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Gene expression profile test helps inform management of high-risk SCC patients
, according to Anna A. Bar, MD.
“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like NCCN, AJCC, or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”
Developed by and commercially available from Castle Biosciences, DecisionDx-SCC classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.
One validity study and three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see Curr Med Res Opin. 2020 Aug;36[8]:1301-7; Curr Med Res Opin. 2020 Aug;36[8]:1295-1300, and J Drugs Dermatol. 2019 Oct 1;18[10]:980-4). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.
The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.
Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.
The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”
The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”
Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”
On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”
DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”
For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.
, according to Anna A. Bar, MD.
“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like NCCN, AJCC, or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”
Developed by and commercially available from Castle Biosciences, DecisionDx-SCC classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.
One validity study and three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see Curr Med Res Opin. 2020 Aug;36[8]:1301-7; Curr Med Res Opin. 2020 Aug;36[8]:1295-1300, and J Drugs Dermatol. 2019 Oct 1;18[10]:980-4). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.
The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.
Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.
The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”
The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”
Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”
On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”
DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”
For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.
, according to Anna A. Bar, MD.
“The incidence of SCC has been growing rapidly, and the disease-related mortality is actually more than that of melanoma,” Dr. Bar, associate professor of dermatology at Oregon Health & Science University, Portland, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“Like many cancers, SCC management plans are guided by the risk of metastasis. The current staging systems, like NCCN, AJCC, or Brigham and Women’s systems, struggle to provide accurate data of the metastatic potential of an individual’s SCC,” she said. “Furthermore, the predictive accuracy of these systems in SCC is variable, and many patients who have high risk factors do not experience poor outcomes, while others initially classified as having less concerning tumors will go on to have metastatic disease. That is where new gene expression tests come into play.”
Developed by and commercially available from Castle Biosciences, DecisionDx-SCC classifies an individual SCC patient’s tumor into one of the categories: low (class 1), moderate (class 2A), or high (class 2B) biologic risk of metastasis. “We’re hoping that DecisionDx results can help make management decisions within established guidelines,” Dr. Bar said. The test is indicated for patients with high-risk features including tumor size greater than 2 cm; tumor location on the head, neck, hands, genitals, feet, or pretibial surface; immunosuppression; a rapidly growing tumor; a tumor with poorly defined borders; a tumor at the site of prior radiation or chronic inflammation; perineural invasion; poorly defined tumor grade, and a deep tumor beyond the subcutaneous fat.
One validity study and three clinical utility studies of DecisionDx-SCC have been published that include data from more than 1,100 patients (see Curr Med Res Opin. 2020 Aug;36[8]:1301-7; Curr Med Res Opin. 2020 Aug;36[8]:1295-1300, and J Drugs Dermatol. 2019 Oct 1;18[10]:980-4). “This is a work in progress,” said Dr. Bar, director of the university’s Mohs micrographic surgery and cutaneous oncology fellowship.
The test was validated in an another study, which was prospectively designed and used archival tissue from 33 independent academic and community centers, including Oregon Health & Science University. All 420 patients in the clinical validation study had one or more high-risk factors, meeting the definition of high risk by NCCN or Mohs Appropriate Use Criteria (AUC). Their mean age was 71 years, 73% were male, 99% were White, and 25% were immune deficient.
Of the 420 patients, 63 had metastasis, and 86% of metastases were located on the head and neck. About 30% of metastasized lesions had perineural involvement, 27% had invasion beyond subcutaneous fat, and metastasized lesions were about 1 cm wider compared with lesions that were not. The overall metastasis rate at 3 years was 15%, “which is similar to that seen in the medical literature for high-risk populations,” Dr. Bar said.
The median time to metastasis was 0.9 years and the 95th percentile was 2.7 years. “This means that the 3-year horizon for identifying events in this study enabled identification of most patients who eventually experienced metastatic events,” she said. In this cohort, approximately half of the metastatic events occurred around 11 months post diagnosis, which “may provide guidance about the timeline and duration of high-intensity follow-up with frequency of clinical visits and imaging for patients at highest risk within the first year.”
The positive predictive value of the DecisionDx-SCC is 52%, meaning that half of class 2B lesions will metastasize. “This compares favorably when you look at the lower positive predictive value of the other staging systems,” Dr. Bar said. “The negative predictive value is 93%, meaning there are not a lot of false negatives. This also compares favorably to the other staging systems.”
Kaplan-Meier analysis of metastasis-free survival showed strong separation between patients with class 1, class 2A, and class 2B results, Dr. Bar said. While the overall risk of metastasis in this patient cohort was 15%, the risk among those with a class 1 result was less than half of that. “Patients with a class 2A result behave similarly to those with traditional risk factors such as deep invasion and poor differentiation, having about a 20% risk of metastasis,” she said. “The class 2B result identifies the most worrisome SCCs, with a greater than 50% risk of metastasis. While the results distribution from routine clinical testing is not yet known, this large validation study of high-risk SCC revealed that approximately half of the patients were class 1, less than half were class 2A, and about 1 in 18 had a class 2B result.”
On univariate analyses with traditional risk factors and use of the Brigham and Women’s staging system, the hazard ratio (HR) for class 2A lesions was 3.2, “which is similar to deep invasion, poor differentiation, or perineural involvement,” Dr. Bar said. At the same time, the HR for class 2B lesions was 11.6, “so class 2B is the strongest predictor of metastasis. The class 2B HR remained statistically significant in the multivariate analysis and is three times higher than that of the next highest HR in this cohort. For example, a high-risk SCC with deep invasion is already two times more likely to metastasize. Adding a class 2B score would be over 14 times more likely to metastasize than a tumor with a class 1 result.”
DecisionDx-SCC test results can inform management decisions within established guidelines. For example, for a high-risk SCC patient who has a class 1 result, or low risk of metastasis, “you may proceed with surgery and clinical nodal exam, and then follow up a couple of times a year,” Dr. Bar said. “For a high-risk patient with a 2A or moderate risk result, you might proceed with surgical treatment plus consider imaging studies such as ultrasound, CT, PET CT, and consider referral to other specialties.”
For a high-risk patient with a 2B or high risk result, she continued, “you may want to proceed with imaging studies right away in addition to surgery and consider consultation with radiation oncology or medical oncology, as well as more frequent follow-up with nodal exams, because the class 2B patients have been shown to have a greater than 50% risk of metastasis.”
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Bar disclosed that Oregon Health & Science University has received research funding from Castle Biosciences.
FROM THE CUTANEOUS MALIGNANCIES FORUM
Adjuvant nivolumab plus ipilimumab shows strong results in resected stage IV melanoma
Results of the
IMMUNED was a multicenter German double-blind, placebo-controlled, phase 2 trial conducted by the Dermatologic Cooperative Oncology Group. It included 167 patients with resected stage IV melanoma and no evidence of disease who were randomized to adjuvant nivolumab (Opdivo) plus placebo, nivolumab plus ipilimumab (Yervoy), or double placebo, with relapse-free survival as the primary outcome, Merrick I. Ross, MD, explained at a forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“The patients who received adjuvant ipilimumab and nivolumab had amazing 24-month outcomes: a relapse-free survival of 70% versus 42% with nivolumab and 14% with placebo,” observed Dr. Ross, professor of surgical oncology and chief of the melanoma section at the University of Texas M.D. Anderson Cancer Center, Houston.
“It’s not a long-term survival outcome, but we’ll see what happens long term. This could be a very interesting approach to move forward with,” he commented.
By way of background, the cancer surgeon noted that nivolumab has achieved standard-of-care status as adjuvant immunotherapy in patients with resected stage IIIB-C and stage IV melanoma, largely on the strength of the CheckMate-238 trial, which randomized 906 such patients at 130 academic centers in 25 countries to 1 year of adjuvant therapy with either intravenous nivolumab or ipilimumab. In the study, nivolumab emerged as the clear winner, with a 4-year recurrence-free survival of 51.7%, compared with 41.2% for ipilimumab, for a 29% relative risk reduction. Ipilimumab was associated with greater toxicity.
The between-group difference in relapse-free survival in the overall study population also held true in the subgroup comprised of 169 CheckMate 238 participants with resected stage IV melanoma and no evidence of disease at enrollment, Dr. Ross noted.
In the IMMUNED trial, the superior outcome achieved with adjuvant nivolumab plus ipilimumab came at the cost of significantly greater toxicity than with nivolumab alone. Treatment-related adverse events led to medication discontinuation in 62% of the dual-adjuvant therapy group, compared with 13% of those on adjuvant nivolumab.
IMMUNED was funded by Bristol-Myers Squibb.
Dr. Ross reported having no financial conflicts regarding his presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Results of the
IMMUNED was a multicenter German double-blind, placebo-controlled, phase 2 trial conducted by the Dermatologic Cooperative Oncology Group. It included 167 patients with resected stage IV melanoma and no evidence of disease who were randomized to adjuvant nivolumab (Opdivo) plus placebo, nivolumab plus ipilimumab (Yervoy), or double placebo, with relapse-free survival as the primary outcome, Merrick I. Ross, MD, explained at a forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“The patients who received adjuvant ipilimumab and nivolumab had amazing 24-month outcomes: a relapse-free survival of 70% versus 42% with nivolumab and 14% with placebo,” observed Dr. Ross, professor of surgical oncology and chief of the melanoma section at the University of Texas M.D. Anderson Cancer Center, Houston.
“It’s not a long-term survival outcome, but we’ll see what happens long term. This could be a very interesting approach to move forward with,” he commented.
By way of background, the cancer surgeon noted that nivolumab has achieved standard-of-care status as adjuvant immunotherapy in patients with resected stage IIIB-C and stage IV melanoma, largely on the strength of the CheckMate-238 trial, which randomized 906 such patients at 130 academic centers in 25 countries to 1 year of adjuvant therapy with either intravenous nivolumab or ipilimumab. In the study, nivolumab emerged as the clear winner, with a 4-year recurrence-free survival of 51.7%, compared with 41.2% for ipilimumab, for a 29% relative risk reduction. Ipilimumab was associated with greater toxicity.
