A case of multiple bone metastases during the course of non‐invasive bladder and prostate cancer

Abstract

Introduction

Secondary bladder tumor is rare. We report a case of a bladder tumor initially thought to be a recurrence of non‐muscle invasive bladder cancer that was ultimately identified as metastasis from gastric cancer treated 16 years prior.

Case presentation

A 75‐year‐old male with a history of gastric, prostate, and recurrent non‐muscle invasive bladder cancer was diagnosed to have multiple bone metastases. Open bone biopsy and cancer gene panel testing identified the primary origin of the metastases as gastric cancer. Retrospective evaluation revealed that what was initially suspected as recurrent bladder tumors were actually metastases from the gastric cancer.

Conclusion

In cases of metastases with an unknown primary origin, detailed evaluation, including biopsy of the metastatic lesion and genomic testing, is recommended.

Abbreviations & Acronyms

BCG

Bacille Calmette‐Guerin

HE

hematoxylin and eosin

HNF

hepatocyte nuclear factor

NMIBC

non‐muscle invasive bladder cancer

PAS

periodic acid‐Schiff

PSA

prostate‐specific antigen

SOX

S‐1 plus oxaliplatin

SRC

signet‐ring cell

TURBT

transurethral resection of bladder tumor

UC

urothelial carcinoma

Keynote message.

A patient with a history of gastric, prostate, and recurrent NMIBC was diagnosed to have multiple bone metastases. Open bone biopsy and cancer gene panel testing identified the primary origin of the metastases as gastric cancer.

Introduction

Secondary bladder tumor is rare, accounting for approximately 2% of all bladder tumors. ¹ According to previous reports, the most common secondary tumors of the bladder result from direct invasion by surrounding organs, such as the colon, with the stomach being the most common site of origin for metastases to the bladder. ¹ , ²

Herein, we report a rare case of bladder tumors that were initially considered recurrent NMIBC but were ultimately diagnosed as metastases from gastric cancer treated 16 years prior.

Case presentation

A 75‐year‐old male was incidentally found to have osteogenic changes in the pelvis and thoracic and lumbar vertebrae on a computed tomography scan performed for follow‐up of an abdominal aortic aneurysm (Fig. 1a). Bone scintigraphy suggested multiple bone metastases (Fig. 1b). The patient had a history of three types of cancer. First, he had undergone a distal gastrectomy for gastric SRC carcinoma, pT2N3aM0, 16 years prior. He had no recurrence or metastasis after the surgery, and follow‐up was completed 5 years postoperatively. Second, he was diagnosed with Gleason score 3 + 3 prostate cancer, T1cN0M0, 3 years prior for which he has been receiving maximum androgen blockade therapy. His initial PSA level of 6.9 ng/mL immediately declined to below 0.01 ng/mL and has remained stable at that level. Third, he had undergone TURBT three times for NMIBC. He was initially diagnosed with UC, G3 pT1, with concomitant carcinoma in situ 3 years prior and underwent an induction course of BCG therapy. The first and second recurrent bladder tumors were treated with BCG induction therapy and BCG maintenance therapy following TURBT, respectively. After 1 year of maintenance therapy, he experienced persistent pain on urination as well as increased urgency and frequency. Cystoscopic findings revealed reddish and irregular mucosa on the posterior wall (Fig. 2a); however, urine cytology remained negative throughout, suggesting that these symptoms and mucosal changes were likely due to BCG therapy. Given the history of these cancers, it was considered unlikely that they were the primary source of the bone metastases. No abnormalities were found on gastrointestinal endoscopic evaluations or in tumor markers. Consequently, an open biopsy was performed to determine the primary origin of the bone metastases. The bone tumor specimens revealed SRC‐like glandular cells on PAS staining (Fig. 3a). Immunohistochemical staining was positive for HNF4α (Fig. 3b) and negative for GATA3 (Fig. 3c), suggesting bone metastasis from gastric cancer. However, the gastrointestinal surgeon considered this unlikely due to the long time that had elapsed since the initial surgery. Cancer gene panel testing was performed and revealed genomic alterations including AKT1 and BAP1. Immunohistochemical staining of BAP1 was positive in bladder tumor specimens taken from the first TURBT (Fig. 4a) but negative in gastric cancer specimens from the distal gastrectomy (Fig. 4b) and the bone biopsy specimens (Fig. 4c). Following the final diagnosis of bone metastasis from gastric cancer, systemic chemotherapy with SOX therapy was initiated.

Fig. 1.

Radiological findings at initial presentation. (a) CT showing osteogenic changes in the pelvis and thoracic and lumber vertebrae. (b) Bone scintigraphy reveals accumulations in the cranial vault, clavicle, vertebrae, and pelvis, suggesting multiple bone metastases.

Fig. 2.

Cystoscopic findings. Cystoscopic findings of the posterior bladder wall. (a) After 1 year of maintenance therapy for recurrent bladder tumors, cystoscopic findings reveal reddish and irregular mucosa on the posterior wall. (b) After SOX therapy, almost all abnormal lesions have disappeared.

