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Breast Implant-Associated Anaplastic Large Cell Lymphoma: An Update
Dermatologic Look-Alikes
CASE #1 Polymorphic Eruption of Pregnancy
Polymorphic eruption of pregnancy (PEP) is a benign, pruritic self-limiting inflammatory skin condition.1-3 Although the disease was described in 1962 as toxemic rash of pregnancy,4 the first report of PEP often is credited to Thomas J. Lawley, MD, who named the condition pruritic urticarial papules and plaques of pregnancy (PUPPP) in 1979.1,3,5,6 PEP also has been referred to as toxic erythema of pregnancy and late-onset prurigo of pregnancy.3 When a simplified nomenclature system for gestational dermatoses was proposed in 1982, PUPPP became known commonly as PEP.6,7
Estimates for the incidence of PEP range from 1 in 120 to 1 in 200 pregnancies.2,6 Although prevalence estimates range from 0.05% to 0.5% overall, prevalence can be as high as 16% in twin pregnancies and 17% in triplet pregnancies.1,3,6 PEP is more common in White women than in non-White women. It also occurs most commonly in primigravid women in the third trimester, although it can occur after delivery. PEP tends not to recur in subsequent pregnancies.1,3,6
One risk factor linked to PEP is larger belly size, which may explain its association with multiple-gestation pregnancies, increased maternal weight gain, increased newborn birth weight, and male sex of the fetus.1,3,6 One study showed an association between PEP and Rh-positive maternal blood.8 More recently, a case of a pregnant woman with COVID-19 with a clinical presentation consistent with PEP was reported.9
The etiology of PEP is uncertain. It has been suggested that stretching of the abdomen late in pregnancy leads to connective tissue damage; exposure to antigens within collagen could induce an allergic-type reaction that starts within the abdominal striae.1-3 Maternal immune hyperactivity could, thus, predispose some women to PEP.3 Deposition of fetal DNA in skin that causes a graft-vs-host disease state in which fetal lymphocytes attack maternal tissues also is theorized to play a role.1,6 The reaction potentially becomes generalized via cross-reactivity to collagen in normal skin.1 An immune tolerance may prevent PEP from recurring in subsequent gestations.1 Placental factors, human chorionic gonadotropin, sex hormones, high progesterone levels, and increased progesterone receptor immunoreactivity also have been implicated in PEP.1,3 There is no evidence supporting an autoimmune etiology.3
PEP presents predominately on the abdomen, initially within the striae, and characteristically spares the periumbilical region.1 The rash erupts with extremely pruritic erythematous and edematous papules that may coalesce into plaques on the abdomen. The eruption can spread to the extremities, trunk, buttocks, thighs, and back. The majority of patients develop polymorphic features, including annular wheals, target lesions, small vesicles, widespread erythema, and eczematous plaques as PEP progresses.1,3,6
In the early stage of PEP, skin biopsy specimens show edema in the epidermis and upper dermis and a deeper dermal perivascular infiltrate of T-helper lymphocytes, mast cells, neutrophils, and sometimes eosinophils.1,3 Mild focal spongiosis also can be found.1 Biopsies taken from resolving lesions show acanthosis with parakeratosis and hyperkeratosis.1,3 Along blood vessels and the dermal-epidermal junction, histologic studies have found minimal granular deposition of immunoglobulin (Ig)A, complement C3, and IgM.1 However, in most cases, deposits of C3 are not found along the basement membrane of the epidermis, and this can be used to differentiate PEP from pemphigoid gestationis.3
PEP cannot be diagnosed definitively based on laboratory test results because such findings usually are within normal limits.1,2 Thus, diagnosis is made according to clinical features as well as biopsy, which can be used to exclude similar diseases, especially conditions that may affect the fetus.2,6 Pemphigoid gestationis is the most important diagnosis to rule out because it is associated with premature births and lower birth weights.1,3 Pemphigoid gestationis tends to appear earlier in pregnancy, does not involve striae, involves the umbilicus, and results in positive immunofluorescence of perilesional skin.1,3 Other conditions to rule out include drug-related skin eruptions, urticaria, viral exanthems, and eczematous dermatitis.1,3
Treatment of PEP typically involves topical corticosteroids and oral antihistamines to address symptoms.1-3 In more severe cases with uncontrollable pruritus that may disturb sleep, short courses of systemic corticosteroids can be used. Nonpharmaceutical options for symptomatic relief include cool baths, light cotton clothing, and emollients.1,3 More recently, intramuscular injections of autologous whole blood have shown success in treating postpartum PEP, although limited data support this treatment.1,3 Rarely, cases with especially severe pruritus warrant induction
A risk factor for PEP is larger belly size, associated with multiple-gestation pregnancies and increased maternal weight.
