July/August 2020 Clinical Advisor by The Clinical Advisor

A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■ Stroke and COVID-19 ■■ Insomnia and ADHD ■■ Contextual Effect in OA ■■ Diabetes Education LEGAL ADVISOR

Outbreak of Scabies Tied to Lawsuit CASE

Unremitting Back Pain in a Woman Following Removal of Kidney Stones

DERMATOLOGY CLINIC

Pigmentary Changes on the Back and Chest

DERMATOLOGIC LOOK-ALIKES

Firm Lesions on the Face

JULY/AUGUST 2020

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INFECTIOUS DISEASES

ACIP Releases 2020 Pediatric and Adult Immunization Schedules Updated information, including that for the measle vaccine, is available online for easy access.

Director Nikki Kean nikki.kean@haymarketmedia.com Associate editor Madeline Morr Assistant editor Michelle Lampariello

Unsure about a diagnosis or treatment?

Production editor Kim Daigneau Group creative director Jennifer Dvoretz Senior production manager Krassi Varbanov Director of audience insights Paul Silver

Ask our

EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

Advisor Forum the color of the affected area was normal, the skin CLINICAL PEARLS felt quite thick and inflexible. These skin changes stopped abruptly at the collar line, below which POISON IVY PREVENTION the skin was entirely normal. Poison ivy season is starting! I recommend that Abundant evidence of sun damage — includ- people take an old pair of knee-high tube socks ing weathering, telangiectasias, solar lentiginosis, and cut off the foot part above the heel. Pull the and numerous actinic keratoses on prominent socks over the arms up to the start of their sleeve areas of his cheeks and ears — was noted. Similar (assuming they are wearing a T-shirt) and tuck changes were noted on the dorsa of both hands into gloves. Use the socks to protect arms when but were not present on his arms and trunk working in the yard or other high-risk poison because he wore long-sleeved shirts when in the ivy areas. They can be rolled off the arms and sun. Although he had worn a wide-brimmed hat thrown away, or washed and re-used. I remind while in the sun during his adult life, he had never people to always wear gloves, and to remove worn anything, such as a bandana, on his neck. the gloves before touching anything, including Always wear The posterior neck is especially susceptible door handles. This significantly reduces the gloves to to the effects of the sun, evidence of which fre- exposure area of skin to poison ivy. —JUDITH protect the quently manifests as it did in this patient. This MCINTOSH, MSN, Kokomo, Indiana skin from condition is called cutis rhomboidalis nuchae (CRN), which represents thickening and weathweath VERRUCA VULGARIS TREATMENT exposure to ering of the epidermis as well as solar elastosis I always recommend candida albicans skin anti- poison ivy, and of the underlying dermis caused by the sun. gen test injections for patients who are not remove them Although this condition is clear evidence of responding well to liquid nitrogen +/- paring for before touching chronic overexposure to the sun, CRN has no verruca vulgaris. A 0.1-mg injection every month anything. malignant potential, and treatment is neither for about 3 months creates an immune response required nor does it exist. against the warts. I have seen resolution of some Besides being common, CRN is unique in its recalcitrant cases that seemed most impossible! presentation, as well as in the patient population —SARAH LUP, PA-C, Chicago, Illinois it affects (eg, older patients with sun damage confined to the posterior neck), so the differen- RETHINKING PRESCRIBING tial is quite narrow. Punch biopsy would resolve DICLEGIS any confusion. Diclegis is the only FDA-approved prescription CRN puts this patient at higher risk for the medication for nausea and vomiting of pregdevelopmentThe of skin caused by sun expo- nancy that is classified as Category A (safe for se cancers are lette rssquamous sure, such asand basal cell carcinoma, cell mom and baby). Before writing a prescription, from prac successe titioconsider ners arou carcinoma, melanoma, and s,others. the price tag. Diclegis with a coupon obseThis nd the coun rvatpatient ions, andcosts approximately and others with similar histories require regular $345 try for 60 tablets. The pearls with who their to share their skin checks by a qualified dermatology provider most common dosagecolle is 2 tablets/dwan but tcan agues. We clinical chall at least once a year. Although this patient would be more. Some patients may obtain insurance invite you enges to participa be advised to protect himself from the sun, this coverage for this medication, but it will likely te. will do little to ward off any future skin cancers still cost something. Let’s break down Diclegis that will have been caused by sun overexposure CONSUL into its 2 active ingredients: doxylamine sucTAT occurring decades earlier. Application of sun- cinate IONand S pyridoxine hydrochloride (vitamin screen to his neck would prevent IRO worsening of B 6). Unless you are writing a prescription for N PILL 2. Cohen SM, Kwo PY, Lim, his CRN. a celebrity, recommend that your patients ON LIVE S AND THEIR JK. ACG clinical of abnorm Send us R ENZ al liver chemis ECT guideline: your purchase over-the-counter doxylamine YMESinsteadEFF Can takin evaluat tries. Am J Gastroe 3. Iron. ion g iron pills nterol. 2017;1 al Institute Reference letters with succinate and vitamin B 6 to take Nation at night elevate liver —AGNES 12:18-35. of Health nih.gov/Iron.h ques website. https:// enzymes? MURPHY, tm. Access for nausea. —AMBER PA-C, Bolognia JL, Jorizzo JL,tions Rapini RP. Dermatology. 1st ed. NewDEW, PCA and , Americus, livertox. ed April 3, commen 2019. Georgia Birmingham, Michigan York: Mosby, 2003;1380-1381. ts to: Liver enzym es Advisor Forum aspartate aminosuch as alanine amino , CASE FILE transfe The Clinica l Advisor, phatase are transferase (AST), and rase (ALT), S www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2019 45 275 7th Aven markers of alkaline phosfunction, and hepat ue, 10th CUTIS RHO should be referre ic injury, not hepat Floor, New Albumin, MBO ic York, d to as liver bilirubin, and chemistries. Contributed by Joe Monr IDALIS NY 10001 measures of prothrombin .You oe, MPAS, hepatocellu time are direct A 78-year-old may conta PA-C lar appropriately ct us heavily lined man presented characterized synthetic function and with thick e-mail at edito by skin on enzymes may are as “liver functio r@ be abnormal n tests.” Liver been present for an his posterior neck ened, clinicaladvis liver diseas that had even in patien indet or.com. Although e. The differe ts without the striking erminate period of Letters are ntial for elevat broad with time. skin chang tomatic, edited many be further define potential causative ed enzymes is insiste they were concerning es were asympfor length factors and and d that he be to his relativ d by the patien should risk factors. 1 clarity. The seen es who t’s by a medical histor The Clinical y and the patient had spent dermatology provider. Almost all Advisor’s policy nearl sun, farmi medications ng, ranching, y his whole life small risk of are associated is to print to his in elevat fishing, and the hepatotoxic 2 ed liver chemistries with at least a a histo property in rural tending author’s name Okla ity. Oral with ry homa or of witho iron skin cance . replacement with the letter r and claim He denied doses has little supplementation at typicaut good health. ed to be . liver or serum or No anony in The skin on enzyme elevati no adverse effects on l mous the patien or overdoses, the ons. However, contributio it in high doses lined and thickened t’s nuchal area was ns will of iron poison can cause acute hepato heavily . The multiple overla toxicity as a ing. be accepted. pping rhom lines joined to form result of ferrous sulfate Toxicity occurs after boidal shape ingestion of (approximat ≥3 g s. toxicity with Altho ely 10 tablets ugh aminotransf ). Severe the upper limit erases greate r overdoses and of normal typically than 25 times occurs with high initial larger serum iron dL). Mild levels to usually self-limmoderate cases of iron (>1000 ug/ whereas severe iting and resolve with poisoning are suppo KUSMIN cases become fatal rapidl 3 rtive care, SKY, PA-C y. —LAURA Referenc es

Advisor F

orum

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44 THE CLINI

1. Approach to the patient with abnorm and functio n tests. UptoD al liver bioche mical ate.com websit uptodate.com e. https://www. /contents/app roach-to-theabnormal-liver patient-with-biochemical -and-functionApril 2, 2019. tests. Access ed

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2 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

CONTENTS J U LY / A U G U S T 2 0 2 0

NEWS 8

Newsline ■■Consensus Statement Outlines Recommendations for DSMES ■■A Closer Look at Stroke in Patients With COVID-19 ■■Insomnia and Alcohol Consumption Linked to ADHD ■■Examining MIS-C Associated With SARS-CoV-2 in

Pediatric Patients ■■Contextual Effect Enhances Management of Knee Osteoarthritis

8 Consensus on diabetes education

FEATURES 3 A Case of Unremitting Back Pain Following 1 Removal of Kidney Stones Unexplained symptoms lead to a surprising diagnosis.

13 MRI results and an oncology consultation

4 ACIP Releases 2020 Pediatric and Adult 2 Immunization Schedules Updated guidance from the Advisory Committee on Immunization Practices.

DEPARTMENTS

27 Lesion in woman with family history of RA

40 Hospital privacy laws disputed in case

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com.

Dermatology Clinic ■■Pigmentary Changes on the Back and Chest ■■Hyperpigmented Lesions on Arms

Dermatologic Look-Alikes ■■Firm Lesions on the Face

Legal Advisor ■■Outbreak of Scabies Tied to Lawsuit

MORE WAYS TO FIND US!

Like us on Facebook facebook.com/TheClinicalAdvisor Visit us on the web ClinicalAdvisor.com Download the app ClinicalAdvisor.com/App

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ClinicalAdvisor.com

NEWS ClinicalAdvisor.com/News

FEATURES ClinicalAdvisor.com/Features

NPs Prescribing More Buprenorphine for OUD

Guidance for the Diagnosis and Management of Ovarian Cysts Ovarian cysts are benign, adnexal masses that most frequently affect premenopausal women of child-bearing age, although fetal, prepubescent, and postmenopausal women may also be diagnosed.

The Comprehensive Addiction and Recovery Act (CARA), which authorized NPs and PAs to prescribe buprenorphine, may have contributed to the increase in prescribing rates.

Guidelines for Use of Probiotics for Managing Gastrointestinal Disorders The guidelines recommend the use of probiotic strains or strain combinations to prevent Clostridioides difficile infections in patients taking antibiotics.

Imaging Predicts Parkinson Disease Progression in Adults Lower gray matter integrity found at the microstructural level may be a prognostic marker for development of mild parkinsonian signs, reflecting earlier changes in the brain structure.

How to Resume Exercise and Training Following COVID-19 Infection Members of the ACC’s Sports & Exercise Cardiology Council, with input from national leaders, provided a consensus framework on return to play in the era of COVID-19.

Exploring the Link Between Migraine & Sleep Disorders Reports of increasing sleep impairment and migraine prevalence in pediatric populations highlight the need to elucidate the nature of the relationship between these conditions.

THE WAITING ROOM

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Tammy Worth Tips for Getting Practices Back to Full Service After COVID-19 Guidance is available to help clinicians get their practices back up and running safely following the COVID-19 pandemic.

MY PRACTICE ClinicalAdvisor.com/MyPractice

Most Clinicians, Pharmacists Favor Medical Cannabis Use Attitudes regarding cannabis were assessed by the perceived effectiveness of CBD/ medical cannabis, regulation and availability of products, and stigma associated with recommending CBD treatment.

6 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

Madeline Morr Response to COVID-19 Identifies Inequalities in Health Care The American College of Physicians statement outlines how the “status quo” created health inequalities that allowed the spread of the COVID-19 virus, and outlines steps on how to move forward.

EXCLUSIVE TO THE WEB AT

Advisor Dx Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues. Check out some of our latest cases below!

