence of symptoms (including focal neurologic deficits); and tumor location, size, and grade. It is important to note that there is limited knowledge looking at the results of various treatment modalities, and no consensus approach has been established.

Conclusion

Our patient’s medical history was remarkable for an intracranial meningioma 11 years prior to the current presentation, and she was found to have biopsy-proven metastatic meningioma without recurrence of the initial tumor. Patients presenting with a scalp nodule warrant a thorough medical history and consideration beyond common cysts and lipomas.

Meningiomas generally present as slow-growing, expanding intracranial lesions and are the most common benign intracranial tumor in adults.¹ Rarely, meningioma exhibits malignant potential and presents as an extracranial soft-tissue mass through extension or as a primary extracranial cutaneous neoplasm. The differential diagnosis of scalp neoplasms must be broadened to include uncommon tumors such as meningioma. We present a rare case of a 68-year-old woman with scalp metastasis of meningioma 11 years after initial resection of the primary tumor.

Case Report

A 68-year-old woman presented for evaluation of an asymptomatic nodule on the left parietal scalp of 2 years’ duration. She denied any headaches, difficulty with balance, vision changes, or changes in mentation. Her medical history was remarkable for a benign meningioma removed from the right parietal scalp 11 years prior without radiation therapy, as well as type 2 diabetes mellitus and arthritis. The patient’s son died from a brain tumor, but the exact tumor type and age at the time of death were unknown. Her current medications included metformin, insulin glargine, aspirin, and a daily multivitamin. She denied any allergies or history of smoking.

Physical examination of the scalp revealed 4 fixed, nontender, flesh-colored nodules: 2 on the left parietal scalp measuring 3.0 cm and 0.8 cm, respectively (Figure 1A); a 0.4-cm nodule on the right posterior occipital scalp; and a 1.6-cm sausage-shaped nodule on the right temple (Figure 1B). No positive lymph nodes were appreciated, and no additional lesions were noted. No additional atypical lesions were noted on full cutaneous examination.

A diagnostic 6-mm punch biopsy of the largest nodule was performed. Intraoperatively, there was no apparent cyst wall, but coiled, loose, stringlike, pink-yellow tissue was removed from the base of the wound before closing with sutures.

The primary histologic finding was cells within fibrous tissue containing delicate round-oval nuclei, inconspicuous nucleoli, and lightly eosinophilic cytoplasm with an indistinct border (Figure 2). Immunohistochemical studies for S100 protein were focal and limited to the cytoplasm of a subset of neoplastic cells (Figure 3). Tumor cells stained positive for epithelial membrane antigen (EMA) and were focally positive for progesterone receptor (Figure 4). Tumor cells were negative for CD31 and CD34. Based on the clinical and histologic findings, a diagnosis of metastatic meningioma of the scalp was made.

Magnetic resonance imaging and positron emission tomography of the head, neck, and chest demonstrated 3 residual subcutaneous nodules on the scalp and an indeterminate subcentimeter nodule in the right lung. The 0.4-cm nodule on the right posterior occipital scalp was removed without complication, and no radiation therapy was administered. The rest of the lesions were monitored. She remained under the close observation of a neurosurgeon and underwent repeat imaging of the scalp nodules and lungs, initially at 3 months and then routinely at the patient’s comfort. The patient currently denies any neurologic symptoms.

Comment

Meningiomas are derived from meningothelial cells found in the leptomeninges and in the choroid plexus of the ventricles of the brain.² They are common intracranial neoplasms that generally are associated with a benign course and present during the fourth to sixth decades of life. Meningiomas constitute 13% to 30% of intracranial neoplasms and usually are female predominant (3:1).^3,4 Rarely, malignant transformation can lead to local and distant metastasis to the lungs,^5,6 liver,⁷ and skeletal system.⁸ In cases of metastatic spread, there is an increased incidence in males versus females.^9-11

Risk Factors
Although many meningiomas are sporadic, numerous risk factors have been associated with the disease development. One study showed a link between exposure to ionizing radiation and subsequent development of meningioma.¹² Another study found a population link between a higher incidence of meningioma and nuclear exposure in Hiroshima, Japan, after the atomic bomb blast in 1980.¹³ There is an increased incidence of meningioma in patients exposed to radiography from frequent dental imaging, particularly when older machines with higher levels of radiation exposure are used.¹⁴Another study demonstrated a correlation between meningioma and hormonal factors (eg, estrogen for hormone therapy) and exacerbation of symptoms during pregnancy.¹⁵ There also is an increased incidence of meningioma in breast cancer patients.⁴ Genetic alterations also have been implicated in the development of meningioma. It was found that 50% of patients with a mutation in the neurofibromatosis 2 gene (which codes for the merlin protein) had associated meningiomas.^16,17 Scalp nodules in patients with neurofibromatosis type 2 increases suspicion of a scalp meningioma and necessitates biopsy.

Clinical Presentation
Cutaneous meningiomas typically present as firm, subcutaneous nodules. Scalp nodules ranging from alopecia^18,19 to hypertrichosis²⁰ have been reported. These neoplasms can be painless or painful, depending on mass effect and location.

Classification
The primary clinical classification system of metastatic meningioma was first described in 1974.²¹ Type 1 meningioma refers to congenital lesions that tend to cluster closer to the midline. Type 2 refers to ectopic soft-tissue lesions that extend to the skin from likely remnants of arachnoid cells. These lesions are more likely to be found around the eyes, ears, nose, and mouth. Type 3 meningiomas extend from intracranial tumors that secondarily involve the skin through proliferation through bone or anatomic defects. Type 3 is the result of direct extension and the location of the cutaneous presentation depends on the location of the intracranial lesion.^4,22,23

Pathology
Meningiomas exhibit a range of morphologic appearances on histopathology. In almost all meningiomas, tumor cells are concentrically wrapped in tight whorls with round-oval nuclei and delicate chromatin, central clearing, and pale pseudonuclear inclusions. Lamellate calcifications known as psammoma bodies are a common finding. Immunohistochemical studies show that most meningiomas are positive for EMA, vimentin, and progesterone receptor. S100 protein expression, if present, usually is focal.

Differential Diagnosis
Asymptomatic nodules on the scalp may present a diagnostic challenge to physicians. Most common scalp lesions tend to be cystic or lipomatous. In children, a broad differential diagnosis should be considered, including dermoid and epidermoid tumors, dermal sinus tumors, hemangiomas, metastasis of another tumor, aplasia cutis congenita, pilomatricoma, and lipoma. In adults, the differential should focus on epidermoid cysts, lipomas, metastasis of other tumors, osteomas, arteriovenous fistulae, and heterotopic brain tissue. Often, microscopic examination is necessary, along with additional immunohistochemical staining (eg, EMA, vimentin).