Continues on page 44
Dermatologic Look-Alikes
of labor for early delivery.1,3 PEP does not pose a risk to the fetus and usually resolves within 4 weeks after delivery, generally with no scarring or postinflammatory hyperpigmentation.1,2
Our patient was diagnosed clinically with PEP, and her pruritus was well controlled with oral antihistamines and topical steroids. The lesions faded over 3 to 4 weeks, and she had no sequelae from the rash. antigens, resulting in the presentation of BP180 to the maternal immune system.16 BP180 proteins in the placenta are then treated as foreign, leading to production of autoantibodies IgG and C3 against the extracellular noncollagenous 16A region of placental BP180, which is then believed to cross-react with BP180 in the skin.10,12,16 An autoimmune response is mounted with the activation of complement, immune complex deposition, chemoattraction of eosinophils, and subsequent degranulation, all of which leads to blister formation.16 Sex hormone fluctuation also has been hypothesized to play a role in the etiology of PG.16
Patients with PG initially present with intense pruritus,10,16 which can have a significant emotional impact.18 Pruritic erythema generally progresses to erythematous papules and plaques, which then progress into clustered papulovesicles or tense bullae.10,17,18 These lesions generally start on the abdomen, often including the umbilicus and periumbilical region and, in most cases, spread to the entire abdomen. The eruption may generalize to other parts of the body, most commonly the trunk and upper and lower extremities. Facial and mucous membrane involvement is rare.10,16,17
Patients commonly experience spontaneous remission in the later stages of pregnancy, although flares can occur after delivery. These flares can be severe but generally resolve within 4 weeks.11,16 Approximately 10% of newborns born to mothers with PG may have neonatal PG due to transfer of antibodies from mother to fetus.12 The eruption in newborns resolves spontaneously.12
Diagnosis of PG is based on a combination of clinical features, histology, and direct immunofluorescence (DIF).10 When needed, indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and immunoblotting may be used.10 HLA profiling also can be performed to look for HLA-DR3, HLA-DR4, or both.10,16
Histology of PG in the early stages, before development of bullae, shows dermal edema and a perivascular infiltrate of eosinophils, histiocytes, and lymphocytes.16,17 When bullae appear, histology shows subepidermal blisters with spongiosis and eosinophilic infiltrate.17 However, such findings also can be present in PEP, and further testing may be needed to differentiate the 2 conditions.16 DIF shows C3 deposition along the dermal-epidermal junction in 100% of PG cases;
CASE #2 Pemphigoid Gestationis
Pemphigoid gestationis (PG) is a blistering autoimmune disease of pregnancy resulting from autoantibodies against BP180, a hemidesmosomal dermoepidermal junction protein also known as BPAG 2 or collagen XVII.10-12 In 1872, John Laws Milton, MD, first described the condition, calling it herpes gestationis, a misnomer because the disease is not associated with a herpesvirus.10,13-15 The name was changed later to pemphigoid gestationis to reflect its autoimmune origin.11,14
Incidence estimates for PG vary between 1 in 20,000 to 1 in 60,000 pregnancies.11,16-18 PG occurs throughout the world and although some sources report no racial predilection,16 others describe increased frequency in individuals with lighter skin.18 The median age of onset of affected women is 26 to 32 years.16 Although PG usually occurs in the second or third trimester, it can occur at any point during the pregnancy or postpartum period.10,16,17 Some reports indicate that nearly half of PG cases occur in primigravids,10,17 whereas others describe a greater susceptibility in multiparous women.16,18
