CASE OF THE WEEK
A 55-year-old male with a long history of HIV presents with multiple ulcerated lesions on the glans penis and penile shaft. He has a history of scrotal squamous cell carcinoma and a non- healing ulcer measuring approximately 1.5 cm by 1.0 cm. The ulcer was biopsied due to suspicion of squamous cell carcinoma. A 55-year-old HIV-positive male with a history of scrotal squamous cell carcinoma presents with multiple ulcerated penile lesions and a non-healing ulcer suspicious for carcinoma. Twitter: Mehrnaz Movssaghi, ID:Mehrnazmvs Contributors :
Dr. Mahmut Akgul, M.D.
Dr. Mehrnaz Movassaghi, M.D.
What is the most likely diagnosis?
Squamous cell carcinoma in situ
Syphilis
Herpes simplex virus (HSV)
Kaposi’s sarcoma
Fungal infection
Which immunohistochemical assays should be performed?
p16
CD3
CD34
HSV-1/HSV-2
Periodic acid–Schiff (PAS)
Quiz 1: Herpes simplex virus (HSV)
Quiz 2: HSV-1/HSV-2
Herpes simplex virus (HSV) infection
Genitourinary herpes caused by herpes simplex virus type 2 (HSV-2) and increasingly by herpes simplex virus type 1 (HSV-1) is a major public health problem due to its high prevalence and recurrence. This review will cover the pathology and histology of genitourinary herpes based on recent studies and case reports. Viral Characteristics HSV-1 and HSV-2 are double-stranded DNA viruses from the Herpesviridae family. They establish latency in sensory neurons and reactivate periodically to cause recurrent lesions. HSV-2 is the main cause of genital herpes, although HSV-1 is becoming more common in genital infections, especially in high-income countries. Upon primary infection, HSV infects epithelial cells and nerve endings and spreads to the sacral ganglia via axonal transport. During reactivation, the virus travels back along the axons to the skin or mucosa, causing ulceration or asymptomatic viral shedding. Viral replication in the nucleus causes cytopathic effects such as ballooning degeneration, multinucleation, and Cowdry type A inclusion bodies. Genitourinary herpes presents with painful vesicular or ulcerative lesions in the genital area. Primary infections may have systemic symptoms like fever, headache, and lymphadenopathy. Recurrent infections are generally milder but occur frequently and affect patients’ quality of life. 89% of HSV-2 patients have at least one recurrence in a year, with a median monthly recurrence rate of 0.34. In immunocompromised patients like those with HIV/AIDS, lesions can be more severe, persistent, and sometimes present as large nodular masses, complicating the diagnosis. The diagnosis is clinical, with laboratory support. Polymerase chain reaction (PCR) is the gold standard for detecting and differentiating HSV-1, HSV-2, and varicella-zoster virus (VZV) due to its high sensitivity and specificity. Histopathological examination of biopsy samples can reveal cytopathic changes and assist in diagnosis, especially in atypical cases. The classic histological features of HSV infection include intraepidermal vesicles or ulcers with dirty necrosis, acantholysis, and characteristic nuclear changes. Key nuclear features are pale intranuclear viral inclusion bodies surrounded by peripheral condensation of native chromatin (chromatin margination), balloon degeneration, nuclear molding, and multinucleation (Tzanck cells). Cowdry type A inclusion bodies, which are eosinophilic nuclear inclusions composed of nucleic acid, may also be observed. Other notable changes include reticular degeneration, where epidermal cells undergo progressive hydropic swelling and cytoplasmic clearing with the remaining peripheral cytoplasmic strands. Cytoplasmic vacuolization and necrosis of older lesions, leaving ghost epithelial cells, are also common. A superficial and deep perivascular and periadnexal lymphocytic infiltrate, lichenoid inflammatory response, intraepithelial lymphocytes, vasculitis, and perineural inflammation may be seen. Neutrophils can be present within vesicles, particularly in resolving lesions. Cytological examination reveals characteristic nuclear changes in epithelial cells, including multinucleation, nuclear molding, chromatin margination, ground-glass nuclei, and eosinophilic intranuclear inclusions. These features are crucial for distinguishing HSV infections from other dermatological conditions. The differential diagnosis of genitourinary herpes includes inflammatory dermatitis (such as erythema multiforme and pemphigus), varicella-zoster virus (VZV) infection, and squamoproliferative neoplasms like squamous cell carcinoma. Unlike HSV infections, these conditions lack characteristic viral cytopathic changes.