Treatment
Treatment options for meningioma include observation, surgical resection, radiotherapy, and systemic therapy, as well as a combination of these modalities. The choice of therapy depends on such variables as patient age; performance status; comorbidities; presence or absence of symptoms (including focal neurologic deficits); and tumor location, size, and grade. It is important to note that there is limited knowledge looking at the results of various treatment modalities, and no consensus approach has been established.

Conclusion

Our patient’s medical history was remarkable for an intracranial meningioma 11 years prior to the current presentation, and she was found to have biopsy-proven metastatic meningioma without recurrence of the initial tumor. Patients presenting with a scalp nodule warrant a thorough medical history and consideration beyond common cysts and lipomas.

Eccrine carcinomas are uncommon cutaneous neoplasms demonstrating nonuniform histologic features, behavior, and nomenclature. Given the rarity of these tumors, no known criteria by which to diagnose the tumor or guidelines for treatment have been proposed. We report a rare case of an immunocompromised patient with a primary squamoid eccrine ductal carcinoma (SEDC) who was subsequently treated with radical resection and axillary dissection. It was later determined that the patient had distant metastasis of SEDC. A review of the literature on the diagnosis, treatment, and surveillance of SEDC also is provided.

Case Report

A 77-year-old man whose medical history was remarkable for chronic lymphocytic leukemia (CLL) and numerous previous basal cell carcinomas and squamous cell carcinomas (SCCs) presented with a 5-cm, stellate, sclerotic plaque on the left chest of approximately 2 years’ duration (Figure 1) and a 3-mm pink papule on the right nasal sidewall of 2 months’ duration. Initial histology of both lesions revealed carcinoma with squamous and ductal differentiation extending from the undersurface of the epidermis, favoring a diagnosis of SEDC (Figure 2). At the time of initial presentation, the patient also had a 6-mm pink papule on the right chest of several months duration that was consistent with a well-differentiated sebaceous carcinoma on histology.

Further analysis of the lesion on the left chest revealed positive staining for cytokeratin (CK) 5/14 and p63, suggestive of a cutaneous malignancy. Staining for S100 protein highlighted rare cells in the basal layer of tumor aggregates. The immunohistochemical profile showed negative staining for CK7, CK5D3, epithelial membrane antigen (EMA), estrogen receptor, progesterone receptor, and human epidermal growth factor 2.

Diagnosis of SEDC of the chest and nasal lesions was based on the morphologic architecture, which included ductal formation noted within the tumor. The chest lesion also had prominent squamoid differentiation. Another histologic feature consistent with SEDC was poorly demarcated, infiltrative neoplastic cells extending into the dermis and subcutis. Although there was some positive focal staining for carcinoembryonic antigen (CEA), variegation within the tumor and the prominent squamoid component might have contributed to this unexpected staining pattern.

The patient was admitted to the hospital for excision of the lesion on the chest wall. Initial workup revealed macrocytic anemia, which required transfusion, and an incidental finding of non–small-cell lung cancer. The chest lesion was unrelated to the non–small-cell lung cancer based on the staining profile. Material from the lung stained positive for thyroid transcription factor 1 (TTF-1) and exhibited rare staining for p63; however, the chest lesion did not stain positive for TTF-1 and had strong staining affinity for p63, indicative of a cutaneous malignancy.

The lesion on the chest wall was definitively excised. Pathologic analysis revealed a dermal-based infiltrative tumor of irregular nests and cords of squamoid cells with focal ductal formation in a fibromyxoid background stroma, suggestive of an adnexal carcinoma with a considerable degree of squamous differentiation and favoring a diagnosis of SEDC. Focal perineural invasion was noted, but no lymphovascular spread was identified; however, metastasis was identified in 1 of 26 axillary lymph nodes. The patient underwent 9 sessions of radiation therapy for the lung cancer and also was given cetuximab.

Three months later, the nasal tumor was subsequently excised in an outpatient procedure, and the final biopsy report indicated a diagnosis of basal cell carcinoma. One-and-a-half years later, in follow-up with surgery after removal of the chest lesion, a 2×3-cm mass was excised from the left neck that demonstrated lymph nodes consistent with metastatic SEDC. Careful evaluation of this patient, including family history and genetic screening, was considered. Our patient continues to follow-up with the dermatology department every 3 months. He has been doing well and has had multiple additional primary SCCs in the subsequent 5 years of follow-up.

Comment

Eccrine carcinoma is the most common subtype of adnexal carcinoma, representing 0.01% of all cutaneous tumors.¹ Squamoid eccrine ductal carcinoma is rare, with as few as 13 cases reported in the literature; 3 of these patients were treated with Mohs micrographic surgery (MMS).^1,2 Recently, two series of 7 and 30 cases, respectively, were longitudinally followed and described.^3,4 We report an additional rare case of SEDC in an immunocompromised patient with distant metastases that was treated with radical resection and axillary dissection.

Eccrine carcinoma is observed clinically as a slow-growing, nodular plaque on the scalp, arms, legs, or trunk in middle-aged and elderly individuals.¹ Squamoid eccrine ductal carcinoma also has been reported in a young woman.⁵ Another immunocompromised patient was identified in the literature with a great toe lesion that showed follicular differentiation along with the usual SEDC features of squamoid and ductal differentiation.⁶ The etiology of SEDC is controversial but is thought to be an SCC arising from eccrine glands, a subtype of eccrine carcinoma with extensive squamoid differentiation, or a biphenotypic carcinoma.^1,7

Histologically, SEDC is poorly circumscribed with an infiltrative growth pattern and deep extension into the dermis and subcutaneous tissue. The lesion is characterized by prominent squamous epithelial proliferation superficially with cellular atypia, keratinous cyst formation, squamous eddies, and eccrine ductal differentiation.¹

The differential diagnosis of SEDC includes SCC; metastatic carcinoma with squamoid features; and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma, and porocarcinoma with squamous differentiation.¹

Immunohistochemistry has a role in the diagnosis of SEDC. Findings include positive staining for S100 protein, EMA, CKs, and CEA. Glandular tissue stains positive for EMA and CEA, supporting an adnexal origin.¹ Positivity for p63 and CK5/6 supports the conclusion that this is a primary cutaneous malignancy, not a metastatic disease.¹

Squamoid eccrine ductal carcinoma has an indeterminate malignant potential. There is a disparity of clinical behavior between SCC and eccrine cancers; however, because squamous differentiation sometimes dominates the histological picture, eccrine carcinomas can be misdiagnosed as SCC.^1,8 Eccrine adnexal tumors are characterized by multiple local recurrences (70%–80% of cases); perineural invasion; and metastasis (50% of cases) to regional lymph nodes and viscera, including the lungs, liver, bones, and brain.¹ Squamous cell carcinoma, however, has a markedly lower recurrence rate (3.1%–18.7% of cases) and rate of metastasis (5.2%–37.8%).¹