Although PG occurs most commonly in pregnant women, it has been diagnosed in women with trophoblastic tumors, such as choriocarcinoma and hydatidiform mole.10,11,17,18 Compared with the general population, patients with PG have increased rates of human leukocyte antigen (HLA)-B8, HLA-DR3, and HLA-DR4 alleles and are more likely to have other autoimmune diseases, such as Hashimoto thyroiditis, Graves disease, systemic lupus erythematosus, vitiligo, ulcerative colitis, alopecia areata, and pernicious anemia.17 In up to 50% of patients, PG recurs in subsequent pregnancies, often more severely.16 There are reports of subsequent pregnancies without PG followed by affected pregnancies; the reason for this variability is unknown.16
It has been proposed that PG arises from abnormal placental expression of major histocompatibility complex (MHC) class II
TABLE. Polymorphic Eruption of Pregnancy vs Pemphigoid Gestationis
Polymorphic Eruption of Pregnancy1-9 Pemphigoid Gestationis10-14,16-19
Dermatologic presentation • Pruritic papules • Urticarial plaques • Progresses to polymorphic features • Intense pruritus • Erythematous papules and plaques • Progresses to clustered papulovesicles, tense bullae
Epidemiology • More prevalent in twin and triplet pregnancies and among primigravid women • More common among White women
Potential risk factors • Larger belly sizes • Increased maternal weight gain and newborn birth weight • Male sex of fetus • Rh-positive maternal blood
Etiology • Uncertain • May be related to abdominal stretching and allergic-like reaction to collagen • Fetal DNA deposition in skin may create a graft-vs-host disease • Abnormal placental expression of MHC II • IgG antibodies and C3 proteins directed against
BP180 or collagen XVII
Characteristic location • Abdomen, within the striae • Spares the periumbilical region
Histology
Diagnosis • Epidermal and dermal edema • Dermal perivascular infiltrate • Mild focal spongiosis • Most cases have no C3 deposits along basement membrane • Early stage: dermal edema, perivascular infiltrate • Late stage: subepidermal blisters, spongiosis, eosinophilic infiltrate • C3 deposits along dermal-epidermal junction
• Clinical, based on symptoms and appearance of lesions • Biopsy with DIF • Clinical, based on symptoms and appearance of lesions • Biopsy with DIF • Indirect immunofluorescence • Immunoblotting • ELISA
• Median age of onset: 26-32 years
• Choriocarcinoma, hydatidiform mole, and trophoblastic tumors • Alleles to HLA-B8, HLA-DR3, and HLA-DR4 • Prior history of pemphigoid gestationis
• Umbilical region of the abdomen • Can spread to trunk and extremities
Treatment • Symptomatic • Topical and systemic corticosteroids • First-generation antihistamines • Cool baths, light cotton clothing, emollients • Symptomatic • Topical and systemic corticosteroids • Oral antihistamines
DIF, direct immunofluorescence; ELISA, enzyme-linked immunosorbent assay; HLA, human leukocyte antigen; Ig, immunoglobulin; MHC II, major histocompatibility complex class II antigens
this is much less common in PEP.3,16 One study found that immunohistochemistry staining shows C4 deposition along the basement membrane in PG that is not present in PEP.19 Thus, this method can help differentiate PG from other gestational dermatoses.16,19
Indirect immunofluorescence shows IgG autoantibodies against the basement membrane zone in 30% to 100% of patients with PG.18 Immunoblotting and ELISA generally reveal autoantibodies against BP180 and, less commonly, BP230.17 Although peripheral eosinophilia can be found and may correlate with PG severity, routine laboratory results in patients with PG generally are within normal limits. Antithyroid antibodies, immunoglobin levels, and erythrocyte sedimentation rates may be elevated.14