DERM DX

Dark Lesion on the Upper Back A 73-year-old man is referred for evaluation of a skin lesion on his upper back. He denies itching, burning, or bleeding associated with the lesion. Examination of the lesion reveals a 1.5-cm, hyperpigmented, hyperkeratotic plaque. Scattered seborrheic keratoses are noted elsewhere on the patient’s body. Axillary and cervical lymph nodes are nonpalpable. CAN YOU DIAGNOSE THIS CONDITION?

• Seborrheic keratosis • Pigmented basal cell carcinoma • Pigmented squamous cell carcinoma • Superficial spreading melanoma ● See the full case at ClinicalAdvisor.com/DermDx_Aug20

In partnership with

ORTHO DX

TheJopa.org

Journal of Orthopedics for Physician Assistants

Pain in the Medial Ankle A 32-year-old woman presents with a 3-month history of pain in her right medial ankle. Her symptoms are intensified during exercise and when she stands while working as a nurse. Physical examination reveals a pes planus deformity and mild hindfoot valgus. Deep palpation of the medial heel causes radiating pain to the plantar aspect of the foot. WHAT IS THE BEST NEXT STEP IN TREATMENT?

• Place the patient in a walking boot • Order a nerve conduction velocity test • Order magnetic resonance imaging of the ankle • Order computed tomographic imaging of the ankle ● See the full case at ClinicalAdvisor.com/OrthoDx_Aug20

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY/AUGUST 2020 7

Newsline

Clinicians are urged to tout the benefits of DSMES with patients.

centers, pharmacies, faith-based organizations, and home settings. It is recommended that providers discuss the benefits and importance of DSMES with all patients with diabetes and support the use of DSMES services at critical times, including diagnosis, annually and/or when treatment targets are not met, when complicating factors arise, and during transitions in life. There are no downsides to DSMES but the potential benefits are numerous, including the option to guide and support patients in implementing treatment plans, avoidance of hospital admissions or visits to the emergency department, improvement of glycemic control and weight management, prevention of hypoglycemia, enhanced self-confidence and self-efficacy, improvement in quality of life, and reduction in all-cause mortality. According to the 2017 National Furthermore, most insurers, including Standards for Diabetes Self-Management Medicare, cover the costs of this modality. It is important to identify and manage Education and Support, DSMES is defined as “[t]he ongoing process of potential barriers to DSMES, includfacilitating the knowledge, skills, and ing health system barriers (eg, a limability necessary for diabetes self- ited number of specialists or access to management as well as activities that services), provider-related barriers (eg, assist a person in implementing and lack of awareness of DSMES services), sustaining the behaviors needed to participant-related barriers (eg, cost issues manage his or her condition on an or medical status), and environmental ongoing basis, beyond or outside of barriers (eg, limited transportation serformal self-management training. This vices or social conditions). DSMES can provide the foundation, process incorporates the needs, goals, and life experiences of the person with as well as the ongoing support, necessary to help patients overcome barridiabetes.” There are various DSMES approaches ers to optimal care. It is vital to adjust and settings that can be offered and and modify DSMES according to the adjusted according to the specific patient’s changing needs throughout needs of each patient.While in the past the continuum of diabetes treatment DSMES services were offered in the and life transitions. Increasing awareform of didactic classes in the hospital or ness and access and addressing barriers a healthcare facility, nowadays DSMES and changes in reimbursement policies services can be incorporated into many are important steps to take to increase settings, including community health uptake of DSMES services.

Consensus Statement Outlines Recommendations for DSMES A CONSENSUS statement published in Diabetes Care outlines the benefits and barriers associated with diabetes self-management education and support (DSMES) in adults with type 2 diabetes. Recognized as one of the core elements of comprehensive diabetes care, DSMES provides a foundation to strengthen the knowledge and skills of patients with diabetes and empower them to manage their disease with confidence. Studies have shown that DSMES may improve clinical, psychosocial, and behavioral outcomes. The current consensus report is a collaboration between the American Diabetes Association, the Association of Diabetes Care and Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Nurse Practitioners, and the American Pharmacists Association.

8 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

Newsline A Closer Look at Stroke in Patients With COVID-19 A LOW RATE of image-confirmed ischemic stroke was found in patients hospitalized with COVID-19 in the New York metropolitan area between March and April, 2020. Patients with COVID-19 and stroke were found to have a higher mortality compared with historic and contemporary controls, according to a study published in Stroke. Three comprehensive stroke centers in the NewYork metropolitan area provided data of acute ischemic stroke in patients with and without COVID-19. A historical control group was included of patients with a discharge diagnosis of ischemic stroke between March and April, 2019. Thirty-two (0.9%) of the 3556 patients who were hospitalized for COVID19 were noted to have ischemic stroke. Cryptogenic stroke was more common in patients with COVID-19 (65.6%) as compared to both contemporary controls

Cryptogenic stroke was seen more often in patients with COVID-19 vs controls.

(30.4%) and historic controls (25.0%). Patients with COVID-19 had higher National Institutes of Health Stroke Scale (NIHSS) scores upon admission and higher peak D-dimer levels compared with contemporary controls. They also were more likely to be younger men with

elevated troponin levels, higher admission NIHSS scores, and higher erythrocyte sedimentation rates compared with historic controls. The researchers noted that the rate of ischemic stroke in infected patients was lower compared with results reported from China. Possible reasons for the difference might be related to race variations and that the low rate of ischemic stroke may be underestimated due to a difficulty in identifying stroke in patients who are critically ill and sedated. “In patients with COVID-19 and ischemic stroke, a majority of strokes were classified as cryptogenic, possibly related to an acquired hypercoagulability, and were associated with increased mortality,” the study authors noted. “Ongoing studies are testing the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention.”

Insomnia and Alcohol Consumption Linked to ADHD Compared with the control group, a lower proportion of patients with ADHD had completed university (34.3% vs 77.8%) or were currently employed (40.2% vs 88.4%). The mean AUDIT sum score was significantly higher in the ADHD group vs controls (13.59 vs 12.32),

the control group reported consuming at least 5 to 6 units of alcohol when drinking. Mean Adult ADHD Self-Report Scale (ASRS) scores were 42.18±12.50 and 21.77±9.78 in the ADHD and control groups, respectively. Insomnia was associated with more severe ASRS scores

Among adults without a clinical diagnosis of ADHD, heavy alcohol use predicted more severe symptoms, and insomnia was linked to more alcohol use and more severe ADHD. suggesting greater severity of alcohol consumption in patients with ADHD. Insomnia was also more frequent in the ADHD group compared with controls (67.2% vs 28.8%). Among participants with insomnia, 46.9% of the ADHD group and 24.6% of

10 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

in patients and controls.Alcohol use may be associated with ADHD symptoms, even among adults without a clinical diagnosis of ADHD. Insomnia was associated with increased alcohol consumption and more severe ADHD symptoms in both groups.

ALCOHOL MISUSE and insomnia were significantly correlated with attentiondeficit/hyperactivity disorder (ADHD) symptom severity, according to study results published in Frontiers in Psychology. Researchers at the University of Bergen in Norway recruited patients with ADHD from a national registry of adults diagnosed between 1997 and 2005, as well as healthy controls randomly recruited from the Medical Birth Registry of Norway.Adults with an ADHD diagnosis (n=235) and controls (n=184) completed a questionnaire assessing insomnia, alcohol consumption, and current ADHD symptoms. The majority of participants were women (ADHD group: 58.7%; control group: 62.0%), and mean age was 37.91±11.2 years in the ADHD group and 36.55±8.2 years in the control group.

Newsline Examining MIS-C Associated With SARS-CoV-2 in Pediatric Patients MULTISYSTEM inflammatory syndrome in children (MIS-C) has been associated with SARS-CoV-2 infection and can potentially damage multiple organ systems in previously healthy children, according to a study published in the New England Journal of Medicine. Researchers studied patients admitted to the hospital from March 15 to May 20, 2020. Six criteria were needed

and the remainder had an epidemiologic link to a person with COVID-19. Median age of patients was 8.3 years; 62% were male, and 73% had previously been healthy. A total of 71% of patients had involvement of at least 4 organ systems, including gastrointestinal (92%), cardiovascular (80%), hematologic, (76%), mucocutaneous (74%), and respiratory (70%) systems. Most patients were cared for

A majority of patients (80%) had cardiovascular involvement: 91% of patients had an echocardiogram, and coronary artery aneurysms were documented in 8%.

to meet MIS-C diagnosis: serious illness leading to hospitalization; patient aged <21 years, fever lasting at least 24 hours; laboratory evidence of inflammation; multisystem organ involvement; and laboratory-confirmed SARS-CoV-2 infection or exposure to a person with confirmed COVID-19. A total of 186 patients were included in the study; the majority of patients (70%) tested positive for SARS-CoV-2 infections by RT-PCR, antibody testing, or both,

MIS-C related to COVID-19 led to serious illness in otherwise healthy children.

in an intensive care unit (80%) and 20% received invasive mechanical ventilation. As of May 20, 2020, a total of 130 patients (70%) had been discharged, 52 (28%) were still hospitalized, and 4 (2%) had died.The 4 patients who died were aged 10 to 16 years; 2 of the children had no underlying medical conditions. At least 90% of MIS-C patients had fever for ≥4 days. A majority of patients (80%) had cardiovascular involvement; a total of 91% of patients had at least 1 echocardiogram, and coronary artery aneurysms were documented in 8% of patients. Respiratory insufficiency or failure occurred in 59% of patients; 78% of these patients had no underlying respiratory conditions. Overall, 20% of patients received invasive mechanical ventilation and 17% received noninvasive mechanical ventilation. Most patients had ≥4 laboratory biomarkers of inflammation.Almost half the patients (49%) received glucocorticoids, 8% received interleukin-6 inhibitors, 13% received an interleukin-1Ra inhibitor, and 77% received intravenous immune globulin.

12 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

Contextual Effect Enhances Management of Knee Osteoarthritis PAIN RELIEF experienced by patients with osteoarthritis (OA) of the knee may be attributed to contextual effect, especially in those patients receiving acupuncture or electrotherapies, according to a study published in Osteoarthritis and Cartilage. “Contextual effect may include the placebo effect, changes attributable to natural history, and effects of cotherapies.These factors can influence therapeutic outcomes substantially,” the researchers said. The research team searched the medical literature to identify knee OA trials. Studies including ultrasound, transcutaneous electrical nerve stimulation, and laser were combined under the term total energy modality (TEM). The contextual effect was calculated by dividing the mean improvement in pain of the placebo group by the mean improvement in pain of the active group, they said. The final analysis consisted of 25 total acupuncture and TEM studies.The age of patients was similar between the 2 groups: the mean age ranged from 57 to 71 years for the acupuncture studies and from 53 to 69 for TEM studies. Pooled analysis found that contextual effects accounted for approximately 61% of the pain relief experienced by patients receiving acupuncture and 69% of the total treatment effect in TEM studies. “Further research is needed to determine how contextual effects vary across treatment approaches and outcome measures, and how to harness the benefits in ways that align with patient goals,” they said. ■

FEATURE: SHANNON E. WHITTEN, MS, NP-C, APRN-BC

A Case of Unremitting Back Pain Following Removal of Kidney Stones Right-sided flank pain has been present for several months and occurs when standing, bending, and lifting — pain only improves when laying down.

49-year-old woman presents to her primary care practice 4 weeks after she underwent a retrograde ureteroscopy on the right side for extraction of an obstructed 6-mm ureteral stone. Since the procedure, the patient has experienced intensifying flank pain on the right side. She notified her urologist, who advised her to follow up with her primary care provider to rule out a nonrenal etiology for the pain. She was instructed to return to the urologist should her symptoms persist.

History

MRI shows compression fractures at T12 and L2 as well as mottled sclerosis seen throughout L4.

