Atypical Hyperplasia of the Breast: Follow-up and Management
CLINICAL ACTIONS:
Atypical hyperplasia of the breast is a benign but high-risk condition that can be either ductal (ADH) or lobular (ALH); these occur with equal frequency and together are found in about 10% of breast biopsies. Either entity confers a long-term risk of breast cancer that approaches 30% at 25 years of follow-up.
Surgically excise atypical hyperplasia when found on a core-needle biopsy
Necessary to avoid missing invasive cancer due to sampling error
DCIS or invasive cancer found in 10 to 20% of cases
Exception: Clinical and radiologic follow-up appropriate when atypical hyperplasia is an incidental finding at the site of a targeted biopsy
Current breast cancer risk assessment models perform poorly among women with atypical hyperplasia
Atypical hyperplasia associated with a relative risk of approximately 4 for future breast cancer
Follow-up screening recommendations include annual mammography, breast awareness, and clinical encounter every 6 to 12 months
Also consider
Tomosynthesis
Annual MRI to begin at diagnosis
Based on emerging evidence, ACOG also recommends consideration of yearly breast MRI for atypical hyperplasia
Encourage pharmacologic risk reduction with either a selective estrogen-receptor modulator (SERM) or an aromatase inhibitor (AI) for prevention of breast cancer
Counsel about healthy lifestyle including ideal body weight and alcohol reduction
Atypical hyperplasia is generally not an indication for surgical risk-reduction / mastectomy
SYNOPSIS:
Atypical hyperplasia of the breast reflects proliferation of dysplastic epithelial cell populations. It is felt to be a transitional zone between benign and malignant breast disease, containing some but not all features of a cancer. Although statistically the long-term risk of breast cancer equals or exceeds that conferred by family history and other risk factors, current guidelines in screening do not reflect this. Similarly, pharmacologic risk reduction strategies have been adopted by <1% of women who could potentially benefit from them.
KEY POINTS:
Atypical lobular hyperplasia is histologically similar to lobular carcinoma in situ, but less extensive
Atypical ductal hyperplasia and ductal carcinoma in situ share histologic features
Both types of hyperplasia share molecular characteristics and gene expression, indicating possibly a continuum of abnormalities
Ulcerative Genital Conditions in the HIV-Positive Woman
Genital, anal, or perianal ulcers are generally caused by syphilis or herpes. Chancroid, lymphogranuloma venereum (LGV), and granuloma inguinale (donovaniasis) are less likely diagnoses; however, all these conditions are associated with increased HIV acquisition and transmission. Guidelines for screening and treatment differ in some cases from those for the HIV-negative patient.
CLINICAL ACTIONS:
Evaluate first for herpes and syphilis first
Other causes such as chancroid and lymphogranuloma venereum should then be considered
Offer HSV type-specific serologic testing on initial HIV evaluation for asymptomatic individuals
HSV DNA polymerase chain reaction (PCR) and viral culture are preferred methods for diagnosis of mucocutaneous HSV lesions caused by HSV
Consider suppression or episodic therapy to decrease clinical manifestations if HSV-2 is detected
Does not reduce risk for HIV transmission or HSV-2 transmission to susceptible sex partners
Generally higher doses/longer duration of treatment are recommended for HIV-positive women
Daily suppression
Acyclovir 400-800 mg BID or TID
or
Valacyclovir 500 mg BID
or
Famciclovir 500 mg BID
Episodic flares
Acyclovir 400 mg TID x 5-10 days
or
Valacyclovir 1 g BID x 5-10 days
or
Famcycolovir 500 mg BID x 5-10 days
Syphilis:
Systemic disease caused by Tremonema Pallidum
Primary syphilis is characterized by genital ulcers, though secondary/ tertiary/latent forms are not
