2024 Case Studies

June 2024 Case Study

Author: Nagasai Adusumilli, MD, MBA¹

1. Department of Dermatology, The George Washington University School of Medicine and Health Sciences

Patient History

A 60-year-old male with a medical history of HIV (updated CD4 count of 30) presented to the emergency department with headaches, disorientation, and acute onset vision loss. He was found to have an increasing number of skin lesions on the face for the past 3 weeks. Multiple well-demarcated, eroded papulonodules were seen on the nose and forehead (Figure 1). A punch biopsy of the dorsal nose showed the findings on hematoxylin and eosin in Figure 2.

Based on the clinical presentation and biopsy findings, which three stains would be most useful to highlight the underlying pathology?

A.) Verhoeff-Van Gieson
B.) Thioflavin T
C.) Periodic acid-Schiff
D.) Von Kossa
E.) Fontana- Masson
F.) Masson trichrome
G.) Toluidine blue
H.) Mucicarmine
I.) Fite
J.) HHV-8

Correct Answer: C, E, H

Explanation/Literature review:

In the setting of AIDS (CD4 count less than 50), the scattered, umbilicated, and eroded papules and nodules across the head and neck distribution (Figure 1) are suspicious for opportunistic infections. Even within just the infectious category, the differential diagnoses are broad, including molluscum, tuberculosis, leishmaniasis, monkeypox, cat scratch, secondary syphilis, and various mycoses. Histoplasma, Cryptococcus, Coccidioides, and Talaromyces are among the deep fungal infections that fit this clinical morphology.¹ Figure 2 shows a dermal infiltrate on high power, with innumerable fungal yeasts of different sizes within clear spaces of circular capsules. Yeasts of variable size and shape clustered within capsules are distinctly characteristic of Cryptococcus, particularly in the context of central nervous system (CNS) symptoms and molluscoid cutaneous findings.² Consequently, a fungal stain like PAS (answer choice C) can help highlight the yeasts.² Although Fontana-Masson is typically used to highlight melanin and the absence of melanin in vitiligo, the pleomorphic cryptococcal yeasts stain yellow-brown to black with Fontana-Masson (answer choice E).^2,3 Mucicarmine (answer choice H) stains pink the organism’s classic polysaccharide capsule,² which serves as the antiphagocytic virulence factor.

Cryptococcus is an encapsulated fungus found in bird droppings, with human transmission occurring through inhalation of the yeasts.⁴ The fungus then lies dormant in the hilar lymph nodes and lungs, walled off with granulomatous inflammation.⁴ During periods of immunocompromise, the fungus proliferates and disseminates throughout the body, including to the brain, bone, and skin.⁴ Cryptococcus demonstrates a tropism for the skin and brain,^5,6 so dermatologists must recognize cutaneous cryptococcal infection both clinically and under histopathology. Meningoencephalitis drives mortality in disseminated cryptococcal infection, so the CNS symptoms seen in this patient case must raise suspicion for disseminated Cryptococcus.⁷ The HIV pandemic led to a spike in incidence in many opportunistic infections, including cryptococcosis.⁸ Now with an estimated global incidence of 1 million cases per year,⁴ cryptococcosis must be on the differential for umbilicated papules and nodules, particularly in patients with immunocompromise. Additional settings of immunocompromise include patients with chronic corticosteroid use, solid organ transplants, and chronic tumor necrosis factor inhibitor use.⁵ Skin-limited disease from traumatic inoculation has been described but is rare.⁷ If Cryptococcus is identified in the skin, investigation for systemic involvement, especially in the CNS and lungs, is crucial.⁷

Incorrect stains in answer choices:³

Verhoeff-Van Gieson (choice A) – elastic fibers stain black. Example conditions: pseudoxanthoma elasticum, anetoderma, cutis laxa.

Thioflavin T (choice B) – amyloid stains yellow-green under fluorescence.

Von Kossa (choice D) – calcium salts stain black. Example conditions: calciphylaxis, calcinosis cutis, pseudoxanthoma elasticum.

Masson trichrome (choice F) – Mature collagen stains blue-green whereas smooth muscle stains red. Example conditions: scar vs. leiomyoma.

Toluidine blue (choice G) – mast cell granules and mucin stain purple. Example conditions: urticaria pigmentosa, connective tissue disease.

Fite (choice I) – partially acid-fast organisms such as Nocardia and atypical mycobacteria stain pink.

HHV-8 (choice J) – Kaposi sarcoma stains brown.

