Clinical Advisor November/December 2022

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A PEER-REVIEWED FORUM FOR NURSE PRACTITIONERS | NOVEMBER/DECEMBER 2022 | FEATURE Arrhythmogenic Right Ventricular Cardiomyopathy: a Case of Mistaken Identity LEGAL ADVISOR Suicide: Are You Liable? CASE Breast Cancer Update: a Diagnosis That Extends Beyond the Patient DERMATOLOGIC LOOK-ALIKES Erythematous Indurated Plaques CARDIOLOGY: ENDOCARDITIS Blood Culture-Negative Endocarditis: Individualized Diagnosis, Management In hospitalized patients,
the mortality rate of endocarditis is approximately 10%.



Nikki Kean

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Yes ICAN Act

The battle over the Improving Care and Access to Nurses (ICAN) Act is heating up. The American Medical Association (AMA) is bombarding the media with press releases over the “dangers” of allowing nonphysicians to treat patients.

“We are deeply concerned that this broad, sweeping bill endangers the care of Medicare and Medicaid patients by expanding the types of services nonphysician practitioners [NPPs] can perform and removing physician involvement in patient care,” the AMA and national specialty and state medical associations said in a letter to leaders in the House of Representatives. It argued that the legislation would allow nurse practitioners (NPs), PAs, and advanced practice registered nurses (APRNs) “to perform tasks and services outside their education and training and could result in increased utilization of services, increased costs, and lower quality of care for our patients.”

The ICAN Act (HR 8812), sponsored by Rep Lucille Roybal-Allard (D-CA) and Rep Dave Joyce (R-OH), would improve health care access for Medicare and Medicaid beneficiaries by removing barriers to practice for NPs, PAs, and other APRNs such as certified nurse midwives, certified registered nurse anesthetists, and clinical nurse specialists, noted the American Association of Nurse Practitioners (AANP). The AANP is urging members to write members of Congress in support of the bill.

The COVID-19 epidemic revealed weaknesses in the medical workforce including high rates of burnout and early retirement as well as physician shortages, particularly in rural areas. The pandemic “proved that when nurses are allowed to practice to the fullest extent of their education and training, access to care increases and patient choice is strengthened. Our laws should reflect this reality,” said Congressman Joyce, co-chair of the Congressional Nursing Caucus.

Allowing NPs and PAs to practice to the full extent of their education and training would address many of these shortfalls and ultimately improve patient outcomes. Write your representatives, and let your voices be heard. • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 1
Copyright © 2022
© FATCAMERA / GETTY IMAGES Follow us on Twitter @ClinicalAdvisor Like us on Facebook Visit us on the web MORE WAYS TO FIND US! Download the app 8 Strong family history of heart disease 25 Rash may be signal of systemic disease 4 Hip pain in a young child FEATURES 8 Arrhythmogenic Right Ventricular Cardiomyopathy: a Case of Mistaken Identity Clinicians should have a high index of suspicion for ARVC in patients with unexplained sudden cardiac arrest, syncope, or arrhythmia and a strong family history of similar events. 15 Blood Culture-Negative Endocarditis: Individualized Diagnosis, Management Primary care providers are on the frontline in the prompt identification of potential blood culture-negative endocarditis cases. 30 Breast Cancer Update: a Diagnosis That Extends Beyond the Patient A case in which genetic testing for breast cancer may have affected the outcome in a 35-year-old woman. DEPARTMENTS 1 From the Director Yes ICAN Act 4 Web Roundup A summary of our most recent opinion, news, and multimedia content from 25 Dermatologic Look-Alikes Erythematous Indurated Plaques 35 Legal Advisor Next of kin brings suit after man with severe depression kills his family and himself. CONTENTS N OV E M B E R / D E C E M B E R 2 0 2 2 35 Suicide: Are You Liable?



High-Dose Superior to


Brady Pregerson, MD

Standard-Dose In

uenza Vaccination in Older Adults

High-dose vaccination was found more e ective than the standard dose in preventing in uenza, emergency visits, and hospital admissions, according to results presented at IDWeek 2022.

CDC Releases Updated Guidance on Prescribing Opioid Pain Medication

The 2022 CDC Clinical Practice Guideline is an update of the 2016 guidelines and is intended to help clinicians weigh the bene ts and risks of opioids and alternative pain treatments for outpatients.

Could Arti cial Sweeteners Increase the Risk for Cardiovascular Disease?

Higher consumption of arti cial sweeteners is associated with an increased risk for cardiovascular events, stated ndings published in the British Medical Journal

PMH-NPs Ready to Fill Gaps in Mental Health Care

Psychiatric-mental health nurses and NPs are ready to ll the gap in mental health care but need funding, advocacy, and more students entering the eld, according to a report presented at APNA 2022.

HepB-CpG Vaccination Achieves Max Seroprotection in

Patients With HIV

Three doses of HepB-CpG vaccine was found to achieve a 100% seroprotection rate among patients with HIV infection.


Violaceous Rash

A man in his mid-60s with a history of gout presents to the emergency department with a 2- to 3-week history of a gradually worsening rash on both lower legs. The patient denies fever or pain but reports the rash sometimes feels slightly itchy. Can you make the diagnosis? See the full case at: case_november_december22

Kristin Della Volpe

PA Job Satisfaction Ranked by Specialty

Overall job satisfaction rates among PAs remain high despite burnout and stress amid the COVID-19 pandemic.


Of cial Blog of The Clinical Advisor

Jim Anderson, MPAS, PA-C, DFAAPA Why Is Methadone So Hard to Prescribe for Opioid Use Disorder?

Jim Anderson, MPAS, PA-C, DFAAPA, wonders if the Substance Abuse and Mental Health Services Administration will make the methadone take-home exibility program enacted during the COVID-19 pandemic permanent.



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 . 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!


New Growth on Neck

A 76-year-old woman presents for removal of a growth on her neck that was rst noted approximately 2 months ago. The growth is frequently irritated by her collar but has never bled. Her medical history is positive for actinic and seborrheic keratoses, one of which is seen proximal to the lesion. She has no history of skin cancer. Examination of the lesion reveals a cutaneous horn arising on a pinkish base.


• Keratoacanthoma

• Verruca vulgaris

• Squamous cell carcinoma

• Acrochordon

● See the full case at


Hip Pain and Limp in Young Child

In partnership with Online CME for Physician Assistants CME4PAC

A 5-year-old boy presents with right hip pain and a limp. The patient’s mother con rms that the child has not had any recent viral infection, fever, chills, or sweats. The child is acting ne other than the limp and occasional complaints of hip pain. On physical examination, the patient has a mild decrease in hip abduction and internal rotation on the right side compared with the left side.


• Activity modi cation based on symptoms

• Physical therapy for hip strengthening

• Hip abduction bracing

• Femoral varus osteotomy

● See the full case at • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 7

Arrhythmogenic Right Ventricular Cardiomyopathy: a Case of Mistaken Identity

Clinicians should consider ARVC in patients with unexplained sudden cardiac arrest, syncope, or arrhythmia and family history of similar events.

A68-year-old White woman is brought to the emergency department by ambulance after experiencing chest pain, palpitations, and shortness of breath for 1 hour prior to arrival. Vital signs recorded by emergency medical technicians on arrival at the patient’s home show a blood pressure of 200/100 mm Hg, pulse of 110 beats per minute, and oxygen saturation of 94% on room air.

The patient has a single-lead electrocardiography recording from her smartwatch showing premature ventricular contractions (PVCs) occurring at a rate of 6 per minute (Figure, page 10).

Electrocardiography in the emergency department shows no evidence of acute coronary syndrome. Cardiac enzymes are negative. The patient has never used tobacco products and has wellcontrolled hypertension and hyperlipidemia. However, the patient reports a strong family history of sudden cardiac arrest and syncope with cardiac arrhythmias from arrhythmogenic right ventricular cardiomyopathy (ARVC). These family members all had a mutation in the desmosomal protein (DSP) gene that controls the interlinking of cardiac cells.