A study of 457 patients with symptomatic first-episode genital herpes found that 89% of HSV-2 patients had at least one recurrence during the follow-up period. The recurrence rate was higher in men and has significant implications for HSV transmission dynamics.
Genitourinary herpes caused by HSV-2 and increasingly by HSV-1 is a diagnostic and therapeutic dilemma. Knowing the histopathology and clinical features is key to diagnosis and management. Further research should focus on developing diagnostic tools and therapeutic modalities to reduce recurrence and improve patient outcomes.
1. Rechenchoski DZ, Faccin-Galhardi LC, Linhares REC, Nozawa C. Herpesvirus: an underestimated virus. Folia Microbiol (Praha). 2017 Mar;62(2):151-156. doi: 10.1007/s12223-016-0482-7. Epub 2016 Nov 17. Erratum in: Folia Microbiol (Praha). 2018 Jan;63(1):123. doi: 10.1007/s12223-017-0539-2. PMID: 27858281.
2. Whitley RJ. Herpes simplex virus. In: Scheld WM, Whitley RJ, Marra CM, editors. Infections of the central nervous system. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2014. p. 137-56.
3. Veraldi S, Fanoni D, Nazzaro G. Herpes zoster of the penis: an immunohistochemistry diagnosis. J Cutan Pathol. 2012 Aug;39(8):811-2. doi: 10.1111/j.1600-0560.2012.01900.x. Epub 2012 May 11. PMID: 22574937.
4. Bowman MS, Lang UE, Leslie KS, Amend G, Breyer BN. Herpes simplex virus-2 associated with a large fungating penile mass. Urol Case Rep. 2021 Feb;36:101594. doi: 10.1016/j.eucr.2021.101594. PMID: 33628318.
5. Torres NI, Castilla V, Bruttomesso AC, Eiras J, Galagovsky LR, Wachsman MB. In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1. Antivir Res. 2012 Mar;95(1):37-48. doi: 10.1016/j.antiviral.2012.04.001. PMID: 22525320.
6. Benedetti J, Corey L, Ashley R. Recurrence rates in genital herpes after symptomatic first- episode infection. Ann Intern Med. 1994 Dec 1;121(11):847-54. doi: 10.7326/0003-4819-121- 11-199412010-00003. PMID: 7978712.
7. Böer A, Herder N, Winter K, Falk T. Herpes folliculitis: clinical, histopathological, and molecular pathologic observations. Br J Dermatol. 2006 Apr;154(4):743-6. doi: 10.1111/j.1365-2133.2005.07118.x. PMID: 16536821.
8. Prasad KM, Watson AM, Dickerson FB, Yolken RH, Nimgaonkar VL. Exposure to herpes simplex virus type 1 and cognitive impairments in individuals with schizophrenia. Schizophr Bull. 2012 Jul;38(5):1137-48. doi: 10.1093/schbul/sbr200. PMID: 22187224.
9. Ronkainen SD, Rothenberger M. Herpes Vegetans: an Unusual and Acyclovir-Resistant Form of HSV. J Gen Intern Med. 2018 Mar;33(3):393. doi: 10.1007/s11606-017-4256-y. Epub 2017 Dec 20. PMID: 29264701; PMCID: PMC5834971.
10. García-Navarro X, Catala A. Mistaken identities: penile herpes zoster. Sex Transm Infect. 2022 Feb;98(1):71. doi: 10.1136/sextrans-2020-054927. Epub 2021 Mar 16. PMID: 33727338.
Dr. Mahmut Akgul, M.D.
Dr. Mehrnaz Movassaghi, M.D.
Albany Medical Center, Department of Pathology and Laboratory Medicine
HSV-1, HSV-2, Genital Lesions, SCC, Herpes simplex virus (HSV), scrotal squamous cell carcinoma, HIV