References:

1. Elewski BE, Hughey LC, Hunt KM, Kay RJ. Chapter 77 – Fungal Diseases. In: Dermatology. 5th Edition. Elsevier; 1343-1375.
2. Elston DM. Chapter 18 – Fungal infections. In: Dermatopathology. 3^rd Elsevier; 306-320.
3. Ferringer T, Ko CJ. Chapter 1 – The basics. In: Dermatopathology. 3^rd Elsevier; 1-35.
4. Meya DB, Williamson PR. Cryptococcal disease in diverse hosts. N Engl J Med. 2024 May 2;390(17):1597-1610. PMID: 38692293.
5. Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2016 Mar;30(1):179-206. PMID: 26897067.
6. Moe K, Lotsikas-Baggili AJ, Kupiec-Banasikowska A, Kauffman CL. The cutaneous predilection of disseminated cryptococcal infection in organ transplant recipients. Arch Dermatol. 2005 Jul;141(7):913-4. PMID: 16027320.
7. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 1;50(3):291-322. PMID: 20047480.
8. Durden FM, Elewski B. Cutaneous involvement with Cryptococcus neoformans in AIDS. J Am Acad Dermatol. 1994 May;30(5 Pt 2):844-8. PMID: 8169258

May 2024 Case Study

Authors: Sara Abdel Azim, MS^1,2, Kamaria Nelson, MD¹, Karl Saardi, MD¹

1. Department of Dermatology, George Washington University School of Medicine and Health Sciences
2. Georgetown University School of Medicine

A 63-year-old female with a past medical history of substance use disorder and breast cancer status post bilateral mastectomy presented with large, violaceous, hemorrhagic purpuric plaques on the chest and bilateral axilla (Fig 1). She had a fever of 104 F and heart rate of 140 bpm. She was admitted to the hospital for atrial fibrillation with rapid ventricular response and was found to be thrombocytopenic with a positive blood culture for streptococcus pyogenes. Coagulation studies revealed a prolonged PTT, an elevated INR level and a low fibrinogen level.

Which of the following is the diagnosis?

A.) Anti-phospholipid syndrome
B.) Calciphylaxis
C.) ANCA associated vasculitis
D.) Purpura fulminans
E.) Warfarin-induced skin necrosis

Correct Answer: D – Purpura fulminans

Explanation/Literature review:

Based on the patient’s manifestation of large, hemorrhagic purpuric plaques, acute systemic infection, and concurrent findings of disseminated intravascular coagulation on laboratory tests, she was diagnosed with purpura fulminans (choice D).

Purpura fulminans is a dermatologic emergency involving dysfunction of hemostasis, leading to a hypercoagulable state and ultimately disseminated intravascular coagulation and dermal vascular thrombosis.¹  Patients present with ecchymotic skin lesions that may progress to gangrene and result in amputation. Acute infectious purpura fulminans is the most common subtype and occurs in the setting of sepsis, with endotoxin producing gram-negative bacteria triggering an acquired consumption of protein C and S and antithrombin III. ^2,3 The most common pathogens are meningococcus and streptococcus pneumoniae, though streptococcus pyogenes has also been implicated.⁴

Antiphospholipid syndrome (APS) (choice A) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin antibody, and anti-B2-glycoprotein antibody, that damage endothelial cells and disrupt procoagulation defenses, promoting thrombosis.⁵ Livedo reticularis the most frequently observed lesion, though APS can also cause ulcerations, digital gangrene, subungual splinter hemorrhages, superficial venous thrombosis, and thrombocytopenic purpura. APS occurs secondary to autoimmune disease, most commonly systemic lupus erythematosus (40% of secondary cases)⁶ or can be primary. Though infections such as borrelia burgdorferi, treponema, HIV, and leptospira have been implicated in the induction of antiphospholipid antibody formation, septicemia is not a common cause of APS and associated disseminated intravascular coagulation is a less common outcome(choice A).⁷

Calciphylaxis  (choice B) is caused by cutaneous arteriolar calcification that leads to subsequent tissue ischemia.⁸ It presents as violaceous or erythematous, painful cutaneous lesions or subcutaneous nodules and nonhealing wounds, commonly involving adipose-dense regions such as the abdomen, thighs, and buttocks. Calciphylaxis most commonly presents in patients with end stage renal disease but can also occur in patients with acute renal failure, normal renal function, or early stages of chronic kidney disease.

Antineutrophilic cytoplasmic antibody (ANCA) (choice C) associated vasculitis are a heterogenous group of autoimmune conditions that cause inflammation of blood vessels.⁹ The most common cutaneous manifestation is palpable purpura, though presentation may consist of polymorphic lesions on a background of livedo reticularis.¹⁰ This group of conditions has multisystemic effects, often involving the kidneys, sinopulmonary tract, gastrointestinal tract, and lungs, depending on subtype. Infection should be excluded before making the diagnosis.