The patient previously tested negative for this gene mutation. Four out of 10 of her first- and second-degree relatives with the DSP gene mutation have been diagnosed with ARVC and have had implantable cardiac defibrillators (ICD) placed. The patient is admitted to the cardiac unit for further evaluation. Computed tomography angiography

8 THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 • Continues on page 10
An estimated 20% of sudden cardiac deaths in younger patients are caused by ARVC.


reveals abnormal wall movement in the left ventricle. Cardiac catheterization is performed the following day and shows a 50% blockage in the left anterior descending artery that does not require stenting. The hospital course is uneventful and the patient is discharged 1 day later with instructions to follow up with her cardiologist. The patient later sought a second opinion at the ARVD/C Program at Johns Hopkins University.


Arrhythmogenic right ventricular cardiomyopathy is an underdiagnosed cause of sudden cardiac arrest, especially in young, athletic adults; although people of all ages may be affected. An estimated one-fifth of cases of sudden cardiac death in people younger than 35 years of age are attributed to ARVC.1 The condition involves progressive remodeling of cardiac muscle with fat and fibrosis and affects primarily the right ventricle, although the left ventricle can also be affected, especially in those with the DSP gene mutation.2

Symptoms of Arrhythmogenic Right Ventricular Cardiomyopathy

Sudden cardiac death is often the first symptom of ARVC. However, many people with ARVC have subtle signs and

often precede the syncopal event. Episodic anginal chest pain that resolves spontaneously may occur in the weeks and months prior to the sudden cardiac arrest. If untreated, ARVC may progress to heart failure and death.1

Family History

The index patient (proband) in this family was a 45-year-old first cousin once removed who experienced sudden cardiac arrest at her home after a vigorous exercise session. She was resuscitated after she collapsed in her front yard.The diagnosis of ARVC was delayed for over a year until her child’s pediatrician suggested genetic testing. Two family members (first cousin and aunt of the proband) subsequently experienced sudden cardiac arrests. The proband’s mother (the patient’s first cousin) experienced a severe cardiac arrhythmia during hospitalization for an unrelated illness prior to the proband’s cardiac event and had an ICD placed. Other family members who tested positive for the same DSP gene mutation included 2 of the proband’s 3 children as well as the proband’s brother and 1 of his 2 children.The proband’s 29-year-old first cousin once removed (the case patient’s great niece) was diagnosed with ARVC after a syncopal event of unknown etiology with elevated cardiac enzymes that was initially diagnosed as enced rapid disease progression with severe heart failure. No

The patient reports a strong family history of sudden cardiac arrest and syncope with cardiac arrhythmias from ARVC.
FIGURE. Smartwatch single-lead electrocardiography recording demonstrates premature ventricular contractions. © KATHY HOLMES DEXTER, MLS, MHA, MPA, PA-C, CAQ-PSYCH


deaths occurred in the case patient’s generation and subsequent generations, but the high incidence of past sudden premature deaths suggested that ARVC was present in the family for several generations. The case patient’s parents were second cousins and the incidents of sudden premature cardiac death occurred in both the paternal and maternal lines, including the patient’s father who died of a sudden cardiac arrest at the age of 56 years.

Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosis

A comprehensive workup for ARVC includes an exercise stress test, echocardiography, and 30-day trial with a Holter monitor. The definitive study for diagnosis of ARVC is cardiac magnetic resonance imaging, but such studies require interpretation by a radiologist with extensive experience with ARVC. Further testing may include an electrophysiology study and cardiac CT angiography. Genetic testing is important for diagnosing the disease, but not all gene mutations that cause ARVC have been identified. Currently, mutations in the following genes have been implicated in ARVC: plakophilin-2 ( PKP2 ), desmoglein-2 ( DSG2 ), desmocollin-2 ( DSC2 ), desmoplakin (DSP), and plakoglobin (JUP).1 All mutations are dominant. The condition has incomplete penetrance as some people with a gene mutation do not show any signs or symptoms of the disorder. Negative genetic testing may not necessarily rule out the diagnosis as ARVC can occur in the absence of identifiable genetic mutations and, thus, may be a gene-elusive disease.3


Arrhythmias can be controlled with appropriate medications, including β-blockers and antiarrhythmic agents. Many patients will require ICD. Cardiac catheter ablation may be necessary to eliminate irritable foci. Lifestyle changes are essential; patients who continue vigorous exercise or endurance sports participation will likely experience a rapid progression of the disease and increase their risk for sudden cardiac arrest. Arrhythmogenic right ventricular cardiomyopathy is progressive and incurable. Heart failure is common and must be treated aggressively to slow progression. When the heart becomes weakened and medical therapy is no longer effective in preventing heart failure, heart transplantation is an option for suitable candidates. Many patients are diagnosed in the second to fourth decades of life and may experience severe distress and disability.4 Family members should undergo genetic testing.5

Case Resolution

The patient in this case underwent a thorough workup at a local cardiac specialty center and the results were reviewed by the ARVD/C center at Johns Hopkins University. She did not have any of the pathologic changes that characterize ARVC, such as scarring of the ventricles. She was eventually diagnosed with a hiatal hernia that, once appropriately treated, resolved the episodic chest pain that she continued to experience after the initial hospitalization. The patient continued to do well with only minor episodes of palpitations, arrhythmias, and chest pain during the 18 months following hospitalization.


Arrhythmogenic right ventricular cardiomyopathy is an underdiagnosed genetic cardiomyopathy that causes significant disability and raises the risk for sudden cardiac death in those affected. Clinicians encountering unexplained sudden cardiac arrest, syncope, or arrhythmia in a patient with a strong family history of similar events or who carries the genetic mutation should suspect ARVC.The condition is treatable and, although progressive, patients can live a normal lifespan with frequent monitoring, medical management, and ICD placement. Heart transplantation may be required to extend life for appropriate candidates. Because of lack of provider education about ARVC and related cardiomyopathies, evaluation of patients at a specialized ARVC center is recommended.6 ■

Kathy Holmes Dexter, MLS, MHA, MPA, PA-C, CAQ-Psych, is an associate professor and assistant dean for Clinical Practice at Augusta University College of Allied Health Sciences in Augusta, Georgia.


1. Smoot K. ARVD/C patient resources. Johns Hopkins Heart and Vascular Institute. Accessed September 22, 2022. heart_vascular_institute/centers_excellence/arvd/patient_resources.html

2. Corrado D, Basso C. Arrhythmogenic left ventricular cardiomyopathy. Heart. 2022;108(9):733-743.

3. Gao C, Pan J, Li J. Refractory electrical storm in a 50-year-old man. Circ Cardiovasc Imaging. 2020;13(7):e010164.

4. Peters MN, Katz MJ, Alkadri ME. Diagnosis of arrhythmogenic right ventricular cardiomyopathy. Proc (Bayl Univ Med Cent). 2012;25(4):349-353.

5.Yuan ZY, Cheng LT, Wang ZF, Wu YQ. Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy. Chin Med J (Engl). 2021;134(15):1771-1779.

6. Sharma A, Assis F, James CA, et al. Misdiagnosis of ARVC leading to inappropriate ICD implant and subsequent ICD removal - lessons learned.

J Cardiovasc Electrophysiol. 2019;30(10):2020-2026. • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 11
A comprehensive workup for ARVC includes an exercise stress test, echocardiography, and 30-day trial with a Holter

Blood Culture-Negative Endocarditis: Individualized Diagnosis, Management

Infective endocarditis affects 15 per 100,000 people in the US.

Epidemiologic considerations for endocarditis are complex as there can be infective and noninfective causes. Once a patient is hospitalized for endocarditis, the mortality rate is estimated to be 10%.1 This underscores the importance of early recognition, workup, and treatment by the primary care provider. However, early diagnosis is complicated by the nonspecific and generalized symptoms of the disease such as fever, chills, weight loss, cough, hemoptysis, and/or malaise.The differential diagnosis for this presentation is sizable.2 In patients with clinical suspicion of endocarditis, prompt workup including 3 sets of blood cultures taken at 30-minute intervals within 48 hours is warranted.2 If the cultures have no growth after 7 days but the clinician still suspects endocarditis, then the search begins for the cause of blood culture-negative endocarditis (BCNE).3

Infective endocarditis affects 15 per 100,000 people in the United States and the number continues to rise.1,4 Blood culture-negative endocarditis represents 2% to 7% of cases of infective endocarditis.5 Patients can present with noninfective BCNE that is related to autoimmune diseases, cancer, and other comorbidities. 6 In clinical practice, confirmation of the appropriate diagnosis in cases of BCNE can be quite challenging. Endocarditis, whether culture positive or negative, requires an individualized treatment plan owing to the diversity in epidemiologic causes.Timely diagnosis is critical in the optimal management of this infection.