Squamoid eccrine ductal carcinoma is classified as one of the less aggressive eccrine tumors, although the low number of cases makes it a controversial conclusion.¹ To our knowledge, no cases of SEDC metastasis have been reported with SEDC. Recurrence of SEDC has been reported locally, and perineural or perivascular invasion (or both) has been demonstrated in 3 cases.¹

Since SEDC has invasive and metastatic potential, as demonstrated in our case, along with elevated local recurrence rates, physicians must be able to properly diagnose this rare entity and recommend an appropriate surgical modality. Due to the low incidence of SEDC, there are no known randomized studies comparing treatment modalities.¹ Other works in the literature have suggested treating SEDC with the same approach as lesions with similar histologic features and behavior, such as eccrine carcinoma and SCC.^1,5-7

Surgical extirpation with complete margin examination is recommended, as SEDC tends to be underestimated in size, is aggressive in its infiltration, and is predisposed to perineural and perivascular invasion. The literature has shown that MMS has demonstrated lower recurrence rates (3.1%–5%) than other treatments at 5-year follow-up for SCC and (0%–5%) for eccrine carcinoma (average follow-up, 31 months).^1,5 Further studies are needed to understand the clinical progression of SEDC, and more experience is necessary with close follow-up of this subset of patients. Follow-up is determined at the present time from anecdotal experience and patient history.

Along with the rarity of SEDC in our patient, the simultaneous occurrence of 3 primary malignancies also is unusual. Patients with CLL have progressive defects of cell- and humoral-mediated immunity, causing immunosuppression. In a retrospective study, Tsimberidou et al⁹ reviewed the records of 2028 untreated CLL patients and determined that 27% had another primary malignancy, including skin (30%) and lung cancers (6%), which were two of the malignancies seen in our patient. The investigators concluded that patients with CLL have more than twice the risk of developing a second primary malignancy and an increased frequency of certain cancer types.⁹ Furthermore, treatment regimens for CLL have been considered to increase cell- and humoral-mediated immune defects at specific cancer sites,¹⁰ although the exact mechanism of this action is unknown. Development of a second primary malignancy (or even a third) in patients with SEDC is increasingly being reported in CLL patients.^9,10

A high index of suspicion with SEDC in the differential diagnosis should be maintained in elderly men with slow-growing, solitary, nodular lesions of the scalp, nose, arms, legs, or trunk.

Eccrine carcinomas are uncommon cutaneous neoplasms demonstrating nonuniform histologic features, behavior, and nomenclature. Given the rarity of these tumors, no known criteria by which to diagnose the tumor or guidelines for treatment have been proposed. We report a rare case of an immunocompromised patient with a primary squamoid eccrine ductal carcinoma (SEDC) who was subsequently treated with radical resection and axillary dissection. It was later determined that the patient had distant metastasis of SEDC. A review of the literature on the diagnosis, treatment, and surveillance of SEDC also is provided.

Case Report

A 77-year-old man whose medical history was remarkable for chronic lymphocytic leukemia (CLL) and numerous previous basal cell carcinomas and squamous cell carcinomas (SCCs) presented with a 5-cm, stellate, sclerotic plaque on the left chest of approximately 2 years’ duration (Figure 1) and a 3-mm pink papule on the right nasal sidewall of 2 months’ duration. Initial histology of both lesions revealed carcinoma with squamous and ductal differentiation extending from the undersurface of the epidermis, favoring a diagnosis of SEDC (Figure 2). At the time of initial presentation, the patient also had a 6-mm pink papule on the right chest of several months duration that was consistent with a well-differentiated sebaceous carcinoma on histology.

Further analysis of the lesion on the left chest revealed positive staining for cytokeratin (CK) 5/14 and p63, suggestive of a cutaneous malignancy. Staining for S100 protein highlighted rare cells in the basal layer of tumor aggregates. The immunohistochemical profile showed negative staining for CK7, CK5D3, epithelial membrane antigen (EMA), estrogen receptor, progesterone receptor, and human epidermal growth factor 2.

Diagnosis of SEDC of the chest and nasal lesions was based on the morphologic architecture, which included ductal formation noted within the tumor. The chest lesion also had prominent squamoid differentiation. Another histologic feature consistent with SEDC was poorly demarcated, infiltrative neoplastic cells extending into the dermis and subcutis. Although there was some positive focal staining for carcinoembryonic antigen (CEA), variegation within the tumor and the prominent squamoid component might have contributed to this unexpected staining pattern.

The patient was admitted to the hospital for excision of the lesion on the chest wall. Initial workup revealed macrocytic anemia, which required transfusion, and an incidental finding of non–small-cell lung cancer. The chest lesion was unrelated to the non–small-cell lung cancer based on the staining profile. Material from the lung stained positive for thyroid transcription factor 1 (TTF-1) and exhibited rare staining for p63; however, the chest lesion did not stain positive for TTF-1 and had strong staining affinity for p63, indicative of a cutaneous malignancy.

The lesion on the chest wall was definitively excised. Pathologic analysis revealed a dermal-based infiltrative tumor of irregular nests and cords of squamoid cells with focal ductal formation in a fibromyxoid background stroma, suggestive of an adnexal carcinoma with a considerable degree of squamous differentiation and favoring a diagnosis of SEDC. Focal perineural invasion was noted, but no lymphovascular spread was identified; however, metastasis was identified in 1 of 26 axillary lymph nodes. The patient underwent 9 sessions of radiation therapy for the lung cancer and also was given cetuximab.

Three months later, the nasal tumor was subsequently excised in an outpatient procedure, and the final biopsy report indicated a diagnosis of basal cell carcinoma. One-and-a-half years later, in follow-up with surgery after removal of the chest lesion, a 2×3-cm mass was excised from the left neck that demonstrated lymph nodes consistent with metastatic SEDC. Careful evaluation of this patient, including family history and genetic screening, was considered. Our patient continues to follow-up with the dermatology department every 3 months. He has been doing well and has had multiple additional primary SCCs in the subsequent 5 years of follow-up.

Comment

Eccrine carcinoma is the most common subtype of adnexal carcinoma, representing 0.01% of all cutaneous tumors.¹ Squamoid eccrine ductal carcinoma is rare, with as few as 13 cases reported in the literature; 3 of these patients were treated with Mohs micrographic surgery (MMS).^1,2 Recently, two series of 7 and 30 cases, respectively, were longitudinally followed and described.^3,4 We report an additional rare case of SEDC in an immunocompromised patient with distant metastases that was treated with radical resection and axillary dissection.