Warfarin-induced skin necrosis (choice E) occurs in individuals under warfarin treatment with a thrombophilic history or after initiating warfarin therapy with a large loading dose or without concomitant heparin

References

1. Bektas F, Soyuncu S. Idiopathic purpura fulminans. Am J Emerg Med. May 2011;29(4):475.e5-6. doi:10.1016/j.ajem.2010.04.022
2. Perera T, Murphy-Lavoie H. Purpura Fulminans. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023.
3. Kim MC, Patel J. Recognition and Management of Acute Purpura Fulminans: A Case Report of a Complication of Neisseria meningitidis Bacteremia. Cureus. Mar 04 2021;13(3):e13704. doi:10.7759/cureus.13704
4. Okuzono S, Ishimura M, Kanno S, et al. Streptococcus pyogenes-purpura fulminans as an invasive form of group A streptococcal infection. Ann Clin Microbiol Antimicrob. Jul 09 2018;17(1):31. doi:10.1186/s12941-018-0282-9
5. Magdaleno-Tapial J, Valenzuela-Oñate C, Pitarch-Fabregat J, et al. Purpura fulminans-like lesions in antiphospholipid syndrome with endothelial C3 deposition. JAAD Case Rep. Oct 2018;4(9):956-958. doi:10.1016/j.jdcr.2018.09.006
6. Bustamant J, Goyal A, Singhal M. Antiphospholipid Syndrome. Treasure Island (FL): StatPearls Publishing. Accessed May 2, 2024. https://www.ncbi.nlm.nih.gov/books/NBK430980/
7. Asherson RA, Espinosa G, Cervera R, et al. Disseminated intravascular coagulation in catastrophic antiphospholipid syndrome: clinical and haematological characteristics of 23 patients. Ann Rheum Dis. Jun 2005;64(6):943-6. doi:10.1136/ard.2004.026377
8. Westphal S, Plumb T. Calciphylaxis. Treasure Island (FL): StatPearls Publishing. Accessed May 2, 2024. https://www.ncbi.nlm.nih.gov/books/NBK519020/
9. Qasim A, Patel J. ANCA Positive Vasculitis. Treasure Island (FL): StatPearls Publishing. Accessed May 2, 2024. https://www.ncbi.nlm.nih.gov/books/NBK554372/

April 2024 Case Study

Author: Adam Rosenfeld, MD¹

1. Department of Dermatology, George Washington University School of Medicine and Health Sciences

A 79-year-old gentleman presented to the ED with altered mental status. The day prior, his family had found him “confused and weak” which resolved by later that evening. However, the next day, he was “dazed” had difficulty walking, which sparked the presentation to the emergency room. On examination, the patient was found to have an erythematous to violaceous, somewhat reticulated plaque on the posterior neck with a background of mottled, reddish-brown patches (figure 1). On the left hand, he was found to have eroded erythematous papules of the MCPs, PIPs, DIPs and in between the joint spaces (figure 2).

Based on the most likely diagnosis, which of the following would not be a reasonable part of the work up in adult patients?

A.) Pulmonary function tests
B.) CA 19-9
C.) CT chest/abdomen/pelvis
D.) MRI brain
E.) EKG/echocardiogram

Correct Answer: D – MRI Brain

Explanation/Literature review:

Poikiloderma of the neck, with classic “Gottron’s papules” on the left hand, are most concerning for a diagnosis of dermatomyositis. Dermatomyositis (DM) is an idiopathic multi-system inflammatory condition that is of presumed autoimmune pathogenesis¹. It classically presents with a symmetric, proximal, extensor inflammatory myopathy and a characteristic cutaneous eruption. Dermatomyositis has a bimodal age distribution, with both adult and juvenile forms. The pathogenesis is believed to be a result of an immune mediated process triggered by external factors (malignancy, infectious agents) in genetically predisposed individuals¹. Additionally, the interferon pathway has recently been implicated as critical in its pathophysiology². Serum antinuclear autoantibodies are often present which further supports an autoimmune etiology. The cutaneous features include pathognomonic findings of Gottron’s papules (pink to violaceous papules on dorsal hands) and heliotrope eruption (pink-violaceous erythema involving the upper eyelids). Other findings include poikiloderma of the upper back (“shawl” sign) and upper chest, nailfold abnormalities (periungal erythema, dilated capillary nail bed loops) as well as scaly erythema of the lateral thighs (holster sign) and scalp involvement³. In juvenile DM, calcinosis cutis is common, particular on the extensor surfaces¹. When evaluating muscle disease, a detailed history assessing proximal muscle groups as well as strength testing should be performed. Cutaneous disease precedes the appearance of myositis by 3-6 months in almost 50% of cases while 10% have myositis prior to any skin findings³. Importantly, DM exists on a spectrum where either skin or muscle phenotype can predominate and can also present as amyopathic. Diagnosis is often made clinically without a skin biopsy however it may be helpful if exam findings are subtle or atypical. Histopathology shows an interface dermatitis with dermal mucin deposition, which would be indistinguishable from lupus erythematosus³. Myositis specific autoantibodies in recent years have been helpful in identifying associated phenotypes. Anti-Mi-2 is associated with both adult and juvenile DM, with milder muscle disease and a good response to treatment¹. Anti-MDA5 is associated with rapidly progressive interstitial lung disease and cutaneous ulcerations³. Anti-TIF-1 gamma and Anti-NXP-2 are most closely associated with malignancy³. Once DM is diagnosed, additional work up is required including but not limited to serum CK/aldolase, EMG or MRI of muscle, pulmonary function tests (answer choice A), EKG/echocardiogram (answer choice E) and barium swallow or manometry¹. Dermatomyositis and its association with malignancy is well known, with a recent study showing the risk to be 6x higher than the general population⁴.  Most common malignancies include ovarian, colon, breast, lung, hematopoietic and nasopharyngeal cancer, particularly in Asian populations⁵. Although no specific guidelines exist, initial work up includes CBC, CMP and UA as well as chest x-ray and age-appropriates screening. CT chest/abdomen/pelvis (answer choice C) is typically performed if the initial work up is worrisome or in patients that are considered high risk. CA 125 and CA 19-9 (answer choice B) can be considered based on individual patient risk factors. Brain MRI (answer choice D) is not routinely part of the work up as brain neoplasms/malignancies are not strongly associated with DM. Treatment includes skin directed therapy with topical steroids, calcineurin inhibitors and photoprotection¹. Historically for patients with severe disease, first line therapy included systemic steroids plus disease modifying antirheumatic drugs such as methotrexate, azathioprine, or mycophenolate mofetil². However, IVIG was recently FDA approved for DM and has shown to be very effective regardless of disease severity⁶. Rituximab or cyclophosphamide are sometimes added, particularly when there is lung or severe muscle involvement⁷.  Apremilast has been shown to help with recalcitrant disease and can be considered as an adjunct treatment⁸. JAK inhibitors as well as more targeted therapy (anti-IFN antibodies) will likely play a more substantial role in the future ^9,.10.