A presumptive diagnosis of syphilis requires a treponemal test (i.e fluorescent treponemal antibody absorbed tests [FTA-ABS]) plus a nontreponemal test (i.e. Venereal Disease Research Laboratory [VDRL] or Rapid Plasma Reagin [RPR])
Screen for syphilis on initial HIV evaluation and annually thereafter
Treatment is the same regardless of HIV status
Penicillin G IM is the preferred treatment for all stages; the preparation (benzathine, aqueous procaine aqueous crystalline), dosage and length of treatment depend on the stage
Chancroid:
Painful, genital ulcers with suppurative lymphadenopathy caused by ducreyi
Treatment is the same regardless of HIV status
Close follow up is required as treatment failure is increased in the HIV positive
Treatment
Azithromycin 1 gm po
or
Ceftriaxone 250 mg IM
or
Ciprofloxacin 500 mg po BID x 3 days
or
Erythromycin 500 mg tid x 7 days
Lymphogranuloma Venereum (LGV)
Tender, unilateral groin/femoral lymphadenopathy with a self-limited genital ulcer/papule caused by C. trachomatis serovars L1, L2, or L3
Proctitis may occur
Diagnose by identifying C. trachomatis from the lesion by culture, direct immunofluorescence or nucleic acid detection
Treatment is the same regardless of HIV status
Treatment
Doxycycline 100 mg BID x 3 weeks
or
Erythromycin base 500 mg QID x 3 weeks
Granuloma Inguinale (Donovanosis):
Painless ulcerative disease characterized by beefy red, highly vascular lesions caused by Klebsiella granulomatis
Diagnose by identifying dark-staining “Donovan Bodies” on biopsy or tissue
Treatment is the same regardless of HIV status
Treatment
Azithromycin 1 gm once/week or 500 mg/day x 3 weeks/until lesions healed
or
Doxycycline 100 mg BID X 3 weeks/until lesions healed
or
Ciprofloxacin 750 mg BID x 3 weeks/until lesions healed
or
Erythromycin base 500 mg QID x 3 weeks/until lesions healed
or
Trimethoprim-sulfamethoxazole double strength BID x 3 weeks/until healed
SYNOPSIS:
Vaginal, vulvar, and sexually transmitted infections may increase the risk of HIV transmission. Prompt diagnosis and treatment decreases the likelihood of transmission; public health standards require providers to presumptively treat any patient, regardless of HIV status, with suspected syphilis immediately and before test results are available. Presumptive treatment of primary herpes is also recommended as early treatment maximizes success.
KEY POINTS:
Genital, anal, or perianal lesions may not necessarily be infectious (e.g. trauma, carcinoma, aphthous, drug eruption, psoriasis)
Medical history and physical exam findings are frequently inaccurate and should be followed by tests that reflect conditions prevalent in the area
Consider biopsy for ulcers not responding to therapy or if the diagnosis is unclear
If HIV status is unknown, HIV testing should be offered to any woman with genital/anal ulcers presenting for treatment.
Diagnosis codes:
D28.9 benign neoplasm of female genital organs, unspecified
The U.S. Department of Health and Human Services (HHS) provides several web based tools to help providers understand and navigate HIPAA and its requirements. Below are summary excerpts from HHS that explain what HIPAA is and whether you, as a provider, fall under its umbrella.
What is HIPAA?
The Standards for Privacy of Individually Identifiable Health Information (“Privacy Rule”) establishes, for the first time, a set of national standards for the protection of certain health information. The U.S. Department of Health and Human Services (“HHS”) issued the Privacy Rule to implement the requirement of the Health Insurance Portability and Accountability Act of 1996 (“HIPAA”). The Privacy Rule standards address the use and disclosure of individuals’ health information—called “protected health information” – by organizations subject to the Privacy Rule — called “covered entities,” as well as standards for individuals’ privacy rights to understand and control how their health information is used. Within HHS, the Office for Civil Rights (“OCR”) has responsibility for implementing and enforcing the Privacy Rule with respect to voluntary compliance activities and civil money penalties.