Eccrine carcinoma is observed clinically as a slow-growing, nodular plaque on the scalp, arms, legs, or trunk in middle-aged and elderly individuals.¹ Squamoid eccrine ductal carcinoma also has been reported in a young woman.⁵ Another immunocompromised patient was identified in the literature with a great toe lesion that showed follicular differentiation along with the usual SEDC features of squamoid and ductal differentiation.⁶ The etiology of SEDC is controversial but is thought to be an SCC arising from eccrine glands, a subtype of eccrine carcinoma with extensive squamoid differentiation, or a biphenotypic carcinoma.^1,7

Histologically, SEDC is poorly circumscribed with an infiltrative growth pattern and deep extension into the dermis and subcutaneous tissue. The lesion is characterized by prominent squamous epithelial proliferation superficially with cellular atypia, keratinous cyst formation, squamous eddies, and eccrine ductal differentiation.¹

The differential diagnosis of SEDC includes SCC; metastatic carcinoma with squamoid features; and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma, and porocarcinoma with squamous differentiation.¹

Immunohistochemistry has a role in the diagnosis of SEDC. Findings include positive staining for S100 protein, EMA, CKs, and CEA. Glandular tissue stains positive for EMA and CEA, supporting an adnexal origin.¹ Positivity for p63 and CK5/6 supports the conclusion that this is a primary cutaneous malignancy, not a metastatic disease.¹

Squamoid eccrine ductal carcinoma has an indeterminate malignant potential. There is a disparity of clinical behavior between SCC and eccrine cancers; however, because squamous differentiation sometimes dominates the histological picture, eccrine carcinomas can be misdiagnosed as SCC.^1,8 Eccrine adnexal tumors are characterized by multiple local recurrences (70%–80% of cases); perineural invasion; and metastasis (50% of cases) to regional lymph nodes and viscera, including the lungs, liver, bones, and brain.¹ Squamous cell carcinoma, however, has a markedly lower recurrence rate (3.1%–18.7% of cases) and rate of metastasis (5.2%–37.8%).¹

Squamoid eccrine ductal carcinoma is classified as one of the less aggressive eccrine tumors, although the low number of cases makes it a controversial conclusion.¹ To our knowledge, no cases of SEDC metastasis have been reported with SEDC. Recurrence of SEDC has been reported locally, and perineural or perivascular invasion (or both) has been demonstrated in 3 cases.¹

Since SEDC has invasive and metastatic potential, as demonstrated in our case, along with elevated local recurrence rates, physicians must be able to properly diagnose this rare entity and recommend an appropriate surgical modality. Due to the low incidence of SEDC, there are no known randomized studies comparing treatment modalities.¹ Other works in the literature have suggested treating SEDC with the same approach as lesions with similar histologic features and behavior, such as eccrine carcinoma and SCC.^1,5-7

Surgical extirpation with complete margin examination is recommended, as SEDC tends to be underestimated in size, is aggressive in its infiltration, and is predisposed to perineural and perivascular invasion. The literature has shown that MMS has demonstrated lower recurrence rates (3.1%–5%) than other treatments at 5-year follow-up for SCC and (0%–5%) for eccrine carcinoma (average follow-up, 31 months).^1,5 Further studies are needed to understand the clinical progression of SEDC, and more experience is necessary with close follow-up of this subset of patients. Follow-up is determined at the present time from anecdotal experience and patient history.

Along with the rarity of SEDC in our patient, the simultaneous occurrence of 3 primary malignancies also is unusual. Patients with CLL have progressive defects of cell- and humoral-mediated immunity, causing immunosuppression. In a retrospective study, Tsimberidou et al⁹ reviewed the records of 2028 untreated CLL patients and determined that 27% had another primary malignancy, including skin (30%) and lung cancers (6%), which were two of the malignancies seen in our patient. The investigators concluded that patients with CLL have more than twice the risk of developing a second primary malignancy and an increased frequency of certain cancer types.⁹ Furthermore, treatment regimens for CLL have been considered to increase cell- and humoral-mediated immune defects at specific cancer sites,¹⁰ although the exact mechanism of this action is unknown. Development of a second primary malignancy (or even a third) in patients with SEDC is increasingly being reported in CLL patients.^9,10

A high index of suspicion with SEDC in the differential diagnosis should be maintained in elderly men with slow-growing, solitary, nodular lesions of the scalp, nose, arms, legs, or trunk.

Eccrine carcinomas are uncommon cutaneous neoplasms demonstrating nonuniform histologic features, behavior, and nomenclature. Given the rarity of these tumors, no known criteria by which to diagnose the tumor or guidelines for treatment have been proposed. We report a rare case of an immunocompromised patient with a primary squamoid eccrine ductal carcinoma (SEDC) who was subsequently treated with radical resection and axillary dissection. It was later determined that the patient had distant metastasis of SEDC. A review of the literature on the diagnosis, treatment, and surveillance of SEDC also is provided.

Case Report

A 77-year-old man whose medical history was remarkable for chronic lymphocytic leukemia (CLL) and numerous previous basal cell carcinomas and squamous cell carcinomas (SCCs) presented with a 5-cm, stellate, sclerotic plaque on the left chest of approximately 2 years’ duration (Figure 1) and a 3-mm pink papule on the right nasal sidewall of 2 months’ duration. Initial histology of both lesions revealed carcinoma with squamous and ductal differentiation extending from the undersurface of the epidermis, favoring a diagnosis of SEDC (Figure 2). At the time of initial presentation, the patient also had a 6-mm pink papule on the right chest of several months duration that was consistent with a well-differentiated sebaceous carcinoma on histology.

Further analysis of the lesion on the left chest revealed positive staining for cytokeratin (CK) 5/14 and p63, suggestive of a cutaneous malignancy. Staining for S100 protein highlighted rare cells in the basal layer of tumor aggregates. The immunohistochemical profile showed negative staining for CK7, CK5D3, epithelial membrane antigen (EMA), estrogen receptor, progesterone receptor, and human epidermal growth factor 2.

Diagnosis of SEDC of the chest and nasal lesions was based on the morphologic architecture, which included ductal formation noted within the tumor. The chest lesion also had prominent squamoid differentiation. Another histologic feature consistent with SEDC was poorly demarcated, infiltrative neoplastic cells extending into the dermis and subcutis. Although there was some positive focal staining for carcinoembryonic antigen (CEA), variegation within the tumor and the prominent squamoid component might have contributed to this unexpected staining pattern.

