Pilomatrix-like High-grade Endometrioid Carcinoma of the Uterine Corpus With Excellent Response to Immune Checkpoint Inhibitor Therapy

To the Editor: Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) of the uterus is a newly described distinct entity with 15 reported cases in the literature. In 2021, Weisman and colleagues shared a series of 5 tumors showing predominantly high-grade endometrioid morphology with conspicuous necrosis and shadow cells resembling cutaneous pilomatrix carcinoma. These tumors were consistently negative for PAX8 and ER, with variable CDX2 positivity and aberrant nuclear beta-catenin expression associated with mutations in exon 3 of CTNNB1. Importantly, all tumors showed aggressive clinical behavior, including early distant metastases1. Earlier this year, the authors subsequently published a series of 8 new cases, 7 of which were MMR-deficient2. Ovarian PiMHEC has also been recently described, totaling 4 cases in the literature, with similar poor prognosis3. Due to its novelty, therapeutic modalities, including immune checkpoint inhibitor therapy (CPI), have not been investigated in PiMHEC. Here, we present a case of PiMHEC with an excellent response to CPI. A 67-year-old presented with postmenopausal bleeding. A transvaginal ultrasound revealed a 3.9 cm endometrial mass invading the myometrium. Endometrial biopsy revealed a FIGO grade 3 endometrial endometrioid carcinoma with foci of geographic necrosis, abrupt keratinization, and ghost cells (Figs. 1A–C). On immunohistochemistry, the tumor was negative for PAX-8, ER, and PR in the high-grade foci (Figs. 1D, E) but positive in the adjacent low-grade component. Diffuse nuclear and cytoplasmic beta-catenin expression was present (Fig. 1F). p53 showed wild-type expression. MMR immunostains showed loss of MLH1 and PMS2 (Figs. 2A, B) with intact MSH2 and MSH6. Molecular analyses performed by Caris Life Sciences identified MSI-high, a high tumor mutational burden (29 mut/Mb) and CTNNB1 (Exon 3| p.G34R), ARID1A, PIK3CA, and PTEN mutations. POLE mutations were not identified. CT and PET scan studies showed enlarged, hypermetabolic pelvic, para-aortic, thoracic, cervical, and axillary lymph nodes. A cervical lymph node biopsy confirmed metastatic carcinoma, consistent with clinical FIGO 2009 stage IVB. The patient completed 6 cycles of chemotherapy with carboplatin, paclitaxel, and CPI with pembrolizumab every 3 weeks, after which CT and PET scans showed dramatically decreased metabolic activity at all metastatic sites. Subsequent cytoreduction with total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy revealed residual tumor invading the inner half of the myometrium (4 mm of 30 mm thick myometrium) with focal lymphovascular invasion. All lymph nodes were negative (0/10). The patient is on cycle 16 of maintenance Pembrolizumab with no evidence of disease (18 months).FIGURE 1: Pilomatrix-like high-grade endometrioid carcinoma (PiMHEC) shows the presence of numerous ghost cells as well as tumor cell necrosis at low (A) and high magnification (B and C). PiMHEC shows the absence of staining with PAX-8 (D) and ER (E), along with diffuse aberrant cytoplasmic and nuclear staining with beta-catenin (F).FIGURE 2: The tumor cells show a loss of expression of MLH1 (A) and PMS2 (B) with positive internal control in the blood vessels.Treatment options for PiMHEC have traditionally included surgery, chemotherapy, and radiotherapy, with MMR-deficient high-grade endometrial cancers (HGECs) generally showing a more favorable prognosis2. Recently, the addition of CPI to standard chemotherapy has become the first-line therapy for HGECs,4,5 regardless of MMR status. However, this regimen has not yet been documented in any reported cases of PiMHEC. While it is unclear if the excellent response in our patient is due to her MMR-deficient status or high tumor mutational burden, the results are promising, suggesting that CPIs may offer significant benefits for patients with this newly identified aggressive cancer. However, longer follow-up and additional studies are necessary to confirm CPI’s efficacy in PiMHEC.