An Expanded Series of Pilomatrix-like High-grade Endometrioid Carcinoma (PiMHEC), Including Both MMR Deficient and MMR Proficient Cases

To the Editor: We appreciate the letter to the editor by Arciuolo et al. 1, in which the authors describe an additional case of what they have kindly termed PiloMatrix-like high-grade endometrioid carcinoma (PiMHEC). In contrast to the cases in our initial series 2 which were all mismatch repair protein (MMR) proficient their case was MMR deficient 1. To review, PiMHEC is a FIGO grade 3 endometrioid adenocarcinoma with pilomatrix carcinoma-like histology, most characteristically recognized by the presence of ghost cells and accompanied by diffusely aberrant nuclear and cytoplasmic beta-catenin expression in the viable tumor cells; CDX2 expression and patchy synaptophysin immunoreactivity are also common 2. These tumors are negative for both PAX8 and estrogen receptors, making their identification at metastatic sites challenging 2. In our initial cohort 2, PiMHEC appeared to be a very aggressive tumor type with a high rate of distant metastasis and mortality. Since the publication of our initial series, all of the patients have now succumbed to their disease within 24 mo of diagnosis, and another subsequently identified patient (previously unpublished) also passed away within this same time frame (median survival of 11.5 mo). The clinicopathologic features of these patients are summarized in Table 1. In their letter, Arciuolo et al. 1 thoughtfully raised the possibility that MMR deficiency may be protective for this otherwise aggressive phenotype, a hope that we also shared. TABLE 1 - Clinicopathological features of PiloMatrix-like high-grade endometrioid carcinoma Case number Age (yr) Size in uterus (cm) LVI CTNNB1 mutation MMR status Stage at presentation Treatment Site(s) of distant metastatic Disease Length of follow-up (mo) Survival MMR proficient cases 1* 60 1.2 N ND R T1bN0M0 S, CT, R Liver, chest wall, brain 12 DOD 2* 65 1.7 Y CTNNB1 (D32Y) R T1bN0M1 S, CT, R Bone, lung, soft tissue 24 DOD 3* 56 U U ND R M1 S, CT Liver 10 DOD 4* 73 3.5 Y CTNNB1 (S37F) R T3aN2aM0 S, CT, R Lung, liver 14 DOD 5* 38 U U CTNNB1 (D32Y) R M1 NAC Lung, bone. Skin and brain 7 DOD 6 62 U U ND R M1 CT, R Lung 11 DOD MMR deficient cases 7 58 1.9 N ND MLH1/PMS2 loss; HM+ cT2cN2M0 ypT2 pNX NAC, S, R NA 24 NED 8 42 7.5 Y ND MLH1/PMS2 loss; HMU T1bN2aM0 S, CT, R NA 13 NED 9 50 4.4 Y CTNNB1 (pT41A) PIK3CA, PTEN Others; MSS, TMB-low MLH1/PMS2 loss; HMU T1bN2aM0 S, CT; CPI x 1 dose Liver, brain 10 DOD 10 43 16 U CTNNB1 PTEN, ARID1B; TMB high MSI high MLH1/PMS2 loss; HMU M1 NAC; CPI planned, but pt passed away before starting Lung, liver, brain, and adrenal glands 3 DOD 11 54 8 EXT ND MLH1/PMS2 loss; HMU T3bN2aM0 S, CT R4 and subcarinal LNs 11 DOD 12 71 5 Y ND MLH1/PMS2 loss; HMU T1aN0M0 S U 9.5 DOD 13 50 6 U ND Isolated MSH6 loss cT2bN2bM1 NAC Inguinal and RP LNs 3 AWD *Cases 1 to 5 were previously published 2; case 6, as well as all MMR deficient cases, are new.AWD indicates alive with disease; c, clinical stage; CPI, immune checkpoint inhibitor therapy; CT, chemotherapy; DOD, died of disease; HM+, MLH1 promoter hypermethylation present; HMU, MLH1 promoter hypermethylation status unknown; LNs, lymph nodes; LVI, lymphovascular invasion in hysterectomy specimen; MMR, mismatch repair protein; MSI, microsatellite instability; N, no; NA, not applicable; ND, not done; NED, no evidence of disease; pt, patient; R, radiation therapy; RP, retroperitoneal; S, surgery; TMB, tumor mutational burden; U, unknown; Y, yes. In the interim, we have identified 7 additional cases of PiMHEC with MMR deficiency (Fig. 1) similar to the case described by Arciuolo et al. 1. Of these 7 patients, 4 have died of their disease within a time frame of 24 mo (median survival of 11 mo). Of the 3 patients who are still alive, one presented with distant metastatic disease, received neoadjuvant chemotherapy and is currently alive with disease at 3 mo follow-up. The other 2 patients presented with the node-positive disease but no distant metastases and are both alive without evidence of disease at 13 and 24 mo follow-up. The clinicopathologic features of these patients are also summarized in Table 1.FIG. 1: PiloMatrix-like high-grade endometrioid carcinoma (PiMHEC) with mismatch repair protein deficiency. (A and B) PiMHEC showing tumor cell necrosis as well as the presence of numerous ghost cells (hematoxylin and eosin, 200× in A, 400× in B). (C) Beta-catenin expression in PiMHEC showing diffusely aberrant cytoplasmic and nuclear staining (DAB, 200×). (D) Loss of expression of MSH6 with working positive internal control cells in the stroma (DAB, 200×).Given the high overall mortality rate of PiMHEC, we suspect that MMR deficiency may not be very protective for this aggressive tumor type. That being said, even in this expanded series, our cohort is small and has limited follow-up. Of note, of the 7 patients with MMR deficient PiMHEC, only one had received a single dose of an immune checkpoint inhibitor late in her disease course just before succumbing to her disease. Accordingly, immunotherapy has not been meaningfully evaluated in patients with this disease and may yet offer hope.