PD-L1 Expressing Recurrent Clear Cell Carcinoma of the Vulva with Durable Partial Response to Pembrolizumab: A Case Report

Figures & data

Table 1 Clinical Presentation and Treatment Summary

Date	Presentation and Treatment
Treatment received at another institution
Apr 2017	Presented with large left vulvar mass and underwent wide local excision of mass with bilateral inguinal lymph node dissection, however surgically inoperable residual nodal disease in left femoral station was noted at end of surgery. Pathology confirmed clear cell adenocarcinoma, final stage was FIGO IVA
Apr - Jul 2017	Received adjuvant carboplatin + paclitaxel for 6 cycles
Sep - Oct 2017	Received adjuvant pelvic radiotherapy to the inguinal region and vulva concurrent with weekly cisplatin
Jan 2018	Symptomatic relapse with palpable lymph nodes in left inguinal region
Jan - Apr 2018	Received second-line carboplatin + docetaxel for 5 cycles, best response was stable disease but suffered disease progression after cycle 5
Apr - Aug 2018	Received third-line ifosfamide + gemcitabine, best response was partial response but suffered disease progression after cycle 4
Aug - Sep 2018	Received fourth-line weekly paclitaxel with disease progression after 2 cycles
Transfer of care to our institution
Sep 2018	Repeat PET/CT scans showed only local disease in the left groin but no distant metastases. Wedge biopsy was performed on recurrent tumor in the left groin showing clear cell adenocarcinoma. PD-L1 CPS was 45
Oct 2018	PET-CT showed new tumor thrombi and worsening pelvic adenopathy. Foundation 1 genetic report sent
Oct 2018 - Sep 2019	Received 16 cycles of fifth-line pembrolizumab. Baseline CA125 298
Dec 2018	Rapid reduction in CA125 to 9.5 after just 2 cycles of pembrolizumab. Significant reduction in size of left groin tumor and improvement in left leg swelling
Jan 2019	Developed new neutropenia, grade 3
Feb 2019	CA125 nadir of 4.6
Mar 2019	Hematology consult and bone marrow examination which diagnosed MDS-EB
May 2019	Nil analgesia requirement and able to walk independently
Jun 2019	Worsening left groin pain; interim PET CT showed left inguinal ulcerative lesion more metabolically active
Sep 2019	Returned to the Philippines, defaulted follow-up in Singapore thereafter
Dec 2019	Developed acute myeloid leukemia
Jan 2020	Demise from acute myeloid leukemia

Table 2 Molecular Profiling of Pre-Pembrolizumab Tumor Biopsy

Gene	Variant
Pathogenic variants
MET	Amplification – equivocal
CDKN2A/B	Loss
TERT	Promoter – 124C>T
TP53	G154S
Variants of uncertain significance
ABL1	T984M
KDR	A1168S
ALK	V163L
MLL3	M69L
BRCA2	R2896H
RB1	P29del
FGFR2	Rearrangement
RUNX1T1	R10T
GPR124	C1196Y
SPEN	V2119I
IGF1R	P842S
TSC2	P1450R

Figure 1 Clinical and Radiologic Response to pembrolizumab; Immunohistochemistry. (A and B) Clinical response to pembrolizumab; (A) Fungating left groin tumor and satellite nodule at baseline (September 2018), prior to starting pembrolizumab (horizontal red arrows); (B) Dramatic clinical response after 3 cycles of pembrolizumab in primary tumor and adjacent satellite nodule (December 2018) (horizontal red arrows). (C and D) Radiologic response to pembrolizumab; (C) Baseline PET-CT showing fungating and intensely FDG-avid mass (SUVmax 19.6) at the left groin (vertical white arrow) with invasion of the adductor compartment of the left thigh; (D) Follow-up PET-CT after 6 months showing marked reduction in size and metabolic uptake (SUVmax = 3.9) of the tumor (vertical white arrow). (E) Hematoxylin and eosin x20 stain confirming clear cell carcinoma: the tumor is composed of nests of cells with round nuclei, prominent nucleoli and ample clear to eosinophilic cytoplasm; (F) Immunohistochemistry for PD-L1 using the Dako 22C3 pharmDx assay, combined positive score of 45.

Figure 2 Relevant Biochemistry and Hematology Indices during pembrolizumab treatment. Rapid reduction in serum CA-125 was observed after commencing pembrolizumab in October 2018, with CA-125 dropping precipitously from a baseline of 298 U/mL to 9.5 U/mL in December 2018, after only 3 cycles of pembrolizumab. CA-125 reached a nadir of 4.6 U/mL in February 2019. Gradual increase in CA-125 coincided with clinical disease progression in June 2019. Worsening neutropenia occurred during the course of pembrolizumab, due to underlying myelodysplastic syndrome, which was later confirmed on bone marrow examination.