At presentation in 2020, the patient reports no significant medical history other than recurrent nephrolithiasis and a diagnosis of cervical human papillomavirus (HPV) 22 years earlier. She has had 6 previous kidney stones: 3 passed spontaneously, 2 were treated with lithotripsy (in 2006 and 2007), and 1 required stone extraction in 2016. The patient is a registered nurse who works 12-hour shifts, which rarely affords her time to hydrate or void at work. She does not take either calcium or vitamin D supplements out of concern of developing additional kidney stones. She runs 1 mile per day and rows 6 miles per week. Her last menstrual cycle was 11 months ago, and her Fracture Risk Assessment Tool (FRAX®) score shows a 10-year risk for osteoporosis-related fracture of 5.3%. She has not had any previous bone density screenings.All other annual screenings including a mammogram, www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY/AUGUST 2020 13

MELANOMA OF UNKNOWN PRIMARY

Carcinomas of unknown primary comprise 2% to 5% of cancers and include epithelial cell line malignancies such as melanoma, sarcoma, and lymphoma. colonoscopy, purified protein derivative skin test, and annual physical examination are up to date and normal. The right-sided flank pain has been present for several months. She describes the pain as 9 out of 10 on visual analog scale, and it occurs upon standing, bending, or lifting and only improves when lying flat. Unlike all previous kidney stones, she denies any dysuria, nausea, vomiting, or colicky pain although she feels a constant pressure over her bladder and right flank. She denies any recent back injury, fever, shortness of breath, chills, myalgias, cough, or change in bladder or bowel habits. The patient does report extreme vasomotor symptoms, which she describes as hot flushes, when bending over. Her current medications include ibuprofen 800 mg every 8 hours and, occasionally, acetaminophen 1 g up to twice daily, which affords short-term pain relief unless she bends forward or moves suddenly. Assessment

The patient’s vital signs are unremarkable (Table). She is a nonsmoker and reports consuming 1 to 2 alcoholic beverages a week. She has a family history of breast, renal, and colon cancer in second-degree relatives. Her pulmonary, cardiac, breast, and abdominal examinations are unremarkable. She has no right upper quadrant pain on palpation and negative Murphy, Rosving, psoas, and obturator signs. There is no appreciable lymphadenopathy. Testing for costovertebral angle tenderness is negative, but palpation at the level of the lower thoracic and upper lumbar spines elicits some focal back pain. TABLE. Summary of Patient’s Vital Signs Vital Signs

Results

Height

5’7”

Weight, kg

70.3

Temperature, °C

Blood pressure, mm Hg

102/74

Heart rate, beats/min

Respiratory rate, breaths/min

Inspection of her back reveals no visible bony abnormalities, swelling, or discoloration. She has a normal bilateral straight leg raise test, and her deep tendon reflexes are normal for both the quadriceps and Achilles tendons.There is no sign of clonus. Back symptoms are present when the patient leans forward. Crepitus is appreciated with a discrete snap in her thoracic spine that produces diaphoresis, nausea, and bilateral facial flushing. Urinalysis is positive for blood and with a negative urine human chorionic gonadotropin test. Urine is submitted for culture and cytology, which reveals atypical urothelial cells with negative culture. Her urologist is consulted, but the physician does not feel the cells are of any significance since a recent computed tomographic (CT) examination showed no signs of mass in the bladder or kidneys.The urologist is requested to provide the CT report and office notes, and a plain film of the spine is ordered, revealing compression fractures at multiple levels. Magnetic resonance imaging was performed, revealing compression fractures at T12 and L2, as well as mottled sclerosis seen throughout L4. A verbal report by the radiologist recommended urgent oncology referral, as these fractures appeared to be metastatic lytic lesions as opposed to simple compression fractures. The patient was referred to a medical oncologist who ordered a 24-hour urine examination for kappa total light chain, lambda total light chain, and monoclonal antibody protein. A dual-energy X-ray absorptiometry scan revealed a T- score of -1.2 in the vertebrae and -1.4 in the hip, confirming a diagnosis of osteopenia, and ruled out a diagnosis of multiple myeloma.With no presence of soft tissue mass as well as a normal mammogram, colonoscopy, and chest radiograph, the patient was told that she had nonpathologic compression fractures.The patient was advised to undergo positron emission tomographic (PET) imaging, but her insurance company refused the approve payment for the scan, even following specialist peer-to-peer review. The patient returned to the primary care office 5 weeks later with complaint of a 2.5 × 2.2 cm nontender, moveable, right-sided submandibular mass. Ultrasound was performed, revealing luminal atypia. The patient was referred to an otolaryngologist for fine needle biopsy. The stain is mildly positive for melanoma markers SOX10 and MART-1 but was read as inconclusive for melanoma due to a lack of additional biomarkers including a more reliable S100 stain. The patient was then referred to a dermatologist who reports finding no abnormal nevus or primary melanoma

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Continues on page 18

MELANOMA OF UNKNOWN PRIMARY

Melanoma of unknown primary can be diagnosed by fine needle aspiration or wide excisional biopsy of a metastatic lymph node or soft tissue. lesions; however, the patient is found to have a high burden of small, dark nevi covering her trunk and extremities. Biopsy of multiple nevi was performed, but all were found to be benign. PET scan was ordered and approved by her insurance company based on the presence of the soft tissue mass. The fluorodeoxyglucose PET scan (Figure) revealed significantly increased uptake in her right submandibular and supraclavicular nodes, a left lower fissural nodule, and a high level of activity in T12 and L2. Diagnosis

The patient was referred to an oncologist specializing in melanoma. During the visit, 4 tissue samples were collected via fine needle biopsy from the submandibular lymph node. Each sample showed tissue consistent with a “metastatic process,” but there were no definitive tissue markers to make an official diagnosis. The surgical oncologist opted to perform a wide excisional biopsy with immunostaining of the submandibular node. The biopsy results were significant for epithelioid histiocytes and a SOX10 biomarker. Comprehensive molecular profiling 26 was submitted and revealed the presence of mutations in the following genes: NRAS, TP53, and MAP2K1. The patient was diagnosed with stage 4 metastatic melanoma of unknown primary (MUP). Melanoma of Unknown Primary

Carcinomas of unknown primary (CUP) comprise approximately 2% to 5% of all cancers and include epithelial cell line

FIGURE: PET scan reveals numerous sites of metastatic melanoma.

malignancies such as melanoma, sarcoma, lymphoma, and germ cell cancers.1 It is important for clinicians to be aware of an unknown primary tumor diagnosis in patients who have metastatic lesions but no identifiable tumor.2 Melanoma must be included in the differential diagnosis for any suspected cancer of unknown primary, as well as for head and neck cancers such as tonsillar, mucosal, and salivary. The incidence of CUP associated with head and neck cancers has been increasing, especially in individuals infected with HPV.3 In most cases of CUP, a tumor is never identified due to partial or complete regression of the original lesion via immune-mediated responses.1 If biopsy of a lymph node is performed and a definitive cell line determined, the diagnosis is that particular cancer plus unknown primary but not CUP alone.2 MUP can be diagnosed with fine needle aspiration or wide excisional biopsy of a metastatic lymph node, or with biopsy of a visible soft tissue metastasis.The original tumor of MUP, however, is usually not found because it has either regressed or is hidden, as in mucosal melanoma (vulvovaginal, gastrointestinal, or sinonasal) or choroidal/uveal melanoma.2 Some lesions present as brain, lung, bone, and soft tissue metastases. Diagnosis is typically made by tissue staining for biologic markers and/or molecular tissue evaluation to identify any obvious genetic mutation(s) consistent with melanoma.2,4 Several genetic melanoma mutations of clinical importance currently exist that are used to guide first-line treatment options; these include mutations of BRAF V600e, NRAS, NF1, and KIT.4 Melanomas arising from intermittently sunexposed skin frequently have mutations in BRAFV600e, which is seen in 50% of affected patients, and in NRAS, which is seen in approximately 20% of affected patients.4 Melanoma is referred to as wild-type in the absence of these mutations.5 Currently there are more treatments approved by the US Food and Drug Administration for individuals with mutation of the BRAF gene — including checkpoint inhibitors and targeted therapies — vs those with mutation of the NRAS gene. However, overall survival does not appear to be improved among patients with mutation of the BRAF gene compared with mutation of the NRAS gene due to the development of drug resistance to targeted therapies over time. No targeted therapies are currently approved for melanoma associated with mutation of NRAS. BRAF and MEK inhibitors are the preferred treatment for patients with mutation of BRAF, but checkpoint inhibitors are often added due to their ability to produce a more sustained response.5,6

18 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

There is no known cure for stage 4 melanoma; the goal of treatment is a sustained response to immunotherapy and targeted therapies. Immunotherapy agents that target programmed death-1 (PD-1 checkpoint inhibitors) and cytotoxic T-lymphocyteassociated protein 4 (CTLA-4 inhibitors) are more likely to be used as first-line therapy for individuals who have BRAF-negative mutations or wild-type melanoma.5 PD-1 checkpoint inhibitors show some age-related variances, including better sustained results in patients aged >60 years due to a more favorable proinflammatory cancer microenvironment with fewer regulatory T cells and more CD8 T cells that kill tumors.5 As the patient in this case had no identifiable skin or mucosal lesions on examination, and her genetic testing was negative for an inheritable melanoma, it is likely her immune system either absorbed the original lesion or her years of cumulative ultraviolet (UV) sun exposure with a high nevi burden caused her melanoma. The patient had an additional mutation of TP53, which is seen in many late-stage cancers. TP53 mutation in melanoma is associated with increasing potential for angiogenesis, chemoresistance, and inhibition of apoptosis.5 The patient had a mutation of NRAS, where glutamine at position 61 is replaced by arginine, lysine, or leucine.4 Treatment

Compared with chemotherapy, the concept of immunotherapy is relatively new to most primary care clinicians. Both targeted therapies and checkpoint inhibitors have a unique set of complications because of their mechanisms of action. Combinations of therapies are more efficacious than monotherapies for the treatment of melanoma; however, these increase the risk of untoward side effects. The patient was started on the PD-1 checkpoint inhibitor ipilimumab at 480 mg administered over 30 minutes and nivolumab, a CTLA-4 inhibitor, at 10 mg/kg administered over 90 minutes every 3 weeks.The patient was scheduled to receive 4 treatments with nivolumab and ipilimumab, and then transition to monthly ipilimumab to continue indefinitely until disease progression or development of toxic effects.The most common side effects of both drugs are chronic pruritic rash, which the patient developed, vitiligo, polyarthralgias, myositis, pericarditis, pneumonitis, adrenal insufficiency, thyroiditis, pituitary dysfunction, liver failure, renal failure, and colitis.7 External beam radiation (EBR) therapy was chosen to control pain from the vertebral metastases and to afford additional time for the immunotherapy to work. EBR is believed to prime the patient’s immune response when used with immunotherapies that target CTLA-4, potentially

increasing overall survival.5 Prior to undergoing radiation, the patient was referred to an orthopedic surgeon who performed a vertebral biopsy and kyphoplasty to stabilize the vertebral fractures.8 An endocrinologist was consulted because of the patient’s osteopenia, hypercalcemia of malignancy, and her prior lack of supplemental calcium and vitamin D intake. Her oncologist agreed to initiate zoledronic acid, a bisphosphonate, because of her vertebral metastatic fractures and because it could further minimize risk of tumor lysis syndrome.8 Additionally, when used with vitamin D, zoledronic acid can stabilize vertebral metastatic lesions specifically in patients with melanoma by reducing the number and size of bone metastases.8 A regimen of vitamin D 1000 IU daily, calcium 1500 mg daily, and zoledronic acid 4 mg intravenous every 4 weeks was initiated. The patient was evaluated monthly. Laboratory assessment included a comprehensive metabolic panel; a complete blood count; and lactic dehydrogenase (LDH), thyroid-stimulating hormone, triiodothyronine, thyroxine, cortisol, and adrenocorticotrophic hormone levels.A normal LDH level has been associated with better overall survival in patients with metastatic melanoma as it is a direct measure of organ tissue damage.9 The patient was scheduled to undergo periodic PET and brain MRI scans to monitor for progression of her disease; 50% of patients with metastatic melanoma will eventually develop brain metastases and another 20% will develop liver metastases.5