The patient was admitted to the hospital for excision of the lesion on the chest wall. Initial workup revealed macrocytic anemia, which required transfusion, and an incidental finding of non–small-cell lung cancer. The chest lesion was unrelated to the non–small-cell lung cancer based on the staining profile. Material from the lung stained positive for thyroid transcription factor 1 (TTF-1) and exhibited rare staining for p63; however, the chest lesion did not stain positive for TTF-1 and had strong staining affinity for p63, indicative of a cutaneous malignancy.

The lesion on the chest wall was definitively excised. Pathologic analysis revealed a dermal-based infiltrative tumor of irregular nests and cords of squamoid cells with focal ductal formation in a fibromyxoid background stroma, suggestive of an adnexal carcinoma with a considerable degree of squamous differentiation and favoring a diagnosis of SEDC. Focal perineural invasion was noted, but no lymphovascular spread was identified; however, metastasis was identified in 1 of 26 axillary lymph nodes. The patient underwent 9 sessions of radiation therapy for the lung cancer and also was given cetuximab.

Three months later, the nasal tumor was subsequently excised in an outpatient procedure, and the final biopsy report indicated a diagnosis of basal cell carcinoma. One-and-a-half years later, in follow-up with surgery after removal of the chest lesion, a 2×3-cm mass was excised from the left neck that demonstrated lymph nodes consistent with metastatic SEDC. Careful evaluation of this patient, including family history and genetic screening, was considered. Our patient continues to follow-up with the dermatology department every 3 months. He has been doing well and has had multiple additional primary SCCs in the subsequent 5 years of follow-up.

Comment

Eccrine carcinoma is the most common subtype of adnexal carcinoma, representing 0.01% of all cutaneous tumors.¹ Squamoid eccrine ductal carcinoma is rare, with as few as 13 cases reported in the literature; 3 of these patients were treated with Mohs micrographic surgery (MMS).^1,2 Recently, two series of 7 and 30 cases, respectively, were longitudinally followed and described.^3,4 We report an additional rare case of SEDC in an immunocompromised patient with distant metastases that was treated with radical resection and axillary dissection.

Eccrine carcinoma is observed clinically as a slow-growing, nodular plaque on the scalp, arms, legs, or trunk in middle-aged and elderly individuals.¹ Squamoid eccrine ductal carcinoma also has been reported in a young woman.⁵ Another immunocompromised patient was identified in the literature with a great toe lesion that showed follicular differentiation along with the usual SEDC features of squamoid and ductal differentiation.⁶ The etiology of SEDC is controversial but is thought to be an SCC arising from eccrine glands, a subtype of eccrine carcinoma with extensive squamoid differentiation, or a biphenotypic carcinoma.^1,7

Histologically, SEDC is poorly circumscribed with an infiltrative growth pattern and deep extension into the dermis and subcutaneous tissue. The lesion is characterized by prominent squamous epithelial proliferation superficially with cellular atypia, keratinous cyst formation, squamous eddies, and eccrine ductal differentiation.¹

The differential diagnosis of SEDC includes SCC; metastatic carcinoma with squamoid features; and eccrine tumors, including eccrine poroma, microcystic adnexal carcinoma, and porocarcinoma with squamous differentiation.¹

Immunohistochemistry has a role in the diagnosis of SEDC. Findings include positive staining for S100 protein, EMA, CKs, and CEA. Glandular tissue stains positive for EMA and CEA, supporting an adnexal origin.¹ Positivity for p63 and CK5/6 supports the conclusion that this is a primary cutaneous malignancy, not a metastatic disease.¹

Squamoid eccrine ductal carcinoma has an indeterminate malignant potential. There is a disparity of clinical behavior between SCC and eccrine cancers; however, because squamous differentiation sometimes dominates the histological picture, eccrine carcinomas can be misdiagnosed as SCC.^1,8 Eccrine adnexal tumors are characterized by multiple local recurrences (70%–80% of cases); perineural invasion; and metastasis (50% of cases) to regional lymph nodes and viscera, including the lungs, liver, bones, and brain.¹ Squamous cell carcinoma, however, has a markedly lower recurrence rate (3.1%–18.7% of cases) and rate of metastasis (5.2%–37.8%).¹

Squamoid eccrine ductal carcinoma is classified as one of the less aggressive eccrine tumors, although the low number of cases makes it a controversial conclusion.¹ To our knowledge, no cases of SEDC metastasis have been reported with SEDC. Recurrence of SEDC has been reported locally, and perineural or perivascular invasion (or both) has been demonstrated in 3 cases.¹

Since SEDC has invasive and metastatic potential, as demonstrated in our case, along with elevated local recurrence rates, physicians must be able to properly diagnose this rare entity and recommend an appropriate surgical modality. Due to the low incidence of SEDC, there are no known randomized studies comparing treatment modalities.¹ Other works in the literature have suggested treating SEDC with the same approach as lesions with similar histologic features and behavior, such as eccrine carcinoma and SCC.^1,5-7

Surgical extirpation with complete margin examination is recommended, as SEDC tends to be underestimated in size, is aggressive in its infiltration, and is predisposed to perineural and perivascular invasion. The literature has shown that MMS has demonstrated lower recurrence rates (3.1%–5%) than other treatments at 5-year follow-up for SCC and (0%–5%) for eccrine carcinoma (average follow-up, 31 months).^1,5 Further studies are needed to understand the clinical progression of SEDC, and more experience is necessary with close follow-up of this subset of patients. Follow-up is determined at the present time from anecdotal experience and patient history.

Along with the rarity of SEDC in our patient, the simultaneous occurrence of 3 primary malignancies also is unusual. Patients with CLL have progressive defects of cell- and humoral-mediated immunity, causing immunosuppression. In a retrospective study, Tsimberidou et al⁹ reviewed the records of 2028 untreated CLL patients and determined that 27% had another primary malignancy, including skin (30%) and lung cancers (6%), which were two of the malignancies seen in our patient. The investigators concluded that patients with CLL have more than twice the risk of developing a second primary malignancy and an increased frequency of certain cancer types.⁹ Furthermore, treatment regimens for CLL have been considered to increase cell- and humoral-mediated immune defects at specific cancer sites,¹⁰ although the exact mechanism of this action is unknown. Development of a second primary malignancy (or even a third) in patients with SEDC is increasingly being reported in CLL patients.^9,10

A high index of suspicion with SEDC in the differential diagnosis should be maintained in elderly men with slow-growing, solitary, nodular lesions of the scalp, nose, arms, legs, or trunk.

Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

Case Report

A 62-year-old black man presented for examination of a dark longitudinal streak located adjacent to the lateral nail fold on the third finger of the left hand. The lesion had been present for several months, during which time it had slowly expanded in size. The fingertip had recently become tender, which interfered with the patient’s ability to work. His past medical history was remarkable for end-stage renal disease secondary to glomerulonephritis with nephrotic syndrome of unclear etiology. He initially was treated by an outside physician using peritoneal dialysis for 3 years until he underwent renal transplantation in 2004 with a cadaveric organ. Other remarkable medical conditions included posttransplantation diabetes, hyperlipidemia, and gout. His multidrug regimen included 2 immunosuppressive medications: oral cyclosporine 125 mg twice daily and oral mycophenolate mofetil 250 mg twice daily.