Primary care providers are on the frontline in the prompt identification of potential blood culture-negative endocarditis cases.


Pertinent Questions for Suspected Blood Culture-Negative Endocarditis Patients3

Have you recently taken antibiotics?

Have you been exposed to cats or homeless shelters?

Have you been exposed to sheep, cattle, or goats?

Have you had intravascular catheter/hemodialysis?

Do you have a history of immunosuppression?

Do you have a history of infective endocarditis?

Do you have a history of PE or DVT?

DVT, deep vein thrombosis; PE, pulmonary embolism

TABLE 2. European Society of Cardiology 2015 Modified Criteria for Diagnosis of Infective Endocarditis2

Major Criteria

• Persistently positive blood cultures from 2 seperate culture sets

• Echocardiogram: vegetation, dehiscense of prosthetic valve, abscess, valvular perforation, or aneurysm

• Abnormal findings around the prosthetic valve 18F-FDG PET/CT (if the prosthesis was implanted for >3 months) or radiolabelled leukocytes


• Cardiac CT demonstrating paravalvular lesions

Minor Criteria

• Predisposing cardiac condition or IV drug use

• Fever >38.0 °C

• Vascular: emboli, hemorrhages, Janeway lesions, aneurysms,

• Immunlogic: glomerulonephritis, Osler nodes, Roth spots, rheumatoid factor

• Positve blood cultures not meeting major criteria

History and Physical Examination

Evaluation of BCNE is challenging. Patient history is often more important than the physical examination when assessing for BCNE. The key questions to ask during the patient history are listed in Table 1 3

First, it is necessary to investigate if the patient has recently taken antibiotics. Antibiotic use is the primary cause of BCNE.7 Inquiring about exposure to farm animal helps determine if serology for Brucella spp or Coxiella burnetti needs to be obtained.6 To recognize Bartonella hensalae, it is appropriate to question patients about exposure to cats, body lice, and residence in a homeless shelter.6

The Duke criteria is a popular tool to aid in diagnosis of endocarditis. The criteria incorporate aspects of patient history, physical examination, and workup. Physical examination findings that must be evaluated when applying the Duke criteria are presence/absence of Osler nodes, Janeway lesions, splinter hemorrhages, petechiae, new regurgitation murmurs, and neurologic changes.8 A new cardiac murmur is present in 85% of patients with BCNE.8 Although not all patients will present with these findings, their correlation with the disease can expedite workup and management for endocarditis.

Diagnosis of infectious endocarditis is established in patients meeting one of the following Duke criteria:

• 2 major clinical criteria; or • 1 major and 3 minor clinical criteria; or • 5 minor clinical criteria

Major and minor criteria were modified by the European Society of Cardiology in 2015 (Table 2).2 A transesophageal echocardiogram is the preferred imaging modality to evaluate for valve insufficiency and/or new vegetation.9

CT, computed tomography; PET, positron emission tomography;

SPECT, single photon emission computerized tomography

If the Duke criteria have been met to establish a diagnosis of endocarditis but the cultures remain negative for 7 days, more extensive investigation into the pathologic cause is needed. The approach begins by obtaining serology for C burnetti, B hensalae, and Brucella spp. 10 If these pathogens are ruled out, then rheumatology and autoimmune workup is warranted to evaluate for a noninfectious cause of endocarditis.3 A study conducted in France reported that 2.5% of 759 cases of BCNE had rheumatic arthritis, Bechet disease, or Libman-Sacks endocarditis.3 The study began by using specific laboratory tests including rheumatoid factor, antinuclear antibody, and anti-DNA antibodies to assist in the diagnosis.3

Histopathology remains the gold standard for pathologic analysis but it is not often feasible. Obtaining samples for a

Patient history is more important than the physical examination when assessing for blood culture-negative endocarditis.

histologic approach is quite invasive and often will only occur if the patient has a planned cardiac surgical procedure.10 Even if tissue samples are obtained, not all tissue is viable for the pathologic stains that would be needed.

In recent years, 16S ribosomal ribonucleic acid polymerase chain reaction (16S rRNA PCR) of excised tissue has played an important role in the diagnostic approach for BCNE.11 If a patient needs surgery for valve repair or vegetation removal, excised tissue should be sent for 16S rRNA PCR. In a prospective study of 819 cases, 16S rRNA PCR identi ed 109 distinct etiologies making it the second most important diagnostic tool (behind serology) for BCNE.11 If the patient’s history includes prior antibiotic use, PCR may demonstrate the presence of staphylococci or streptococci bacteria (responsible for 45% to 60% of culture-negative endocarditis cases).3

If the workup fails to reveal the underlying pathogen or cause, serology workup on Mycoplasma pneumonia, Legionella spp, and Chlamydia spp should be obtained.10 Serology tests are last-line options because of low prevalence of Chlamydia spp As of 2017, only approximately 15 cases attributed to Chlamydia spp and 9 cases attributed to Mycoplasma pneumonia have been reported.10 If all diagnostic testing for endocarditis has been exhausted and no pathogen or comorbidity has been identi ed as the cause of the patient’s illness, it is time to investigate other conditions in the di erential diagnosis

including atrial myxoma, antiphospholipid syndrome, and acute rheumatic fever.6


Though treatment of endocarditis is tailored to each patient depending on history, epidemiology, risk factors, and comorbidities, empirical management is warranted.The American Heart Association (AHA) recommends treating patients empirically for acute BCNE with vancomycin and cefepime.1

For patients with subacute BCNE, AHA recommends vancomycin and ampicillin/sulbactam.6 These treatments are initiated while the speci c pathogen for BCNE is being identi ed.

The HACEK group of organisms includes Haemophilus parain uenzae, Aggregatibacter spp (aphrophilus and actinomycetemcomitans), Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae They are responsible for 1.5% to 2% of all infective endocarditis and are managed with third-generation cephalosporins such as ceftriaxone.7 The HACEK organisms are fastidious, gram-negative bacilli that require special growth medium or longer incubation times to be isolated. If patients with HACEK infective endocarditis are treated promptly, they have an 80% to 90% chance of survival.7

Tailoring treatment and patient management to the speci c organism in BCNE results in a wide array of pharmacological choices as well as duration of therapy. Treatment times range from 3 months to greater than 18 months depending on the organism identi ed. Coxiella burnetii (Q fever) and Tropheryma whipplei are treated with doxycycline and hydroxychloroquine.2 Brucella spp are best managed with doxycycline, cotrimoxazole, and rifampin.2 The preferred approach to treatment of Bartonella spp includes doxycycline and gentamicin.2 Fungal endocarditis is best treated with amphotericin B.2 Again owing to the diversity of organisms associated with BCNE, the list of treatment recommendations for this diagnosis is extensive. Providers must use current and updated resources to select optimal pharmacological agent(s) and duration of treatment.

If a patient with endocarditis is found to have a comorbidity thought to ultimately be responsible for the disease (ie, systemic lupus erythematous [SLE]), then referral to appropriate specialist is necessary.3

Prophylactic treatment may be warranted to prevent future complications that can arise from BCNE.Anticoagulation should be discussed as atrial brillation is a common complication of • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 17
The American Heart Association recommends treating patients empirically for acute BCNE with vancomycin and cefepime. The American Heart Association recommends treating patients empirically for acute BCNE with which 2 agents? ■ Ampicillin and sulbactam ■ Vancomycin and cefepime ■ Vancomycin and ampicillin ■ Empiric treatment is not recommended 41.18% 8.82% 27.94% For more polls, visit POLL POSITION Continues on page 24 22.06%

TABLE 3. Surgical Indications for Endocarditis6

Patients with valve dysfunction who develop symptoms of heart failure

Resistant fungi or organisms

Heart block, aortic abscess, and destructive penetrating lesions

Persistent infection >5-7 days postantibiotic initiation determined by fever or bacteremia

Recurrent emboli or enlarging vegetations when on organism-specific antibiotic therapy Severe valve vegetation

2. Habib G, Lancellotti P, Antunes MJ, et al; ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: The task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36(44):3075-3128.