POLL POSITION Which of the following is not a genetic mutation of melanoma? 12.64% ■ BRAF 31.03%

■ KIT ■ MSH2 ■ NRAS

27.59% 28.74%

For more polls, visit ClinicalAdvisor.com/Polls.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY/AUGUST 2020 19

MELANOMA OF UNKNOWN PRIMARY

Genetic mutations, diffuse nevi, and chronic skin exposure to UV light — no matter the source — are all independent risk factors for melanoma. There is no known cure for stage 4 melanoma.The goal of treatment is sustained response to immunotherapy and targeted therapies, and eventually a PET scan showing no evidence of disease. A diagnosis of melanoma carries a poor prognosis, and stage 4 melanoma has a 5-year survival rate of approximately 22.5%.5 However, patients receiving treatment with the newer PD-1 and CTLA-4 inhibitors have shown improved overall responses of up to 57%.5,10 Other therapies that have shown benefit in the treatment of melanoma include interleukin 2 (IL-2) therapy with or without adoptive cell therapy with tumor-infiltrating lymphocytes.5 Chemotherapy and IL-2 therapy are still used, although the response is not as robust as that seen with the newer immunotherapies and checkpoint inhibitors.1,5 Role of Primary Care NPs and PAs

Primary care clinicians should be aware that melanoma is not just skin cancer. Genetic mutations, diffuse nevi, and chronic skin exposure to UV light (no matter the source) are all independent risk factors for melanoma. It can appear as completely invisible and go undetected on examination, and it can exist as a genetic mutation without any obvious skin lesion(s). Patients with melanoma have a 74% risk of passing the genetic mutation to their offspring.11 Genetic testing is available for familial melanoma; for those who test positive, the current recommendation remains skin and symptom surveillance and risk reduction. Mutations in CDKN2A, BAP1 and MC1R genes are responsible for this non-sun-related genetic form of melanoma.5,11 It is important to educate patients about the importance of annual skin checks as most melanomas arise from chronic, sustained UV exposure with visible abnormalities. Skin examinations should include the perineum as well other non-sun-exposed areas such as nails, hands, and feet because acral-lentiginous melanomas can be easily missed. Patients should also undergo routine eye examinations to detect uveal and choroidal melanoma, which may not be found until they have already metastasized.12 Because of the effectiveness of immunotherapy, melanoma is becoming a chronic illness, making it important to maintain health screenings. Patients should be counseled to apply sunscreen products daily, wear 100% UVA and UVB sunglasses and UV-protected clothing and hats when outdoors, and avoid chronic sunlight exposure including tanning beds. Non-estrogen-containing contraception methods should be recommended for any woman with metastatic disease who still ovulates. Estrogen-containing products including

soy milk and phytoestrogens should be avoided due to risk of coagulopathies. Fertility-sparing measures should be a consideration for those with metastatic melanoma who want to have children. Cancer Advocate

Be a cancer advocate for your patients. Always consult your patient’s oncologist if you are unsure of a treatment decision that could affect or alter chemotherapy or immunotherapy. The management of immune-related adverse events includes the use of oral or intravenous corticosteroids plus treatment of the affected organ. Hormone replacement is often required for the management of hypothyroidism and hydrocortisone is often required for the management of adrenal insufficiency, which may be transient or permanent. Immune-mediated colitis may require treatment with oral steroids or budesonide; infliximab or vedolizumab may be indicated for refractory cases.13 Consultation with a cancer navigator is beneficial, especially for patients who experience job or insurance loss. Navigators can help patients obtain insurance coverage, assist with cumbersome paperwork for disability, and help patients connect with pharmaceutical companies that can donate costly cancer treatments until insurance is obtained or treatment approved. Consider referring patients to research hospitals that offer clinical trials and ancillary support services.The physical and emotional turmoil these patients and their families experience is overwhelming and often financially devastating. Palliative care can be a useful modality for the management of pain and the treatment of anxiety and depression.This service has the potential to reduce duplication of services and diminish the risk of polypharmacy. Clinicians have an obligation to refer patients to make sure they receive appropriate, adequate, and safe pain management. Cannabis and cannabidiol (CBD)-containing products are immune modulators that may diminish the efficacy of immunotherapy.14 Though CBD preparations may offer relief for patients treated with chemotherapy, they may pose harm to those receiving immunotherapy and could affect overall survival.14 Outcome

The patient in this case developed ipilimumab/nivolumabinduced colitis, hepatitis, and adrenal insufficiency after

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Continues on page 22

MELANOMA OF UNKNOWN PRIMARY

Always consult your patient’s oncologist if you are unsure of a treatment decision that could affect or alter chemotherapy or immunotherapy. her third treatment, necessitating the discontinuation of all immunotherapy. Treatment was initiated with oral prednisone 60 mg/d for 6 weeks after administration of intravenous hydrocortisone sodium succinate 100 mg and replacement of potassium 40 mEq for significant gastrointestinal losses. Of clinical importance, prednisone does not appear to diminish the effects of immunotherapy even after discontinuation for toxicities. The American Society of Clinical Oncology presented new clinical trial data in the summer of 2019 reporting that patients who developed severe-grade toxicities such as hepatitis, adrenal insufficiency, thyroiditis, or colitis had improved overall survival of 84%, 74%, and 65% at 1, 2, and 3 years, respectively. Regardless of disease stage, PD-1 positive/negative status, or LDH level, all cohorts on immunotherapy experienced improved survival.15,16 The patient will remain off of all immunotherapy for a minimum of 6 weeks followed by a re-evaluation for the use of nivolumab as maintenance monotherapy after the autoimmune effects have stabilized.

3. D’Souza G, Dempsey A. The role of HPV in head and neck cancer and review of the HPV vaccine. Prev Med. 2011:53 Suppl 1:S5-S11. 4. Wilson M, Nathanson K. Molecular testing in melanoma. Cancer J. 2012:18(2):117-123. 5. Riker A. Melanoma: A Modern Mutidisciplinary Approach. 1st ed. New Orleans, LA: Springer International Publishing; 2018. 6. Mackiewicz J, Mackiewicz A. BRAF and MEK inhibitors in the era of immunotherapy in melanoma patients. Contemp Oncol. 2018;22(1A):68-72. 7. Benfaremo D, Manfredi L, Luchetti MM, Gabrielli A. Musculoskeletal and rheumatic diseases induced by immune checkpoint inhibitors: a review of the literature. Curr Drug Safety. 2018;13(3):150-164. 8. Polascik T, Mouraviev V. Zoledronic acid in the management of metastatic bone disease. Ther Clin Risk Manag. 2008:4(1):261-268. 9. Petrelli F, Ardito R, Merelli B, et al. Prognostic and predictive role of elevated lactate dehydrogenase in patients with melanoma treated with immunotherapy and BRAF inhibitors: a systematic review and meta-analysis. Melanoma Res. 2019:29(1):1-12. 10. Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res. 2019;38(1):255. 11. Harrison P. Family history of melanoma increases skin CA risk—highest for lesions on trunk, extremities. Medpage Today. https://www.medpagetoday.

Summary

com/dermatology/skincancer/81144. Published July 22, 2019. Accessed

Research is moving in the direction of customized medicine utilizing biomarkers to determine what treatments may work best for the individual rather than a blanket approach to treatment. Many of the novel immunotherapies have effects that overlap and are capable of targeting multiple cancers. Nivolumab is an example of an immunotherapy that is being used in the treatment of melanoma, urothelial cancers, and non-small cell lung cancer.17,18 As science advances we will be seeing more people living with late-stage cancer.Although there is currently no cure for late-stage melanoma, treatments are clearly improving survival rates. ■

May 1, 2020. 12. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83(8):1664-1678. 13. Ernstoff M, Puzanov I, Robert C, Diab A, Hersey P. SITC’s Guide to Managing Immunotherapy Toxicity. 1st ed. New York, NY: Demos Medical Publishing; 2019. 14. Taha T, Meiri D, Talhamy S, Wollner M, Peer A, Bar-Sela G. Cannabis impacts tumor response rate to nivolumab in patients with advanced malignancies. Oncologist. 2019:24(4):549-554. 15. Wang Y, Abu-Sbeih H, Mao E, et al. Immune-checkpoint inhibitor-induced

Shannon E.Whitten, MS, NP-C,APRN-BC, is a nurse practitioner at Washington Country Primary Care in Sandersville, Georgia. She manages chronic and acute medical conditions at the outpatient clinic, and she works as a medical provider at the Washington County Sherriff’s Office detention center.

diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer. 2018;6(1):37. 16. Atkins, MB, Kirkwood JM, Wolchok JD, et al. Long-term follow-up of CA209-004: a phase 1 dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma. J Clin Oncol. 2018;36(4):391-398.

References

17. Schummer P, Schilling B, Gesierich A. Long-term outcomes in BRAF-

1. Löffler H, Neben K, Krämer A. Cancer of unknown primary: epidemiology

mutated melanoma treated with combined targeted therapy or immune

and pathogenesis. Radiologe. 2014;54(2):107-111.

checkpoint blockade: are we approaching a true cure [published online

2. Dyrvig AK, Yderstraede K, Gerke O, et al. Cancer of unknown primary:

Mar 2, 2020]? Am J Clin Dermatol. doi:10.1007/s40257-020-00509-z

registered procedures compared with national integrated cancer pathway for

18. Riley RS, June CH, Mitchell MJ. Delivery technologies for cancer

illuminating external validity. Medicine (Baltimore). 2017;96(16):e6693.

immunotherapy. Nat Rev Drug Discov. 2019;18(3):175-196.

22 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

FEATURE: MARY KOSLAP-PETRACO, DNP, PPCNP-BC, CPNP, FAANP

ACIP Releases 2020 Pediatric and Adult Immunization Schedules Updates to the pediatric immunization schedules and significant revisions to the adult schedules reflect the best available evidence for 2020.