Fig. 3.

Pathological findings of bone metastases specimens. (a) PAS staining reveals signet ring cell‐like glandular cells (inside the white square). (b) Immunohistochemical staining is positive for HNF4α. (c) Immunohistochemical staining is negative for GATA3.

Fig. 4.

Further pathological evaluations. Immunohistochemical staining for BAP1: (a) in the initial TURBT specimens; (b) in the gastrectomy specimens; and (c) in the tumor lesion (blue square) of the bone biopsy specimens; (d) in the second TURBT specimens; (e) in the third TURBT specimens. HE staining and immunohistochemical staining for HNF4α and GATA3 on the (f) initial, (g) second, and (h) third TURBT specimens.

We further evaluated all TURBT specimens. Careful evaluation with HE staining revealed SRC‐like glandular cells in the second and third TURBT specimens (Fig. 4g,h on HE staining). Immunohistochemical staining was negative for HNF4α (Fig. 4f on HNF4α staining) and positive for GATA3 (Fig. 4f on GATA3 staining) and BAP1 (Fig. 4a) in the first TURBT specimens. In contrast, the second and third TURBT specimens showed the opposite findings (Fig. 4d,e,g,h). Subsequently, the bladder tumor lesions from the second and third TURBTs, initially thought to be bladder cancer recurrences, were ultimately diagnosed as metastases from gastric cancer. After starting SOX therapy, his urinary symptoms disappeared and cystoscopic findings revealed that the previously reddish and irregular mucosa on the posterior wall had clearly improved (Fig. 2b).

Discussion

In the present case, we initially diagnosed the tumor located in the posterior wall of the bladder in the second and third TURBT specimens as recurrent NMIBC. At the time of these TURBTs, we had only informed the pathologist of the patient's history of prostate cancer but not gastric cancer. Consequently, only immunohistochemical staining for PSA was performed, which was negative for the bladder tumors. Additionally, there was a significantly long interval between the history of primary gastric SRC carcinoma and the discovery of bladder tumors in the second and third TURBTs. Gastric SRC carcinoma has aggressive behavior and typically has a shorter time to metastasize compared to conventional gastric adenocarcinoma. ³ While there have been reports of metastasis occurring as late as 7 years after the diagnosis of primary gastric SRC carcinoma, more than half of the previous studies reported synchronous metastasis with the primary diagnosis. ³ , ⁴ Based on this information, we misdiagnosed our case as recurrent NMIBC using specimens taken from the second/third TURBT.

The bone biopsy specimen revealed SRC‐like glandular cells on PAS staining, which were immunohistochemically positive for HNF4α and negative for GATA3. HNF4α is expressed in the epithelial cells of the gastrointestinal tract, liver, pancreas, and the proximal tubules of the kidney. The expression of HNF4α is generally retained in tumors originating from HNF4α‐positive organs. ⁵ Notably, HNF4α positivity in gastric cancer is reported to be 99%, ⁶ , ⁷ whereas its expression in the bladder is limited. ⁵ , ⁸ GATA3 is a general marker for UC, with positivity reported to be 67–97% ⁹ ; however, it is generally reported to be negative in gastric SRC carcinoma. ¹⁰ , ¹¹ Therefore, the bone metastases were highly suspected to originate from gastric SRC carcinoma. Moreover, we also evaluated BAP1 expression in the specimens immunohistochemically due to the detection of BAP1 alterations in bone specimen by gene panel testing. BAP1 is a tumor suppressor, and it has been reported that gastric cancer with SRC carcinoma has a significantly higher frequency of BAP1 mutations compared to gastric cancer without SRC. ¹²

Based on the results of immunostaining with HNF4α, GATA3, and BAP1, the bladder tumors, previously thought to be recurrence of NMIBC, were identified as metastases from gastric SRC carcinoma. The improvement in bladder irritability and abnormal findings of bladder mucosae after the initiation of systemic therapy for gastric cancer also supports this conclusion. This case underscores the importance of not being constrained by conventional thinking in cancer care and utilizing various modalities to achieve an accurate diagnosis.

Author contributions

Keisuke Matsubara: Conceptualization; investigation; visualization; writing – original draft. Nozomi Hayakawa: Conceptualization; resources; project administration; writing – review and editing. Yohei Kubota: Resources; visualization; writing – review and editing. Nobuyuki Ohike: Resources; visualization; writing – review and editing. Yu Sunakawa: Supervision; writing – review and editing. Junki Koike: Supervision; writing – review and editing. Eiji Kikuchi: Project administration; writing – review and editing; supervision.

Conflict of interest

Nozomi Hayakawa received honorarium for lectures from Nippon Kayaku Co., Ltd. Eiji Kikuchi received honorarium for lectures from Nippon Kayaku Co., Ltd.

The other authors declare no conflicts of interest to declare.

Approval of the research protocol by an Institutional Reviewer Board

Not applicable.

Informed consent

Written informed consent has been obtained from the patient.

Registry and the Registration No. of the study/trial

Not applicable.