A broad, irregular, black, pigmented, subungual band was noted on the left third finger. The lesion appeared to emanate from below the nail cuticle and traveled along the nail longitudinally toward the distal tip. The band appeared darker at the edge adjacent to the lateral nail fold and grew lighter near the middle of the nail where its free edge was noted to be irregular. A slightly thickened lateral nail fold with an irregular, small, sawtoothlike hyperkeratosis and hyperpigmentation also was noted (Figure 1).

Subungual melanoma, onychomycosis, squamous cell carcinoma (SCC), and a verruca copresenting with onychomycosis were considered in the differential diagnosis. The patient underwent nail avulsion and biopsy of the nail bed as well as the nail matrix. Histopathology was notable for malignant dyskeratosis with a lack of nuclear maturation, occasional mitoses, multinucleation, and individual cell keratinization (Figure 2). Immunostaining for S100 was negative, while staining for cytokeratins AE1/AE3 was positive. Deposition of melanin pigment in the malignant dyskeratotic cells was noted. Periodic acid–Schiff staining identified pseudohyphae without invasion of the nail plate. A diagnosis of pigmented SCC (pSCC) was made. The patient’s nail also was sent for fungal cultures that later grew Candida glabrata and Candida parapsilosis.

The patient underwent Mohs micrographic surgery for removal of the pSCC, which was found to be more extensive than originally suspected and required en bloc excision of the nail repaired with a full-thickness skin graft from the left forearm. The area healed well with some hyperpigmentation (Figure 3).

Comment

Among the various types of skin cancer, an estimated 700,000 patients are diagnosed with SCC annually, making it the second most common form of skin cancer in the United States.¹ Basal cell carcinoma (BCC) is the most common skin cancer among whites in the United States, while in contrast SCC is the most common skin cancer in patients with skin of color.² Only an estimated 2% to 5% of all SCCs are pigmented, and this variant is more commonly seen in patients with skin of color.^3-5 One analysis of 52 cases of pSCC showed that common features included a flat or slightly raised appearance and hyperpigmentation with varying levels of scaling.⁶ Studies have shown an altered presentation of pSCC in black skin with increased melanin production and thickness of the stratum corneum in contrast with cases seen in white patients.⁷ Other potential features include scaling, erosive changes, and sharply demarcated borders. Squamous cell carcinoma typically occurs in sun-exposed areas, reflecting its association with UV light damage; however, SCC in skin of color patients has been noted to occur in sun-protected areas and in areas of chronic scarring.⁸ Pigmented SCC also appears to follow this distribution, as affected areas are not necessarily in direct exposure to the sun. Pigmented SCCs have been associated with pruritus and/or burning pain, which also was seen in our case when our patient complained of tenderness at the site.

We describe the case of a subungual pSCC clinically presenting as longitudinal melanonychia. Pigmented SCC presenting as longitudinal melanonychia was first described by Baran and Simon in 1988.⁹ Since that time, it has been reported that approximately 10% of subungual pSCCs clinically present as longitudinal melanonychia.^10,11 A retrospective study reviewing 35 cases of SCC of the nail apparatus found that 5 (14.3%) cases presented as longitudinal melanonychia.¹⁰ Another retrospective study found that 6 of 51 (11.8%) cases of SCCs affecting the nail unit presented as the warty type of SCC in association with longitudinal melanonychia.¹² Cases of pSCC in situ appearing as longitudinal melanonychia also have been reported.^13,14

Risk factors for the development of pSCC include advanced age, male sex, presence of human papilloma virus, and use of immunosuppressants.¹⁵ Male predominance and advanced age at the time of diagnosis (mean age, 67 years) have been observed in pSCC cases.¹⁶ It is now well established that renal transplant recipients have an increased risk of SCC, with a reported incidence rate of 5% to 6%.¹⁶ When these patients develop an SCC, they typically follow a more aggressive course. Renal transplantation has a higher ratio than cardiac transplantation for SCC development (2.37:1), whereas cardiac transplantation is associated with a higher risk of BCC development.¹⁷ A study of 384 transplant recipients found that 96 (25.0%) had a postsurgical nonmelanoma skin cancer (NMSC), with a ratio of SCC to BCC of 1.2:1.¹⁶ The calculated incidence of NMSC at 10 and 20 years posttransplantation was 24.2% and 54.4%, respectively. Another study also determined that SCC rates (50.0%) in postrenal transplant recipients were approximately twice that of BCC (27.0%).¹⁸

A daily regimen of immunosuppressive medications such as cyclosporine and mycophenolate mofetil showed an increased risk for development of NMSC.¹⁵ Immunosuppressive medications play an important role in the pathogenesis of SCC due to a direct oncogenic effect as well as impairment of the immune system’s ability to fight precancerous developments.¹⁵ A 4-year study of 100 renal transplant recipients using mycophenolate mofetil as part of an immunosuppressive regimen reported 22% NMSC findings among 9 patients.¹⁹ On average, patients developed an NMSC approximately 61 months posttransplantation, with a wide range from 2 to 120 months.

Advanced age was another important risk factor, with each decade of life producing a 60% increase in instantaneous risk of SCC development for transplant recipients.¹⁵ A steady increase in risk was related to the length of time adhering to an immunosuppressive regimen, especially from 2 to 6 years, and then remaining constant in subsequent years. For older patients on immunosuppressant regimens for more than 8 years, the calculated relative risk was noted to be over 200 times greater than the normal population’s development of skin cancers.¹⁸

Conclusion

Although cases of pSCC presenting as longitudinal melanonychia have previously been reported,^9-14,20 our case is unique in that it describes pSCC in a renal transplant recipient. Our patient had many of the known risk factors for the development of pSCC including male sex, advanced age, skin of color, history of renal transplantation, and immunosuppressive therapy. Although regular full-body skin examinations are an accepted part of renal transplantation follow-up due to SCC risk, our case emphasizes the need to remain vigilant due to possible atypical presentations among the immunosuppressed. The nail unit should not be overlooked during the clinical examination of renal transplant recipients as demonstrated by our patient’s rare presentation of pSCC in the nail.