Recent measles outbreaks reinforce the benefits of immunizations.

mmunizations are recommended for individuals of all ages, from infants to the elderly. Each year the Advisory Committee on Immunization Practices (ACIP) issues annual updates to the child/adolescent and adult immunization schedules based on the best available evidence.1 The ACIP offers the guidelines necessary to ensure nurse practitioners (NPs) and physician assistants (PAs) use the best available evidence every year to offer the strongest protection against preventable diseases to their patients. In 2020, there has been an increased effort to streamline the information presented and make it more user-friendly. The cover sheet of the pediatric/ adolescent schedule now includes information for reporting vaccine-preventable diseases and a link to the Vaccine Adverse Event Reporting System (VAERS).2 VAERS is now online, and it is easy to report an adverse event following an immunization. If an individual or provider believes that an injury has occurred due to a vaccine, a report to VAERS should be submitted. VAERS is a passive system but has always been very successful in detecting adverse events. For example, the increased risk for intussusception following the first rotavirus vaccine was detected by VAERS.3 The cover sheet also has a link to the complete ACIP recommendations and their General Best Practice Guidelines for Immunizations.The US Centers for Disease Control Prevention (CDC) provides vaccine schedules in the form of a userfriendly app that can be downloaded; this tool

24 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

provides easy access to schedules for the various age groups, as well as footnotes related to the individual vaccines.4 2020 Updates

Pediatrics/Adolescents Catch-up vaccination for Haemophilus influenzae type b (Hib) is not recommended for previously unvaccinated children aged ≥5 years (60 months) unless the children are at high risk. Catch-up vaccination for hepatitis A (Hep A) is recommend for all children and adolescents aged 2 to 18 years who have not previously been vaccinated. The children should complete a 2-dose series, with a minimum interval between doses of 6 months.5 The “special situations” of the hepatitis B (Hep B) vaccine section contains information regarding populations for whom revaccination may be recommended. Those recommendations include infants born to mothers who test positive for hepatitis B virus infection, as well as patients undergoing hemodialysis and other immunocompromised patients.6 Guidance regarding vaccination for children who received the meningococcal conjugate (MenACWY) vaccine prior to age 10 has been added to the MenACWY note. Booster doses of the vaccine should be administered to children with the following conditions: complement component deficiencies (C3, C5-C9, properdin, factor D, and factor H), HIV, and functional or anatomic asplenia (including sickle cell disease), as well as patients taking complement inhibitors (ie, eculizumab, ravulizumab). Booster doses should be administered as follows: • If most recent dose before age 7 years, administer the booster dose 3 years later • If most recent dose at age ≥7 years, administer the booster dose 5 years later • Administer booster doses every 5 years thereafter throughout life or as long as the person remains at increased risk for meningococcal disease7 The recommendations for adolescents has also been amended. For children in whom boosters are not recommended, administer MenACWY according to the recommended adolescent schedule with 1 primary dose at 11 to 12 years of age and 1 booster dose at age 16 years.7 For children who are at high risk for meningococcal disease, the CDC recommends booster doses after completion of the primary series, but the dosing schedules are different for Menveo® and Menactra®. Menveo® can be used for children with anatomic or functional asplenia, HIV infection, and persistent complement component deficiency, as well as those who are taking complement inhibitor. Menactra® can be used for selected conditions, but the dosing schedules are different (Table).7 The serogroup B meningococcal (MenB) vaccination recommendations have been updated to include booster doses in “special situations” and in an outbreak setting. Children aged

≥10 years with persistent complement deficiency, those who use complement inhibitors; persons with asplenia; microbiologists; and those determined by public health officials to be at increased risk during an outbreak should receive MenB vaccine. The first booster dose should be given 1 year after the primary series and repeated every 2 to 3 years as long as the increased risk is present. Booster doses are not recommended for healthy adolescents routinely vaccinated with MenB vaccine.8 A recent study evaluated the efficacy of vaccination with the multicomponent meningococcal group B (4CMenB) vaccine for actual vs expected incidence of the disease in young children. The study concluded that the 4CMenB vaccine had a positive effect against meningococcal group B disease. Protection from the disease lasted ≥2 years after receiving 3 doses.9 In an Australian study, researchers looked at whether the 4CMenB vaccine can build herd immunity in teenagers. The results of the study indicated that the vaccine does not invoke heard immunity, making it even more imperative that children receive the vaccine when they are young.10 Detailed information has been added regarding which oral polio vaccine (OPV) doses may be counted toward the US vaccination requirements. Doses of OPV administered before April 1, 2016, should be counted (unless specifically noted as administered during a campaign). Doses of OPV administered outside the United States on or after April 1, 2016, should not be counted; however, doses of inactivated polio vaccine (IPV) or trivalent OPV (tOPV) are counted. For those vaccinated outside the United States, the total number of doses needed to complete either mixed OPV-IPV or OPV-only series is the same as that recommended by the CDC.11 As part of the World Health Organization’s polio eradication strategy, withdrawal of OPVs began in April 2016 with a switch from tOPV to bivalent OPV.12 TABLE. Recommended MenACWY Vaccination Schedule for High-Risk Children7 Vaccine Brand

Dosing Schedule

Menveo

For all high-risk patients: • Dose 1 at age 8 weeks; 4-dose series at 2, 4, 6, 12 months • Dose 1 at age 7-23 months: 2-dose series (dose 2 ≥12 weeks after dose 1 and after the first birthday) • Dose 1 at age 24 months or older: 2-dose series ≥8 weeks apart

Menactra®

For persistent complement component deficiency or is taking a complement inhibitor: • Age 9-23 months: 2 doses ≥12 weeks apart • Age 24 months or older: 2 doses ≥8 weeks apart For children with anatomic or functional asplenia, sickle cell disease, or HIV infection: • Age 24 months or older: 2 doses ≥8 weeks apart • Vaccine not recommended for children age 9-23 months

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY/AUGUST 2020 25

2020 IMMUNIZATION SCHEDULES

The Tdap (tetanus, diphtheria, pertussis) note has been updated to allow either Td or Tdap for decennial tetanus booster doses and catch-up series doses in persons who have previously received Tdap. Additionally, the note has been edited to reflect recent updates to the clinical guidance for children aged 7 to 18 years who received doses of Tdap or DTaP at age 7 to 10 years. A dose of Tdap or DTaP administered at 10 years of age may now be counted as the adolescent Tdap booster. A dose of Tdap or DTaP administered between 7 and 9 years of age should not be counted as the adolescent dose, and a Tdap booster dose should be administered at 11 to 12 years of age. The DTaP note has been updated to reflect that dose 5 is not necessary if dose 4 was administered at age ≥4 years and at least 6 months after dose 3.5

Mary Koslap-Petraco, DNP, PPCNP-BC, CPNP, FAANP, is an adjunct clinical assistant professor at Stony Brook School of Nursing and a consultant for the Immunization Action Coalition. She is also the owner of Pediatric Nurse Practitioner House Calls. References 1. Centers for Disease Control and Prevention. Advisory Committee on Immu nization Practices (ACIP).Vaccine recommendations and guidelines of the ACIP. https://www.cdc.gov/vaccines/hcp/acip-recs/index.html. Accessed June 25, 2020. 2. Vaccine Adverse Even Reporting System. https://vaers.hhs.gov/. Accessed June 25, 2020. 3. Centers for Disease Control and Prevention. Suspension of rotavirus vaccine after reports of intussusception — United States, 1999. MMWR Morb Mortal Wkly Rep. 1999;48:577-581.

Adults Pneumococcal vaccine recommendations for adults have been updated. One dose of pneumococcal polysaccharide vaccine (PPSV23) is recommended for those aged 19 to 64 years with chronic medical conditions (diabetes or chronic heart [excluding hypertension], lung, or liver disease) or alcoholism, or who are current cigarette smokers. Individuals aged ≥19 years with conditions that compromise the immune system (congenital or acquired immunodeficiency [including B- and T-lymphocyte deficiency, complement deficiencies, phagocytic disorders, or HIV infection], chronic renal failure, nephrotic syndrome, leukemia, lymphoma, Hodgkin disease, generalized malignancy, iatrogenic immunosuppression [eg, drug or radiation therapy], solid organ transplant, multiple myeloma), or anatomical or functional asplenia (including sickle cell disease and other hemoglobinopathies) have a different vaccination schedule.The new schedule includes: • 1 dose PCV13 followed by 1 dose PPSV23 ≥8 weeks later, then another dose PPSV23 ≥5 years after previous PPSV23 • At age ≥65 years, administer 1 dose PPSV23 ≥5 years after most recent PPSV23 (note: only 1 dose PPSV23 is recommended at age ≥65 years) For patients aged ≥19 years with cerebrospinal fluid leak or cochlear implant, the dosing schedule includes: • 1 dose PCV13 followed by 1 dose PPSV23 ≥8 weeks later • At age ≥65 years, administer another dose PPSV23 ≥5 years after PPSV23 (note: only 1 dose PPSV23 is recommended at age ≥65 years)13 Although zoster vaccine was not updated in the 2020 schedule, it is important to note recommendations for this critical vaccine. For individuals aged ≥50 years, a 2-dose series of recombinant zoster vaccine (RZV; Shingrix®) given 2 to 6 months apart is recommended (minimum interval: 4 weeks; repeat dose if administered too soon) regardless of previous herpes zoster or history of live zoster vaccine (ZVL; Zostavax®) vaccination (administer RZV at least 2 months after ZVL).14 Testing for varicella antibody prior to or after giving the vaccine is not recommended.15 ■

4. Centers for Disease Control and Prevention. CDC vaccine schedules app for health care providers. https://www.cdc.gov/vaccines/schedules/hcp/ schedule-app.html. Accessed June 25, 2020. 5. Robinson CL, Bernstein H, Poehling K, Romero JR, Szilagyi P. Advisory Committee on Immunization Practices recommended immunization schedule for children and adolescents aged 18 years or younger — United States, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:130-132. 6. Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infec tion in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67(No. RR-1):1-31. 7. Centers for Disease Control and Prevention. Administering meningococcal vaccines. https://www.cdc.gov/vaccines/vpd/mening/hcp/administering-vaccine. html. July 26, 2019. Accessed June 25, 2020. 8. Immunization Action Coalition. Ask the Experts: Meningitis B vaccine. https://www.immunize.org/askexperts/experts_meningococcal_b.asp. Accessed June 25, 2020. 9. Ladhani SN, Andrews N, Parikh SR, et al.Vaccination of infants with meningo coccal group B vaccine (4CMenB) in England. N Engl J Med. 2020;382(4):309-317. 10. Marshall HS, McMillan M, Koehler AP, et al. Meningococcal B vaccine and menin gococcal carriage in adolescents in Australia. N Engl J Med. 2020;382(4):318-327. 11. Marin M, Patel M, Oberste S, Pallansch MA. Guidance for assessment of polio virus vaccination status and vaccination of children who have received poliovirus vaccine outside the United States. MMWR Morb Mortal Wkly Rep. 2017;66:23-25. 12. World Health Organization. Replacing trivalent OPV with bivalent OPV. https://www.who.int/immunization/diseases/poliomyelitis/endgame_objective2/ oral_polio_vaccine/en/. Accessed June 25, 2020. 13. Freedman MS, Hunter P, Ault K, Kroger A. Advisory Committee on Immuniza tion Practices recommended immunization schedule for adults aged 19 years or older — United States, 2020. MMWR Morb Mortal Wkly Rep. 2020;69:133-135. 14. Centers for Disease Control and Prevention. Immunization Schedules. Recommended adult immunization schedule for ages 19 years or older, United States, 2020. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult. html#note-zoster. February 3, 2020. Accessed June 25, 2020. 15. Immunization Action Coalition. Ask the Experts: Zoster vaccine. https:// www.immunize.org/askexperts/experts_zos.asp#:~:text=No.,or%20after%20 giving%20the%20vaccine. July 11, 2019. Accessed July 25 2020.