The between-group difference in relapse-free survival in the overall study population also held true in the subgroup comprised of 169 CheckMate 238 participants with resected stage IV melanoma and no evidence of disease at enrollment, Dr. Ross noted.
In the IMMUNED trial, the superior outcome achieved with adjuvant nivolumab plus ipilimumab came at the cost of significantly greater toxicity than with nivolumab alone. Treatment-related adverse events led to medication discontinuation in 62% of the dual-adjuvant therapy group, compared with 13% of those on adjuvant nivolumab.
IMMUNED was funded by Bristol-Myers Squibb.
Dr. Ross reported having no financial conflicts regarding his presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Results of the
IMMUNED was a multicenter German double-blind, placebo-controlled, phase 2 trial conducted by the Dermatologic Cooperative Oncology Group. It included 167 patients with resected stage IV melanoma and no evidence of disease who were randomized to adjuvant nivolumab (Opdivo) plus placebo, nivolumab plus ipilimumab (Yervoy), or double placebo, with relapse-free survival as the primary outcome, Merrick I. Ross, MD, explained at a forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
“The patients who received adjuvant ipilimumab and nivolumab had amazing 24-month outcomes: a relapse-free survival of 70% versus 42% with nivolumab and 14% with placebo,” observed Dr. Ross, professor of surgical oncology and chief of the melanoma section at the University of Texas M.D. Anderson Cancer Center, Houston.
“It’s not a long-term survival outcome, but we’ll see what happens long term. This could be a very interesting approach to move forward with,” he commented.
By way of background, the cancer surgeon noted that nivolumab has achieved standard-of-care status as adjuvant immunotherapy in patients with resected stage IIIB-C and stage IV melanoma, largely on the strength of the CheckMate-238 trial, which randomized 906 such patients at 130 academic centers in 25 countries to 1 year of adjuvant therapy with either intravenous nivolumab or ipilimumab. In the study, nivolumab emerged as the clear winner, with a 4-year recurrence-free survival of 51.7%, compared with 41.2% for ipilimumab, for a 29% relative risk reduction. Ipilimumab was associated with greater toxicity.
The between-group difference in relapse-free survival in the overall study population also held true in the subgroup comprised of 169 CheckMate 238 participants with resected stage IV melanoma and no evidence of disease at enrollment, Dr. Ross noted.
In the IMMUNED trial, the superior outcome achieved with adjuvant nivolumab plus ipilimumab came at the cost of significantly greater toxicity than with nivolumab alone. Treatment-related adverse events led to medication discontinuation in 62% of the dual-adjuvant therapy group, compared with 13% of those on adjuvant nivolumab.
IMMUNED was funded by Bristol-Myers Squibb.
Dr. Ross reported having no financial conflicts regarding his presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Why a mycosis fungoides diagnosis takes so long
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
Dermatopathologist Michi M. Shinohara, MD, is often asked why it takes so long to diagnose mycosis fungoides. Her reply: Early histopathologic findings in mycosis fungoides (MF) can be subtle, and accurate diagnosis is aided by taking multiple skin biopsies from different sites sequentially over time when there’s diagnostic uncertainty.
“Take multiple biopsies. There is clear literature that taking multiple biopsies from different areas of the body can really increase the sensitivity and specificity of TCR/PCR [T-cell receptor gene PCR clonality studies],” she said at a virtual forum on cutaneous malignancies jointly presented by the Postgraduate Institute for Medicine and Global Academy for Medical Education.
Patients with MF carry multiple subclones, and by taking multiple skin biopsies, different expression patterns may be revealed.
“MF is incredibly mutationally complex, and that has implications for therapy. There is certainly no single, nor even a few, targetable mutations. There are over 50 driver mutations known in CTCL [cutaneous T-cell lymphoma] involving more than a dozen signaling pathways,” said Dr. Shinohara, codirector of the cutaneous lymphoma clinic at the Seattle Cancer Care Alliance and director of dermatopathology at the University of Washington, Seattle.
MF is a lymphoma of skin-resident memory T-cells, the same T-cells involved in the pathogenesis of fixed drug eruption. MF accounts for about half of primary CTCLs. Traditionally, the average time from appearance of skin lesions to definitive diagnosis of MF is 3-6 years.
The International Society for Cutaneous Lymphomas diagnostic algorithm emphasizes that accurate diagnosis of MF requires clinical and histopathologic correlation supported by immunohistochemistry and TCR/PCR or other molecular studies. In an independent validation study, the algorithm demonstrated a sensitivity of 87.5% and specificity of 60% for diagnosis of MF.
Using this algorithm, a diagnosis of MF requires 4 points or more. A maximum of 2 points is available for the key clinical findings of variably sized persistent patches and/or plaques on non–sun-exposed areas, with poikiloderma. Another maximum of 2 points is awarded for the classic histopathologic findings consistent with MF and other forms of cutaneous T-cell lymphoma – namely, a superficial lymphoid infiltrate with epidermotropic but not spongiotic atypia. A positive immunohistochemical study is worth 1 point, and another point is granted for a positive result from a molecular study; both the immunohistochemical and molecular studies should “almost always” be done in patients with suspected MF, whereas a bone marrow biopsy is almost never appropriate.
The challenge for dermatopathologists in making an early diagnosis of MF is that, in patch-stage disease, many of the patient’s own cytotoxic CD8+ T-cells are present in the biopsy specimen battling the malignancy. These tumor-fighting cells often mask the malignant T-cells, clouding the picture under the microscope and putting the 2-point maximum for histopathologic findings out of reach. However, as the patient progresses to plaques, tumors, and erythroderma, the proportion of malignant T-cells increases and the diagnosis becomes easier, Dr. Shinohara explained.
In cases where histopathologic uncertainty exists, the immunohistochemistry and molecular studies become particularly important because, when positive, they can raise a patient’s score up to the 4-point diagnostic threshold. Dr. Shinohara focused on recent advances in molecular studies because that’s where the action is of late in the field of MF diagnostics.
High-throughput sequencing and other molecular studies
Three molecular study options are available for the diagnosis of MF: TCR/PCR, which is the traditional clonality study; next-generation high-throughput DNA sequencing; and flow cytometry.
A TCR/PCR study showing a monoclonal T-cell clone on a more subdued polyclonal background is highly suggestive of MF, as opposed to other inflammatory dermatoses. Early in the disease, however, the pattern can be oligoclonal, an inconclusive result. This point is where taking multiple biopsies from different skin sites becomes extremely helpful to amplify TCR/PCR’s sensitivity and specificity. Indeed, investigators at Stanford (Calif.) University have reported that TCR/PCR analysis showing an identical T-cell clone in biopsy specimens from two different skin sites had 82.6% sensitivity and 95.7% specificity for unequivocal MF.
High-throughput sequencing of the T-cell receptor gene has greater specificity for diagnosis of MF than TCR/PCR, and with similar sensitivity.
“The sensitivity of high-throughput sequencing is okay, but really we want it to be helpful in those wishy washy cases where we get an oligoclonal result on TCR/PCR; that’s, I think, an ideal use for it,” Dr. Shinohara said.
In addition to its role in establishing the diagnosis of MF, high-throughput sequencing shows promise for two other potential applications: detection of residual disease following stem cell transplantation and risk stratification in patients with early-stage disease.
Citing a landmark Stanford retrospective cohort analysis of actuarial disease-specific survival in 525 patients with MF and Sezary syndrome, she noted that the majority of patients had stage IA or IB disease – meaning patches and/or plaques on less than or more than 10% of their body surface area – and the survival curves of these patients with early-stage CTCL were flat.
“Most patients are going to live for decades with their disease if they have early disease, and that’s very reassuring for patients,” the dermatopathologist observed.
And yet, early-stage disease does not follow an indolent lifelong course in a subset of patients; rather, their disease becomes aggressive and resistant to all treatments short of stem cell transplantation. Investigators at Harvard University, Boston, have reported that high-throughput sequencing of the T-cell receptor beta gene in lesional skin biopsies is a powerful tool for early identification of this high-risk subpopulation of patients with early-stage MF. They demonstrated in a cohort of 141 patients with early-stage MF, then again in a validation cohort of 69 others, that a tumor clone frequency (TCF) greater than 25% in lesional skin, as measured by high-throughput sequencing, was a more powerful predictor of disease progression than any of the established prognostic factors.
In the discovery set, a TCF in excess of 25% was associated with a 4.9-fold increased likelihood of reduced progression-free survival; in the validation set, the risk was 10-fold greater than in patients with a lesser TCF. These were significantly greater risks than those seen with other proposed biomarkers of diminished progression-free survival, including the presence of plaques; stage IB, as opposed to IA, disease; large-cell transformation; age greater than 60 years; and elevated lactate dehydrogenase levels.
Although this groundbreaking work requires confirmation in another dataset, “this may be something we evolve towards doing in patients with early disease to pick out those who may have bad outcomes later,” Dr. Shinohara commented.
Still, she stressed, molecular studies will never replace histopathologic analysis for diagnosis of MF. “Judicious use of molecular studies may help in establishing the diagnosis, but I don’t think any one molecular study is ever going to be our home run,” she said.
She reported no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
FROM THE CUTANEOUS MALIGNANCIES FORUM
Palpation key when evaluating the skin for suspected MCC
“The lack of a pathognomonic appearance is often what precludes an early diagnosis of this cancer,” Dr. Thakuria, a dermatologist at Brigham and Women’s Hospital, Boston, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and the Global Academy for Medical Education. “MCCs can vary in appearance in their color, from pink to red to purple, or sometimes they have no color at all. They can be exophytic and obvious, or subtle, deeper tumors. These tumors are generally firm and nontender and are characterized by rapid growth, which is usually but not exclusively the feature that prompts biopsy.”
The typical patient with MCC is elderly, with an average age of 75 years. It affects males more than females by an approximately 2:1 ratio and tends to occur in fair-skinned individuals, although MCC does develop in skin of color. “While the majority of patients with this disease are immunocompetent, immunosuppressed patients are overrepresented in this disease, compared with the general population,” she said.
The clinical differential diagnosis is broad and includes both malignant and benign tumors, which requires a high index of suspicion. Most primary lesions are located on the head and neck, lower limb, and upper limb, but they may appear in non–sun exposed areas, such as the buttocks, as well.