3. Katsouli A, Massad MG. Current issues in the diagnosis and management of blood culture-negative infective and non-infective endocarditis. Ann Thorac Surg. 2013;95(4):1467-1474.

4. Jamil M, Sultan I, Gleason TG, et al. Infective endocarditis: trends, surgical outcomes, and controversies. J Thorac Dis. 2019;11(11):4875-4885.

5. Sheibani H, Salari M, Azmoodeh E, Kheirieh A, Chaghazardi S. Culturenegative endocarditis with neurologic presentations and dramatic response to heparin: a case report. BMC Infect Dis. 2020;20(1):476.

valvular vegetation.The AHA also recommends anticoagulation for BCNE patients with a prior history of atrial fibrillation, prosthetic valve, deep vein thrombosis, pulmonary embolism, and/or coronary artery disease.1 Surgery is indicated in a handful of circumstances as demonstrated in Table 3 6


Blood culture-negative endocarditis can be a challenging diagnosis to confirm. Primary care providers are on the frontline in the prompt identification of potential BCNE cases, allowing for prioritization of workup, management, and improved patient outcomes. A thorough history and physical examination are critical in the initial evaluation of patients with suspected BCNE. Blood culture-negative endocarditis warrants a multidisciplinary approach involving the primary care provider, cardiologist, cardiothoracic surgeon, and potentially other medical specialists (as appropriate for the patient/case) to achieve the goal of prompt and successful evaluation, management, and recovery. ■

Brittany Yacavone, PA-C, is scheduled to start the Piedmont Heart Advanced APP Fellowship Training Program in Advanced Cardiology at Piedmont Hospital in Atlanta, Georgia, in fall 2023; Elizabeth Prince-Coleman, MPA, PA-C, has been a practicing PA for almost 9 years with Augusta University Health. She also serves as the program director for the Augusta University PA Program.


1. Wei XB, Huang JL, Liu YH, et al. Incidence, risk factors and subsequent prognostic impact of new-onset atrial fibrillation in infective endocarditis. Circ J. 2020;84(2):262-268.

6. Baddour LM, Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-486.

7. Revest M, Egmann G, Cattoir V, Tattevin P. HACEK endocarditis: state-of-theart. Expert Rev Anti Infect Ther. 2016;14(5):523-530.

8. McDonald JR. Acute infective endocarditis. Infect Dis Clin North Am. 2009;23(3):643-664.

9. Wang A, Gaca JG, Chu VH. Management considerations in infective endocarditis: a review. JAMA. 2018;320(1):72-83.

10. Subedi S, Jennings Z, Chen SC. Laboratory approach to the diagnosis of culture-negative infective endocarditis. Heart Lung Circ. 2017;26(8):763-771.

11. Godfrey R, Curtis S, Schilling WH, James PR. Blood culture negative endocarditis in the modern era of 16S rRNA sequencing. Clin Med (Lond). 2020;20(4):412-416.

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and mobile vegetation >10 mm
vegetation >10 mm on anterior leaflet

Dermatologic Look-Alikes

Erythematous Indurated Plaques


A 32-year-old Black woman presents with a severalmonth history of tender red lesions. She has had no prior illnesses, has no history of similar lesions, and takes no medications.The patient notes that the lesions started to appear on her upper thigh and spread to her chest and arms. She has recently felt fatigued and experienced some joint pain but is otherwise feeling well. On examination, erythematous indurated plaques are found on her left upper chest and right proximal arm. On the left thigh, an older lesion that progressed to a slightly hyperpigmented patch with subcutaneous atrophy is found.

A 15-year-old otherwise healthy girl presents with a 5-month history of a progressive rash.The lesions began on her lower legs and spread to her trunk. Other than the rash, the patient reports that she is otherwise feeling well. She tried over-the-counter topical steroids on the rash with minimal improvement. On physical examination, scattered erythematous to violaceous plaques are found on her legs, dorsal feet, and abdomen. An older lesion on her right dorsal foot shows a central indurated yellow-white sclerotic plaque with an erythematous to violaceous border. • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 25

Dermatologic Look-Alikes

Lupus Profundus

Lupus profundus, also known as lupus erythematosus panniculitis, occurs in 1% to 3% of patients with cutaneous lupus erythematosus (LE).1-5 Lupus profundus may occur in patients with concurrent systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), or may manifest as an isolated incident lacking other cutaneous or systemic findings.1,2 Kaposi first described lupus profundus in patients with LE in 1883, and the disease was coined lupus erythematosus of Kaposi-Irgang by Arnold in 1956.1,3,5,6

Lupus profundus could serve as a precursor or signify recurrence in patients diagnosed with systemic lupus erythematosus.1-3 Of patients diagnosed with lupus profundus, 3% to 30% have SLE and these patients tend to have mild systemic involvement, though cases of severe systemic involvement have been reported.2 Discoid lupus erythematosus is also strongly associated with lupus profundus, with 70% of patients with lupus profundus displaying discoid lesions.4,7 Lupus profundus occurs twice as often in women as in men, mainly affecting women between 20 and 60 years of age.2,4,5 Cases in children younger than 12 years of age are rare.6

The etiology of lupus profundus is not completely understood due to the lack of specific research on its pathogenesis, though immune complex disease may play a role as indicated by the association with multiorgan disease and deep local lesional morphology.2 Recurrent lupus profundus may be associated with SLE, diabetes mellitus, glomerulonephritis, tuberculosis, and prior trauma to the area.3,4

Lesions from lupus profundus present as well-defined, erythematous, tender, indurated plaques, and subcutaneous nodules.1-3,6 Some lesions may develop overlying ulcerations or drainage. Discoid lupus erythematosus lesions may arise within lupus profundus lesions or elsewhere on the body.2,3 Discoid lupus erythematosus lesions present with a discoid plaque with scale that heals with scarring, follicular plugging, and atrophy.7 Lesions of lupus profundus are most commonly found on the face, breasts, trunk, buttocks, and proximal extremities, and lipoatrophy of the shoulders is characteristic of the disease.2,4,5 Healed lupus profundus nodules appear atrophic and hyperpigmented.3,5,6 Some patients with lupus profundus experience severe pain associated with active lesions, extensive cutaneous involvement causing disfigurement, major depression secondary to their skin disease and disfigurement,

chronic fatigue, headaches, and severe comorbidities in those with systemic involvement.2

Diagnosis is made via clinical and histologic findings. Excisional wedge biopsies may be needed to adequately analyze the subcutis.5 Histologic analysis reveals lobular lymphocytic panniculitis.6,7 Lymphoid follicles with germinal centers are present in 50% of cases.5 Lymphoplasmacytic infiltrate may have lymphocytic nuclear dust, which is another clue in the diagnosis of lupus profundus as this is not common in other forms of panniculitis.1,6,8 Another characteristic feature is hyaline sclerosis of fat lobules with some extension into interlobular septae.2 Occasional histologic features include mucin deposits, lymphocytic vasculitis, granulomatous reactions, eosinophils, calcification, and overlying features of DLE (epidermal atrophy, interface change, superficial, and deep perivascular and periadnexal inflammation, basement membrane thickening, and increased dermal mucin).1,3,4

Though laboratory tests may be normal, lupus profundus may be associated with several abnormalities including positive antinuclear antibody (ANA) and/or lupus band test, hypocomplementemia, leukopenia, rheumatoid factor, increased erythrocyte sedimentation rate, and false-positive syphilis serology.1-3

Diseases that may mimic lupus profundus include poststeroid panniculitis, cold panniculitis, pancreatic panniculitis, erythema induratum, erythema nodosum, morphea profunda, WeberChristian disease, and subcutaneous panniculitis-like T-cell lymphoma (SPTCL).1,3,5 The histologic finding of lymphoid follicles in subcutaneous fat can be seen in erythema nodosum, morphea, erythema induratum, and panniculitis associated with dermatitis.1 Lupus profundus can be almost indistinguishable from SPTCL clinically; however, the diseases have unique

histological and T-cell rearrangement and immunohistochemical studies can be used to differentiate the diagnoses.1,5,8 A helpful histologic clue that points towards SPTCL is rimming of atypical cells around fat droplets, though this feature has also been seen rarely in cases of lupus profundus.5 Lupus profundus appears most like morphea profunda in the later stages and can also be histologically similar; thus, careful clinical, histologic, and laboratory evaluation is needed to determine the diagnosis.5 First-line treatment for most patients with lupus profundus is oral antimalarials such as hydroxychloroquine, quinacrine, and chloroquine.2,3,5,6 Some patients may need to be treated

Oral hydroxychloroquine, quinacrine, or chloroquine are first-line treatments for lupus profundus in most patients.

with a combination of antimalarials if they do not respond to monotherapy.2,4,6 Systemic glucocorticoids should only be used for resistant and disseminated lesions.4 Intralesional corticosteroids should be avoided as they usually have little effect and can exacerbate nodules. Some success has been seen in treatment with azathioprine, dapsone, cyclosporine, mycophenolate mofetil, or thalidomide. If all other therapies fail, surgical removal or debridement may be an option.4,5

The patient in this case was diagnosed with lupus profundus via punch biopsy; on further laboratory evaluation, she had elevated ANA titer and met diagnostic criteria for SLE. She was started on hydroxychloroquine, which is improving her cutaneous and systemic symptoms.