Case Report

A 62-year-old black man presented for examination of a dark longitudinal streak located adjacent to the lateral nail fold on the third finger of the left hand. The lesion had been present for several months, during which time it had slowly expanded in size. The fingertip had recently become tender, which interfered with the patient’s ability to work. His past medical history was remarkable for end-stage renal disease secondary to glomerulonephritis with nephrotic syndrome of unclear etiology. He initially was treated by an outside physician using peritoneal dialysis for 3 years until he underwent renal transplantation in 2004 with a cadaveric organ. Other remarkable medical conditions included posttransplantation diabetes, hyperlipidemia, and gout. His multidrug regimen included 2 immunosuppressive medications: oral cyclosporine 125 mg twice daily and oral mycophenolate mofetil 250 mg twice daily.

A broad, irregular, black, pigmented, subungual band was noted on the left third finger. The lesion appeared to emanate from below the nail cuticle and traveled along the nail longitudinally toward the distal tip. The band appeared darker at the edge adjacent to the lateral nail fold and grew lighter near the middle of the nail where its free edge was noted to be irregular. A slightly thickened lateral nail fold with an irregular, small, sawtoothlike hyperkeratosis and hyperpigmentation also was noted (Figure 1).

Subungual melanoma, onychomycosis, squamous cell carcinoma (SCC), and a verruca copresenting with onychomycosis were considered in the differential diagnosis. The patient underwent nail avulsion and biopsy of the nail bed as well as the nail matrix. Histopathology was notable for malignant dyskeratosis with a lack of nuclear maturation, occasional mitoses, multinucleation, and individual cell keratinization (Figure 2). Immunostaining for S100 was negative, while staining for cytokeratins AE1/AE3 was positive. Deposition of melanin pigment in the malignant dyskeratotic cells was noted. Periodic acid–Schiff staining identified pseudohyphae without invasion of the nail plate. A diagnosis of pigmented SCC (pSCC) was made. The patient’s nail also was sent for fungal cultures that later grew Candida glabrata and Candida parapsilosis.

The patient underwent Mohs micrographic surgery for removal of the pSCC, which was found to be more extensive than originally suspected and required en bloc excision of the nail repaired with a full-thickness skin graft from the left forearm. The area healed well with some hyperpigmentation (Figure 3).

Comment

Among the various types of skin cancer, an estimated 700,000 patients are diagnosed with SCC annually, making it the second most common form of skin cancer in the United States.¹ Basal cell carcinoma (BCC) is the most common skin cancer among whites in the United States, while in contrast SCC is the most common skin cancer in patients with skin of color.² Only an estimated 2% to 5% of all SCCs are pigmented, and this variant is more commonly seen in patients with skin of color.^3-5 One analysis of 52 cases of pSCC showed that common features included a flat or slightly raised appearance and hyperpigmentation with varying levels of scaling.⁶ Studies have shown an altered presentation of pSCC in black skin with increased melanin production and thickness of the stratum corneum in contrast with cases seen in white patients.⁷ Other potential features include scaling, erosive changes, and sharply demarcated borders. Squamous cell carcinoma typically occurs in sun-exposed areas, reflecting its association with UV light damage; however, SCC in skin of color patients has been noted to occur in sun-protected areas and in areas of chronic scarring.⁸ Pigmented SCC also appears to follow this distribution, as affected areas are not necessarily in direct exposure to the sun. Pigmented SCCs have been associated with pruritus and/or burning pain, which also was seen in our case when our patient complained of tenderness at the site.

We describe the case of a subungual pSCC clinically presenting as longitudinal melanonychia. Pigmented SCC presenting as longitudinal melanonychia was first described by Baran and Simon in 1988.⁹ Since that time, it has been reported that approximately 10% of subungual pSCCs clinically present as longitudinal melanonychia.^10,11 A retrospective study reviewing 35 cases of SCC of the nail apparatus found that 5 (14.3%) cases presented as longitudinal melanonychia.¹⁰ Another retrospective study found that 6 of 51 (11.8%) cases of SCCs affecting the nail unit presented as the warty type of SCC in association with longitudinal melanonychia.¹² Cases of pSCC in situ appearing as longitudinal melanonychia also have been reported.^13,14

Risk factors for the development of pSCC include advanced age, male sex, presence of human papilloma virus, and use of immunosuppressants.¹⁵ Male predominance and advanced age at the time of diagnosis (mean age, 67 years) have been observed in pSCC cases.¹⁶ It is now well established that renal transplant recipients have an increased risk of SCC, with a reported incidence rate of 5% to 6%.¹⁶ When these patients develop an SCC, they typically follow a more aggressive course. Renal transplantation has a higher ratio than cardiac transplantation for SCC development (2.37:1), whereas cardiac transplantation is associated with a higher risk of BCC development.¹⁷ A study of 384 transplant recipients found that 96 (25.0%) had a postsurgical nonmelanoma skin cancer (NMSC), with a ratio of SCC to BCC of 1.2:1.¹⁶ The calculated incidence of NMSC at 10 and 20 years posttransplantation was 24.2% and 54.4%, respectively. Another study also determined that SCC rates (50.0%) in postrenal transplant recipients were approximately twice that of BCC (27.0%).¹⁸

A daily regimen of immunosuppressive medications such as cyclosporine and mycophenolate mofetil showed an increased risk for development of NMSC.¹⁵ Immunosuppressive medications play an important role in the pathogenesis of SCC due to a direct oncogenic effect as well as impairment of the immune system’s ability to fight precancerous developments.¹⁵ A 4-year study of 100 renal transplant recipients using mycophenolate mofetil as part of an immunosuppressive regimen reported 22% NMSC findings among 9 patients.¹⁹ On average, patients developed an NMSC approximately 61 months posttransplantation, with a wide range from 2 to 120 months.

Advanced age was another important risk factor, with each decade of life producing a 60% increase in instantaneous risk of SCC development for transplant recipients.¹⁵ A steady increase in risk was related to the length of time adhering to an immunosuppressive regimen, especially from 2 to 6 years, and then remaining constant in subsequent years. For older patients on immunosuppressant regimens for more than 8 years, the calculated relative risk was noted to be over 200 times greater than the normal population’s development of skin cancers.¹⁸

Conclusion

Although cases of pSCC presenting as longitudinal melanonychia have previously been reported,^9-14,20 our case is unique in that it describes pSCC in a renal transplant recipient. Our patient had many of the known risk factors for the development of pSCC including male sex, advanced age, skin of color, history of renal transplantation, and immunosuppressive therapy. Although regular full-body skin examinations are an accepted part of renal transplantation follow-up due to SCC risk, our case emphasizes the need to remain vigilant due to possible atypical presentations among the immunosuppressed. The nail unit should not be overlooked during the clinical examination of renal transplant recipients as demonstrated by our patient’s rare presentation of pSCC in the nail.

