A novel histopathological grading system based on tumour budding and cell nest size has recently been shown to outperform conventional (WHO‐based) grading algorithms in several tumour entities such as lung, oral, and oesophageal squamous cell carcinoma (SCC) in terms of prognostic patient stratification. Here, we tested the prognostic value of this innovative grading approach in two completely independent cohorts of SCC of the uterine cervix. To improve morphology‐based grading, we investigated tumour budding activity and cell nest size as well as several other histomorphological factors (e.g., keratinization, nuclear size, mitotic activity) in a test cohort (n = 125) and an independent validation cohort (n = 122) of cervical SCC. All parameters were correlated with clinicopathological factors and patient outcome. Small cell nest size and high tumour budding activity were strongly associated with a dismal patient prognosis (p < 0.001 for overall survival [OS], disease‐specific survival, and disease‐free survival; test cohort) in both cohorts of cervical SCC. A novel grading algorithm combining these two parameters proved to be a highly effective, stage‐independent prognosticator in both cohorts (OS: p < 0.001, test cohort; p = 0.001, validation cohort). In the test cohort, multivariate statistical analysis of the novel grade revealed that the hazard ratio (HR) for OS was 2.3 for G2 and 5.1 for G3 tumours compared to G1 neoplasms (p = 0.010). In the validation cohort, HR for OS was 3.0 for G2 and 7.2 for G3 tumours (p = 0.012).In conclusion, our novel grading algorithm incorporating cell nest size and tumour budding allows strongly prognostic histopathological grading of cervical SCC superior to WHO‐based grading. Therefore, our data can be regarded as a cross‐organ validation of previous results demonstrated for oesophageal, lung, and oral SCC. We suggest this grading algorithm as an additional morphology‐based parameter for the routine diagnostic assessment of this tumour entity.

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Hypertrophic herpes simplex genitalis (HHSG) is an uncommon anogenital manifestation of herpes simplex virus (HSV) infection in immunocompromised patients. To date, 24 cases of HHSG have been reported; 23 of them were affected human immune deficiency virus (HIV) type 1-positive patients. We describe the case of a 44-year-old African HIV-1-positive woman who presented with painful ulcerated nodular lesions of the vulva and perianal area measuring up to 7 cm in diameter. Macroscopically, the lesions were highly suspicious of widely invasive cancer. The histologic workup of the resection specimen revealed patchy high-grade vulvar intraepithelial neoplasia Grade 3 (VIN 3) and 2 microscopic foci of superficially invasive squamous cell carcinoma. The nodular lesions were caused by massive tumefactive plasma cell-rich inflammatory infiltrates extending into the subcutis. Multinucleated herpes simplex virus 1 and herpes simplex virus 2-positive epithelial cells with glassy intranuclear inclusions were detected at the borders of the ulcerations, consistent with HHSG. Despite repeated surgery and medical treatment, the patient had 3 recurrences of HHSG within 18 months. The presence of intraepithelial neoplasia in HHSG lesions is relatively rare and has been described in 6 of 18 resected HHSG lesions in the literature so far. With regard to invasive malignancy, the present case is the first report of a superficially invasive squamous cell carcinoma associated with HHSG. Awareness of this condition is necessary to avoid misinterpretation of HHSG as widely invasive squamous cell carcinoma with the hazard of surgical and oncological overtreatment.

Adjuvant therapy has so far not shown any overall survival benefit, and the focus is therefore on primary surgery. In future studies, the entities should be investigated separately in relation to prognostic factors and effective therapeutic management.