One prospective study of 195 MCC patients found that 56% of clinicians presumed that these tumors were benign at the time of biopsy, and 32% were thought to have a cyst or acneiform lesion. The study authors summarized key clinical features of MCC with the acronym AEIOU: A stands for asymptomatic or nontender; E stands for expanding rapidly, usually over a duration less than 3 months; I stands for immunosuppression; O stands for patient older than age 50 years; and U stands for UV exposed skin location. The researchers found that 89% of the patients studied met three or more of the AEIOU criteria.
Dr. Thakuria, codirector of the Merkel Cell Carcinoma Center of Excellence at the Dana-Farber/Brigham and Women’s Cancer Center and assistant professor of dermatology at Harvard University, both in Boston, shared the following tips for dermatologic evaluation when MCC is suspected:
- Measure and record the clinical diameter of the lesions. “This helps you determine the T staging later, and from there can help you decide on proper treatment,” she said.
- Inspect and palpate the surrounding skin to look for in-transit metastases. “This may actually upstage the patient.”
- For a subcutaneous nodule, hub your punch biopsy. “These tumors can be centered in the deep dermis or fat,” Dr. Thakuria said. “If you really suspect MCC and you don’t get a result on your first biopsy, you may want to consider doing a second deeper biopsy, perhaps even a telescoping biopsy. This is especially true if your first biopsy was via shave technique and showed normal skin.”
- Refer to surgical oncology and radiation oncology ASAP. “You want to call them to ensure speedy consultation, within 1 week if possible,” she said. “Remember that all clinically node-negative MCCs warrant consideration of sentinel lymph node biopsy, regardless of tumor size. Upstaging will occur in 25%-32% of patients.”
Staging workup includes a full skin and lymph node exam to identify in-transit metastases and regional lymphadenopathy. “Palpation is key,” Dr. Thakuria said. “Next, you want to do some form of radiographic examination, so either a scalp to toes PET/CT or CT scan of the chest, abdomen, and pelvis. Finally, sentinel lymph node biopsy is going to be important if you have a clinically node-negative patient but you want to pathologically stage the person appropriately.” Although not formally part of the staging workup, she recommends ordering an AMERK test at diagnosis. AMERK detects antibodies to a Merkel cell polyomavirus oncoprotein, which is a marker of disease status present in about half of MCC patients. It falls with the treatment of cancer and rises with recurrence.
Discussing prognosis with MCC patients “can be challenging and uncomfortable, but even more so if you’re unfamiliar with some of the nuances of the terminology that is used,” Dr. Thakuria said. “Patients who go to Google are often going to encounter overall survival numbers, which are going to be worse than disease-specific numbers in any disease because they take into account death from any cause. This effect is heightened in MCC because this is cancer of predominately older adults, so there are other competing causes of death in this population, which drags down the overall survival estimates.”
Another point to remember when discussing survival with patients is that advances in immunotherapy are not necessarily reflected in national databases. “This is important, because usually in any cancer there’s a 5- to 10-year lag in survival information,” she said. “The last 5 years have brought an incredible change to MCC because of the advent of immunotherapy. Now we’re seeing incredible responses [in the clinic], but we’re not yet seeing those reflected in our survival tables.”
According to an analysis of prognostic factors from 9,387 MCC cases, nodal status is one of most important predictors of lower survival at 5 years, compared with having local disease: 35% versus 51%, respectively. Among patients with macroscopic lymph nodes, having known primary disease is associated with a lower survival at 5 years, compared with having unknown primary disease (27% vs. 42% at five years).
Dr. Thakuria concluded her presentation by recommending a three-step plan for surveillance, starting with a full skin and lymph node exam every 3-6 months for the first 3 years and every 6-12 months thereafter. Second, she advised routine imaging for high risk patients (American Joint Committee on Cancer stage 2 and above) and symptom-directed imaging for low-risk patients. Finally, she recommended the AMERK test every 3 months for the first 2-3 years in patients who were seropositive at diagnosis. A rising titer may be an early indicator of recurrence.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Thakuria reported having no financial disclosures.
“The lack of a pathognomonic appearance is often what precludes an early diagnosis of this cancer,” Dr. Thakuria, a dermatologist at Brigham and Women’s Hospital, Boston, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and the Global Academy for Medical Education. “MCCs can vary in appearance in their color, from pink to red to purple, or sometimes they have no color at all. They can be exophytic and obvious, or subtle, deeper tumors. These tumors are generally firm and nontender and are characterized by rapid growth, which is usually but not exclusively the feature that prompts biopsy.”
The typical patient with MCC is elderly, with an average age of 75 years. It affects males more than females by an approximately 2:1 ratio and tends to occur in fair-skinned individuals, although MCC does develop in skin of color. “While the majority of patients with this disease are immunocompetent, immunosuppressed patients are overrepresented in this disease, compared with the general population,” she said.
The clinical differential diagnosis is broad and includes both malignant and benign tumors, which requires a high index of suspicion. Most primary lesions are located on the head and neck, lower limb, and upper limb, but they may appear in non–sun exposed areas, such as the buttocks, as well.
One prospective study of 195 MCC patients found that 56% of clinicians presumed that these tumors were benign at the time of biopsy, and 32% were thought to have a cyst or acneiform lesion. The study authors summarized key clinical features of MCC with the acronym AEIOU: A stands for asymptomatic or nontender; E stands for expanding rapidly, usually over a duration less than 3 months; I stands for immunosuppression; O stands for patient older than age 50 years; and U stands for UV exposed skin location. The researchers found that 89% of the patients studied met three or more of the AEIOU criteria.
Dr. Thakuria, codirector of the Merkel Cell Carcinoma Center of Excellence at the Dana-Farber/Brigham and Women’s Cancer Center and assistant professor of dermatology at Harvard University, both in Boston, shared the following tips for dermatologic evaluation when MCC is suspected:
- Measure and record the clinical diameter of the lesions. “This helps you determine the T staging later, and from there can help you decide on proper treatment,” she said.
- Inspect and palpate the surrounding skin to look for in-transit metastases. “This may actually upstage the patient.”
- For a subcutaneous nodule, hub your punch biopsy. “These tumors can be centered in the deep dermis or fat,” Dr. Thakuria said. “If you really suspect MCC and you don’t get a result on your first biopsy, you may want to consider doing a second deeper biopsy, perhaps even a telescoping biopsy. This is especially true if your first biopsy was via shave technique and showed normal skin.”
- Refer to surgical oncology and radiation oncology ASAP. “You want to call them to ensure speedy consultation, within 1 week if possible,” she said. “Remember that all clinically node-negative MCCs warrant consideration of sentinel lymph node biopsy, regardless of tumor size. Upstaging will occur in 25%-32% of patients.”
Staging workup includes a full skin and lymph node exam to identify in-transit metastases and regional lymphadenopathy. “Palpation is key,” Dr. Thakuria said. “Next, you want to do some form of radiographic examination, so either a scalp to toes PET/CT or CT scan of the chest, abdomen, and pelvis. Finally, sentinel lymph node biopsy is going to be important if you have a clinically node-negative patient but you want to pathologically stage the person appropriately.” Although not formally part of the staging workup, she recommends ordering an AMERK test at diagnosis. AMERK detects antibodies to a Merkel cell polyomavirus oncoprotein, which is a marker of disease status present in about half of MCC patients. It falls with the treatment of cancer and rises with recurrence.
Discussing prognosis with MCC patients “can be challenging and uncomfortable, but even more so if you’re unfamiliar with some of the nuances of the terminology that is used,” Dr. Thakuria said. “Patients who go to Google are often going to encounter overall survival numbers, which are going to be worse than disease-specific numbers in any disease because they take into account death from any cause. This effect is heightened in MCC because this is cancer of predominately older adults, so there are other competing causes of death in this population, which drags down the overall survival estimates.”
Another point to remember when discussing survival with patients is that advances in immunotherapy are not necessarily reflected in national databases. “This is important, because usually in any cancer there’s a 5- to 10-year lag in survival information,” she said. “The last 5 years have brought an incredible change to MCC because of the advent of immunotherapy. Now we’re seeing incredible responses [in the clinic], but we’re not yet seeing those reflected in our survival tables.”
According to an analysis of prognostic factors from 9,387 MCC cases, nodal status is one of most important predictors of lower survival at 5 years, compared with having local disease: 35% versus 51%, respectively. Among patients with macroscopic lymph nodes, having known primary disease is associated with a lower survival at 5 years, compared with having unknown primary disease (27% vs. 42% at five years).
Dr. Thakuria concluded her presentation by recommending a three-step plan for surveillance, starting with a full skin and lymph node exam every 3-6 months for the first 3 years and every 6-12 months thereafter. Second, she advised routine imaging for high risk patients (American Joint Committee on Cancer stage 2 and above) and symptom-directed imaging for low-risk patients. Finally, she recommended the AMERK test every 3 months for the first 2-3 years in patients who were seropositive at diagnosis. A rising titer may be an early indicator of recurrence.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Thakuria reported having no financial disclosures.
“The lack of a pathognomonic appearance is often what precludes an early diagnosis of this cancer,” Dr. Thakuria, a dermatologist at Brigham and Women’s Hospital, Boston, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and the Global Academy for Medical Education. “MCCs can vary in appearance in their color, from pink to red to purple, or sometimes they have no color at all. They can be exophytic and obvious, or subtle, deeper tumors. These tumors are generally firm and nontender and are characterized by rapid growth, which is usually but not exclusively the feature that prompts biopsy.”
The typical patient with MCC is elderly, with an average age of 75 years. It affects males more than females by an approximately 2:1 ratio and tends to occur in fair-skinned individuals, although MCC does develop in skin of color. “While the majority of patients with this disease are immunocompetent, immunosuppressed patients are overrepresented in this disease, compared with the general population,” she said.
The clinical differential diagnosis is broad and includes both malignant and benign tumors, which requires a high index of suspicion. Most primary lesions are located on the head and neck, lower limb, and upper limb, but they may appear in non–sun exposed areas, such as the buttocks, as well.