Case Report

A 62-year-old black man presented for examination of a dark longitudinal streak located adjacent to the lateral nail fold on the third finger of the left hand. The lesion had been present for several months, during which time it had slowly expanded in size. The fingertip had recently become tender, which interfered with the patient’s ability to work. His past medical history was remarkable for end-stage renal disease secondary to glomerulonephritis with nephrotic syndrome of unclear etiology. He initially was treated by an outside physician using peritoneal dialysis for 3 years until he underwent renal transplantation in 2004 with a cadaveric organ. Other remarkable medical conditions included posttransplantation diabetes, hyperlipidemia, and gout. His multidrug regimen included 2 immunosuppressive medications: oral cyclosporine 125 mg twice daily and oral mycophenolate mofetil 250 mg twice daily.

A broad, irregular, black, pigmented, subungual band was noted on the left third finger. The lesion appeared to emanate from below the nail cuticle and traveled along the nail longitudinally toward the distal tip. The band appeared darker at the edge adjacent to the lateral nail fold and grew lighter near the middle of the nail where its free edge was noted to be irregular. A slightly thickened lateral nail fold with an irregular, small, sawtoothlike hyperkeratosis and hyperpigmentation also was noted (Figure 1).

Subungual melanoma, onychomycosis, squamous cell carcinoma (SCC), and a verruca copresenting with onychomycosis were considered in the differential diagnosis. The patient underwent nail avulsion and biopsy of the nail bed as well as the nail matrix. Histopathology was notable for malignant dyskeratosis with a lack of nuclear maturation, occasional mitoses, multinucleation, and individual cell keratinization (Figure 2). Immunostaining for S100 was negative, while staining for cytokeratins AE1/AE3 was positive. Deposition of melanin pigment in the malignant dyskeratotic cells was noted. Periodic acid–Schiff staining identified pseudohyphae without invasion of the nail plate. A diagnosis of pigmented SCC (pSCC) was made. The patient’s nail also was sent for fungal cultures that later grew Candida glabrata and Candida parapsilosis.

The patient underwent Mohs micrographic surgery for removal of the pSCC, which was found to be more extensive than originally suspected and required en bloc excision of the nail repaired with a full-thickness skin graft from the left forearm. The area healed well with some hyperpigmentation (Figure 3).

Comment

Among the various types of skin cancer, an estimated 700,000 patients are diagnosed with SCC annually, making it the second most common form of skin cancer in the United States.¹ Basal cell carcinoma (BCC) is the most common skin cancer among whites in the United States, while in contrast SCC is the most common skin cancer in patients with skin of color.² Only an estimated 2% to 5% of all SCCs are pigmented, and this variant is more commonly seen in patients with skin of color.^3-5 One analysis of 52 cases of pSCC showed that common features included a flat or slightly raised appearance and hyperpigmentation with varying levels of scaling.⁶ Studies have shown an altered presentation of pSCC in black skin with increased melanin production and thickness of the stratum corneum in contrast with cases seen in white patients.⁷ Other potential features include scaling, erosive changes, and sharply demarcated borders. Squamous cell carcinoma typically occurs in sun-exposed areas, reflecting its association with UV light damage; however, SCC in skin of color patients has been noted to occur in sun-protected areas and in areas of chronic scarring.⁸ Pigmented SCC also appears to follow this distribution, as affected areas are not necessarily in direct exposure to the sun. Pigmented SCCs have been associated with pruritus and/or burning pain, which also was seen in our case when our patient complained of tenderness at the site.

We describe the case of a subungual pSCC clinically presenting as longitudinal melanonychia. Pigmented SCC presenting as longitudinal melanonychia was first described by Baran and Simon in 1988.⁹ Since that time, it has been reported that approximately 10% of subungual pSCCs clinically present as longitudinal melanonychia.^10,11 A retrospective study reviewing 35 cases of SCC of the nail apparatus found that 5 (14.3%) cases presented as longitudinal melanonychia.¹⁰ Another retrospective study found that 6 of 51 (11.8%) cases of SCCs affecting the nail unit presented as the warty type of SCC in association with longitudinal melanonychia.¹² Cases of pSCC in situ appearing as longitudinal melanonychia also have been reported.^13,14

Risk factors for the development of pSCC include advanced age, male sex, presence of human papilloma virus, and use of immunosuppressants.¹⁵ Male predominance and advanced age at the time of diagnosis (mean age, 67 years) have been observed in pSCC cases.¹⁶ It is now well established that renal transplant recipients have an increased risk of SCC, with a reported incidence rate of 5% to 6%.¹⁶ When these patients develop an SCC, they typically follow a more aggressive course. Renal transplantation has a higher ratio than cardiac transplantation for SCC development (2.37:1), whereas cardiac transplantation is associated with a higher risk of BCC development.¹⁷ A study of 384 transplant recipients found that 96 (25.0%) had a postsurgical nonmelanoma skin cancer (NMSC), with a ratio of SCC to BCC of 1.2:1.¹⁶ The calculated incidence of NMSC at 10 and 20 years posttransplantation was 24.2% and 54.4%, respectively. Another study also determined that SCC rates (50.0%) in postrenal transplant recipients were approximately twice that of BCC (27.0%).¹⁸

A daily regimen of immunosuppressive medications such as cyclosporine and mycophenolate mofetil showed an increased risk for development of NMSC.¹⁵ Immunosuppressive medications play an important role in the pathogenesis of SCC due to a direct oncogenic effect as well as impairment of the immune system’s ability to fight precancerous developments.¹⁵ A 4-year study of 100 renal transplant recipients using mycophenolate mofetil as part of an immunosuppressive regimen reported 22% NMSC findings among 9 patients.¹⁹ On average, patients developed an NMSC approximately 61 months posttransplantation, with a wide range from 2 to 120 months.

Advanced age was another important risk factor, with each decade of life producing a 60% increase in instantaneous risk of SCC development for transplant recipients.¹⁵ A steady increase in risk was related to the length of time adhering to an immunosuppressive regimen, especially from 2 to 6 years, and then remaining constant in subsequent years. For older patients on immunosuppressant regimens for more than 8 years, the calculated relative risk was noted to be over 200 times greater than the normal population’s development of skin cancers.¹⁸

Conclusion

Although cases of pSCC presenting as longitudinal melanonychia have previously been reported,^9-14,20 our case is unique in that it describes pSCC in a renal transplant recipient. Our patient had many of the known risk factors for the development of pSCC including male sex, advanced age, skin of color, history of renal transplantation, and immunosuppressive therapy. Although regular full-body skin examinations are an accepted part of renal transplantation follow-up due to SCC risk, our case emphasizes the need to remain vigilant due to possible atypical presentations among the immunosuppressed. The nail unit should not be overlooked during the clinical examination of renal transplant recipients as demonstrated by our patient’s rare presentation of pSCC in the nail.