CASE #2 Morphea

Morphea, also referred to as localized scleroderma, is an autoimmune disease that results in fibrosis of the skin and underlying tissues.9,10 It causes sclerosis of tissues derived from the primitive mesoderm; on rare occasions, it may include the central nervous system when present on the face and head.9,10 Unlike systemic scleroderma, which includes the presence of sclerodactyly, Raynaud phenomenon, and internal organ involvement, localized scleroderma is confined to the skin, subcutaneous tissue, and bone.9 Five classifications of morphea were originally described by Peterson et al.These include plaque, generalized, bullous, linear, and deep morphea.9,11,12

The incidence of morphea has been reported as 0.4 to 2.7 per 100,000 people, with an equal prevalence of disease in children and adults.9 The mean age of presentation in children is between 2 and 14 years and in adults is in the mid-40s.9 An increased predominance is found in females with the ratio of affected females to males reported as roughly 2.5-5:1.9,12,13 Approximately 72.7% to 82% of patients diagnosed with morphea are reported to be White individuals.9,13

The etiology of morphea is unclear but it is thought to be due to a multifactorial process that ultimately results in an imbalance between collagen production and destruction.9,13 Genetic predisposition, autoimmune dysregulation, and environmental factors may play a role in its pathogenesis; HLA class II allele DRB1*04:04 and class I allele HLA-B*37 have the strongest association with morphea.13,14 Autoimmune dysregulation is

supported by the higher levels of interleukin (IL)-4 cytokine and cell adhesion molecules detected in these patients.11,13 Increased reports of autoimmune diseases in both children and adults with morphea have been documented with up to 2% to 5% of children and 30% of adults diagnosed with concomitant autoimmune disease.9 An autoimmune cause is further supported by the presence of positive autoantibody titers. Antinuclear antibody is detected in 20% to 80% of patients and antitopoisomerase II alpha antibody is detected in 76% of patients with morphea.9 An increased prevalence of single-stranded DNA antibodies, antihistone antibodies, and rheumatoid factor also are found.9 Trauma, radiation, infection, and medications are also thought to play important roles in the pathogenesis of morphea.9,11 Clinically, morphea presents with erythematous, inflamed, and ill-defined plaques that may be itchy and tender.9,13 With time, these lesions develop a white center surrounded by a violaceous border.9,13 Plaques are typically self-limited and resolve within a few years.13 Once the active stage subsides, patients may develop hyper- or hypopigmentation of the involved skin.9,13 Excess collagen deposition in lesions destroys the normal structures of the skin, resulting in hairless, anhidrotic plaques.13 In some cases, the lesions do not resolve and patients have ongoing symptoms.13 Of the 5 clinical subsets of morphea, plaque morphea is the most common in adults and linear morphea is the most common in children.9

On histology, morphea presents with a perivascular infiltrate of lymphocytes in the reticular dermis and swelling of the endothelial cells.9 Plasma cells are found in up to 75% of lesions.15 In the later stages of the disease, the collagen bundles of the reticular dermis become hypertrophied and extend into the subcutaneous fat, giving the appearance of “fat trapping” in the dermis.9 Loss of eccrine glands and blood vessels occurs.9

Morphea is typically diagnosed clinically, however, a skin biopsy extending into the subcutaneous fat may be needed to confirm the diagnosis. A positive antinuclear antibody, antihistone antibody, and single-stranded DNA antibody may be present in some patients, but there is little clinical utility for autoantibody testing.13,15 Peripheral eosinophilia and elevated inflammatory markers may also help to confirm the diagnosis.13,15 Imaging with magnetic resonance imaging and ultrasonography may be a useful adjunct to clinical examination • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 27
Excess collagen deposition in the lesions destroys normal structures of the skin, resulting in hairless, anhidrotic plaques.

Dermatologic Look-Alikes

TABLE. Lupus Profundus vs Morphea

Lupus Profundus1-8 Morphea9-15

Dermatologic presentation

• Well-defined, tender, indurated plaques

• Subcutaneous nodules

• Overlying skin may appear normal or show signs of ulceration, scarring, or lesions from DLE

Characteristic locations

• Face

• Breasts

• Trunk

• Buttocks

• Proximal extremities, especially shoulders

• Active stage, early: erythematous, inflamed, and ill-defined violaceous plaques

• Active stage, late: plaques with a white sclerotic center surrounded by a violaceous border

• Postinflammatory stage: hairless, anhidrotic plaques with hypo- or hyperpigmentation

• Varies depending on subclassification but most often on the trunk


• 1%-3% of cutaneous lupus erythematosus patients

• Twice as often in women vs men

• Mainly affects patients 20-60 years of age

Potential risk factors

• Systemic lupus erythematosus

• Diabetes mellitus

• Glomerulonephritis

• Tuberculosis

• Trauma


• None confirmed

• Immune complex disease may play a role


• Lobular lymphocytic panniculitis

• Lymphoid follicles with germinal centers present in 50% of cases

• Lymphocytic nuclear dust in infiltrate

• Hyaline sclerosis of fat lobules with some extension into interlobular septae

• Occasional histologic features: mucin deposits, lymphocytic vasculitis, granulomatous reactions, eosinophils, calcification, and overlying features of DLE

• Incidence of 0.4-2.7 per 100,000 people

• Equal prevalence in children and adults

• Mean age of presentation in children is 2-14 years

• Mean age of presentation in adults is 45 years

• 2.5-5 times more common in females vs males

• More common in White patients

• Autoimmune disease

• Trauma

• Radiation

• Infection

• Medications

• None confirmed

• Genetics, autoimmune dysregulation, and environmental factors may play a role

• Lymphocytic perivascular infiltrate in the reticular dermis

• Swelling of the endothelial cells

• Presence of plasma cells

• Later stage with hypertrophy of collagen bundles in the reticular dermis, fat trapping, and loss of both eccrine glands and blood vessels


• History and physical examination

• Excisional wedge or punch biopsies

• Immunofluorescence


• Low doses of antimalarials

• Topical or systemic steroids

• Systemic immunosuppressants

• Azathioprine, dapsone, and thalidomide

• Surgical debridement or excision

• History and physical examination

• Biopsy of the subcutaneous fat

• Topical, intralesional, or systemic steroids

• Phototherapy with UV-A light

• Methotrexate

• Combination of above treatments in severe cases

DLE, discoid lupus erythematosus

to determine the depth of involvement. In the evaluation of morphea, it is important to consider a variety of conditions in the differential diagnosis including systemic sclerosis, radiation dermatitis, lipodermatosclerosis, lupus profundus, mycosis fungoides, and necrobiosis lipoidica.15 Systemic sclerosis cannot be differentiated from morphea by histopathology alone, so it is necessary to search for other examination clues in these patients. The presence of nail fold capillary changes and sclerodactyly suggests the diagnosis of systemic sclerosis.9 Lipodermatosclerosis may also be difficult to distinguish from morphea because of its overlapping clinical and diagnostic features. The presence of venous hypertension and involvement of the medial malleolus favor the diagnosis of lipodermatosclerosis.15 Lupus profundus also shares several clinical, laboratory, and histopathologic features with morphea, but can be differentiated by the lack of prominent sclerosis in the dermis and subcutaneous tissue.5

Once the diagnosis of morphea is confirmed, several different treatment options may be considered. For patients with superficial lesions, topical treatment with corticosteroids for 3 to 4 weeks is appropriate.13 Topical tacrolimus can also be used.13 For patients with more widespread lesions, phototherapy with UV-A light may be considered as it has better penetration than UV-B, but both are ineffective for morphea that involves the subcutaneous tissue, muscle, or bone.10,13 In cases where phototherapy is not available, high-potency topical corticosteroids, intralesional corticosteroids, or topical tacrolimus may be considered.13 Rapidly progressive disease requires systemic therapy with oral or intravenous corticosteroids or methotrexate.13 Methotrexate combined with systemic steroids is most effective for severe cases.10,13 Mycophenolate mofetil may be considered as an alternative to methotrexate.13

The prognosis of morphea is generally good, especially in cases with superficial lesions.13 Morphea that extends deeper into the bone may result in functional disability and joint contractures.13

The patient in this case was diagnosed with generalized morphea, which was confirmed via punch biopsy. Given the extensive involvement, she is currently being treated with systemic steroids and methotrexate. ■

Briana Fernandez and Sidra Deen are medical students at Baylor College of Medicine in Houston, Texas; Tara L. Braun, MD, is a dermatologist at Elite Dermatology in Houston, Texas.