One prospective study of 195 MCC patients found that 56% of clinicians presumed that these tumors were benign at the time of biopsy, and 32% were thought to have a cyst or acneiform lesion. The study authors summarized key clinical features of MCC with the acronym AEIOU: A stands for asymptomatic or nontender; E stands for expanding rapidly, usually over a duration less than 3 months; I stands for immunosuppression; O stands for patient older than age 50 years; and U stands for UV exposed skin location. The researchers found that 89% of the patients studied met three or more of the AEIOU criteria.
Dr. Thakuria, codirector of the Merkel Cell Carcinoma Center of Excellence at the Dana-Farber/Brigham and Women’s Cancer Center and assistant professor of dermatology at Harvard University, both in Boston, shared the following tips for dermatologic evaluation when MCC is suspected:
- Measure and record the clinical diameter of the lesions. “This helps you determine the T staging later, and from there can help you decide on proper treatment,” she said.
- Inspect and palpate the surrounding skin to look for in-transit metastases. “This may actually upstage the patient.”
- For a subcutaneous nodule, hub your punch biopsy. “These tumors can be centered in the deep dermis or fat,” Dr. Thakuria said. “If you really suspect MCC and you don’t get a result on your first biopsy, you may want to consider doing a second deeper biopsy, perhaps even a telescoping biopsy. This is especially true if your first biopsy was via shave technique and showed normal skin.”
- Refer to surgical oncology and radiation oncology ASAP. “You want to call them to ensure speedy consultation, within 1 week if possible,” she said. “Remember that all clinically node-negative MCCs warrant consideration of sentinel lymph node biopsy, regardless of tumor size. Upstaging will occur in 25%-32% of patients.”
Staging workup includes a full skin and lymph node exam to identify in-transit metastases and regional lymphadenopathy. “Palpation is key,” Dr. Thakuria said. “Next, you want to do some form of radiographic examination, so either a scalp to toes PET/CT or CT scan of the chest, abdomen, and pelvis. Finally, sentinel lymph node biopsy is going to be important if you have a clinically node-negative patient but you want to pathologically stage the person appropriately.” Although not formally part of the staging workup, she recommends ordering an AMERK test at diagnosis. AMERK detects antibodies to a Merkel cell polyomavirus oncoprotein, which is a marker of disease status present in about half of MCC patients. It falls with the treatment of cancer and rises with recurrence.
Discussing prognosis with MCC patients “can be challenging and uncomfortable, but even more so if you’re unfamiliar with some of the nuances of the terminology that is used,” Dr. Thakuria said. “Patients who go to Google are often going to encounter overall survival numbers, which are going to be worse than disease-specific numbers in any disease because they take into account death from any cause. This effect is heightened in MCC because this is cancer of predominately older adults, so there are other competing causes of death in this population, which drags down the overall survival estimates.”
Another point to remember when discussing survival with patients is that advances in immunotherapy are not necessarily reflected in national databases. “This is important, because usually in any cancer there’s a 5- to 10-year lag in survival information,” she said. “The last 5 years have brought an incredible change to MCC because of the advent of immunotherapy. Now we’re seeing incredible responses [in the clinic], but we’re not yet seeing those reflected in our survival tables.”
According to an analysis of prognostic factors from 9,387 MCC cases, nodal status is one of most important predictors of lower survival at 5 years, compared with having local disease: 35% versus 51%, respectively. Among patients with macroscopic lymph nodes, having known primary disease is associated with a lower survival at 5 years, compared with having unknown primary disease (27% vs. 42% at five years).
Dr. Thakuria concluded her presentation by recommending a three-step plan for surveillance, starting with a full skin and lymph node exam every 3-6 months for the first 3 years and every 6-12 months thereafter. Second, she advised routine imaging for high risk patients (American Joint Committee on Cancer stage 2 and above) and symptom-directed imaging for low-risk patients. Finally, she recommended the AMERK test every 3 months for the first 2-3 years in patients who were seropositive at diagnosis. A rising titer may be an early indicator of recurrence.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Thakuria reported having no financial disclosures.
FROM THE CUTANEOUS MALIGNANCIES FORUM
Mitotic rate makes comeback as melanoma prognosticator
at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
Dr. Kashani-Sabet, a dermatologist, director of the melanoma research program, and senior scientist at the California Pacific Medical Center Research Institute, San Francisco, was first author of a large recently published study that made a strong case for reincorporation of mitotic index into the American Joint Cancer Committee (AJCC) melanoma staging system.
Mitotic index was included in the 7th edition of the AJCC classification system, but was dropped from the current 8th edition in part because of concern it could potentially lead to overtreatment of patients with very thin melanomas of less than 0.5-mm thickness.
However, mitotic rate, like tumor thickness, is a continuous variable. And like tumor thickness, mitotic rate has a nonlinear relationship with survival. That’s why the AJCC staging system utilizes unequally spaced tumor thickness cut points of 1, 2, and 4 mm to define T1-T4 disease. But until the study led by Dr. Kashani-Sabet, optimal cut points for mitotic rate hadn’t been defined.
He and his coinvestigators at Melanoma Institute Australia collected a dataset comprising 5,050 patients with primary cutaneous melanoma in Australia and Northern California, all of whom either died of metastatic melanoma or remained distant metastasis–free for at least 8 years of follow-up. Median follow-up of the cohort was 9.5 years.
The investigators developed computer-generated cut points for mitotic rate and its impact on survival for each melanoma T category, then assessed their value in randomly split training and validation sets from their large cohort. For T1 melanoma, the optimal cut point proved to be 2 mitoses/mm2; more than two was independently associated with increased mortality risk. For T2 disease, the optimal cut point was 4, for T3 it was 6, and for T4 it was 7 mitoses/mm2.
A key study finding: In a multivariate regression analysis, tumor thickness was associated with survival, with an odds ratio of 1.58, ulceration had an odds ratio of 1.55, and mitotic rate by cut point had an odds ratio of 5.38. Each of these three characteristics was independently associated with survival (P < .00005). Dr. Kashani-Sabet said that, despite the more than threefold greater odds ratio for mitotic rate, compared with ulceration, in a Kaplan-Meier analysis, the survival impact of ulceration being present was “virtually identical” to an elevated mitotic rate in each T category.
He and his coinvestigators proposed a revised T-category system which incorporates this new insight. There is no change in tumor thickness to define T1-T4 melanoma: T1 is less than 1.0 mm, T2 is greater than 1-2.0 mm, T3 is greater than 2.01-4.0 mm, and T4 is greater than 4.0 mm. But now, within each T category the proposal is that the “a” designation indicates neither ulceration nor an elevated mitotic rate is present, while “b” means ulceration and/or an elevated mitotic rate using the optimal cut point for that T category is present. In their Australian/Northern California dataset, these new T categories showed a distinct separation in cumulative survival.
Dr. Kashani-Sabet and coworkers have submitted a proposal to validate their results using the AJCC database. Based upon a first look at the numbers, “We think it’s really very likely that these observations can be reproduced in this most important of datasets,” he predicted.
During a panel discussion, Sancy Leachman, MD, PhD, offered a recent example from her own practice where an elevated mitotic index as defined by Dr. Kashani-Sabet and coworkers served as a red flag.
“I had a patient with a 0.3-mm melanoma with three mitoses. I did a sentinel lymph node biopsy on the patient, and she was positive,” said Dr. Leachman, professor and chair of the department of dermatology at Oregon Health & Science University, Portland.
Dr. Kashani-Sabet commented that, while an elevated mitotic index is clearly not an absolute requirement for metastasis, when present it’s a prognostically important finding.
Moreover, as adjuvant therapies of proven value in node-positive disease increasingly come under study in node-negative melanoma, it will be critical to identify the high-risk node-negative subgroup for whom such therapies should be targeted.
“While T4 tumors and ulcerated melanomas are clearly high risk, they’re not going to capture every patient who has a very high risk of distant metastases and death. I think mitotic rate is another pathway to identify patients who very well might benefit and should be candidates for inclusion in those adjuvant therapy trials as we’re moving more into node-negative patients,” according to Dr. Kashani-Sabet.
He reported having no financial conflicts of interest regarding his presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
Dr. Kashani-Sabet, a dermatologist, director of the melanoma research program, and senior scientist at the California Pacific Medical Center Research Institute, San Francisco, was first author of a large recently published study that made a strong case for reincorporation of mitotic index into the American Joint Cancer Committee (AJCC) melanoma staging system.
Mitotic index was included in the 7th edition of the AJCC classification system, but was dropped from the current 8th edition in part because of concern it could potentially lead to overtreatment of patients with very thin melanomas of less than 0.5-mm thickness.
However, mitotic rate, like tumor thickness, is a continuous variable. And like tumor thickness, mitotic rate has a nonlinear relationship with survival. That’s why the AJCC staging system utilizes unequally spaced tumor thickness cut points of 1, 2, and 4 mm to define T1-T4 disease. But until the study led by Dr. Kashani-Sabet, optimal cut points for mitotic rate hadn’t been defined.
He and his coinvestigators at Melanoma Institute Australia collected a dataset comprising 5,050 patients with primary cutaneous melanoma in Australia and Northern California, all of whom either died of metastatic melanoma or remained distant metastasis–free for at least 8 years of follow-up. Median follow-up of the cohort was 9.5 years.
The investigators developed computer-generated cut points for mitotic rate and its impact on survival for each melanoma T category, then assessed their value in randomly split training and validation sets from their large cohort. For T1 melanoma, the optimal cut point proved to be 2 mitoses/mm2; more than two was independently associated with increased mortality risk. For T2 disease, the optimal cut point was 4, for T3 it was 6, and for T4 it was 7 mitoses/mm2.
A key study finding: In a multivariate regression analysis, tumor thickness was associated with survival, with an odds ratio of 1.58, ulceration had an odds ratio of 1.55, and mitotic rate by cut point had an odds ratio of 5.38. Each of these three characteristics was independently associated with survival (P < .00005). Dr. Kashani-Sabet said that, despite the more than threefold greater odds ratio for mitotic rate, compared with ulceration, in a Kaplan-Meier analysis, the survival impact of ulceration being present was “virtually identical” to an elevated mitotic rate in each T category.