The most relevant conditions in the differential diagnosis for PG include the dermatoses of pregnancy including PEP, atopic eruption of pregnancy (AEP), and intrahepatic cholestasis of pregnancy (ICP). AEP is common and can be differentiated from PG because it occurs earlier, within the first and second trimesters of pregnancy. PG can be differentiated from PEP, which is clinically the most similar condition, through biopsy and DIF; PEP also characteristically spares
Dermatologic Look-Alikes
the umbilicus. Patients with ICP present with pruritus and develop secondary skin lesions from scratching. Jaundice and elevated bile acid levels in serum also can occur in patients with ICP, distinguishing this condition from PG.16 Other conditions to rule out include erythema multiforme, dermatitis herpetiformis, allergic contact dermatitis, bullous pemphigoid, cicatricial pemphigoid, drug-induced bullous disorders, linear IgA dermatosis, and acute urticaria.14,18
Treatment of PG is designed to treat itching and prevent new blisters. Management depends on the severity of the case. Mild, localized cases can be treated with topical corticosteroids and oral antihistamines. Severe cases may warrant systemic oral corticosteroid taper (prednisone or prednisolone at a dose ranging from 0.3 mg/kg to 0.5 mg/kg, tapered down over time).16,18
This patient’s clinical presentation and biopsy were consistent with PG. She was initially treated with topical steroids, which did not control her symptoms, and her rash continued to progress. She was started on oral prednisone, which controlled her symptoms and improved her rash. Her rash did not are after delivery or during prednisone taper. ■
Dina Zamil, BS, is a medical student at Baylor College of Medicine,Tara L. Braun, MD, is a resident in the Department of Dermatology at Baylor College of Medicine, Carly Dunn, MD, is resident in the Department of Dermatology at Baylor College of Medicine, and Christopher Rizk, MD, is a dermatologist a liated with Baylor College of Medicine in Houston, Texas.
References
1. Chouk C, Litaiem N. Pruritic urticarial papules and plaques of pregnancy. In: StatPearls. StatPearls Publishing; 2020. Updated August 14, 2020. Accessed April 17, 2021. http://www.ncbi.nlm.nih.gov/books/NBK539700/ 2. Sävervall C, Sand FL, Thomsen SF. Dermatological diseases associated with pregnancy: pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. Dermatol Res Pract. 2015;2015:979635. 3. Brandão P, Sousa-Faria B, Marinho C, Vieira-Enes P, Melo A, Mota L. Polymorphic eruption of pregnancy: review of literature. J Obstet Gynaecol. 2017;37(2):137-140. 4. Bourne G. Toxaemic rash of pregnancy. Proc R Soc Med. 1962;55(6): 462-464. 5. Lawley TJ, Hertz KC, Wade TR, Ackerman AB, Katz SI. Pruritic urticarial papules and plaques of pregnancy. JAMA. 1979;241(16):1696-1699. 6. Taylor D, Pappo E, Aronson IK. Polymorphic eruption of pregnancy. Clin Dermatol. 2016;34(3):383-391. 7. Holmes RC, Black MM. The speci c dermatoses of pregnancy: a reappraisal with special emphasis on a proposed simpli ed clinical classi cation. Clin Exp Dermatol. 1982;7(1):65-73. 8. Ghazeeri G, Kibbi AG, Abbas O. Pruritic urticarial papules and plaques of pregnancy: epidemiological, clinical, and histopathological study of 18 cases from Lebanon. Int J Dermatol. 2012;51(9):1047-1053. 9. Proietti I, Bernardini N, Tolino E, et al. Polymorphic eruption of pregnancy as a possible COVID-19 manifestation. Dermatol Ther. 2020;33(6):e14117. 