The patient's course is outlined in Fig. 1a.
A 58-year-old, previously healthy, white female presented to her primary care provider (PCP) with the desire to remove a right posterior scalp cyst for cosmesis. This non-inflamed, non-draining, painless, 1-2 cm cyst had been present for close to 10 years without change in size or fluctuance. The cyst was initially drained by the PCP, but, when it recurred 6 months later, the PCP excised the cyst and sent the specimen for routine pathology. The initial read of the tissue sample was high-grade invasive carcinoma with squamous features and arising in association with a PTT. Based on the pathology, the PCP referred the patient to a plastic surgeon for a more definitive excision of the lesion and repair of the defect. The lesion was excised with negative margins and pathology read as invasive high-grade squamous cell carcinoma (SCC). Eight months post resection, the lesion recurred locally along with a palpable right posterior cervical lymph node (LN). A positron emission tomography (PET) scan at that time demonstrated hypermetabolic activity in the posterior occiput and in a posterior neck LN. Fine needle aspiration (FNA) of both the primary scalp lesion and LN were completed, and pathology was reported as SCC, similar to the primary lesion.
With a working diagnosis of locally advanced SCC, the patient's care was referred to a tertiary care center. There, a dermatopathologist re-evaluated the previous biopsy specimens and altered the diagnosis from SCC to MPTT (Fig. 1b). Subsequently, the patient was referred to a head and neck surgeon for modified radical posterior neck and lymph node dissection. Intraoperative findings uncovered the presence of nodal metastases to the posterior neck with extranodal extension, extensive perineural invasion of the spinal accessory nerve, and jugular venous invasion of the MPTT. After surgery, the case was discussed at a multi-disciplinary tumor board, and a common head and neck cancer protocol of adjuvant chemotherapy (weekly carboplatin plus paclitaxel) with concurrent radiation was recommended. The patient tolerated the adjuvant chemoradiotherapy with expected toxicities including nausea and fatigue.
Fifteen months after her neck dissection (1 year after completing chemoradiotherapy), FNA of a suspicious right paraspinal LN at C5 documented disease recurrence. The patient underwent a revision neck dissection (extending from the sternocleidomastoid, anteriorly, to halfway down the trapezius, posteriorly) with final pathology specimens consistent with metastatic MPTT. A subsequent PET scan demonstrated hypermetabolic activity in a right supraclavicular LN, multiple mediastinal LNs, and in a 0.8 x 1.1 cm right lower lung lobe parenchymal nodule. An endobronchial ultrasound (EBUS) and transbronchial needle aspiration (TBNA) showed involvement of level 4 and 7 mediastinal LN by carcinoma. Molecular profiling of the tissue using a multiplexed PCR assay (SNaPshot) identified a PIK3CA c.G3140A (p.H1047R) mutation. Given the paucity of evidence for this mutation in this cancer, the patient was treated with a standard regimen for metastatic SCC (consisting of docetaxel and cisplatin every three weeks). At the same time, the patient was put on the waitlist for NCT01219699, a phase I study of oral BYL719 (alpelisib, a PI3Kalpha-selective inhibitor) in adult patients with advanced solid malignancies, whose tumors have an alteration of the PIK3CA gene.
Seven months after completion of her second chemotherapy regimen, the patient was found to have progressive metastatic pulmonary disease on routine computerized tomography (CT) scan (she was asymptomatic at this time). The patient then enrolled in the trial of alpelisib at 450 mg daily. Her only suspected adverse effects related to the study drug were nausea and weight loss. After 3 months of treatment, she demonstrated a partial response per RECIST (Fig. 1c and S1). Additionally, an on-treatment research biopsy, obtained 3 months after the start of alpelisib, demonstrated a significant reduction in proliferation as assessed by Ki67 staining (Fig. 1d, e).
Four months after starting the study drug, the patient developed a community acquired pneumonia (CAP), and the treatment was suspended. Although the CAP resolved both clinically and radiographically, the patient was started on 2 L/min oxygen due to a persistent cough that was not responsive to therapy. It was unclear if the patient had progressive disease or a drug-related pneumonitis at this time (although this is not a known adverse effect of alpelisib). Two months after stopping alpelisib, a surveillance CT scan demonstrated peritoneal carcinomatosis. Within days of this CT scan, the patient was admitted to the hospital with increased work of breathing requiring 4 L/min oxygen. The patient opted for no aggressive measures and was symptomatically treated until her death a week later.
Prior to her passing, the patient consented to a rapid autopsy, which revealed the suspected cause of death to be widely metastatic MPTT. There were innumerable metastases in the lungs, the largest being 3.0 x 3.0 x 2.2 cm in dimension (Fig. S2a). Another heavily involved site was the liver, which contained multiple metastases, the largest being 3.5 x 2.5 x 0.6 cm in dimension (Fig. S2b). The cancer also was found to involve a papillary muscle of the heart, the pericardium, fundus of the stomach, ileum, colon, omentum, right ovary, soft tissues of the neck, both adrenal glands, and the pelvic peritoneum. Interestingly, many of the lesions identified at autopsy were not visualized on the CT scan taken two weeks prior to the patient's death. Neuropathology demonstrated no evidence of CNS metastases. No microbiological evidence of pneumonia was found in the lungs, and cultures did not grow any causative pathogenic bacteria or fungi.