He and his coinvestigators proposed a revised T-category system which incorporates this new insight. There is no change in tumor thickness to define T1-T4 melanoma: T1 is less than 1.0 mm, T2 is greater than 1-2.0 mm, T3 is greater than 2.01-4.0 mm, and T4 is greater than 4.0 mm. But now, within each T category the proposal is that the “a” designation indicates neither ulceration nor an elevated mitotic rate is present, while “b” means ulceration and/or an elevated mitotic rate using the optimal cut point for that T category is present. In their Australian/Northern California dataset, these new T categories showed a distinct separation in cumulative survival.
Dr. Kashani-Sabet and coworkers have submitted a proposal to validate their results using the AJCC database. Based upon a first look at the numbers, “We think it’s really very likely that these observations can be reproduced in this most important of datasets,” he predicted.
During a panel discussion, Sancy Leachman, MD, PhD, offered a recent example from her own practice where an elevated mitotic index as defined by Dr. Kashani-Sabet and coworkers served as a red flag.
“I had a patient with a 0.3-mm melanoma with three mitoses. I did a sentinel lymph node biopsy on the patient, and she was positive,” said Dr. Leachman, professor and chair of the department of dermatology at Oregon Health & Science University, Portland.
Dr. Kashani-Sabet commented that, while an elevated mitotic index is clearly not an absolute requirement for metastasis, when present it’s a prognostically important finding.
Moreover, as adjuvant therapies of proven value in node-positive disease increasingly come under study in node-negative melanoma, it will be critical to identify the high-risk node-negative subgroup for whom such therapies should be targeted.
“While T4 tumors and ulcerated melanomas are clearly high risk, they’re not going to capture every patient who has a very high risk of distant metastases and death. I think mitotic rate is another pathway to identify patients who very well might benefit and should be candidates for inclusion in those adjuvant therapy trials as we’re moving more into node-negative patients,” according to Dr. Kashani-Sabet.
He reported having no financial conflicts of interest regarding his presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education.
Dr. Kashani-Sabet, a dermatologist, director of the melanoma research program, and senior scientist at the California Pacific Medical Center Research Institute, San Francisco, was first author of a large recently published study that made a strong case for reincorporation of mitotic index into the American Joint Cancer Committee (AJCC) melanoma staging system.
Mitotic index was included in the 7th edition of the AJCC classification system, but was dropped from the current 8th edition in part because of concern it could potentially lead to overtreatment of patients with very thin melanomas of less than 0.5-mm thickness.
However, mitotic rate, like tumor thickness, is a continuous variable. And like tumor thickness, mitotic rate has a nonlinear relationship with survival. That’s why the AJCC staging system utilizes unequally spaced tumor thickness cut points of 1, 2, and 4 mm to define T1-T4 disease. But until the study led by Dr. Kashani-Sabet, optimal cut points for mitotic rate hadn’t been defined.
He and his coinvestigators at Melanoma Institute Australia collected a dataset comprising 5,050 patients with primary cutaneous melanoma in Australia and Northern California, all of whom either died of metastatic melanoma or remained distant metastasis–free for at least 8 years of follow-up. Median follow-up of the cohort was 9.5 years.
The investigators developed computer-generated cut points for mitotic rate and its impact on survival for each melanoma T category, then assessed their value in randomly split training and validation sets from their large cohort. For T1 melanoma, the optimal cut point proved to be 2 mitoses/mm2; more than two was independently associated with increased mortality risk. For T2 disease, the optimal cut point was 4, for T3 it was 6, and for T4 it was 7 mitoses/mm2.
A key study finding: In a multivariate regression analysis, tumor thickness was associated with survival, with an odds ratio of 1.58, ulceration had an odds ratio of 1.55, and mitotic rate by cut point had an odds ratio of 5.38. Each of these three characteristics was independently associated with survival (P < .00005). Dr. Kashani-Sabet said that, despite the more than threefold greater odds ratio for mitotic rate, compared with ulceration, in a Kaplan-Meier analysis, the survival impact of ulceration being present was “virtually identical” to an elevated mitotic rate in each T category.
He and his coinvestigators proposed a revised T-category system which incorporates this new insight. There is no change in tumor thickness to define T1-T4 melanoma: T1 is less than 1.0 mm, T2 is greater than 1-2.0 mm, T3 is greater than 2.01-4.0 mm, and T4 is greater than 4.0 mm. But now, within each T category the proposal is that the “a” designation indicates neither ulceration nor an elevated mitotic rate is present, while “b” means ulceration and/or an elevated mitotic rate using the optimal cut point for that T category is present. In their Australian/Northern California dataset, these new T categories showed a distinct separation in cumulative survival.
Dr. Kashani-Sabet and coworkers have submitted a proposal to validate their results using the AJCC database. Based upon a first look at the numbers, “We think it’s really very likely that these observations can be reproduced in this most important of datasets,” he predicted.
During a panel discussion, Sancy Leachman, MD, PhD, offered a recent example from her own practice where an elevated mitotic index as defined by Dr. Kashani-Sabet and coworkers served as a red flag.
“I had a patient with a 0.3-mm melanoma with three mitoses. I did a sentinel lymph node biopsy on the patient, and she was positive,” said Dr. Leachman, professor and chair of the department of dermatology at Oregon Health & Science University, Portland.
Dr. Kashani-Sabet commented that, while an elevated mitotic index is clearly not an absolute requirement for metastasis, when present it’s a prognostically important finding.
Moreover, as adjuvant therapies of proven value in node-positive disease increasingly come under study in node-negative melanoma, it will be critical to identify the high-risk node-negative subgroup for whom such therapies should be targeted.
“While T4 tumors and ulcerated melanomas are clearly high risk, they’re not going to capture every patient who has a very high risk of distant metastases and death. I think mitotic rate is another pathway to identify patients who very well might benefit and should be candidates for inclusion in those adjuvant therapy trials as we’re moving more into node-negative patients,” according to Dr. Kashani-Sabet.
He reported having no financial conflicts of interest regarding his presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
FROM THE CUTANEOUS MALIGNANCIES FORUM
For SCC, legs are a high-risk anatomic site in women
When Maryam M. Asgari, MD, reviewed results from a large population-based study published in 2017, which found that a large proportion of cutaneous squamous cell carcinomas were being detected on the lower extremities of women, it caused her to reflect on her own clinical practice as a Mohs surgeon.
“I was struck by the number of times I was seeing women present with lower extremity SCCs,” Dr. Asgari, professor of dermatology, Harvard Medical School, Boston, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education. “When female patients push you for a waist-up skin exam, try to convince them that the legs are an important area to look at as well.”
In an effort to ascertain if there are sex differences in the anatomic distribution of cutaneous SCC, she and her postdoctoral fellow, Yuhree Kim, MD, MPH, used an institutional registry to identify 618 non-Hispanic White patients diagnosed with 2,111 SCCs between 2000 and 2016. They found that men were more likely to have SCCs arise on the head and neck (52% vs. 21% among women, respectively), while women were more likely to have SCCs develop on the lower extremity (41% vs. 10% in men).
“When we looked at whether these tumors were in situ or invasive, in women, the majority of these weren’t just your run-of-the-mill in situ SCCs; 44% were actually invasive SCCs,” Dr. Asgari said. “What this is getting at is to make sure that you’re examining the lower extremities when you’re doing these skin exams. Many times, especially in colder weather, your patients will come in and request a waist-up exam. For women, you absolutely have to examine their lower extremities. That’s their high-risk area for SCCs.”
, she continued. According to 2020 data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results SEER program, the incidence of KC in the United States is estimated to be 3.5 million cases per year, while all other cancers account for approximately 1.8 million cases per year.
To make matters worse, while the incidence of many other cancers have plateaued or even declined over time in the United States, data from a population-based cohort at Kaiser Permanente Northern California show that the incidence of BCCs rose between 1998 and 2012, estimated to occur in about 2 million Americans each year.
Dr. Asgari noted that the incidence of KCs can be difficult to quantify and study. “Part of the reason is that they’re not reported to traditional cancer registries like the SEER program,” she said. “You can imagine why. The sheer volume of KC dwarfs all other cancers, and oftentimes KCs are biopsied in dermatology offices. Sometimes, dermatologists even read their own biopsy specimens, so they don’t go to a central pathology repository like other cancers do.”
The best available research suggests that patients at the highest risk of KC include men and women between the ages of 60 and 89. Dr. Asgari said that she informs her patients that people in their 80s have about a 20-fold risk of BCC or SCC compared with people in their 30s. “I raise this because a lot of time the people who come in for skin cancer screenings are the ‘worried well,’ ” she said. “They can be at risk, but they’re not our highest risk subgroup. They come in proactively wanting to have those full skin screens done, but where we really need to be focusing is in people in their 60s to 80s.”
Risk factors can be shared or unique to each tumor type. Extrinsic factors include chronic UV exposure, ionizing radiation, and tanning bed use. “Acute UV exposures that give you a blistering sunburn puts you at risk for BCC, whereas chronic sun exposures puts you at risk for SCC,” she said. “Tanning bed use can increase the risk for both types, as can ionizing radiation, although it ups the risk for BCCs much more than it does for SCCs.” Intrinsic risk factors for both tumor types include fair skin, blue/green eyes, blond/red hair, male gender, having pigment gene variants, and being immunosuppressed.
By race/ethnicity, the highest risk for KC in the United States falls to non-Hispanic Whites (a rate of 150-360 per 100,000 individuals), while the rate among blacks is 3 per 100,000 individuals. “In darker skin phenotypes, sun exposure tends to be less of a risk factor,” Dr. Asgari said. “They can rise on sun-protected areas and are frequently associated with chronic inflammation, chronic wounds, or scarring.”
In a soon-to-be published study, Dr. Asgari and colleagues sought to examine the association between genetic ancestry and SCC risk. The found that people with northwestern European ancestry faced the highest risk of SCC, especially those with Irish/Scottish ancestry. Among people of Hispanic/Latino descent, the highest risk of SCC came in those who had the most European ancestry.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Asgari disclosed that she receives royalties from UpToDate.