Incorrect answer choices

(choice A) – Pulmonary complications are a well-known cause of morbidity and mortality in dermatomyositis and are a critical part of the work up.

(choice B) – CA19-9 screens for pancreatic cancer and is sometimes indicated as part of the work up based on patient risk factors.

(choice C) – CT chest/abdomen/pelvis is often indicated in adult patients to evaluate for malignancy.

(choice E) – EKG or echocardiogram is performed as conduction defects or other arrhythmias can be seen and do not always present with symptoms.

References

1. 1. Bolognia, J., Schaffer, J., & Cerroni, L. (2018). Dermatology (Fourth edition.). Philadelphia,Pa: Elsevier.
   2. Bolko L, Jiang W, Tawara N, Landon-Cardinal O, Anquetil C, Benveniste O, Allenbach Y. The role of interferons type I, II and III in myositis: A review. Brain Pathol. 2021 May;31(3):e12955. doi: 10.1111/bpa.12955. PMID: 34043262; PMCID: PMC8412069.
   3. Cobos GA, Femia A, Vleugels RA. Dermatomyositis: An Update on Diagnosis and Treatment. Am J Clin Dermatol. 2020 Jun;21(3):339-353. doi: 10.1007/s40257-020-00502-6. PMID: 32096127.
   4. Hu T, Vinik O. Dermatomyositis and malignancy. Can Fam Physician. 2019 Jun;65(6):409-411. PMID: 31189628; PMCID: PMC6738379.
   5. Leatham H, Schadt C, Chisolm S, Fretwell D, Chung L, Callen JP, Fiorentino D. Evidence supports blind screening for internal malignancy in dermatomyositis: Data from 2 large US dermatology cohorts. Medicine (Baltimore). 2018 Jan;97(2):e9639. doi: 10.1097/MD.0000000000009639. PMID: 29480875; PMCID: PMC5943873.
   6. Werth VP, Aggarwal R, Charles-Schoeman C, Schessl J, Levine T, Kopasz N, Worm M, Bata-Csörgő Z. Efficacy of intravenous immunoglobulins (IVIg) in improving skin symptoms in patients with dermatomyositis: a post-hoc analysis of the ProDERM study. EClinicalMedicine. 2023 Oct 2;64:102234. doi: 10.1016/j.eclinm.2023.102234. PMID: 37799613; PMCID: PMC10550512.
   7. (n.d.). Retrieved April 10,2024, from https://www.uptodate.com/contents/diagnosis-and-differential-diagnosis-of-dermatomyositis-and-polymyositis-in-adults.
   8. Bitar C, Ninh T, Brag K, Foutouhi S, Radosta S, Meyers J, Baddoo M, Liu D, Stumpf B, Harms PW, Saba NS, Boh E. Apremilast in Recalcitrant Cutaneous Dermatomyositis: A Nonrandomized Controlled Trial. JAMA Dermatol. 2022 Dec 1;158(12):1357-1366. doi: 10.1001/jamadermatol.2022.3917. PMID: 36197661; PMCID: PMC9535502.
   9. Paik JJ, Lubin G, Gromatzky A, Mudd PN Jr, Ponda MP, Christopher-Stine L. Use of Janus kinase inhibitors in dermatomyositis: a systematic literature review. Clin Exp Rheumatol. 2023 Mar;41(2):348-358. doi: 10.55563/clinexprheumatol/hxin6o. Epub 2022 Jun 28. PMID: 35766013; PMCID: PMC10105327.
   10. Aggarwal, R., Domyslawska, I., Carreira, P., Fiorentino, D., Sluzevich, J., Werth, V., Banerjee, A., Chu, M., Oemar, B., Salganik, M., Sloan, A., Vincent, M., & Peeva, E. (2023, June 1).POS1207 efficacy and safety of ANTI-IFNΒ-SPECIFIC monoclonal antibody, PF-06823859, on myositis: Phase 2 study in patients with moderate-to-severe dermatomyositis. Annals of the Rheumatic Diseases. https://ard.bmj.com/content/82/Suppl_1/936.1.citation-tools