26 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

Dermatology Clinic CASE #1

Pigmentary Changes on the Back and Chest ELEANOR JOHNSON, BA;YELENA DOKIC, BSA; CHRISTOPHER RIZK, MD

A 28-year-old Black man presents with a 2-year history of dyspigmentation of his back and chest. The patient notes that the lesions initially had red borders but these have faded over the past several months. Physical examination reveals circular, ashy-gray macules distributed diffusely over his back and chest. The patient denies pain or pruritus and takes no medication. He notes that he recently travelled to Mexico. He has been relatively unconcerned about the lesions and only sought medical care to rule out cancer. What is your diagnosis? Turn to page 28

CASE #2

Hyperpigmented Lesions on Arms SAMANTHA MORGAN, BS; ELEANOR JOHNSON, BA; CHRISTOPHER RIZK, MD

A 45-year-old woman presents with oval-shaped lesions on her arms that she first noted a few months ago. The lesions began as an area of discrete erythema, progressed to induration, and then became dark, smooth, and shiny. She has a family history of rheumatoid arthritis. On examination, the patient has multiple hyperpigmented and hypopigmented indurated plaques with a shiny surface; her nails and fingertips are normal, and autoantibody tests were negative. What is your diagnosis? Turn to page 29 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY/AUGUST 2020 27

Dermatology Clinic CASE #1

Erythema Dyschromicum Perstans

Erythema dyschromicum perstans (EDP) was first presented in 1957 by Ramirez,1 who reported on a large number of patients in El Salvador who developed progressive, ash-colored lesions.2,3 EDP is a rare, chronic disorder of pigmentation that manifests as gray or blue-brown macules in individuals with darker white to brown skin types.2,4 The lesions appear suddenly and first present with erythematous and slightly raised margins that fade over several months.3 The lesion can be a single round or oval macule measuring approximately 3 mm in diameter or it can progress to become large confluent patches that affect the majority of the bodyâ&#x20AC;&#x2122;s skin surface.3,4 The trunk is the area most frequently affected, but symmetric areas of hyperpigmentation can appear on the extremities, neck, and face.2,4,5 The palms of the hands, soles of the feet, and mucous membranes are usually spared.4 Most patients experience no symptoms associated with EDP; however, a minimal number of patients have experienced pruritus.3,5 The etiology of EDP is unknown. It is postulated that an autoimmune response to dermal CD8-positive T lymphocytes and epidermal keratinocyte intracellular adhesion molecules may damage melanocytes and basal cell keratinocytes. Various genetic risk factors have been studied, and human leukocyte antigen (HLA)-DR mutations have been linked to this condition.2 EDP is generally considered an idiopathic disease, although exposure to certain chemicals (cobalt, ammonium nitrate, and dithiazide iodide contrast for radiographs), medical conditions (hypothyroidism), and infections (HIV, chronic hepatitis, and intestinal parasites) have been associated with the development of EDP.3,4 EDP was first described in Latin Americans and is more prevalent in people of Hispanic descent. The typical age of onset is approximately 30 years, but some cases develop in children.3,5 Affected children are usually White and have a more favorable prognosis than their adult counterparts, with approximately 50% achieving remission.4 Evidence is conflicting regarding sexual bias.3 EDP is classified as a macular pigmentation of uncertain etiology along with ashy dermatosis and lichen planus pigmentosus (LPP).6 Whether or not EDP is a separate diagnosis from LPP has been an topic of controversy; however, a global consensus was reached in 2014 that these are separate conditions.4,6 LPP predominantly involves the head and neck; thus, lesions involving the trunk or extremities are more likely to

be EDP. Another key historical feature specific to EDP is the erythematous border associated with its early active phase.6,7 Ashy dermatitis and EDP can be synonymous if there is an unclear history of an erythematous border.6 It is also possible to have multiple disease processes occurring simultaneously. Patients have been reported to have both EDP and LPP. It is also possible to have other autoimmune skin diseases, such as vitiligo, occur concurrently with EDP.4 On histologic examination, LPP and EDP are identical.6 Common findings include epidermal thinning with widening of intracellular spaces, lymphocytic infiltrate in the papillary dermis, presence of dermal melanophages, and vacuolization of basal cells.2,3 Because histology and physical examination cannot be used to distinguish these conditions, history is crucial for determining the correct diagnosis.

EDP is considered idiopathic, although medical conditions, infections, and chemical exposure may increase risk. Other hyperpigmented etiologies often included in the differential diagnosis are fixed-drug eruption, melanoma, Addison disease, melasma, lentigines, macular amyloidosis, and confluent papillomatosis.5,7 Differentiating these diseases from EDP can be achieved via a combination of history and physical, histologic, serologic, and biopsy findings. As current therapies for EDP have minimal benefit, it is reasonable to simply offer reassurance that this is a benign condition.3 If a patient wants to pursue treatment, options include topical creams, oral agents, and laser therapy.5 Topical corticosteroids have been used with some success but have been associated with long-term side effects.8 Oral agents such as antibiotics, vitamins, antihistamines, chloroquine, clofazimine, dapsone, and isotretinoin are thought to work because of their anti-inflammatory agents, but they have been shown to have unreliable efficacy.5 Symptoms often recur once medications are stopped, so patients may need life-long treatment, which again comes with potential side effects.5 The patient in this case was given the diagnosis of EDP and educated on the benign nature of the condition. He elected not to undergo any treatment as the lesions did not bother him cosmetically. Eleanor Johnson, BA, and Yelena Dokic, BSA, are both medical students at Baylor College of Medicine. Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston,Texas.

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References 1. Ramirez CO. Los cenicientos: problema clinico, Presented at: Proceedings of the First Central American Congress of Dermatology; San Salvador, El Salvador; December 5-8, 1957. 2. Leung N, Oliveira M, Selim MA, McKinley-Grant L, Lesesky E. Erythema dyschromicum perstans: a case report and systematic review of histologic presentation and treatment. Int J Womens Detmatol. 2018;4(4): 216-222. 3. Torrelo A, Zaballos P, Colmenero I, Mediero IG, De Prada I, Zambrano A. Erythema dyschromicum perstans in children: a report of 14 cases. J Eur Acad Dermatol Venereol. 2005;19(4):422-426. 4. Tamer F. Coexistence of erythema dyschromicum perstans and vitiligo: a case report and review of the literature. Acta Dermatovenerol Alp Pannonica Adriat. 2016;25(4):77-78. 5. Wang F, Zhao YK, Wang Z, Liu JH, Luo DQ. Erythema dyschromicum perstans response to isotretinoin. JAMA Dermatol.152(7):841-842. 6. Kumarasinghe SPW, Pandya A, Chandran V, et al. A global consensus statement on ashy dermatosis, erythema dyschromicum perstans, lichen planus pigmentosus, idiopathic eruptive macular pigmentation, and Riehl’s melanosis. Int J Dermatol. 2019;58(3):263-272. 7. Chandran V, Kumarasinghe SP. Macular pigmentation of uncertain aetiology revisited: two case reports and a proposed algorithm for clinical classification. Australas J Dermatol. 2017;58(1):45-49. 8. Mahajan V, Chauhan P, Mehta K, Sharma A. Erythema dyschromicum perstans: response to topical tacrolimus Indian J Dermatol. 2015;60(5):525.

CASE #2

Morphea

Morphea, also known as localized scleroderma, refers to a broad spectrum of sclerotic skin diseases. The clinical presentation varies from mild asymptomatic sclerotic lesions to severe sclerosis involving muscles and joints that carries the risk of physical impairment.1-3 The annual incidence of morphea in the United States is 2.7 per 100,000.1 White women are most commonly affected.1,2 This condition has a bimodal population distribution, affecting both children and adults. The peak incidence of onset for pediatric patients is between 7 and 11 years of age; the peak age of onset in adults is between 44 and 47 years.2,3 Pediatric patients have a higher frequency of deep tissue involvement and a longer disease duration, leading to a higher morbidity.1

Although the pathogenesis of morphea is still being studied, it is thought that the disease results from vascular dysfunction, immune dysregulation, and extensive extracellular matrix formation.2 Susceptibility mechanisms (genetics and autoimmunity) and external stimuli (vaccination and friction) are thought to play a role in disease development.2,4 The likely pathogenesis involves a triggering event in a susceptible individual followed by recruitment of keratinocytes and fibroblasts, activation of epidermal-dermal signaling pathways, and increased immunoinflammation.4 Approximately 10% to 30% of patients with morphea have a positive family history of autoimmune disease.1 Therefore, it is theorized that there may be a genetic component to this condition. Epigenetic and genetic markers for morphea are currently under investigation.1,5 A study of 329 patients revealed that 16% developed lesions at surgical sites, injection sites, or penetrating trauma sites, suggesting that skin trauma may also be associated with the development of morphea.6 Morphea has also been reported as a rare side effect of radiation therapy or treatment with tumor necrosis factor-α inhibitors.2,7 Classification of morphea is based on the pattern and depth of lesions and includes circumscribed morphea, linear morphea, generalized morphea, pansclerotic morphea, and mixed morphea.2,8 Other classification schemes include eosinophilic fasciitis within the morphea spectrum.2 • Circumscribed morphea is further divided into superficial and deep morphea. Circumscribed superficial morphea, characterized by plaques limited to the dermis of the trunk, waist, and submammary region, is the most common subtype in adults and presents with local discomfort and disfigurement.2,8 Circumscribed deep morphea may extend into subcutaneous tissue, is often located symmetrically in the lower extremities, and has the potential to cause contractures and tissue atrophy.8 • Linear morphea is characterized by unilateral, deep, bandlike cutaneous sclerosis and is the most common subtype in childhood-onset morphea.2,8 Limb-length differences and subcutaneous atrophy can occur. • Generalized morphea is more common in adults than children and is characterized by large superficial plaques that spare the hands, face, and feet.8 • Pansclerotic morphea affects the skin, subcutaneous tissue, muscle, and bone.The lesion may also involve other areas of the body without internal organ involvement.2 • Mixed morphea is a combination of at least 2 subtypes. In the literature, the order of the concomitant subtypes, specified in brackets, will follow their predominant representation in the individual patient (ie, mixed morphea [linear-circumscribed]).2

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Dermatology Clinic • Eosinophilic fasciitis is characterized by symmetric deep sclerosis of the extremities after the development of pitting edema and erythema; systemic symptoms of weight loss and myalgia may often be present.2 Lesions have an early inflammatory stage followed by a sclerosing stage, then an atrophic stage. During the early stage, lesions are erythematous but as they progress they may develop a purple ring (“lilac ring”) around the fibrotic center.5 Morphea most commonly affects the chest and abdomen.6 Recurrences occur in approximately 20% to 40% of patients and are associated with early disease onset, linear distribution subtype, and initial sclerosis involving muscle and cartilage.9 Histologically, morphea is characterized by an infiltrate of lymphocytes and plasma cells in a perivascular and perieccrine distribution.2 Sclerotic skin demonstrates thick and homogeneous collagen bundles at varying levels of the dermis.2 Morphea may be further characterized by sclerosis pattern (confined to papillary dermis, reticular dermis, subcutis, or throughout), degree and location of inflammation, and which cell type is present.2 Early lesions may be mistaken for lichen sclerosis, erythema migrans, post-inflammatory hyperpigmentation, lipodystrophy, and scarring.5 Systemic sclerosis, pseudoscleroderma,

therapy for limited skin lesions includes topical corticosteroids, topical calcipotriol, and/or ultraviolet A1 phototherapy.2,5 Topical therapies are often sufficient for superficial lesions due to the high rate of spontaneous remission in 3 to 5 years.8 Systemic therapies, such as methotrexate and/or systemic corticosteroids, are used in forms of morphea with extensive skin involvement or those affecting adipose tissue, joints, fascia, and muscle.5,8 Long-term use of oral systemic corticosteroids alone is not indicated due to high recurrence rates.2 Based on clinical features and pathologic examination, the patient in this case was diagnosed with circumscribed superficial morphea. She was prescribed a high-potency topical corticosteroid to be applied once a day for 4 weeks. Mild improvement was noted at 1-month follow-up. She continued to be followed in the clinic and showed gradual improvement over several years. ■ Samantha Morgan, BS, and Eleanor Johnson, BA, are medical students at Baylor College of Medicine. Christopher Rizk, MD, is a dermatologist affiliated with Elite Dermatology in Houston,Texas. References 1. Torok KS, Li SC, Jacobe HM, et al. Immunopathogenesis of pediatric localized scleroderma. Front Immunol. 2019;10:908-908.

Morphea is thought to result in vascular dysfunction, immune dysregulation, and extensive extracellular matrix formation.

