PMC7713560_01
Pathologic confirmation of clear cell carcinoma of the cervix. (A) Primary clear cell carcinoma of the cervix, showing hyperchromatic tumor cell nests in the stroma at left and normal endocervical glandular epithelium at the right (x40). (B) The tumor cells grow in small nests and trabeculae and have vesicular nuclei with prominent nucleoli. Mitotic figures are sparse, as is typical of this tumor type. The cells have abundant amphophilic to clear cytoplasm (x400). (C) An immunohistochemical stain for hepatocyte nuclear factor 1-beta, which is a marker of clear cell carcinoma, shows strong positive nuclear staining in the tumor cells, a positive test result (x200).
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Biopsy of an exophytic mass protruding into the vagina confirmed a human papillomavirus-/p16-negative CCAC (Fig 1). CD8+ lymphocytes were absent (Appendix Fig A1).
Radiographic response to checkpoint blockade. (A) Patient developed a new hypermetabolic pulmonary nodule in the right upper lobe (blue arrow), along with prominent hypermetabolic prevascular nodes (red arrow). (B) After initial nivolumab therapy, patient's right upper lobe nodule decreased in size (blue arrow), and the prevascular node had nearly resolved (red arrow). (C) Approximately 16 months after initial recurrent disease, the pulmonary nodule has nearly completely resolved (blue arrow), and no new pathologic nodes have developed.
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Sixteen months after entering remission, surveillance positron emission tomography (PET)-computed tomography (CT) revealed new hypermetabolic disease, including a new right upper lobe (RUL) pulmonary nodule, enlarged prevascular right internal mammary, and right paratracheal nodes (Fig 2A) and a left supraclavicular node. Findings from WGS and targeted sequencing were concordant (Appendix Fig A2). After four doses of nivolumab monotherapy, PET-CT scan showed decreased size and hypermetabolism of the RUL pulmonary nodule and the prevascular lymph node (Fig 2B). One month later, nivolumab monotherapy was restarted, and the patient achieved a complete radiographic remission, which has persisted for 18 months (Fig 2C).
Biopsy of supraclavicular node confirms metastatic disease. (A) Metastatic clear cell carcinoma in a supraclavicular lymph node. The tumor cells line glands or grow in nests and are surrounded by lymphocytes, seen at the lower left (x200). (B) Metastatic clear cell carcinoma in a supraclavicular lymph node. The tumor cells are mainly polygonal with abundant clear or amphophilic cytoplasm and vesicular nuclei with prominent nucleoli. The appearance is similar to that seen in the cervical primary (x400). (C) Metastatic clear cell carcinoma in a supraclavicular lymph node. An immunohistochemical stain for PD-L1 shows minimal staining in the tumor cells and staining of scattered lymphoid cells around the tumor (x200).
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Biopsy of the supraclavicular node confirmed recurrence of CCAC (Fig 3). RNA-seq demonstrated normal expression of PD-L1 at diagnosis and relapse (Appendix Fig A3) and also detected the chromosome 20 amplification and 1p deletion at diagnosis.
High neoepitope burden compared with pediatric neuroblastoma and adult prostate adenocarcinoma cohorts using Prediction of T-Cell Epitopes for Cancer Therapy (ProTECT) neoepitope analysis. Box-and-whisker plots display the interquartile range (box) and outlier thresholds (whiskers) for the Therapeutically Applicable Research to Generate Effective Treatments neuroblastoma and The Cancer Genome Atlas prostate adenocarcinoma data sets. A solid black line represents the patient. CACC, clear cell adenocarcinoma of the cervix.
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The tumor's neoepitope burden was a statistical outlier relative to these cohorts, crossing the outlier thresholds for both (Fig 4).
Mutational signature analysis identifies five active signatures. (A) Each signature is shown as a segment on the plot, with the names of the signatures overlaid. The size of the segment corresponds to its weight. The greater the weight, the more active the signature is (ie, the more mutations it has caused). (B) Plot of the mutational spectrum of the patient's diagnostic sample alongside the five active signatures.
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APOBEC mutational signature frequency in a large pediatric cancer cohort. (A) Numbers of pediatric cancer samples with one or both APOBEC signatures (signatures 2 and 13). Fourteen (1.5%) of 915 samples from Ma et al display both signatures. (B) Violin plot of the fraction of mutations in each sample attributed to the combined APOBEC signatures. Samples with both signatures are shown in blue, samples with one or neither signature are shown in gray, and the patient sample is shown in red.
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Using pediatric cancer genomic and transcriptomic data from 915 tumor samples published by Ma et al, we determined that 98 (10.7%) of 915 had signature 2, 17 (1.9%) had signature 13, and only 14 (1.5%) had both APOBEC signatures (Fig 6).