A major goal of the Privacy Rule is to assure that individuals’ health information is properly protected while allowing the flow of health information needed to provide and promote high quality health care and to protect the public’s health and well-being. The Rule strikes a balance that permits important uses of information, while protecting the privacy of people who seek care and healing. Given that the health care marketplace is diverse, the Rule is designed to be flexible and comprehensive to cover the variety of uses and disclosures that need to be addressed.
Are you a ‘covered entity’?
Every health care provider, regardless of the size of their clinical practice, who electronically transmits health information in connection with certain transactions, is a covered entity. These transactions include claims, benefit eligibility inquiries, referral authorization requests, or other transactions for which HHS has established standards under the HIPAA Transactions Rule. Using electronic technology, such as email, does not mean a health care provider is a covered entity; the transmission must be in connection with a standard transaction. The Privacy Rule covers a health care provider whether it electronically transmits these transactions directly or uses a billing service or other third party to do so on its behalf. Health care providers include all “providers of services” (e.g., institutional providers such as hospitals) and “providers of medical or health services” (e.g., non-institutional providers such as physicians, dentists and other practitioners) as defined by Medicare, and any other person or organization that furnishes, bills, or is paid for health care.
Marfan Syndrome: a Reportable ACMG Secondary Finding
WHAT IS IT?
Marfan syndrome is a genetic, multi-systemic disorder that affects connective tissue. It occurs in 1 out of every 5,000-10,000 individuals and is caused by pathogenic variants in the Fibrillin 1 (FBN1) gene. Penetrance is high, and most individuals with a mutation will have some finding related to the disorder.
Marfan syndrome is considered a classic example of variable expressivity, as some individuals may have mild symptoms and signs, such as skeletal changes, while others may have life-threatening effects if left unchecked, such as risk for aortic rupture.
There are rigorous clinical criteria required for diagnosis of Marfan syndrome. In addition, there is clinical and genetic overlap with other related disorders.
Referral to a medical genetic service is required to determine if an individual is suspected of having Marfan syndrome, Loews-Dietz syndrome or Familial Thoracic Aortic Aneurysms and Dissections
Multiple speciality services may be involved in management; however, referral to cardiology is critical
NOTE: Because medical interventions can prevent severe morbidity and mortality, Marfan syndrome and related disorders are on the ACMG list of secondary findings. In summary, the ACMG document on reporting such findings makes the following recommendations:
In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge
An individual can ‘opt out’ of receiving secondary findings
KEY CLINICAL POINTS:
Findings may appear in childhood or adulthood
While height is the clinical characteristic most noted in Marfan syndrome, it is important to take in to account familial background – is the individual taller than expected for his/her family?
Phenotype-Genotype correlation is poor
Genetic consultation and multi-disciplinary team management is essential to maximize outcomes and prevent untoward events such that life expectancy can equal that of unaffected populations
Treatment and prevention of serious manifestations such as dissecting aortic aneurysm may include medication, such as beta-blockers and/or surgeries
Patients may be cautioned to avoid: contact sports, cardiovascular stimulants, LASIK correction and activities that cause joint injury or pain
Pneumothorax prevention may include avoiding breathing against resistance (such as horn instruments)
Consider Marfan syndrome or any related disorders a high risk pregnancy due to risk of aortic dissection – arrange for high risk referral preconception if possible
CLINICAL FINDINGS:
It is important to keep in mind, given the variable expressivity of Marfan syndrome, this list includes most possible findings, but any single affected individual will likely manifest only some of the following:
Eye:
Myopia
Ectopia lentis (lens displacement)
