Case Presentation: A 67-year-old never-smoker male with no medical or surgical history presented to his primary care physician with progressive malaise. He was referred to the hospital when blood work returned with hypercalcemia. On evaluation, the patient endorsed a two-month history of chills, dyspnea, unsteady gait, and anorexia with 15-pound weight loss. He was previously employed as an industrial hygienist, and was responsible for overseeing cleanup at the World Trade Center (WTC) site after the terrorist attacks on 9/11.
On admission vitals were: T 98.3°F, HR 105 bpm, BP 160/89 mm Hg, and SPO2 94% on room air. Physical examination revealed an ill-appearing man in no acute distress with point tenderness along the lumbar spine. Admission labs were significant for WBC 15.3 K/µL, Hgb 10.1 g/dL, platelet 47 K/µL, creatinine 1.5 mg/dL, and calcium 13.9 mg/dL. Chest CT was positive for lytic lesions throughout the spine, sternum and bilateral ribs.

A bone marrow biopsy was performed to rule out multiple myeloma, however pathology instead revealed carcinoma of unknown primary with plasmacytoid features. Careful review of the imaging revealed focal bladder wall thickening, so a cystoscopy was performed and confirmed diagnosis of metastatic plasmacytoid urothelial carcinoma (PUC).

The patient was not a chemotherapy candidate due to his poor functional status (ECOG 4; bed bound, cannot perform self-care), worsening cytopenias and impaired renal function. Compassionate use of Atezolizumab, a monoclonal antibody to PD-L1 was instead selected. Despite treatment, the patient expired 11 days later.

Discussion: 17 years after the attacks on 9/11, the long-term health consequences are still being uncovered. There is a clear link between site exposure and development of malignancies, including bladder cancer. PUC is a rare and aggressive variant of bladder cancer, and to the best of our knowledge we are the first to report a case of PUC linked to WTC exposure.

PUC was first described in 1991 in a patient who was also thought to have multiple myeloma due to presence of anemia and osteolytic lesions. Morphologically, PUC resembles plasma cells due to the loss of E-cadherin expression, which has been linked to a somatic CHD-1 mutation. The loss of E-cadherin expression enhances cell migration and helps explains why PUC is often diagnosed at a later stage and is associated with a more aggressive clinical course. Although PUC is currently treated the same as other histologic types of bladder cancer, it has a distinct molecular profile, and research is ongoing with the goal of finding therapeutic targets to these mutations.

Conclusions: Patients with WTC exposure are at high risk of uncommon cancers such as PUC, an aggressive variant of bladder cancer associated with carcinogen exposure. Because PUC can resemble multiple myeloma, confirmatory biopsy is necessary for diagnosis. Optimal treatment of metastatic PUC is not yet defined, especially in patients who cannot tolerate chemotherapy.