2. Mertens JS, Seyger MMB, Thurlings RM, Radstake TRDJ, de Jong EMGJ. Morphea and eosinophilic fasciitis: an update. Am J Clin Dermatol. 2017;18(4):491-512. 3. Mertens JS, Seyger MMB, Kievit W, et al. Disease recurrence in localized scleroderma: a retrospective analysis of 344 patients with paediatric‐ or adult‐onset disease. Br J Dermatol. 2015;172(3):722-728. 4. Saracino AM, Denton CP, Orteu CH. The molecular pathogenesis

and mixed connective tissue disease are included in the differential diagnosis of generalized morphea.5 Morphea can be differentiated from systemic sclerosis through the absence of Raynaud phenomenon, gastrointestinal problems, sclerodactyly, and nailfold capillary changes.2 The diagnosis of morphea is largely based on clinical findings.The Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) may be helpful in diagnosing and monitoring the disease in adults and children.2,5 There are no serologic markers specific for morphea; therefore, antibody screening is only indicated in cases of unclear presentation or to confirm or rule out systemic sclerosis.2,5 Eosinophilic fasciitis is the exception to this, as routine testing of absolute eosinophil count and inflammatory markers is recommended in the initial phase of the disease and for the detection of disease reactivation.2 When choosing a treatment, it is important to consider disease activity, depth of involvement, and side effects. Standard

of morphoea: from genetics to future treatment targets. Br J Dermatol. 2017;177(1):34-46. 5. Kreuter A, Krieg T, Worm M, et al. German guidelines for the diagnosis and therapy of localized scleroderma. J Dtsch Dermatol Ges. 2011;14(2):199-216. 6. Grabell D, Hsieh C, Andrew R, et al. The role of skin trauma in the distribution of morphea lesions: a cross-sectional survey of the Morphea in Adults and Children Cohort IV. J Am Acad Dermatol. 2014;71(3):493-498. 7. Trivedi A, DeWitt CM, McGevna L. Radiation-induced circumscribed superficial morphea after brachytherapy for endometrial adenocarcinoma. Int J Womens Dermatol. 2017;3(4):234-236. 8. Martini G, Fadanelli G, Agazzi A, Vittadello F, Meneghel A, Zulian F. Disease course and long-term outcome of juvenile localized scleroderma: experience from a single pediatric rheumatology centre and literature review. Autoimmun Rev. 2018;17(7):727-734. 9. Litaiem N, Bacha T, Drissi H, Zeglaoui F. An evaluation of long‐term outcomes and recurrence rates in patients with morphea. Int J Dermatol. 2019;58(4):E90-E92.

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Dermatologic Look-Alikes Firm Lesions on the Face CYNTHIA TRUONG, BS; YELENA DOKIC, BSA; CHRISTOPHER RIZK, MD

CASE #1

CASE #2

A 65-year-old, fair-skinned man presents to the dermatology clinic for evaluation of a 1-cm pearly, pink papule on his right cheek that first appeared approximately 1 year ago.The patient reports that the lesion has gradually been increasing in size and is firm, nonpainful, and nonpruritic. On examination, areas in the papule are identified that contain thin blood vessels arranged radially around a central blood vessel.The patient is taking metformin for diabetes and lisinopril for hypertension. He has a 10-pack-per-year history of cigarette smoking. He is a retired construction worker.

A 62-year-old man presents to the dermatology clinic for evaluation of multiple 1-cm pink macular lesions on his face, cheek, and forehead. He first noticed a small red spot on his cheek approximately 1 year ago, when it started slowly growing.The patient reports that the lesion is nonpainful and nonpruitic. Other than the lesions of his face, he is relatively healthy. He reports no recent history of fever, fatigue, or weight loss. He does not use any moisturizers or topical creams nor has he used topical treatments for the lesions. He is not taking any medications.

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Dermatologic Look-Alikes CASE #1

Basal Cell Carcinoma

Basal cell carcinoma (BCC), the most commonly diagnosed skin cancer, arises from the basal epidermis of the skin.1 The absolute number of cases of BCC remains challenging to ascertain since nonmelanoma skin cancers are usually excluded from cancer registry statistics. However, the American Cancer Society estimated that in 2012, 5.4 million cases of nonmelanoma skin cancer were diagnosed in 3.3 million people, and of those cases, 80% were BCC.1 BCC is most often diagnosed in White adults and is less common in darker-skinned populations.2,3 The incidence of BCC increases with age and is 2-fold higher in older men than women.3 Sun exposure is the most important environmental risk factor for BCC.4 The timing, pattern, and intensity of ultraviolet (UV) radiation are all important modulators of risk. Recreational exposure to sunlight, especially in childhood or adolescence, and intense intermittent sun exposure are associated with a higher risk of BCC, while average annual cumulative sunlight exposure appears not to increase risk.4 Other risk factors for BCC include red or blond hair, fair complexion, and light eye color.1,4,5 Pharmacologic agents, such as psoralen with ultraviolet A (PUVA) therapy, significantly increase the risk of squamous cell carcinoma (SCC) but only moderately increase the risk of BCC.5,6 The use of photosensitizing medications such as tetracyclines increases vulnerability of the skin to UV radiation and thus has been implicated in risk of developing BCC.4 The use of tanning beds, particularly early in life, is associated with an increase in risk of all forms of nonmelanoma skin cancer.4,7 Exposure to ionizing radiation and arsenic, as well as immunosuppression, especially in the context of organ transplantation, are also linked to the development of BCC.5 Once a patient develops BCC, the risk of a subsequent BCC increases 10-fold.5 Activation of the hedgehog signaling pathway is present in both sporadic and genetic cases of BCC.8 Secreted sonic hedgehog protein inhibits the patched homolog 1 protein (PTCH1), halting its suppressive effects on intracellular signaling, such as its suppression of smoothened signaling.8 For example, loss of function of PTCH1 has been identified in sporadic BCC, while germline mutations in human patched 1 gene (PTCH1) are seen in Gorlin syndrome.9,10 Additionally, mutations in tumor-suppressor gene TP53 are found in approximately 50% of sporadic BCC cases.8

BCC is generally seen on areas of the skin most exposed to sun, such as the head and neck (80%), trunk (15%), and arms and legs (5%).11 BCC is classified into 3 forms: nodular, superficial, and morpheaform. • Nodular BCC is the most common and presents as a pearly papule or nodule with arborizing telangiectasias and a rolled border, at times with central ulceration.8 • Superficial BCC presents as a well-circumscribed, scaly, erythematous patch or plaque.12 The edge of these lesions may display a thin, rolled border with crusting or fine translucent small papules. Both nodular and superficial BCC can contain melanin, imparting brown, blue, or black color to these lesions. • Morpheaform BCC (also known as sclerosing, fibrosing, or infiltrative BCC) typically appears as an indurated, whitish, scar-like plaque with indistinct margins.8 On histopathologic examination, all subtypes of BCC display aggregations of basaloid keratinocytes, often with peripheral palisading, extending from epidermis to dermis. Histopathology can distinguish more indolent BCC subtypes (nodular and superficial) from more aggressive ones (morpheaform).8

Once a patient develops basal cell carcinoma (BCC), the risk of developing a subsequent BCC increases 10-fold. The differential diagnosis for BCC ranges from benign conditions such as sebaceous hyperplasia, keratoacanthoma, inflammatory dermatoses, molluscum contagiosum, intradermal melanocytic nevus, and fibrous papule of the nose, to malignancies such as SCC, cutaneous B-cell lymphoma, melanoma, and Merkel cell carcinoma.13 The diagnosis of BCC can be made by an experienced clinician on visual inspection or by dermoscopy.8 Several characteristics can distinguish benign growths from BCC. Sebaceous hyperplasia, for example, can be differentiated from BCC by its yellowish coloration and central pore.14 Keratoacanthoma, unlike BCC, usually presents with a central keratin plug.15 Dermatitis or psoriasis generally respond to the application of topical steroids, while BCC will not.14 A pigmented BCC can be differentiated from malignant melanoma by the presence of a pearly, rolled border; however, any lesion with atypical characteristics such as melanin production must undergo biopsy. On histologic examination, melanoma will display large atypical melanocytes invading the epidermis and dermis.14

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BCC can be pathologically distinguished from cutaneous B-cell lymphoma by the presence of basaloid aggregates that are connected to the epidermis, while B-cell lymphoma always spares the epidermis.14 Immunohistochemistry will reveal positivity for markers such as CD20, CD79a, CD10, or BCL6 in B-cell lymphoma, but not BCC.16 SCC also presents on sun-exposed sites of skin; however, in contrast with BCC, SCC is usually a flaky, red, sometimes pruritic plaque or nodule.14 On histologic examination, SCC often displays keratin pearls, while BCC does not.14 Prognosis is very good for BCC lesions as they rarely metastasize. Thus, the goal of treatment is to remove the lesion entirely and maximally preserve function and cosmesis.14 Lower-risk BCCs are often managed with electrodesiccation and curettage or surgical excision.17 Lower-risk BCCs less commonly can be treated with topical 5-fluorouracil or imiquimod, cryotherapy, or photodynamic therapy.17 Mohs surgery provides the highest cure rate and is the treatment of choice when a lesion is designated to be at high risk for recurrence and when anatomy and function need to be preserved.14 More recently, hedgehog pathway inhibitors, such as vismodegib, have been indicated in the treatment of locally advanced, multiple, or metastatic BCC.14 Because of the uncomplicated location and small size of the lesion in this case, the patient underwent excisional biopsy. Histopathology showed aggregates of basophilic, basaloid cells with peripheral palisading extending from the epidermis to the dermis, confirming a diagnosis of nodular BCC. The patient chose to undergo Mohs surgery to ensure clear surgical margins with little cosmetic disturbance.

CASE #2

Primary Cutaneous B-Cell Lymphoma

B-cell lymphomas are a class of lymphoproliferative disorders that can originate in the lymph nodes, skin, or gastrointestinal tract. One form of nonHodgkin B-cell lymphoma is primary cutaneous B-cell lymphoma (PCBCL), a rare subclass that originates in the skin.18 Though its incidence is on the rise, PCBCL is currently estimated to comprise 20% to 25% of all cutaneous lymphomas.19 PCBCL can be divided into 3 general subclasses: primary cutaneous follicle center lymphoma (CFCL), primary cutaneous marginal zone lymphoma (CMZL),

and primary cutaneous diffuse large B-cell lymphoma of the leg (LBCL-L). In general, PCBCL occurs most frequently in White men and adults >50 years of age. CFCL and CMZL are often seen in middle-aged men, while LBCL-L is more often seen in elderly women.19 CFCL is the most common subtype of PCBCL.19 It grows slowly over months to years and is found as a nonpainful, nonpruritic solitary lesion or cluster of several nodular lesions on the head or trunk.19 CFCLs are slightly raised and smooth, appear pink or reddish, and usually do not ulcerate. CFCL is thought to arise from B cells in mature germinal centers.20

The differential diagnosis of PCBCL includes arthropod bites, basal cell carcinoma, and other cutaneous lymphomas. Almost all cases CFCL express B-cell markers CD19, CD20, and CD79a, and most cases express B-cell lymphoma (BCL)6 but not BCL-2.20 CMZL is the second most common subtype of PCBCL. It is similar to MALT (mucosa-associated lymphoid tissue) lymphoma and also presents as pink or red papules, nodules, and/or tumors.16 CMZL is also slow-growing and can be found anywhere on the body. LBCL-L is the least common, most aggressive subtype of PCBCL.19 These tumors most often appear on one or both of the lower legs of elderly women; however, 10% to 15% of these tumors involve sites other than the legs and, unlike other forms of PCBCL, extracutaneous dissemination is common.21 LBCL-L presents as red or bluish-red lesions that can grow quickly and ulcerate. LBCL-L often shows translocations in the MYC, BCL6, and IgH genes, and in contrast to CFCL, LBCL-L expresses BCL-2.16 When PCBCL is confined to the skin, the prognosis is very favorable, with an estimated 5-year survival rate of 95%.22 The exception is LBCL-L, which has a 5-year survival rate of approximately 70%.19 The rate of recurrence of PCBCL is approximately 50%; however, this disease rarely develops into a systemic lymphoma.22 There are no known risk factors or identifiable hereditary tendency for the development of PCBCL. The differential diagnosis of PCBCL includes arthropod bites, basal cell carcinoma, and other cutaneous lymphomas. PCBCL should be suspected in a patient who presents with a suspicious skin lesion without signs of systemic lymphoma. A biopsy is required to evaluate the growth