1. Massone C, Kodama K, Salmhofer W, et al. Lupus erythematosus panniculitis (lupus profundus): clinical, histopathological, and molecular analysis of nine cases. J Cutan Pathol. 2005;32(6):396-404.

2. Grossberg E, Scherschun L, Fivenson DP. Lupus profundus: not a benign disease. Lupus. 2001;10(7):514-516.

3. Díaz-Jouanen E, DeHoratius RJ, Alarcón-Segovia D, Messner RP. Systemic lupus erythematosus presenting as panniculitis (lupus profundus). Ann Intern Med. 1975;82(3):376-9.

4. Strober BE. Lupus panniculitis (lupus profundus). Dermatol Online J. 2001;7(2):20.

5. Arps DP, Patel RM. Lupus profundus (panniculitis): a potential mimic of subcutaneous panniculitis-like T-cell lymphoma. Arch Pathol Lab Med. 201;137(9):1211-1215.

6. Fox JN, Klapman MH, Rowe L. Lupus profundus in children: treatment with hydroxychloroquine. J Am Acad Dermatol. 1987;16(4):839-844.

7. Wimmershoff MB, Hohenleutner U, Landthaler M. Discoid lupus erythematosus and lupus profundus in childhood: a report of two cases. Pediatr Dermatol. 2003;20(2):140-145.

8. Bosisio F, Boi S, Caputo V, et al. Lobular panniculitic infiltrates with overlapping histopathologic features of lupus panniculitis (lupus profundus) and subcutaneous T-cell lymphoma: a conceptual and practical dilemma. Am J Surg Pathol. 2015;39(2):206-211.

9. Fett N, Werth VP. Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol. 2011;64(2):217-228.

10. Fett N, Werth VP. Update on morphea: part II. Outcome measures and treatment. J Am Acad Dermatol. 2011;64(2):231-242.

11. Peterson LS, Nelson AM, Su WP. Classification of morphea (localized scleroderma). Mayo Clin Proc. 1995;70(11):1068-1076.

12. Mayes MD. Classification and epidemiology of scleroderma. Semin Cutan Med Surg. 1998;17(1):22-26.

13. Penmetsa GK, Sapra A. Morphea. In: StatPearls. StatPearls Publishing; August 8, 2022.

14. Jacobe H, Ahn C, Arnett FC, Reveille JD. Major histocompatibility complex class I and class II alleles may confer susceptibility to or protection against morphea: findings from the Morphea in Adults and Children cohort. Arthritis Rheumatol. 2014;66(11):3170-3177.

15. Florez-Pollack S, Kunzler E, Jacobe HT. Morphea: current concepts. Clin Dermatol. 2018;36(4):475-486. • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 29
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Breast Cancer Update: a Diagnosis That Extends Beyond the Patient

The authors present a case in which genetic testing for breast cancer may have affected outcomes in a 35-year-old woman.

When is genetic testing for breast cancer warranted?

Awell-appearing 35-year-old woman presents to her primary care provider with a complaint of a mass in her left breast. She has no significant medical history; however, her mother has had recurrent breast cancer.The patient had one pregnancy with an uncomplicated vaginal delivery at age 30. Her daughter was breastfed for 8 months. The patient’s age at menarche was 11 years old.

She has never had a mammogram. However, her chief complaint and family history indicate the need for further workup with clinical breast examination and referral for ultrasonography.

History and Physical Examination

The patient first noticed the mass in the shower 3 months ago. She says the mass has stayed constant in size and is occasionally painful without radiating pain. She denies fatigue, weight loss, fever, night sweats, chest pain, shortness of breath, or changes in bowel movements. She reports no limitation in movement, muscle weakness, dysmenorrhea, or menorrhagia. Her last menses was 5 days ago.

The patient takes drospirenone and ethinyl estradiol 3 mg/0.02 mg tablets once a day for birth control. She also takes over-the-counter biotin 5000 µg once a day. She denies any drug or food allergies.

The patient is a florist and keeps physically active with her job. She also states she likes to run 3 times a week. She eats a healthy diet that includes fish and vegetables. She denies any history

PharmD, MPA,

of tobacco use. She reports drinking two 8-ounce glasses of red wine a week.

The patient is married and states she is sexually active only with her husband. She has a healthy 5-year-old daughter. Her mother is healthy but has a history of recurrent breast cancer. Her mother was first diagnosed with breast cancer when she was 40 years old and again at age 50 years. Her mother’s first breast cancer was treated with a double mastectomy with reconstruction and chemotherapy. The second breast cancer was treated successfully with local excision and chemotherapy. Her father has hypertension and arthritis. She has a brother who is healthy. The patient has no other pertinent family history to report.

The patient appears to be in no acute distress and is alert and oriented times 4. She is dressed and groomed appropriately. Her vitals are shown in Table 1.

The patient’s breasts, areolas, and nipples are symmetric and the skin in these areas is light pink without signs of dimpling or discharge. Upon palpation with vertical strip method, a single fixed firm mass in the right upper quadrant of the left breast is found measuring 2 cm from the areola.The mass measures approximately 1.3 cm × 1.6 cm. No enlargement of bilateral axillary or supraclavicular nodes is present.

Diagnostic Studies and Treatment

The ultrasonography report shows a suspicious mass on the left breast in the right upper quadrant (Figure below demonstrates an example of similar findings).1 She is scheduled for same-day bilateral mammography. Her bilateral mammography report confirms a suspicious mass on the left breast in the right upper quadrant indicating a need for core needle biopsy.

Upon follow-up, the pathology report is consistent with luminal A invasive ductal carcinoma. She is referred to a surgical

TABLE 1. Vital Signs

Height, in 60

Weight. lb 142

BMI 22.9

Blood pressure, mm Hg 117/80

Respiratory rate, bpm 16 Temperature, °F 98.2 bpm, breaths per minute

oncologist and treated with neoadjuvant chemotherapy and a double mastectomy with reconstruction.

Genetic Testing

The patient is referred by her primary care physician to a genetic counselor because of the patient’s young age at breast cancer diagnosis and family history. The genetic counselor recommended BRCA testing for all first-degree relatives. The patient, her mother, and her daughter were all found to be BRCA1 positive. Her brother refused testing at this time.