When Maryam M. Asgari, MD, reviewed results from a large population-based study published in 2017, which found that a large proportion of cutaneous squamous cell carcinomas were being detected on the lower extremities of women, it caused her to reflect on her own clinical practice as a Mohs surgeon.
“I was struck by the number of times I was seeing women present with lower extremity SCCs,” Dr. Asgari, professor of dermatology, Harvard Medical School, Boston, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education. “When female patients push you for a waist-up skin exam, try to convince them that the legs are an important area to look at as well.”
In an effort to ascertain if there are sex differences in the anatomic distribution of cutaneous SCC, she and her postdoctoral fellow, Yuhree Kim, MD, MPH, used an institutional registry to identify 618 non-Hispanic White patients diagnosed with 2,111 SCCs between 2000 and 2016. They found that men were more likely to have SCCs arise on the head and neck (52% vs. 21% among women, respectively), while women were more likely to have SCCs develop on the lower extremity (41% vs. 10% in men).
“When we looked at whether these tumors were in situ or invasive, in women, the majority of these weren’t just your run-of-the-mill in situ SCCs; 44% were actually invasive SCCs,” Dr. Asgari said. “What this is getting at is to make sure that you’re examining the lower extremities when you’re doing these skin exams. Many times, especially in colder weather, your patients will come in and request a waist-up exam. For women, you absolutely have to examine their lower extremities. That’s their high-risk area for SCCs.”
, she continued. According to 2020 data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results SEER program, the incidence of KC in the United States is estimated to be 3.5 million cases per year, while all other cancers account for approximately 1.8 million cases per year.
To make matters worse, while the incidence of many other cancers have plateaued or even declined over time in the United States, data from a population-based cohort at Kaiser Permanente Northern California show that the incidence of BCCs rose between 1998 and 2012, estimated to occur in about 2 million Americans each year.
Dr. Asgari noted that the incidence of KCs can be difficult to quantify and study. “Part of the reason is that they’re not reported to traditional cancer registries like the SEER program,” she said. “You can imagine why. The sheer volume of KC dwarfs all other cancers, and oftentimes KCs are biopsied in dermatology offices. Sometimes, dermatologists even read their own biopsy specimens, so they don’t go to a central pathology repository like other cancers do.”
The best available research suggests that patients at the highest risk of KC include men and women between the ages of 60 and 89. Dr. Asgari said that she informs her patients that people in their 80s have about a 20-fold risk of BCC or SCC compared with people in their 30s. “I raise this because a lot of time the people who come in for skin cancer screenings are the ‘worried well,’ ” she said. “They can be at risk, but they’re not our highest risk subgroup. They come in proactively wanting to have those full skin screens done, but where we really need to be focusing is in people in their 60s to 80s.”
Risk factors can be shared or unique to each tumor type. Extrinsic factors include chronic UV exposure, ionizing radiation, and tanning bed use. “Acute UV exposures that give you a blistering sunburn puts you at risk for BCC, whereas chronic sun exposures puts you at risk for SCC,” she said. “Tanning bed use can increase the risk for both types, as can ionizing radiation, although it ups the risk for BCCs much more than it does for SCCs.” Intrinsic risk factors for both tumor types include fair skin, blue/green eyes, blond/red hair, male gender, having pigment gene variants, and being immunosuppressed.
By race/ethnicity, the highest risk for KC in the United States falls to non-Hispanic Whites (a rate of 150-360 per 100,000 individuals), while the rate among blacks is 3 per 100,000 individuals. “In darker skin phenotypes, sun exposure tends to be less of a risk factor,” Dr. Asgari said. “They can rise on sun-protected areas and are frequently associated with chronic inflammation, chronic wounds, or scarring.”
In a soon-to-be published study, Dr. Asgari and colleagues sought to examine the association between genetic ancestry and SCC risk. The found that people with northwestern European ancestry faced the highest risk of SCC, especially those with Irish/Scottish ancestry. Among people of Hispanic/Latino descent, the highest risk of SCC came in those who had the most European ancestry.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Asgari disclosed that she receives royalties from UpToDate.
When Maryam M. Asgari, MD, reviewed results from a large population-based study published in 2017, which found that a large proportion of cutaneous squamous cell carcinomas were being detected on the lower extremities of women, it caused her to reflect on her own clinical practice as a Mohs surgeon.
“I was struck by the number of times I was seeing women present with lower extremity SCCs,” Dr. Asgari, professor of dermatology, Harvard Medical School, Boston, said during a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medical Education. “When female patients push you for a waist-up skin exam, try to convince them that the legs are an important area to look at as well.”
In an effort to ascertain if there are sex differences in the anatomic distribution of cutaneous SCC, she and her postdoctoral fellow, Yuhree Kim, MD, MPH, used an institutional registry to identify 618 non-Hispanic White patients diagnosed with 2,111 SCCs between 2000 and 2016. They found that men were more likely to have SCCs arise on the head and neck (52% vs. 21% among women, respectively), while women were more likely to have SCCs develop on the lower extremity (41% vs. 10% in men).
“When we looked at whether these tumors were in situ or invasive, in women, the majority of these weren’t just your run-of-the-mill in situ SCCs; 44% were actually invasive SCCs,” Dr. Asgari said. “What this is getting at is to make sure that you’re examining the lower extremities when you’re doing these skin exams. Many times, especially in colder weather, your patients will come in and request a waist-up exam. For women, you absolutely have to examine their lower extremities. That’s their high-risk area for SCCs.”
, she continued. According to 2020 data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results SEER program, the incidence of KC in the United States is estimated to be 3.5 million cases per year, while all other cancers account for approximately 1.8 million cases per year.
To make matters worse, while the incidence of many other cancers have plateaued or even declined over time in the United States, data from a population-based cohort at Kaiser Permanente Northern California show that the incidence of BCCs rose between 1998 and 2012, estimated to occur in about 2 million Americans each year.
Dr. Asgari noted that the incidence of KCs can be difficult to quantify and study. “Part of the reason is that they’re not reported to traditional cancer registries like the SEER program,” she said. “You can imagine why. The sheer volume of KC dwarfs all other cancers, and oftentimes KCs are biopsied in dermatology offices. Sometimes, dermatologists even read their own biopsy specimens, so they don’t go to a central pathology repository like other cancers do.”
The best available research suggests that patients at the highest risk of KC include men and women between the ages of 60 and 89. Dr. Asgari said that she informs her patients that people in their 80s have about a 20-fold risk of BCC or SCC compared with people in their 30s. “I raise this because a lot of time the people who come in for skin cancer screenings are the ‘worried well,’ ” she said. “They can be at risk, but they’re not our highest risk subgroup. They come in proactively wanting to have those full skin screens done, but where we really need to be focusing is in people in their 60s to 80s.”
Risk factors can be shared or unique to each tumor type. Extrinsic factors include chronic UV exposure, ionizing radiation, and tanning bed use. “Acute UV exposures that give you a blistering sunburn puts you at risk for BCC, whereas chronic sun exposures puts you at risk for SCC,” she said. “Tanning bed use can increase the risk for both types, as can ionizing radiation, although it ups the risk for BCCs much more than it does for SCCs.” Intrinsic risk factors for both tumor types include fair skin, blue/green eyes, blond/red hair, male gender, having pigment gene variants, and being immunosuppressed.
By race/ethnicity, the highest risk for KC in the United States falls to non-Hispanic Whites (a rate of 150-360 per 100,000 individuals), while the rate among blacks is 3 per 100,000 individuals. “In darker skin phenotypes, sun exposure tends to be less of a risk factor,” Dr. Asgari said. “They can rise on sun-protected areas and are frequently associated with chronic inflammation, chronic wounds, or scarring.”
In a soon-to-be published study, Dr. Asgari and colleagues sought to examine the association between genetic ancestry and SCC risk. The found that people with northwestern European ancestry faced the highest risk of SCC, especially those with Irish/Scottish ancestry. Among people of Hispanic/Latino descent, the highest risk of SCC came in those who had the most European ancestry.
Global Academy for Medical Education and this news organization are owned by the same parent company.
Dr. Asgari disclosed that she receives royalties from UpToDate.
FROM THE CUTANEOUS MALIGNANCIES FORUM
What happened to melanoma care during COVID-19 sequestration
Initial evidence suggests that the , Rebecca I. Hartman, MD, MPH, said at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medication Education.
This is not what National Comprehensive Cancer Network officials expected when they issued short-term recommendations on how to manage cutaneous melanoma during the first wave of the COVID-19 pandemic. Those recommendations for restriction of care, which Dr. Hartman characterized as “pretty significant changes from how we typically practice melanoma care in the U.S.,” came at a time when there was justifiable concern that the first COVID-19 surge would strain the U.S. health care system beyond the breaking point.
The rationale given for the NCCN recommendations was that most time-to-treat studies have shown no adverse patient outcomes for 90-day delays in treatment, even for thicker melanomas. But those studies, all retrospective, have been called into question. And the first real-world data on the impact of care restrictions during the lockdown, reported by Italian dermatologists, highlights adverse effects with potentially far-reaching consequences, noted Dr. Hartman, director of melanoma epidemiology at Brigham and Women’s Hospital and a dermatologist, Harvard University, Boston.
Analysis of the impact of lockdown-induced delays in melanoma care is not merely an academic exercise, she added. While everyone hopes that the spring 2020 COVID-19 shelter-in-place was a once-in-a-lifetime event, there’s no guarantee that will be the case. Moreover, the lockdown provides a natural experiment addressing the possible consequences of melanoma care delays on patient outcomes, a topic that for ethical reasons could never be addressed in a randomized trial.
The short-term NCCN recommendations included the use of excisional biopsies for melanoma diagnosis whenever possible; and delay of up to 3 months for wide local excision of in situ melanoma, any invasive melanoma with negative margins, and even T1 melanomas with positive margins provided the bulk of the lesion had been excised. The guidance also suggested delaying sentinel lymph node biopsy (SLNB), along with increased use of neoadjuvant therapy in patients with clinically palpable regional lymph nodes in order to delay surgery for up to 8 weeks. Single-agent systemic therapy at the least-frequent dosing was advised in order to minimize toxicity and reduce the need for additional health care resources: for example, nivolumab (Opdivo) at 480 mg every 4 weeks instead of every 2 weeks, and pembrolizumab (Keytruda) at 400 mg every 6 weeks, rather than every 3 weeks.