Risk for retinal detachment, glaucoma and cataracts
Skeletal:
Excessive growth with dolichostenomelia of long bones
Overgrowth of ribs causing pectus excavatum or pectus carinatum
Joint laxity and arachnodactyly (long, slender digits) which leads to classic finding of the positive ‘wrist sign’ and ‘thumb sign’
Facial and dental features:
Long narrow face, with deep set eyes, flat cheekbones and receding chin
High arched palate with overcrowding of teeth
Cardiovascular: connective tissue in the aorta can be affected leading to risk of aortic dilatation/dissection/rupture, aortic valve regurgitation, left heart failure
Children with severe Marfan syndrome may be affected with mitral valve prolapse and heart failure and managed surgically
Other systems:
Dural ectasia can result in back and leg pain, causing weakness and numbness
Pneumothorax from lung bullae
RELATED DISORDERS:
Loeys-Dietz syndrome: This syndrome is also characterized by skeletal characteristics commonly associated with Marfan syndrome, such as pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly and club foot (talipes equinovarus). Facial features can be prominent in severe cases, including craniosynostosis and wide spaced eyes, as well as cleft palate. However, the major distinguishing findings are related to vascular abnormalities leading to aneurysms and possible dissection beyond the aortic root – such as the cerebral, thoracic and abdominal arteries, and in some cases arterial tortuosity
Findings may appear in childhood or adulthood
Mutations that can lead to severe disease are found in TGFBR1, TGFBR2, and SMAD3 genes
Due to emphasis on cardiovascular manifestations, individuals are cautioned against contact sports or drugs that stimulate cardiovascular output
Familial Thoracic Aortic Aneurysms and Dissections (TAAD): Similar to Marfan syndrome and Loews-Dietz syndrome, there is increased risk of aortic aneurysm, dissection and rupture. In the case of TAAD, it is the thoracic aorta (usually ascending) that is most prominently affected. However, the abdominal aorta and brain vasculature may demonstrate abnormal dilatation. Skeletal anomalies can overlap with Marfan syndrome, including tall stature, joint laxity, and pectus excavatum and pectus carinatum. Other findings may include livedo reticularis (purplish skin discoloration due to constriction of dermal capillaries particularly in mutations in ACTA2). There is also increased risk of coronary artery disease and stroke.
Findings may appear in childhood or adulthood
Mutations that can lead to severe disease are found in ACTA2, TGFBR1, TGFBR2, MYH11, FBN1 and SMAD3
MOLECULAR GENETICS & COUNSELING:
What gene/protein is affected and what does it do?
FBN1: mutations in FBN1 gene cause Marfan syndrome
Fibrillin: protein is a key component of extracellular microfibrils and can be found in both elastic and non-elastic tissues in multiple organ systems
Inheritance:
Marfan syndrome is an autosomal dominant disorder
75% of individuals will inherit a mutation from one of his/her parents; in the other 25%, there is a de novo mutation
Risks to family members and future offspring:
If a parent of an affected individual carries the pathogenic variant, the brothers and sisters of that individual have a 50% chance of having the variant
In the case of a de novo mutation, there is still a low risk to brothers and sisters because of the possibility that a parent may have germline mosaicism
Offspring have a 50% chance of inheriting the variant and therefore having Marfan syndrome
Preimplantation genetics and prenatal testing is available
Intellectual Disability (formerly known as mental retardation)
Official definition
Characterized by significant limitations both in intellectual functioning (IQ <70-75) and in adaptive behavior, which covers many everyday social and practical skills; originates before age 22 (American Association on Intellectual and Developmental Disabilities [AAIDD])
It is no longer defined by IQ alone, rather IQ is only part of the evaluation
CAUSE:
Intellectual disability can have many and varied etiologies, including
Acquired
Examples: Infection or injury
Genetic
Chromosomal
Examples: Down syndrome or microdeletion syndrome
Molecular / Single Gene Disorder
Example: Fragile X syndrome
KEY POINTS:
Practical Definitions
Normal Intelligence
As an adult, able to reason, solve problems, think abstractly, comprehend complex ideas, and learn from experience
IQ >85
Learning, not intellectual, disability