10. Intong LR, Murrell DF. Pemphigoid gestationis: pathogenesis and clinical features. Dermatol Clin. 2011;29(3):447-452, ix. 11. Sadik CD, Lima AL, Zillikens D. Pemphigoid gestationis: toward a better understanding of the etiopathogenesis. Clin Dermatol. 2016;34(3): 378-382. 12. Cohen S, Strowd LC, Pichardo RO. Pemphigoid gestationis: a case series and review of the literature. J Dermatolog Treat. 2018;29(8):815-818. 13. Milton J. The Pathology and Treatment of Diseases of the Skin. Hardwicke; 1872. 14. Lipozencˇic´ J, Ljubojevic S, Bukvic´-Mokos Z. Pemphigoid gestationis. Clin Dermatol. 2012;30(1):51-55. 15. Black MM. The Neil Smith Memorial Lecture: John Laws Milton. The founder of St John’s Hospital for Diseases of the Skin. Clin Exp Dermatol. 2003;28(1):89-91. 16. Sävervall C, Sand FL, Thomsen SF. Pemphigoid gestationis: current perspectives. Clin Cosmet Investig Dermatol. 2017;10:441-449. 17. Daniel BS, Murrell DF. Review of autoimmune blistering diseases: the pemphigoid diseases. J Eur Acad Dermatol Venereol. 2019;33(9):1685-1694. 18. Fong M, Gandhi GR, Gharbi A, Hafsi W. Pemphigoid gestationis. In: StatPearls. StatPearls Publishing; 2021. Updated March 21, 2021. Accessed April 16, 2021. http://www.ncbi.nlm.nih.gov/books/NBK470287/ 19. Kwon EJ, Ntiamoah P, Shulman KJ. The utility of C4d immunohistochemistry on formalin- xed paraf n-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am J Dermatopathol. 2013;35(8):787-791.
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LEGAL ADVISOR
CASE
Missed Cues Lead to Abrupt Death
Physician assistant fails to recognize patient’s risk for sudden cardiac arrest.
ANN W. LATNER, JD
Mr A was a 45-year-old physician assistant (PA) who had been working in a midsized practice with several physicians, PAs, and nurse practition- ers for the past 6 years. He liked working with Dr S, his supervising physician, and appreciated having the autonomy to see his own patients.
One of Mr A’s patients was Mr P, a married security guard with 2 daughters in their 20s. The patient’s medical history included hypertension, dyslipidemia, situational anxiety, and seasonal allergies. One day, Mr P called the office to make an appointment, complaining of shortness of breath. Four days later, Mr P came in for his appointment with Mr A.
Mr P noted that for the past 3 months he has been getting winded very easily. “It’s worse if I try to exercise — then I huff and puff and can’t catch my breath,” noted Mr P. He also said he has heartburn and that when he exercises, his jaw hurts.
When questioned about the frequency of his symptoms, Mr P described the issues as intermittent but said he felt heartburn or “pressure” during light exercise. “I know I could stand to lose some weight or get in better shape,“ noted Mr P, “but when I try to push myself, I [get] out of breath and [feel] pressure in my ribs, so I stop.”
Mr P’s complaints of dyspnea on exertion, jaw pain, and epigastric pain are noted in his medical record. Mr A also recorded the patient’s vital signs: height, 5’6”; weight, 189 lb; BMI, 28.84. His sitting blood pressure was measured twice (150/88 mm Hg and 138/90 mm Hg). Oxygen saturation rate was 96% on room air.
Mr A noted in the record a normal physical examination and regular heart rate and rhythm, with normal S1 and S2 without murmurs, rubs, gallops, or clicks. An electrocardiogram was performed and showed a normal sinus rhythm.
Given the new onset of dyspnea on exertion associated with jaw and epigastric discomfort, Mr A planned to order stress echocardiography and have Mr P return in 2 to 4 weeks for a
One of the most challenging jobs of a clinician is recognizing when something should be treated as an emergency.
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.