March 2024 Case Study

Authors: Cleo Whiting, BA¹, Emily Murphy, MD¹, Karl Saardi, MD¹

1. Department of Dermatology, George Washington University School of Medicine and Health Sciences

A 57-year-old female with a past medical history of hypertension presented with numerous pink to skin-colored, soft, mildly tender papules and nodules on the right posterior shoulder, upper arm, and forearm (figure 1A and 1B) that appeared 15 years ago. She also complained of several deeper and larger growths on the bilateral thighs and left hip that appeared a few years ago. A shave biopsy of one of the papules was performed (figure 2A and 2B, hematoxylin-eosin staining). Immunohistochemistry was positive for S100 and negative for smooth muscle actin. A buccal swab was obtained for sequencing of the NF1 gene and the results were negative for pathogenic mutations.

Based on the clinical presentation and biopsy findings, what risks should the patient be counseled about?

A.) None, reassurance only
B.) Risk of renal cell carcinoma
C.) Risk of malignant peripheral nerve sheath tumor
D.) Potential inheritance of condition by offspring
E.) B & D
F.) C & D

Correct Answer: F

Explanation/Literature review:

Given the segmental distribution of biopsy-confirmed neurofibromas and negative genetic testing, the patient was diagnosed with mosaic neurofibromatosis type 1 (NF1). Also referred to as segmental or localized NF1, this condition results from a post-zygotic pathogenic mutation in one copy of the NF1 gene.¹ Mosaic NF1 is a rare, heterogeneous disorder characterized by localized cutaneous or neural findings typical of generalized NF1, such as neurofibromas, intertriginous freckling, and multiple, large cafe-au-lait macules.² The affected NF1 gene encodes for the tumor suppressor protein neurofibromin, a GTPase-activating protein that regulates the RAS-MAPK pathway; biallelic loss of function of NF1 leads to the development of neurofibromas and other NF1-associated tumors.³

There are no specific guidelines for the management of mosaic NF1, although individuals with this condition may experience complications typical of generalized NF1, including the transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumors (MPNSTs) (choice C), so reassurance alone is not appropriate (choice A).^2,4,5 Although rare, gonadal mosaicism is also possible and offspring of the individual can acquire generalized NF1 (choice D).⁵ The diagnostic criteria for mosaic NF1 have been recently re-established, and revealing NF1 mutations in affected skin, but not in seemingly unaffected tissues like saliva and blood, is one way to make the diagnosis.⁶

While individuals with mosaic NF1 have an increased risk of malignancy during their lifetime, renal cell carcinoma is associated with hereditary leiomyomatosis and renal cell cancer [HLRCC], also known as Reed syndrome,⁷ and neurofibromatosis type 2 (choice B, E).⁸ Characterized by cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma, HLRCC is caused by a pathogenic mutation in the fumarate hydratase gene and inherited in an autosomal dominant pattern with variable penetrance.⁷

References

1. Tinschert S, Naumann I, Stegmann E, et al. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet. 2000;8(6):455-459. doi:10.1038/sj.ejhg.5200493
2. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56(11):1433-1443. doi:10.1212/wnl.56.11.1433
3. Maertens O, De Schepper S, Vandesompele J, et al. Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet. 2007;81(2):243-251. doi:10.1086/519562
4. Stewart DR, Korf BR, Nathanson KL, Stevenson DA, Yohay K. Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20(7):671-682. doi:10.1038/gim.2018.28
5. García-Romero MT, Parkin P, Lara-Corrales I. Mosaic Neurofibromatosis Type 1: A Systematic Review. Pediatr Dermatol. 2016;33(1):9-17. doi:10.1111/pde.12673
6. Legius E, Messiaen L, Wolkenstein P, et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med. 2021;23(8):1506-1513. doi:10.1038/s41436-021-01170-5
7. Scharnitz T, Nakamura M, Koeppe E, et al. The spectrum of clinical and genetic findings in hereditary leiomyomatosis and renal cell cancer (HLRCC) with relevance to patient outcomes: a retrospective study from a large academic tertiary referral center. Am J Cancer Res. 2023;13(1):236-244. Published 2023 Jan 15.
8. Paintal A, Tjota MY, Wang P, et al. NF2-mutated Renal Carcinomas Have Common Morphologic Features Which Overlap With Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: A Comprehensive Study of 14 Cases. Am J Surg Pathol. 2022;46(5):617-627. doi:10.1097/PAS.0000000000001846

February 2024 Case Study

Authors: Nagasai Adusumilli, MD, MBA1

1. Department of Dermatology, The George Washington University School of Medicine and Health Sciences

A 75-year-old male with a medical history of metastatic renal cell carcinoma, undergoing treatment with multiple systemic therapies, presented with 3 weeks of pink lesions on his hands, feet, and scrotum, with exquisite pain limiting ability to hold a pen and ambulate. Findings on the hands and feet are shown in Figure 1, and scrotal findings are shown in Figure 2. Notably, mucosa of the eyes, nose, mouth, urethral meatus, and anus were not involved. The patient experienced symptomatic improvement with 2 days of high potency topical corticosteroids and topical keratolytics.