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Dermatologic Look-Alikes Basal Cell Carcinoma (BCC)1-17

Cutaneous B-Cell Lymphoma16,18-26

Dermatologic Presentation

• Nodular: pearly papule(s) with rolled border and overlying telangiectasias, sometimes with central depression or ulcer; can be pigmented • Superficial: red, scaling, crusted eczematous-appearing patch • Morpheaform: whitish, scar-like, slightly depressed patch or plaque

• Follicular and marginal zone types: pink, raised, smooth papules that rarely ulcerate • Leg type: red or bluish-red papules or plaques that can ulcerate

Associations

• Fair skin, difficulty tanning, significant history of sun exposure • Multiple BCCs are associated with Gorlin syndrome

• Slow growing, nonpainful, nonpruritic solitary lesion

Etiology

• Ultraviolet radiation, arsenic ingestion, genetic predisposition, exposure to x-ray radiation • Mutations in smoothened or patched genes in the hedgehog pathway

• Clonal B-cell proliferation, derived from mature germinal centers

Location

• Sun-exposed areas (head, trunk, arms, legs)

• Follicular and marginal zone types: head or trunk • Lower leg

Histology

• Uniform basophilic basaloid cells with large nucleus and scant cytoplasm • Extends from epidermis to dermis • Peripheral palisading in nodular BCC

• Dense, dermal, hyperchromatic lymphoid infiltrate • Positive immunostaining for B-cell markers and BCL-6 or BCL-2

Diagnosis

• History and physical examination • Shave or punch biopsy

• History and physical examination • Excisional or punch biopsy

Treatment

• Surgical excision or Mohs • Electrodessication and curettage • Radiotherapy • Cryotherapy • Topical 5-fluorouracil or imiquimod

• Local radiation • Chemotherapy • Rituximab

pattern, morphology, and immunohistochemistry of the lesion.21 Excisional biopsy is preferred to punch biopsy in most cases.21 Pathologic examination confirming PCBCL usually displays a B-cell infiltrate that spares the epidermis, with a follicular or diffuse pattern comprising centrocytes and centroblasts.21 Immunohistochemistry will display panB-cell markers (CD19, CD20, and CD79a).21,23 Inflammation with follicular hyperplasia that can occur in infection or arthropod bites may mimic PCBCL.24 The follicles in PCBCL, however, are more ill-defined and lack tingible body macrophages. Immunostaining for proliferation (Ki67) will show a smaller percentage of Ki67-positive cells in PCBCL than in an infection, and PCBCL will demonstrate a homogeneous region of BCL-6-positive or BCL-2-positive B cells.24 Basal cell carcinoma (BCC) is a neoplasm that may mimic PCBCL. Both BCC and PCBCL may present as shiny, smooth, raised lesions on the head or trunk. On histopathologic examination, however, BCC will contain a mass of

basophilic basaloid keratinocytes that have a connection to the epidermis.20 In contrast, PCBCL will contain follicles or sheets of B cells that exclude the epidermis. Additionally, on histology, BCCs may exhibit peripheral palisading, and this is not seen in PCBCL. It is particularly important to distinguish PCBCL from systemic follicular lymphoma. Non-Hodgkin lymphomas can present in the skin either primarily or as a result of dissemination from systemic disease.25 On biopsy, the follicular centers of both tumors may resemble each other and will both stain for CD19, CD20, and BCL-6 or BCL-2 and will be negative for the T-cell markers CD5 or CD3.25 Clinically, patients with systemic lymphoma usually have fever, fatigue, and weight loss, while patients with PCBCL generally present without these symptoms.18 Additionally, the t(14;18) chromosomal translocation found in most systemic follicular lymphomas is not seen in PCBCL.25 T-cell lymphomas of the skin can be distinguished from PCBCL through the expression of T-cell markers CD5 and CD3.20

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Because CFCL and CMZL are slow-growing, indolent lymphomas, they can often be treated with local radiation targeted to the lesion(s) or surgical excision.26 Topical or injected chemotherapy may also be used.26 Rituximab, a monoclonal anti-CD20 antibody, can be used in the management of extensive indolent PCBCL.26 Multi-agent chemotherapy, radiation, and rituximab in combination may be used in the treatment of LBCL-L.26 Patients with LBCL-L should also undergo positron emission tomographic (PET) imaging to evaluate for extracutaneous dissemination. The patient in this case underwent biopsy, and pathologic examination revealed a dense, homogeneous follicle of lymphocytes confined to the dermis. Immunohistochemistry showed the presence of pan-B cell markers (CD19, CD20, and CD79a) and positive BCL-6 but negative BCL-2 staining. Fluorescence in situ hybridization for t(14;18) was negative. No extracutaneous disease was identified on PET imaging, confirming a diagnosis of CFCL.The patient underwent local radiation therapy, with complete remission of the disease. ■

10. Kim MY, Park HJ, Baek SC, Byun DG, Houh D. Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias. J Dermatol Sci. 2002;29(1):1-9. 11. Rubin AI, Chen EH, Ratner D. Basal-cell carcinoma. N Engl J Med. 2005;353(21):2262-2269. 12. McCormack CJ, Kelly JW, Dorevitch AP. Differences in age and body site distribution of the histological subtypes of basal cell carcinoma: a possible indicator of differing causes. Arch Dermatol. 2007;133(5):593-596. 13. Sariya D, Ruth K, Adams-McDonnell R, et al. Clinicopathologic correlation of cutaneous metastases: experience from a cancer center. Arch Dermatol. 2007;143(5):613-620. 14. Marks J, Miller J. Lookingbill and Marks’ Principles of Dermatology. 6th ed. Elsevier Health Sciences; 2018:42-44. 15. Markowitz O, Utz S. Differentiating early stage cystic keratoacanthoma, nodular basal cell carcinoma, and excoriated acne vulgaris by clinical exam, dermoscopy, and optical coherence tomography: a report of 3 cases. J Clin Aesthet Dermatol. 2015;8(4):48-50. 16. Willemze R, Kerl H, Sterry W, et al. EORTC classification for primary cutaneous lymphomas: a proposal from the Cutaneous Lymphoma Study Group of the European Organization for Research and Treatment of Cancer.

Cynthia Truong, BS, andYelena Dokic, BSA, are medical students at Baylor College of Medicine, and Christopher Rizk, MD, is a certified dermatologist at Elite Dermatology in Houston,Texas.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY/AUGUST 2020 35

LEGAL ADVISOR CASE

Outbreak of Scabies Tied to Lawsuit A nurse’s investigation of the source of a scabies outbreak leads to her dismissal. BY ANN W. LATNER, JD

Ms D had worked as an oncology nurse in the cancer unit of a local hospital for almost 10 years, and she cared for medical and surgical patients as well as cancer patients. In mid-December, Ms D developed an itchy rash. A few weeks later, she learned that several other nurses working on the oncology floor had developed similar rashes. Ms D began to suspect that the rashes were caused by a patient in the oncology unit who had been treated in November.The patient, Mrs S, was bedridden and experienced multiple health issues including a thick, itchy rash that covered her body. In mid-January, Ms D reported to employee health services that she and at least 1 other hospital employee had rashes that she believed to be caused by scabies. Ms D was directed to Ms J, the hospital’s director of infection prevention and control. She told the director that she and another employee had been experiencing a rash for several weeks and that she believed they had contracted the rash from the former patient, Mrs S. Ms D was told that she should have reported her concerns sooner.“Rashes are supposed to be reported immediately,” stated Ms J. She instructed

The desire to track down the source of a cutaneous infection causes a nurse to break hospital privacy rules.

the nurse to see a dermatologist. Ms J reviewed the chart of the former patient with the hospital’s chief medical officer, who was an infectious disease specialist, and they concluded that the former patient was not the source of the rash. The next day, Ms D called employee health services to inform them that she had consulted with a dermatologist and was diagnosed with scabies. Upon hearing this, Ms J notified the county health department of a scabies outbreak in the hospital. She also prepared and distributed a memorandum to hospital employees and volunteers about the symptoms and management of the condition. Ms D remained concerned that the former patient was the source of her infection despite disagreement from hospital administration following an internal investigation. During Ms D’s examination by the dermatologist, the physician noted that people

40 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

Continues on page 42

Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

LEGAL ADVISOR with a weakened immune system may develop scabies in a more severe, highly contagious form. He showed Ms D a picture of the condition, and it closely resembled the rash she had seen on Mrs S. Ms D decided to visit Mrs S at a skilled nursing facility where the patient had been discharged to determine if she had been treated for scabies.The patient was confused and did not recognize the nurse. The patient did not speak English, but Ms D was able to converse with her in Spanish. The following day, Ms D called Ms J to tell her that she had visited the former patient to find out if she was being treated for scabies. Ms J informed Ms D that by visiting the patient, she may have violated the patient’s privacy and that her actions were completely inappropriate. Ms J notified the hospital’s privacy director and the hospital began an investigation. In the meantime, Ms D called the county health department to report the scabies outbreak although it had already been reported by the hospital.

The hospital claimed the firing was due to a privacy violation, while the nurse held it was in retaliation for reporting the outbreak. The hospital investigated Ms D’s visit to the skilled nursing facility. Through a translator, the patient reported that Ms D looked familiar, but she did not know who she was.The patient reported that Ms D had asked whether she had been treated for scabies, as some of the nurses at the hospital had been treated for the rash and they wanted to make sure that the patient was treated.The patient was upset and worried that she had made someone ill. After several investigatory hearings and a call to the hospital’s lawyer, the hospital administration concluded that Ms D had violated hospital privacy policy and HIPAA by improperly disclosing protected health information in a non-job function. After several internal hearings and appeals, Ms D was fired. Ms D hired an attorney and sued the hospital, claiming that she was fired in retaliation for reporting the outbreak.The hospital made a motion for summary judgment, asking that the case be dismissed. The lower court granted the hospital’s motion and dismissed the case. Ms D appealed.

A summary judgment motion is granted only if there are no material issues of fact in dispute, and instead the issue is one of law. The appeals court noted that the hospital had reported the outbreak to health authorities first; therefore, Ms D was not a whistleblower and could not have been fired in retaliation for reporting the outbreak. In addition, the other employees who reported the rash were not terminated. The sole reason for Ms D’s termination, agreed the court, was her violation of the hospital’s privacy policies. The appeals court agreed with the lower court and dismissed Ms D’s case against the hospital. Protecting Yourself

It is worth noting that Ms D did not access medical records or use protected health information to locate the patient.This was confirmed by the hospital during its investigation. Instead, Ms D’s familiarity with the patient’s condition and family circumstances allowed her to deduce that she may have been released to a nearby skilled nursing facility. Ms D then went to the facility as a visitor and asked for the patient by name. The court held, however, that Ms D admittedly acted outside the scope of her work when she went to visit the patient, violating the hospital’s privacy policies. The hospital was in its right to terminate her employment, noted the court, and Ms D had not made a convincing argument that she was fired in retaliation for anything other than violating hospital privacy policy. This case illustrates the importance of knowing the privacy policy of your employer. A person can be fired for a violation of their employer’s policies, even if it is not a HIPAA violation. Ms D’s stated concerns for the patient did not outweigh her responsibility to her employer. ■ Ann W. Latner, JD, a former criminal defense attorney, is a freelance medical writer in Port Washington, New York.

Legal Background

On appeal, Ms D’s attorney contended that there were triable issues of fact concerning the hospital’s retaliatory intent or animus in terminating Ms D’s employment. The hospital maintained that Ms D’s termination was not because of her reporting the outbreak but because she violated hospital policies and HIPAA by going to a skilled nursing facility to check on a discharged former patient. 42 THE CLINICAL ADVISOR • JULY/AUGUST 2020 • www.ClinicalAdvisor.com

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