So, that’s what the NCCN recommended. Here’s what actually happened during shelter-in-place as captured in Dr. Hartman’s survey of 18 U.S. members of the Melanoma Prevention Working Group, all practicing dermatology in centers particularly hard-hit in the first wave of the pandemic: In-person new melanoma patient visits plunged from an average of 4.83 per week per provider to 0.83 per week. Telemedicine visits with new melanoma patients went from zero prepandemic to 0.67 visits per week per provider, which doesn’t come close to making up for the drop in in-person visits. Interestingly, two respondents reported turning to gene-expression profile testing for patient prognostication because of delays in SLNB.
Wide local excision was delayed by an average of 6 weeks in roughly one-third of melanoma patients with early tumor stage disease, regardless of margin status. For patients with stage T1b disease, wide local excision was typically performed on time during shelter-in-place; however, SLNB was delayed by an average of 5 weeks in 22% of patients with positive margins and 28% of those with negative margins. In contrast, 80% of patients with more advanced T2-T4 melanoma underwent on-schedule definitive management with wide local excision and SLNB, Dr. Hartman reported.
Critics have taken issue with the NCCN’s conclusion that most time-to-treatment studies show no harm arising from 90-day treatment delays. A review of the relevant published literature by Dr. Hartman’s Harvard colleagues, published in July, found that the evidence is mixed. “There is insufficient evidence to definitively conclude that delayed wide resection after gross removal of the primary melanoma is without harm,” they concluded in the review.
Spanish dermatologists performed a modeling study in order to estimate the potential impact of COVID-19 lockdowns on 5- and 10-year survival of melanoma patients. Using the growth rate of a random sample of 1,000 melanomas to model estimates of tumor thickness after various delays, coupled with American Joint Committee on Cancer survival data for different T stages, they estimated that 5-year survival would be reduced from 94.2% to 92.3% with a 90-day delay in diagnosis, and that 10-year survival would drop from 90.0% to 87.6%.
But that’s merely modeling. Francesco Ricci, MD, PhD, and colleagues from the melanoma unit at the Istituto Dermopatico dell’Immacolata, Rome, have provided a first look at the real-world impact of the lockdown. In the prelockdown period of January through March 9th, 2020, the referral center averaged 2.3 new melanoma diagnoses per day. During the Rome lockdown, from March 10th through May 3rd, this figure dropped to a mean of 0.6 melanoma diagnoses per day. Postlockdown, from May 4th to June 6th, the average climbed to 1.3 per day. The rate of newly diagnosed nodular melanoma was 5.5-fold greater postlockdown, compared with prelockdown; the rate of ulcerated melanoma was 4.9-fold greater.
“We can hypothesize that this may have been due to delays in diagnosis and care,” Dr. Hartman commented. “This is important because we know that nodular melanoma as well as ulceration tend to have a worse prognosis in terms of mortality.”
The mean Breslow thickness of newly diagnosed melanomas was 0.88 mm prelockdown, 0.66 mm during lockdown, and 1.96 mm postlockdown. The investigators speculated that the reduced Breslow thickness of melanomas diagnosed during lockdown might be explained by a greater willingness of more health-conscious people to defy the shelter-in-place instructions because of their concern about a suspicious skin lesion. “Though it is way too early to gauge the consequences of such diagnostic delay, should this issue be neglected, dermatologists and their patients may pay a higher price later with increased morbidity, mortality, and financial burden,” according to the investigators.
Dr. Hartman observed that it will be important to learn whether similar experiences occurred elsewhere during lockdown.
Another speaker, John M. Kirkwood, MD, said he has seen several melanoma patients referred from outside centers who had delays of up to 3 months in sentinel lymph node management of T2 and T3 tumors during lockdown who now have widespread metastatic disease.
“Now, is that anecdotal? I don’t know, it’s just worrisome to me,” commented Dr. Kirkwood, professor of medicine, dermatology, and translational science at the University of Pittsburgh.
Merrick Ross, MD, professor of surgical oncology at M.D. Anderson Cancer Center, Houston, recalled, “There was a period of time [during the lockdown] when we weren’t allowed to do certain elective procedures, if you want to call cancer surgery elective.”
“It’s too soon to talk about outcomes because a lot of patients are still in the process of being treated after what I would consider a significant delay in diagnosis,” the surgeon added.
An audience member asked if there will be an opportunity to see data on the damage done by delaying melanoma management as compared to lives saved through the lockdown for COVID-19. Dr. Ross replied that M.D. Anderson is in the midst of an institution-wide study analyzing the delay in diagnosis of a range of cancers.
“In our melanoma center it is absolutely clear, although we’re still collecting data, that the median tumor thickness is much higher since the lockdown,” Dr. Ross commented.
Dr. Hartman said she and her coinvestigators in the Melanoma Prevention Working Group are attempting to tally up the damage done via the lockdown by delaying melanoma diagnosis and treatment. But she agreed with the questioner that the most important thing is overall net lives saved through shelter-in-place.
“I’m sure that, separately, nondermatologists – perhaps infectious disease doctors and internists – are looking at how many lives were saved by the lockdown policy. So I do think all that data will come out,” Dr. Hartman predicted.
She reported having no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
SOURCE: Hartman, R. Cutaneous malignancies forum.
Initial evidence suggests that the , Rebecca I. Hartman, MD, MPH, said at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medication Education.
This is not what National Comprehensive Cancer Network officials expected when they issued short-term recommendations on how to manage cutaneous melanoma during the first wave of the COVID-19 pandemic. Those recommendations for restriction of care, which Dr. Hartman characterized as “pretty significant changes from how we typically practice melanoma care in the U.S.,” came at a time when there was justifiable concern that the first COVID-19 surge would strain the U.S. health care system beyond the breaking point.
The rationale given for the NCCN recommendations was that most time-to-treat studies have shown no adverse patient outcomes for 90-day delays in treatment, even for thicker melanomas. But those studies, all retrospective, have been called into question. And the first real-world data on the impact of care restrictions during the lockdown, reported by Italian dermatologists, highlights adverse effects with potentially far-reaching consequences, noted Dr. Hartman, director of melanoma epidemiology at Brigham and Women’s Hospital and a dermatologist, Harvard University, Boston.
Analysis of the impact of lockdown-induced delays in melanoma care is not merely an academic exercise, she added. While everyone hopes that the spring 2020 COVID-19 shelter-in-place was a once-in-a-lifetime event, there’s no guarantee that will be the case. Moreover, the lockdown provides a natural experiment addressing the possible consequences of melanoma care delays on patient outcomes, a topic that for ethical reasons could never be addressed in a randomized trial.
The short-term NCCN recommendations included the use of excisional biopsies for melanoma diagnosis whenever possible; and delay of up to 3 months for wide local excision of in situ melanoma, any invasive melanoma with negative margins, and even T1 melanomas with positive margins provided the bulk of the lesion had been excised. The guidance also suggested delaying sentinel lymph node biopsy (SLNB), along with increased use of neoadjuvant therapy in patients with clinically palpable regional lymph nodes in order to delay surgery for up to 8 weeks. Single-agent systemic therapy at the least-frequent dosing was advised in order to minimize toxicity and reduce the need for additional health care resources: for example, nivolumab (Opdivo) at 480 mg every 4 weeks instead of every 2 weeks, and pembrolizumab (Keytruda) at 400 mg every 6 weeks, rather than every 3 weeks.
So, that’s what the NCCN recommended. Here’s what actually happened during shelter-in-place as captured in Dr. Hartman’s survey of 18 U.S. members of the Melanoma Prevention Working Group, all practicing dermatology in centers particularly hard-hit in the first wave of the pandemic: In-person new melanoma patient visits plunged from an average of 4.83 per week per provider to 0.83 per week. Telemedicine visits with new melanoma patients went from zero prepandemic to 0.67 visits per week per provider, which doesn’t come close to making up for the drop in in-person visits. Interestingly, two respondents reported turning to gene-expression profile testing for patient prognostication because of delays in SLNB.
Wide local excision was delayed by an average of 6 weeks in roughly one-third of melanoma patients with early tumor stage disease, regardless of margin status. For patients with stage T1b disease, wide local excision was typically performed on time during shelter-in-place; however, SLNB was delayed by an average of 5 weeks in 22% of patients with positive margins and 28% of those with negative margins. In contrast, 80% of patients with more advanced T2-T4 melanoma underwent on-schedule definitive management with wide local excision and SLNB, Dr. Hartman reported.
Critics have taken issue with the NCCN’s conclusion that most time-to-treatment studies show no harm arising from 90-day treatment delays. A review of the relevant published literature by Dr. Hartman’s Harvard colleagues, published in July, found that the evidence is mixed. “There is insufficient evidence to definitively conclude that delayed wide resection after gross removal of the primary melanoma is without harm,” they concluded in the review.
Spanish dermatologists performed a modeling study in order to estimate the potential impact of COVID-19 lockdowns on 5- and 10-year survival of melanoma patients. Using the growth rate of a random sample of 1,000 melanomas to model estimates of tumor thickness after various delays, coupled with American Joint Committee on Cancer survival data for different T stages, they estimated that 5-year survival would be reduced from 94.2% to 92.3% with a 90-day delay in diagnosis, and that 10-year survival would drop from 90.0% to 87.6%.
But that’s merely modeling. Francesco Ricci, MD, PhD, and colleagues from the melanoma unit at the Istituto Dermopatico dell’Immacolata, Rome, have provided a first look at the real-world impact of the lockdown. In the prelockdown period of January through March 9th, 2020, the referral center averaged 2.3 new melanoma diagnoses per day. During the Rome lockdown, from March 10th through May 3rd, this figure dropped to a mean of 0.6 melanoma diagnoses per day. Postlockdown, from May 4th to June 6th, the average climbed to 1.3 per day. The rate of newly diagnosed nodular melanoma was 5.5-fold greater postlockdown, compared with prelockdown; the rate of ulcerated melanoma was 4.9-fold greater.