Based on the clinical presentation, which of the following categories of medications has been most extensively implicated for this drug reaction?

A.) PD-1 inhibitors
B.) Beta-lactam antibiotics
C.) Aromatic anticonvulsants
D.) Sulfonamides
E.) Multikinase inhibitors

Correct Answer: E.) Multikinase inhibitors

Explanation of Correct Answer:

This patient’s clinical history and findings of multiple tender, pink-red thin macules and patches with a dusky center in the interdigital spaces of the hands, on the palmar surfaces of the fingers, and on the heels of the feet, along with scrotal desquamation, were consistent with hand-foot skin reaction (HFSR) and scrotal erythema, secondary to axitinib, a tyrosine kinase inhibitor of the vascular endothelial growth factor (VEGF) pathway. HFSR is classically characterized by discrete, exquisitely painful lesions with a halo of erythema, and hyperkeratotic lesions localized to sites of high contact, friction, and pressure, such as tips of fingers and toes, skin overlying metacarpophalangeal or interphalangeal joints, and heels.^1,2 HFSR tends to develop within 2-4 weeks of starting multikinase inhibitors, such as sorafenib, sunitinib, cabozantinib, and axitinib (choice E), with pain that can impair range of motion, weight bearing, and overall function.^1,2 Although scrotal involvement secondary to multikinase inhibitors is not as common, scrotal erythema, desquamation, and even ulceration have been reported.³

As newer immunotherapies and small molecule inhibitors are increasingly approved for more indications, identifying common and distinct drug reactions is integral to dermatology. Although skin reactions to any medication can be varied and atypical for individual patients, the morphology can be the key to diving deeper into the medical history to pinpoint the culprit, particularly as comorbidities and polypharmacy increase. Adverse skin eruptions from programmed cell death protein 1 (PD-1) inhibitors (choice A), such as pembrolizumab and nivolumab, more frequently present as morbilliform dermatoses, pruritus, lichenoid eruptions, psoriasiform dermatitis, and bullous pemphigoid.⁴ Although beta-lactam antibiotics encompass many medications, such as penicillins, cephalosporins, carbapenems, and monobactams, with a wide range of clinical presentations for drug reactions, the class overall is one of the most common causes of acute generalized exanthematous pustulosis⁵ (choice B). Aromatic anticonvulsants, such as phenytoin, carbamazepine, and phenobarbital (choice C) are commonly implicated in drug induced hypersensitivity syndrome (DIHS), previously drug reaction with eosinophilia and systemic symptoms (DRESS), and in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).⁵ Similarly, drug reactions from sulfonamides (choice D) have multiple possible presentations, but exanthematous eruption, fixed drug eruption, and SJS/TEN are the most characteristic.⁵

HFSR is often used interchangeably with palmoplantar erythrodysthesia, or hand-foot syndrome, which was initially described as a subset of toxic erythema of chemotherapies, such as taxanes, cytarabine, capecitabine, anthracyclines, and systemic 5-fluorouracil. Although HFSR can clinically appear similar to hand-foot syndrome, they are separate drug reactions, with the localized hyperkeratotic lesions with a rim of erythema distinct from the symmetric erythema, edema, paresthesia, and dysesthesia seen with hand-foot syndrome from cytotoxic chemotherapies. A high density of eccrine glands is thought to drive the skin manifestations of hand-foot syndrome⁵ whereas inhibited vascular repair mechanisms in fibroblasts and endothelial cells via VEGF and platelet-derived growth receptor (PDGFR) are hypothesized to predispose areas of trauma to HFSR.⁶ In fact VEGF and PDGFR inhibitors, such as sorafenib, sunitinib, cabozantinib, and axitinib are among the multikinase inhibitors reported to cause HFSR.^1,3,6

Contrary to the nomenclature, the tender erythematous patches and plaques are not limited to just the hands and feet. Flexural surfaces and bony prominences can also be affected. Identifying that each figure of this case illustrates areas of high friction or pressure is key to clinching the diagnosis, even without knowing the specific medications that can treat metastatic renal cell carcinoma. Grading the severity of cutaneous adverse events dictates the overall management strategy.⁷ Because these symptoms are limiting self-care activities of daily living, this patient has a grade 3 cutaneous adverse event,⁷ warranting collaboration with oncology colleagues to consider dose reduction, discontinuation, or temporary cessation of the causative anticancer agent.¹ In the interim, high potency topical corticosteroids and topical keratolytics, such as urea cream, may provide symptomatic relief.^1,8

