Unconventional Histopathological Features With KIAA1549::BRAF Fusion in Advanced Prostatic Adenocarcinoma

Introduction

KIAA1549::BRAF fusion is a frequent genetic change in juvenile pilocytic astrocytoma ¹ and is also identified in other central nervous system tumors such as diffuse leptomeningeal glioneuronal tumors and glioblastoma.^2,3 KIAA1549::BRAF fusion is a tandem duplication at 7q34, where the N-terminal regulatory region of the BRAF gene is lost, and the BRAF kinase domain is retained and constitutively activated. ⁴ The fusion product leads to downstream activation of the mitogen-activated protein kinase (MAPK) pathway associated with proliferation, differentiation, survival, migration, and angiogenesis. ⁵ Outside the central nervous system, KIAA1549::BRAF fusion has been rarely reported in soft tissue neoplasms.^6,7 Although rare patient reports of prostatic adenocarcinoma with KIAA1549::BRAF fusion have been reported previously,^8,9 we present a patient report of prostatic adenocarcinoma with KIAA1549::BRAF fusion and unusual histologic features.

Case Report

A 66-year-old man with a past medical history of cerebrovascular disease presented to the emergency department with acute renal failure. Bedside ultrasonography showed bilateral hydronephrosis. Computed tomography (CT) scans revealed an indeterminate soft tissue mass in the right inferior pelvis with bony destruction extending through the right superior pubic ramus. Additionally, there were sclerotic lesions in the left ischium and proximal left femur, suggestive of metastatic disease. Serum prostate-specific antigen (PSA) levels were 7 ng/mL. A CT-urogram revealed an infiltrative mass centered in the prostate either arising from or extending into the urinary bladder and multifocal liver lesions. A CT-guided biopsy of the pubic lytic mass was performed and the biopsy revealed high-grade adenocarcinoma (Figure 1). The tumor cells were diffusely positive for keratin −20 (KRT20), NK3 Homeobox 1 (NKX3.1), and PSA. There was focal positivity for epithelial membrane antigen. The tumor cells were negative for KRT7, p40, and paired-box gene 8. A diagnosis of metastatic prostatic adenocarcinoma was rendered. The patient received bicalutamide therapy, abiraterone acetate/prednisone chemotherapy, and radiation therapy in the left femoral/hip region. Subsequently, a channel transurethral resection of the prostate (TURP) was performed. The TURP specimen revealed diffusely infiltrative sheets of tumor cells with abundant clear finely vacuolated cytoplasm and large hyperchromatic, pleomorphic nuclei with irregular folded nuclear membranes, distinct from prototypical prostatic adenocarcinoma (Figure 2). The tumor cells were positive for NKX3.1 (Figure 3) and were negative for GATA3. Later, an ultrasound-guided liver biopsy was performed on a liver lesion located within the low hepatic segment VI. The liver biopsy specimen revealed metastatic adenocarcinoma with similar morphology and immunophenotype as described above. The patient was placed on a combination carbotaxel/docetaxel and leuprolide therapy but had a poor clinical response. A solid tumor next-generation sequencing (NGS) panel was attempted on the liver biopsy specimen to explore possible targetable mutations. Extracted DNA and RNA from formalin-fixed paraffin-embedded tissue were prepared for hybrid-capture of 170 gene regions, including 55 fusion targets, followed by multiplex polymerase chain reaction amplification and sequencing using 101 × 2-cycle chemistry. Samples were sequenced to obtain >500× average coverage and >99% of targeted regions showed over 100× coverage. The pan-solid tumor NGS panel detected a fusion transcript involving KIAA1549 exon 16 and BRAF exon 10. Additionally, the sequencing analysis detected variants of strong or potential clinical significance in the phosphatidylinositol 3-kinase, phosphatase and tensin homolog, and tumor protein 53 genes. Due to a lack of documented targetable mutations, the patient was enrolled in a research trial group to receive CD73 inhibitor LY3475070 in combination with pembrolizumab. However, the disease progressed with new and enlarging hepatic and abdominal nodal metastases. The patient elected palliative care and eventually died of the disease within 4 years of the initial diagnosis.

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Figure 1.

Pubic lytic mass—diffusely infiltrative sheets of tumor cells with abundant vacuolated cytoplasm and large hyperchromatic nuclei (hematoxylin and eosin [H&E], 200×).

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Figure 2.

Transurethral resection of the prostate (TURP) specimen—tumor cells with pleomorphic nuclei with irregular folded nuclear membranes and finely vacuolated clear cytoplasm (hematoxylin and eosin [H&E], 400×).

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Figure 3.

Diffuse and strong positivity for NKX3.1 (immunohistochemistry [IHC], 400×).

Discussion

RAF pathway gene rearrangements are present in 1% to 2% of prostatic adenocarcinoma. ¹⁰ Only one of the 2 previously described prostatic adenocarcinoma with KIAA1549::BRAF fusion had a description of the histologic features. This tumor presented with mixed acinar and ductal features.^8,9 In comparison, the tumor in our patient report had a more unconventional morphology. Others have reported unusual histologic features in prostatic adenocarcinoma with different BRAF fusions (SND1::BRAF fusion and FAM131A::BRAF), describing adenosquamous/sarcomatoid differentiation and pleomorphic giant cell differentiation, respectively. ¹¹ Rearrangements of the BRAF kinase cause constitutive activation of the kinase function that leads to cancer development and progression by upregulating the Ras-Raf-MEK-ERK axis. ¹² The tumor described in our patient report had diffuse KRT20 positivity which is a rare occurrence in prostatic adenocarcinoma. Interestingly, prostatic adenocarcinoma with KRT20 positivity has been associated with higher Gleason scores of 7 or more. ¹³

A preclinical study in pilocytic astrocytoma has shown that treatment with targeted therapy against BRAF-V600E mutation (PLX4720, a research analogue of vemurafenib) leads to paradoxical activation of the downstream MAPK signaling in a setting of KIAA1549::BRAF fusion. One of the mutant fusion constructs used in this study (KIAA1549 exon 16-BRAF exon 9 fusion) was very similar to the fusion found in our patient report (KIAA1549 exon 16-BRAF exon 10 fusion). ¹³ Although BRAF inhibitor therapy was not instituted in our patient, one patient report of prostatic adenocarcinoma with SND1::BRAF fusion has been reported to have responded to MAPK inhibitor therapy (trametinib). Interestingly, in that patient, the tumor had a mesenchymal–epithelial transition (MET) mutation and the patient had initially failed to respond to MET inhibitor therapy. This was hypothesized to be due to the potentiation of the downstream MAPK pathway by the additional BRAF fusion protein. ¹⁴ Thus, BRAF fusions appear to not only play a role in promoting cancer progression but could also lead to resistance to other targeted therapies.

Conclusion

We present a patient report of an advanced and aggressive prostatic adenocarcinoma with an unusual morphology that revealed a KIAA1549::BRAF fusion. Further investigation is needed to determine if the distinctive histology observed in this tumor consistently correlates with KIAA1549::BRAF fusion in prostatic adenocarcinoma, potentially guiding earlier molecular testing and expanding treatment options for patients with similar presentations.