“We can hypothesize that this may have been due to delays in diagnosis and care,” Dr. Hartman commented. “This is important because we know that nodular melanoma as well as ulceration tend to have a worse prognosis in terms of mortality.”
The mean Breslow thickness of newly diagnosed melanomas was 0.88 mm prelockdown, 0.66 mm during lockdown, and 1.96 mm postlockdown. The investigators speculated that the reduced Breslow thickness of melanomas diagnosed during lockdown might be explained by a greater willingness of more health-conscious people to defy the shelter-in-place instructions because of their concern about a suspicious skin lesion. “Though it is way too early to gauge the consequences of such diagnostic delay, should this issue be neglected, dermatologists and their patients may pay a higher price later with increased morbidity, mortality, and financial burden,” according to the investigators.
Dr. Hartman observed that it will be important to learn whether similar experiences occurred elsewhere during lockdown.
Another speaker, John M. Kirkwood, MD, said he has seen several melanoma patients referred from outside centers who had delays of up to 3 months in sentinel lymph node management of T2 and T3 tumors during lockdown who now have widespread metastatic disease.
“Now, is that anecdotal? I don’t know, it’s just worrisome to me,” commented Dr. Kirkwood, professor of medicine, dermatology, and translational science at the University of Pittsburgh.
Merrick Ross, MD, professor of surgical oncology at M.D. Anderson Cancer Center, Houston, recalled, “There was a period of time [during the lockdown] when we weren’t allowed to do certain elective procedures, if you want to call cancer surgery elective.”
“It’s too soon to talk about outcomes because a lot of patients are still in the process of being treated after what I would consider a significant delay in diagnosis,” the surgeon added.
An audience member asked if there will be an opportunity to see data on the damage done by delaying melanoma management as compared to lives saved through the lockdown for COVID-19. Dr. Ross replied that M.D. Anderson is in the midst of an institution-wide study analyzing the delay in diagnosis of a range of cancers.
“In our melanoma center it is absolutely clear, although we’re still collecting data, that the median tumor thickness is much higher since the lockdown,” Dr. Ross commented.
Dr. Hartman said she and her coinvestigators in the Melanoma Prevention Working Group are attempting to tally up the damage done via the lockdown by delaying melanoma diagnosis and treatment. But she agreed with the questioner that the most important thing is overall net lives saved through shelter-in-place.
“I’m sure that, separately, nondermatologists – perhaps infectious disease doctors and internists – are looking at how many lives were saved by the lockdown policy. So I do think all that data will come out,” Dr. Hartman predicted.
She reported having no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
SOURCE: Hartman, R. Cutaneous malignancies forum.
Initial evidence suggests that the , Rebecca I. Hartman, MD, MPH, said at a virtual forum on cutaneous malignancies jointly presented by Postgraduate Institute for Medicine and Global Academy for Medication Education.
This is not what National Comprehensive Cancer Network officials expected when they issued short-term recommendations on how to manage cutaneous melanoma during the first wave of the COVID-19 pandemic. Those recommendations for restriction of care, which Dr. Hartman characterized as “pretty significant changes from how we typically practice melanoma care in the U.S.,” came at a time when there was justifiable concern that the first COVID-19 surge would strain the U.S. health care system beyond the breaking point.
The rationale given for the NCCN recommendations was that most time-to-treat studies have shown no adverse patient outcomes for 90-day delays in treatment, even for thicker melanomas. But those studies, all retrospective, have been called into question. And the first real-world data on the impact of care restrictions during the lockdown, reported by Italian dermatologists, highlights adverse effects with potentially far-reaching consequences, noted Dr. Hartman, director of melanoma epidemiology at Brigham and Women’s Hospital and a dermatologist, Harvard University, Boston.
Analysis of the impact of lockdown-induced delays in melanoma care is not merely an academic exercise, she added. While everyone hopes that the spring 2020 COVID-19 shelter-in-place was a once-in-a-lifetime event, there’s no guarantee that will be the case. Moreover, the lockdown provides a natural experiment addressing the possible consequences of melanoma care delays on patient outcomes, a topic that for ethical reasons could never be addressed in a randomized trial.
The short-term NCCN recommendations included the use of excisional biopsies for melanoma diagnosis whenever possible; and delay of up to 3 months for wide local excision of in situ melanoma, any invasive melanoma with negative margins, and even T1 melanomas with positive margins provided the bulk of the lesion had been excised. The guidance also suggested delaying sentinel lymph node biopsy (SLNB), along with increased use of neoadjuvant therapy in patients with clinically palpable regional lymph nodes in order to delay surgery for up to 8 weeks. Single-agent systemic therapy at the least-frequent dosing was advised in order to minimize toxicity and reduce the need for additional health care resources: for example, nivolumab (Opdivo) at 480 mg every 4 weeks instead of every 2 weeks, and pembrolizumab (Keytruda) at 400 mg every 6 weeks, rather than every 3 weeks.
So, that’s what the NCCN recommended. Here’s what actually happened during shelter-in-place as captured in Dr. Hartman’s survey of 18 U.S. members of the Melanoma Prevention Working Group, all practicing dermatology in centers particularly hard-hit in the first wave of the pandemic: In-person new melanoma patient visits plunged from an average of 4.83 per week per provider to 0.83 per week. Telemedicine visits with new melanoma patients went from zero prepandemic to 0.67 visits per week per provider, which doesn’t come close to making up for the drop in in-person visits. Interestingly, two respondents reported turning to gene-expression profile testing for patient prognostication because of delays in SLNB.
Wide local excision was delayed by an average of 6 weeks in roughly one-third of melanoma patients with early tumor stage disease, regardless of margin status. For patients with stage T1b disease, wide local excision was typically performed on time during shelter-in-place; however, SLNB was delayed by an average of 5 weeks in 22% of patients with positive margins and 28% of those with negative margins. In contrast, 80% of patients with more advanced T2-T4 melanoma underwent on-schedule definitive management with wide local excision and SLNB, Dr. Hartman reported.
Critics have taken issue with the NCCN’s conclusion that most time-to-treatment studies show no harm arising from 90-day treatment delays. A review of the relevant published literature by Dr. Hartman’s Harvard colleagues, published in July, found that the evidence is mixed. “There is insufficient evidence to definitively conclude that delayed wide resection after gross removal of the primary melanoma is without harm,” they concluded in the review.
Spanish dermatologists performed a modeling study in order to estimate the potential impact of COVID-19 lockdowns on 5- and 10-year survival of melanoma patients. Using the growth rate of a random sample of 1,000 melanomas to model estimates of tumor thickness after various delays, coupled with American Joint Committee on Cancer survival data for different T stages, they estimated that 5-year survival would be reduced from 94.2% to 92.3% with a 90-day delay in diagnosis, and that 10-year survival would drop from 90.0% to 87.6%.
But that’s merely modeling. Francesco Ricci, MD, PhD, and colleagues from the melanoma unit at the Istituto Dermopatico dell’Immacolata, Rome, have provided a first look at the real-world impact of the lockdown. In the prelockdown period of January through March 9th, 2020, the referral center averaged 2.3 new melanoma diagnoses per day. During the Rome lockdown, from March 10th through May 3rd, this figure dropped to a mean of 0.6 melanoma diagnoses per day. Postlockdown, from May 4th to June 6th, the average climbed to 1.3 per day. The rate of newly diagnosed nodular melanoma was 5.5-fold greater postlockdown, compared with prelockdown; the rate of ulcerated melanoma was 4.9-fold greater.
“We can hypothesize that this may have been due to delays in diagnosis and care,” Dr. Hartman commented. “This is important because we know that nodular melanoma as well as ulceration tend to have a worse prognosis in terms of mortality.”
The mean Breslow thickness of newly diagnosed melanomas was 0.88 mm prelockdown, 0.66 mm during lockdown, and 1.96 mm postlockdown. The investigators speculated that the reduced Breslow thickness of melanomas diagnosed during lockdown might be explained by a greater willingness of more health-conscious people to defy the shelter-in-place instructions because of their concern about a suspicious skin lesion. “Though it is way too early to gauge the consequences of such diagnostic delay, should this issue be neglected, dermatologists and their patients may pay a higher price later with increased morbidity, mortality, and financial burden,” according to the investigators.
Dr. Hartman observed that it will be important to learn whether similar experiences occurred elsewhere during lockdown.
Another speaker, John M. Kirkwood, MD, said he has seen several melanoma patients referred from outside centers who had delays of up to 3 months in sentinel lymph node management of T2 and T3 tumors during lockdown who now have widespread metastatic disease.
“Now, is that anecdotal? I don’t know, it’s just worrisome to me,” commented Dr. Kirkwood, professor of medicine, dermatology, and translational science at the University of Pittsburgh.
Merrick Ross, MD, professor of surgical oncology at M.D. Anderson Cancer Center, Houston, recalled, “There was a period of time [during the lockdown] when we weren’t allowed to do certain elective procedures, if you want to call cancer surgery elective.”
“It’s too soon to talk about outcomes because a lot of patients are still in the process of being treated after what I would consider a significant delay in diagnosis,” the surgeon added.
An audience member asked if there will be an opportunity to see data on the damage done by delaying melanoma management as compared to lives saved through the lockdown for COVID-19. Dr. Ross replied that M.D. Anderson is in the midst of an institution-wide study analyzing the delay in diagnosis of a range of cancers.
“In our melanoma center it is absolutely clear, although we’re still collecting data, that the median tumor thickness is much higher since the lockdown,” Dr. Ross commented.
Dr. Hartman said she and her coinvestigators in the Melanoma Prevention Working Group are attempting to tally up the damage done via the lockdown by delaying melanoma diagnosis and treatment. But she agreed with the questioner that the most important thing is overall net lives saved through shelter-in-place.
“I’m sure that, separately, nondermatologists – perhaps infectious disease doctors and internists – are looking at how many lives were saved by the lockdown policy. So I do think all that data will come out,” Dr. Hartman predicted.
She reported having no financial conflicts regarding her presentation.
Global Academy for Medical Education and this news organization are owned by the same company.
SOURCE: Hartman, R. Cutaneous malignancies forum.
REPORTING FROM THE CUTANEOUS MALIGNANCIES FORUM