References:

1. Lacouture ME, Wu S, Robert C, at al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008 Sep;13(9):1001-11. PMID: 18779536.
2. Kaul S, Kaffenberger BH, Choi JN, Kwatra SG. Cutaneous adverse reactions of anticancer agents. Dermatol Clin. 2019 Oct;37(4):555-568. PMID: 3146695.
3. Zuo RC, Apolo AB, DiGiovanna JJ, et al. Cutaneous adverse effects associated with the tyrosine-kinase inhibitor cabozantinib. JAMA Dermatol. 2015 Feb;151(2):170-7. PMID: 25427282.
4. Adusumilli NC, Friedman AJ. Treating cutaneous immune-related adverse events from immune checkpoint blockade. J Drugs Dermatol. 2021 Oct 1;20(10):1133-1134. PMID: 34636526.
5. Valeyrie-Allanore L, Obeid G, Revuz J. Chapter 21 – Drug Reactions. In: Dermatology. Fourth Edition. Elsevier; 348-375.
6. Fischer A, Wu S, Ho AL, Lacouture ME. The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and meta-analysis. Investigational new drugs. 2013;31(3):787-797. PMID: 23345001.
7. NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 data files. 2017. https://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed 20 Jan 2024.
8. Ren Z, Zhu K, Kang H, et al. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015 Mar 10;33(8):894-900. PMID: 25667293.

January 2024 Case Study

Authors: Sapana Desai & Nidhi Shah

A 29-year-old Caucasian male with history of asthma and atopic dermatitis presents with a multifocal, burning, and pruritic rash that erupted three weeks ago. On physical exam, there are innumerable, erythematous, reddish-brown papules, some with central hemorrhagic crusting spread along the chest, abdomen, and upper extremities, Figure 1. Dermatopathology findings from a subsequent punch biopsy are shown in Figure 2.

Which of the following diagnosis is the patient at an increased risk of developing?

A) Dermatomyositis
B) Postherpetic Neuralgia
C) Acute Myelogenous Leukemia
D) Mucha-Habermann Disease
E) Iron Deficiency Anemia

.           

Answer: (D) Mucha-Habermann Disease

Explanation of Correct Answer:

This patient’s clinical presentation coupled with a biopsy revealing vacuolar interface dermatitis, lymphocytes in every vacuole, erythrocyte extravasation, keratinocyte necrosis, and superficial and deep perivascular lymphoid infiltrative, is indicative of pityriasis lichenoides et varioliformis acuta (PLEVA).¹

PLEVA is an idiopathic, benign, cutaneous inflammatory dermatosis with increased predilection for the trunk, proximal extremities, and flexural regions. The eruption is polymorphous, as lesions exist in all stages of development, and successive crops of lesions can last from a few weeks to months or even years before resolution.^1,2 The disease does not discriminate by race or gender and primarily affects children and young adults, with a slight male predominance. While exact etiology and pathogenesis of PLEVA remains unknown, it is speculated to be an inflammatory reaction triggered by certain infectious agents with pathogens such as Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), varicella-zoster virus (VZV), Group A Streptococcus, and herpes simplex virus type 2, an inflammatory response secondary to T-cell dyscrasia, or an immune complex-mediated hypersensitivity.² PLEVA may also develop following the use of certain medications including but not limited to atezolizumab, pembrolizumab, and topical diphenylcyclopropenone.^1,2,3

Although rare, Mucha-Habermann disease (D) may follow an existing diagnosis of PLEVA or occur de novo.^2,3 Patients affected by FUMHD present with necrotic papules that progress to plaques and large coalescent ulcers. Skin ulceration can be extensive and painful, including oral and genital mucosa. Common systemic symptoms include high fever, abdominal pain, diarrhea, central nervous system manifestations, joint pain, respiratory complications, and death.^1,2,3

Explanation of Incorrect Answers:

Dermatomyositis (A) is an inflammatory myopathy with autoimmune pathogenesis affecting women more commonly than men, with a bimodal peak of incidence between ages 5 and 14 and ages 45 and 65. Clinical presentation classically encompasses a heliotrope rash (periorbital erythema with edema, occasionally involving the cheeks and nose), Holster sign (symmetric poikiloderma of the lateral thighs below the greater trochanter), and V-sign (confluent erythematous patches over the upper central chest and lower anterior neck).^3,4  Dermatomyositis is sub-classified into adult-onset disease and juvenile disease (JDM). Serum antinuclear autoantibodies are often present, as are other myositis-specific autoantibodies, which are useful as prognostic indicators while aiding in diagnosis and management of disease. Dermatomyositis is related to and possibly results from an immune-mediated process triggered by outside factors like drugs, infectious agents, and malignancy in individuals with genetic predisposition.⁴