Breast cancer is the second most common cancer in women with 1 in every 8 women worldwide being diagnosed.2 Noninvasive neoplasms are confined to the milk ducts and glands, including ductal carcinoma in situ (DCIS) and lobular carcinoma in situ • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 31
FIGURE . Example of ultrasonography findings in a woman with invasive ductal carcinoma (left, transverse image; right, longitudinal image).1 © REPRINTED FROM JANG, ET AL / WOLTERS KLUWER HEALTH, INC 1

(LCIS). However, these can both grow into invasive types once they move into the adipose tissue where the nerves, lymph, and vessels are located. These invasive types of breast cancer are infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC).These tumors have a higher risk for metastasis, the most common sites being brain, bone, lungs, and liver.3

Another invasive form of breast cancer is a locally advanced type called inflammatory breast cancer (IBC), which is characterized by rapid onset of erythema and edema. This form is often misdiagnosed as cellulitis or inflamed tissue. Although the incidence of this type of breast cancer is low at 2% to 4%, it is imperative to correctly identify because it accounts for 7% of all breast cancer-related mortality.4

Overall, however, most cases of breast cancer are not high risk, with a survival rate of more than 90%.5 The overall risk is largely determined by tumor staging and grading. Staging is focused on tumor size as well as disease spread to lymph nodes and grading is focused on the histologic characteristics of the tumor.6

The development of breast cancer is a multistep process that stems from 2 different theories centered on cellular mutation into tumor cells.2 This process is influenced by genetic and epigenetic factors.The most well-known genetic factors include the antioncogenes breast cancer susceptibility 1 and 2 (BRCA1 and BRCA2) genes.2 The epigenetic factors are divided into modifiable and nonmodifiable risk factors. Modifiable risk factors include premenopausal obesity, use of hormone-replacement therapy, alcohol consumption, smoking, not breastfeeding, and physical inactivity. Nonmodifiable risk factors include age greater than 65,White race, and family history.5 Other risk factors are related to estrogen levels including early menarche, late menopause, nulligravida, advanced maternal age, dense breasts, and higher bone density.2,3


Clinical breast symptoms (eg, mass, pain, nipple discharge) are common in women, with only 3% to 6% resulting from breast cancer.7,8 The majority of these symptoms are caused by benign conditions such as fibroadenoma and fibrocystic breast disease.9 Fibroadenoma is the most common benign lesion of the breast with an incidence of 25%.8 The clinical presentation of breast cancer and fibroadenoma is similar with the most common symptom being a new mass. However, only 8% of patients presenting with a palpable mass will have breast cancer.8

Breast cancer patient presentation can be divided into nonbreast symptoms and breast symptoms, with the latter being more prevalent. The most common breast symptom is a new mass. Other symptoms include nipple abnormalities, breast pain, and breast skin abnormalities.8 Approximately 1 in 6 women with breast cancer presents without a breast mass, and those with nonmass symptoms (eg, nipple abnormalities and breast ulceration,

infection, or inflammation) or both a breast mass and non-mass symptoms are more likely to wait 90 days or more to seek care compared with those with a breast mass only.10 Therefore, it is important to educate patients on symptoms of breast cancer to decrease the time it takes patients to present for evaluation.

History and Physical Examination

The primary care provider should obtain an extensive personal and family medical history to identify breast cancer risk factors such as race, heritage, past medical history of cancer, family history of cancer, diet, physical activity, and substance abuse. Additionally, the history should include age at menarche, age at menopause, number of and age at pregnancies, duration of breastfeeding, use of hormone replacement therapy, and bone density.3

Physical examination should be conducted in both seated and supine positions. It should start with the patient seated with hands on hips, inspecting for any nipple discharge, asymmetry, skin retraction, edema, erythema, or hypertrophy. Next, the provider should palpate for any enlarged axillary, supraclavicular, or cervical lymph nodes. Lastly, the provider should palpate the patient’s breasts using the circular or vertical strip method. Masses that are greater than 1 cm, fixed, hard, and heterogenous in texture should raise suspicion for malignancy and require further workup. Additionally, further workup is indicated if an axillary or supraclavicular lymph node is palpated with or without the presence of a mass.The examination documentation should include all the above findings with the circumferential location on the breast and distance from the areola.8

Screening Guidelines

Breast cancer screening guidelines differ based on individual risk level.The most common recommendation for average-risk persons is biennial mammography at 50 to 74 years of age as shown in Table 2. 6,11,12 High-risk individuals are recommended to have an annual breast MRI and mammogram starting at age 30 to 40 years.11,12 High-risk individuals are those with

TABLE 2. Breast Cancer Screening Guidelines6,11,12

USPSTF (2016)ACS (2015) ACOG (2017)

Age 40 to 49 y: Women should make individual decisions and consult with their clinicians

Age 50-74 y: Every 2 y

Age 40-44 y: Optional

Age 45-54 y: Annually

Age >55 y: Every 1-2 y

Mammogram every 1-2 y starting at age 40-50 y and ending at age 75 y based on shared decisionmaking

ACOG, American College of Obstetricians and Gynecologists; ACS, American Cancer Society; USPSTF, United States Preventative Services Task Force


a lifetime risk of 20% or greater using a risk assessment tool, positive genetic test for a BRCA1 or BRCA2 mutation, firstdegree relative with a BRCA1 or BRCA2 mutation, chest radiation before age 30 years, or Li-Fraumeni syndrome or other high-risk predisposition syndromes.13,14

Diagnostic Studies

Upon suspicious findings on physical examination or mammography, additional imaging modalities should be used to further evaluate the area. Ultrasound is a fast and cost-effective way to differentiate between cystic and solid tumors especially in women with dense breasts. Magnetic resonance imaging is used less commonly because of cost and time but can be useful in higher-risk populations.5

If indicated based on imaging results, further workup is performed by biopsy.3 Tumor type is based on the level of tissue invasion found on biopsy (invasive or noninvasive) and is then categorized into subtypes based on tumor markers, which include estrogen, progesterone, and human epidermal growth factor 2 receptors.15 The staging of the tumor is based on the tumor, node, metastasis (TNM) system, which takes into account tumor type and the subtype, metastasis, and lymph node involvement.3,16 The 2 latter categories are not determined until the time of surgery. However, if a lymph node is suspicious on imaging, a biopsy of the node will be conducted at the same time as the breast biopsy.

The grading of the tumor is based on the Nottingham Grading System (NGS), which determines the degree of differentiation from normal breast epithelial cells. Grade 1 is considered a well-differentiated tumor, grade 2 is considered a moderately differentiated tumor, and grade 3 is considered a poorly differentiated tumor.The grade of the tumor has shown to be equally important in prognostic value compared with tumor staging; therefore, both factors should be taken into account when counseling patients on prognosis and treatment.17

Genetic Screening

Genetic mutations cause 5% to 10% of all breast cancers, with the BRCA1 and BRCA2 mutations accounting for 30% of these cases.18 Additional genes that contribute substantial risk include ATM, CHEK2, and PALB2. 19 These genetic mutations are associated with a higher lifetime risk for breast cancer, younger age at onset, and aggressive disease stage.20 The BRCA1 mutation increases the lifetime risk for breast cancer to 50% to 65% ; the BRCA2 mutation increases the risk to 40% to 55%.The BRCA1 and BRCA2 mutations also increase the lifetime risk for pancreatic, prostate, and ovarian cancer. Notably, ovarian cancer lifetime risk increases with BRCA1 to 40% to 65% and BRCA2 to 15% to 25%.18 The ATM mutation carries a 12.8% to 32.3% lifetime risk for breast

cancer in addition to an increased risk for ovarian, pancreatic, and prostate cancer.The CHEK2 mutation carries a 15.2% to 37.3% lifetime risk for breast cancer as well as an increased risk for colorectal cancer. The PALB2 mutation carries a 21.5% to 49.2% lifetime risk for breast cancer as well as an increased risk for pancreatic cancer.19

Genetic testing allows providers to identify at-risk patients and offer individualized education and preventative recommendations such as increased surveillance, use of chemoprevention agents, and prophylactic double mastectomy, with the latter showing the greatest risk reduction.18,21

However, it is important to know when to offer genetic testing because it can also come with disadvantages such as cancerassociated anxiety and depression. Testing may identify other unknown mutations that do not have associated counseling and guidelines available yet. Genetic testing may also be costly. Although the test should be covered as preventative medicine, the cost still varies greatly depending on documented risk, laboratory pricing, and insurance coverage. Furthermore, even though a positive result can result in decreased future costs, the initial cost for preventative measures is still substantial.19

Utilizing genetic testing in patients who qualify offers them the unmatched power of knowing they have the gene and ability to take control of their personal and their family’s future health with increased surveillance or preventative measures. Moreover, taking into account the lifetime risk using a risk calculator may qualify them for insurance coverage for both surveillance and preventative strategies.