As an adult, able to learn/understand complex information, but may require nontraditional teaching approaches
Normal IQ
Borderline intellectual disability
As an adult, able to learn/understand simplified information and probably able to live independently
Low normal IQ 75-85
Mild intellectual disability
As an adult, able to participate in most family activities and perform many independent tasks, but likely to need supervision similar to a middle school individual
Communication, conversation, and language are more concrete and immature than expected
IQ 50-75
Moderate intellectual disability
As an adult, able to participate in most family activities but likely to need supervision similar to a grade school person
Marked differences in conceptual skills
IQ 35-55
Severe intellectual disability
As an adult, attainment of conceptual skills is limited
Skills are similar to a toddler/preschool person (< 5-6 year old) requiring care and supervision accordingly
IQ 20-40
Profound intellectual disability
As an adult, very limited understanding of symbolic communication in speech or gesture
Skills are similar to an infant/toddler requiring care and supervision accordingly; dependent on others for all aspects of daily physical care, health, and safety
Pelvic inflammatory disease (PID) is an inflammatory disorder of the upper female genital tract that includes endometritis, salpingitis, tubo-ovarian abscess and pelvic peritonitis. Symptoms may be obvious (high fever, severe lower abdominal pain, peritoneal signs), subtle (abnormal bleeding, vaginal discharge, dyspareunia) or absent.
Assume PID in a patient with lower abdominal/pelvic pain if
Sexually active and/or at risk: adolescents, women attending STD clinics, those in communities with high rates of gonorrhea or chlamydia
One or more of the following on pelvic exam:
Cervical motion tenderness (CMT)
Uterine tenderness
Adnexal tenderness
Other causes (ectopic pregnancy, ovarian cyst, appendicitis, functional pain) are unlikely
Additional criteria to support the diagnosis of PID
Oral temperature >101°F (>38.3°C)
Abnormal cervical mucopurulent discharge or cervical friability
Abundant WBCs on saline microscopy of vaginal fluid
Elevated erythrocyte sedimentation rate (ESR)
Elevated C-reactive protein (CRP)
Positive gonorrhea/chlamydia trachomatis culture
Most specific criteria for diagnosing PID
Endometrial biopsy for evidence of endometritis
Transvaginal ultrasound or MRI demonstrating thickened fluid filled fallopian tubes, or tubo-ovarian collection, or tubal hyperemia
Laparoscopic findings consistent with PID
The CDC cautions that laparoscopy “is not easily justifiable when symptoms are mild or vague. Moreover, laparoscopy will not detect endometritis and might not detect subtle inflammation of the fallopian tubes.”
SYNOPSIS:
Pelvic inflammatory disease comprises a spectrum of disorders ranging from asymptomatic to debilitating. Acute PID may be difficult to diagnose because of the wide variation in symptoms and signs. The diagnosis of PID is usually based on clinical findings noted above.
KEY POINTS:
Wet Prep (saline preparation of vaginal fluid)
Most women with PID have either mucopurulent cervical discharge or evidence of WBCs on a microscopic evaluation
If the cervical discharge appears normal and no WBCs are observed on the wet prep of vaginal fluid, the diagnosis of PID is unlikely
Consider alternative causes of pain
A wet prep of vaginal fluid also can detect the presence of concomitant infections (e.g., BV and trichomoniasis)
PID is usually, but not always, seen in the presence of gonorrhea or chlamydia trachomatis infections
Typical vaginal flora, cytomegalovirus, mycoplasma may be associated with PID
Many episodes of PID go unrecognized with potential long-term sequelae of infertility or chronic pain
Healthcare providers should maintain a low threshold for the diagnosis of PID
It is better to overtreat than to undertreat
All women diagnosed with PID should be tested for HIV as well as gonorrhea and chlamydia
Treatment should not be delayed until test results are available if there is a clinical suspicion of PID
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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
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Disclaimer
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presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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