PMC7884751_01
Radiographic evidence of hyperprogression and inflammation following dual immune checkpoint inhibition. Pre-treatment CT chest with a lung metastasis (A); solid arrow) and a normal abdominal CT (B). Three weeks after ipilimumab and nivolumab, prior lung metastasis grew (C; solid arrow) and new metastasis developed (C; dotted arrow). In addition, abdominal distention, omental caking, peritoneal metastases, and pelvic ascites developed as shown in axial (D) and mid-sagittal (E) abdominal/pelvic CT.
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Due to > 2 months lapse since her diagnosis without initiation of therapy, she was restaged with PET/CT which demonstrated distant osseous and visceral metastases involving lungs as well as progression of distant and regional nodal metastases and primary vagina melanoma ( Figures 1A, B ). CT showed rapid progression of known and new metastatic disease including omental caking, peritoneal metastases, pelvic ascites, and lung nodules ( Figures 1C-E ). CT-guided core biopsy of an omental mass confirmed metastatic melanoma.
Histological evaluation of tumor tissue and endomyocardial biopsy. H&E staining of the pre-treatment primary vaginal melanoma specimen (A) reveals epithelioid morphology and largely negative staining for PD-L1. This is in stark contrast to the metastatic omental specimen from three weeks post-ICI (B), which exhibited small cell morphology and was positive for PD-L1 (100x images, insets are 400x; clone 22C3 used for PD-L1 stain). The omental metastasis stained positive for Mel-A and Ki67 (C, 100x images). Endomyocardial biopsy confirms myocarditis (D, 100x).
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Analysis of the initial primary vaginal melanoma specimen revealed epithelioid morphology, and tumor cell staining for PD-L1 was almost completely negative ( Figure 2A ). Due to the drastic difference in morphology, we completed an additional stain demonstrating strong positivity of the metastatic tumor cells to a specific melanocytic marker (Mel-A), which confirmed the biopsy tissue was indeed metastatic melanoma ( Figures 2B, C ). Also consistent with rapid clinical and radiographic disease progression, the omental lesion was highly proliferative with 60% of cells staining positive for Ki67 ( Figure 2C ). The biopsy demonstrated a solitary focus of interstitial lymphocytic infiltrate in association with focal myocyte injury ( Figure 2D ).
Analysis of T cell infiltrate in pre and post treatment tumor tissue. CD8+, PD-1+ cells were essentially absent from the pre-treatment primary vaginal melanoma specimen (A), but were abundant in the metastatic omental specimen from three weeks post-ICI (B). The CD+PD-1+ T cells within the omental metastasis were largely negative for Granzyme B, T1A-1, and Foxp3 (All images 100x).
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Assessment of the T cell infiltrate within the tumors revealed minimal CD8+ or PD-1+ T cells in the primary vaginal lesion (5-10% and 1% of total cells, respectively) ( Figure 3A ), which were predominantly distributed in the areas adjacent to rather than within the tumor foci. Interestingly, the metastatic omental specimen contained a much more robust CD8+ T cell infiltrate (~30% of total cells), which also showed a consistent staining pattern with PD-1, suggesting that the T cells were antigen-engaged ( Figure 3B ). TIA-1 (an RNA-binding protein associated with cytolytic granules), suggesting the CD8+ T cells were not capable of tumor cell killing. The presence of FoxP3+ cells was also assessed as others have reported that immunosuppressive regulatory T cells (Tregs) could be responsible for rapid progression following ICI. Treg component was minimal at approximately 3% of total cells in the most densely staining area ( Figure 3B ).