The recommendations offered by the American Society of Breast Surgeons, National Comprehensive Cancer Network, and US Preventive Services Task Force help to guide primary care providers in selecting patients who would benefit from genetic testing.11,22,23 Although the guidelines differ between these organizations, they all agree that testing is recommended for women with breast cancer onset before age 50 years, triplenegative breast cancer, or 2 or more primary breast cancers. Testing is also recommended for women without breast cancer who have a first or second-degree relative with early-onset breast cancer, relative with recurrent breast cancer, 2 or more relatives with breast cancer, male relative with breast cancer, or family member with a known mutation

The organizations have differing recommendations regarding genetic screening for patients of Ashkenazi Jewish heritage, personal history of ovarian cancer, and family history of pancreatic or prostate cancer.

Case Resolution

In the case patient, the suspicion for malignancy is initially low given her age, nonsmoking status, and healthy lifestyle; however, a detailed history revealed multiple risk factors for breast cancer. • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 33

Her only modifiable risk factor was alcohol consumption, but nonmodifiable risk factors included White race, early menarche, and first-degree relative with early-onset breast cancer. Based on these factors, her lifetime risk is calculated at 21.4% on the National Cancer Institute’s Breast Cancer Risk Assessment Tool.13 Additionally, her history revealed risk factors that met the criteria for genetic testing including a first-degree relative with early-onset breast cancer and a relative with recurrent breast cancer. Her positive BRCA1 mutation testing result increased her lifetime risk even further.

This case highlights the role a primary care provider plays in identifying patient risk and adjusting screening and genetic testing recommendations. If the patient’s primary care provider had calculated her lifetime risk for breast cancer before age 30 based on her history, increased screening with mammography and MRI would have been recommended at an earlier age. Additionally, BRCA1 genetic mutation identification would have increased screening recommendations and referral to an oncologist to discuss preventative measures such as bilateral mastectomy or endocrine therapy. Furthermore, if the patient’s mother had been appropriately referred for genetic counseling and testing because of her early-onset breast cancer, the patient would have been referred for testing at an earlier point.

In conclusion, primary care providers are in a position to identify breast cancer risk factors by taking a thorough patient history.Average-risk patients should be counseled on screening recommendations and lifestyle changes to decrease modifiable risk factors. High-risk patients should be counseled on these measures with the addition of genetic counseling or oncologist referral.These interventions result in earlier breast cancer detection and improved prognosis for not only the patient but also their immediate family members. ■

Shannon Stevenson, PA-C, is a critical care physician assistant at Trident Hospital in Charleston, SC. Kelly S. Reed, PharmD, MPA, PA-C, is an assistant professor in the Physician Assistant Program at Augusta University in Augusta, Georgia.


1. Jang JY, Kim SM, Kim JH, et al. Clinical significance of interval changes in breast lesions initially categorized as probably benign on breast ultrasound. Medicine (Baltimore). 2017;96(12):e6415.

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Suicide: Are You

This case involves a depressed patient who, after 3 months of outpatient treatment, purchased a shotgun and killed his wife, 3 children, and himself. The family’s next of kin brought a wrongful death action alleging that the patient’s health care providers had committed medical malpractice leading to the deaths.The question presented was whether the clinicians have a duty of care to the patient and his family in the absence of foreseeability of harm or a custodial relationship with the patient.

Facts of the Case

Mr B was a 45-year-old, married businessman with 3 children. He had his own web-based business with several employees. Mr B went to his medical center’s urgent care clinic complaining of difficulty sleeping and chest tightness, which he attributed to work-related stress due to financial difficulties with his business. The PA who saw him at this visit concluded that his symptoms were caused by anxiety and prescribed alprazolam.Two days later, Mr B saw his primary care provider (PCP) and reported low mood for the last 2 to 3 weeks and recent weight loss of

20 to 30 pounds. Mr B’s vital signs were normal and he denied any suicidal or homicidal ideation. The PCP prescribed sertraline 50 mg and told Mr B to return in 5 weeks if he didn’t feel better.

Mr B returned to the urgent care clinic in 9 days complaining that sertraline wasn’t working and the alprazolam doses wore off too quickly. He was asked again about suicidal ideation and again denied having any such thoughts.At this appointment, he was prescribed lorazepam for anxiety and zolpidem for sleep. Next, the patient saw his PCP again and had lost another 11 pounds.The physician increased the sertraline dose to 100 mg and changed the sleep medication to trazodone out of concern for possible interactions between zolpidem and lorazepam.The PCP referred Mr B for mental health counseling.

Approximately 2 weeks later, Mr B had a diagnostic assessment with Ms N, an advanced practice

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. • THE CLINICAL ADVISOR • NOVEMBER/DECEMBER 2022 35
Did the clinicians have a duty of care to the patient and his family in the absence of foreseeability of harm or a custodial relationship with the patient?
Is a clinician liable for not properly treating a patient who later dies by suicide?

registered nurse (APRN) who worked in the psychiatry department of a medical center. Ms N administered the Patient Health Questionnaire-9 (PHQ-9) to Mr B, which indicated that he was severely depressed. She diagnosed the patient with “major depression, single episode, severe, without psychosis.” Mr B denied any suicide attempts or plans but admitted to some idle thoughts of it. Ms N con cluded that it was too early in the treatment to assess the efficacy of the sertraline dose and she referred the patient for therapy.

Mr B had 3 therapy sessions with a social worker. The social worker administered the PHQ-9 at the first visit but not at the next 2 appointments.The PHQ-9 that was administered continued to show that the patient was severely depressed and had experienced thoughts of suicide but had no intent or plan to do so. Over the next few weeks, Mr B’s sertra line dose was raised to 150 mg per day but he continued to report depression and anxiety. He then saw Ms N who changed his antidepressant from sertraline to escitalopram. At that appointment, he also admitted to thinking about suicide on “several days” but specifically denied suicidal/ homicidal “ideation, intent or plan.” The appointment lasted approximately 15 minutes. It was the last time Mr B would see a health care practitioner. He postponed his next therapy appointment and shortly after purchased a shotgun and killed his wife, children, and himself.

The next of kin filed a wrongful death action against the medical center alleging that the medical center had commit ted malpractice in its treatment of Mr B and that appropriate treatment would have prevented him from killing his family and himself.

revived the claims for both Mr B’s and his family’s deaths. The medical center appealed and the case went to the state’s Supreme Court.

Legal Background

The state’s highest court ultimately held that the medical center and its employees would have to stand trial for Mr B’s death, but not for the deaths of his family members. The medical center argued that a malpractice claim shouldn’t proceed if a patient dies by suicide. The Court disagreed stating that it did not hold that the medical center had a duty to control Mr B or prevent his suicide but it did have a duty to provide treatment that met the standard of care. And because it was unclear whether the treatment by the PCP, APRN, and social worker met the standard of care, the issue would have to go to a jury to decide. However, the Court absolved the medical center of responsibility for the deaths of Mr B’s family, holding that Mr B’s killing of his wife and children was unforeseeable as a matter of law and that the medical center owed no legal duty of care to the patient’s family in this case. The case was sent back to the trial court for a jury trial to determine whether the medical center’s clinicians failed to meet the standard of care when treating Mr B for depression and anxiety.

Protecting Yourself

The medical center moved for summary judgment, asking the court to dismiss the case. The court granted the defendant’s motion, concluding that the medical center did not owe a duty to Mr B or his family because the medical center had no duty to control or protect Mr B absent a custodial “spe cial relationship” that was not present given the outpatient nature of the treatments. The court held that Mr B’s actions were unforeseeable since he had never made threats of vio lence or engaged in prior violent acts.The plaintiff appealed. The appeals court reversed the lower court’s decision and

Expert testimony presented by the plaintiff in this case was critical of the actions of the clinicians. The expert opined that the patient was never notified about “black box warn ings” about the antidepressants he was taking and that he was prescribed too low a dose of sertraline for his size. The expert also noted that trazodone is known to inhibit the effectiveness of SSRI antidepressants including both sertraline and escitalopram. The expert asserted that the clinicians spent inadequate time with Mr B — noting that his last appointment with Ms N was only 15 minutes and that in one case his medication was adjusted over the phone without an in-person visit. The expert concluded by faulting the clinic for not referring Mr B to a psychiatrist, given his serious depression, and not asking for permission to contact his family.

The PHQ-9 is valuable but only if used consistently and if the results are acted upon. It was clear that Mr B’s symptoms were not improving during his course of treatment.Whether the clinicians are liable for not properly treating him will ultimately be determined by a jury. ■

The state’s Supreme Court held that the medical center and its employees have to stand trial for Mr B’s death.