Postherpetic neuralgia (B) is regarded as the most common long-term complication of reactivation of the varicella-zoster virus (VZV), also known as shingles.^3,5 VZV is characterized by prodrome of pain/burning followed by the onset of a rash by 7 to 10 days. The distinctive rash presents as crops of erythematous vesicles that evolve into pustules and crusts, often in a dermatomal distribution. The hallmark clinical manifestation of postherpetic neuralgia is a lancinating/burning pain in a unilateral dermatomal pattern that persists for three or more months after the onset of a herpes zoster outbreak.⁵ Well-established risk factors for postherpetic neuralgia include age, severe immunosuppression, the presence of a prodromal phase, allodynia, ophthalmic involvement, and diabetes mellitus.^3,5 Although treatment for postherpetic neuralgia is challenging, traditional non-invasive first-line therapeutic approaches include oral and topical medications, such as gabapentin, pregabalin, tricyclic antidepressants, and lidocaine 5% patch.³

Sweet syndrome is associated with Acute Myelogenous Leukemia (C), a myeloproliferative disorder. Sweet syndrome, or acute febrile neutrophilic dermatosis, is a rare cutaneous disorder characterized by the abrupt development of painful, tender, erythematous plaques or nodules, fever greater than 38^*C, and a nodular perivascular neutrophilic dermal infiltrate without evidence of vasculitis on histologic examination.^6,7 Sweet syndrome may occur before, at the time of or after the diagnosis of malignancy. When associated with malignancy, it is more likely to be associated with older age of onset and cytopenia, and accounts for 15-20% of total cases of Sweet syndrome.⁶ While the exact pathogenesis of Sweet syndrome is elusive, genetic factors such as HLA-B54, MEFV gene mutations, and chromosome 3q abnormalities have shown to be contributory.^6,7

Iron Deficiency Anemia (E) may be associated with Blue Rubber Bleb Nevus Syndrome [BRBNS/ Bean’s Syndrome]. Patients have characteristic cutaneous findings of multiple blue to violaceous soft and compressible nodules on the skin or mucous membranes that present at birth or in early childhood and develop numerous venous malformations involving the skin and gastrointestinal tract over their’ lifetime.^8,9 Typical lesions range in size from a few millimeters to up to 4 centimeters in diameter, are rubbery in consistency, and gradually evolve with time eliciting pain most prevalent at night.⁸ Uniquely, lesions swell in gravity-dependent positions, and patients exhibit focal areas of hyperhidrosis overlying these lesions. Although most cases of BRBNS are sporadic, autosomal dominant inheritance has been suggested, as well as studies reporting stem cell factor/c-kit signaling systems contributing to vascular overgrowth. Lower gastrointestinal bleeding is the most common symptom ranging from obscure to massive bleeding leading to severe iron deficiency anemia. Other rare complications may include perforation, intussusception, intestinal torsion, disseminated intravascular coagulation, and thrombocytopenia.^8,9

References

1. Pereira, N., Brinca, A., Brites, M., Juliao, M. Tellechea, O., Goncalo, M. Pityraisis Lichenoides et Varioliformis Acuta: Case Report and Review of the Literature. Case Rep Dermatol. March 2012; 4(1): 61-65.
2. Teklehaimanot, F., Gade, A., Rubenstein, R. Pityriasis Lichenoides Et Varioliformis Acuta (PLEVA). StatPearls. 2023.
3. Bolognia, J., Schaffer, J., & Cerroni, L. (2018). Dermatology (Fourth edition.). Philadelphia,Pa: Elsevier.  of clinical medicine. Retrieved August 11, 2022, from https://pubmed.ncbi.nlm.nih.gov/32516921/
4. DeWane ME, Waldman R, Lu J. Dermatomyositis: clinical features and pathogenesis. Journal of the American Academy of Dermatology. 2020 Feb 1;82(2):267-81.
5. Gruver, C., Guthmiller, K. Postherpetic Neuralagia. 2023.
6. Guarneri, C., Wollina, U., Lotti, T., Maximov, G., Lozev, I., Gianfaldoni, S., Pidakev, I., Lotti, J., Tchernev, G. Sweet’s Syndrome (SS) in the Course of Acute Myeloid Leukemia. Open Access Maced Journal Medical Sciences. January 2018; 6(1): 105-107.
7. Vashisht, P., Goyal, A., Holmes, M. Sweet Syndrome. 2023.
8. Moghadam, A., Bagheri, M., Eslami, P., Farokhi, E., Asl, A., Khavaran, K., Iravani, S., Saeedi, S., Mehrvar, A., Dooghaie-Moghadam, M. Blue Rubber Bleb Nevus Syndrome because of 12 Years of Iron Deficiency Anemia in a Patient by Double Balloon Enteroscopy; A Case Report and Review of Literature. Middle East Journal of Digestive Diseases. 2021; 13(2): 153-159.
9. Hu, Z, Lin, X., Zhong, J., He, Qingfang., Peng, Q., Xiao, J., Chen, B., Zheng, J. Blue Rubber Bleb Nevus Syndrome with the Complication of Intussusception: A Case Report and Literature Review. Medicine (Baltimore). 2020; 99(28).