Penile metastasis from colon cancer with BRAFV600E mutation treated with BRAF/MEK-targeted therapy plus cetuximab: A case report

Abstract

BACKGROUND

The incidence of colon cancer has been progressively increasing over time, whereas penile metastasis of colon cancer has remained exceedingly uncommon. Since the prognosis for colon cancer with BRAF^V600E mutation is relatively unfavorable, further exploration and investigation are still required to develop treatment strategies for such rare cases.

CASE SUMMARY

About one year after surgery and chemotherapy, a 50-year-old patient with sigmoid colon cancer developed a mass at the base of the patient's penis, accompanied by severe tenderness and pain during urination. With disease progression, multiple metastatic nodules also emerged in other regions of the penis, including the coronal sulcus. The nodules located in the coronal sulcus were excised for histopathological examination. The histopathological findings revealed that the nodules were metastases originating from the sigmoid colon cancer, with a BRAF^V600E mutation detected. This prompted a modification of the therapy regimen of cetuximab, dabrafenib and trametinib, which effectively held back the progression of penile metastasis in the patient.

CONCLUSION

Combining the BRAF/MEK-targeted therapy with cetuximab demonstrates a favorable therapeutic response in BRAF^V600E-mutated colon cancer with penile metastasis.

Key Words: Colon cancer; Penile metastasis; BRAF^V600E mutation; Targeted therapy; Case report

Core Tip: Despite the increasing incidence and prevalence of colorectal cancer among malignant tumors, penile metastasis originating from colorectal cancer remains a rare occurrence. The precise mechanism underlying penile metastasis of colorectal cancer remains elusive, and its specific treatment remains a subject of controversy, particularly in patients with BRAF^V600E mutation, which often signifies an unfavorable prognosis. In our case, the treatment of BRAF/MEK-targeted therapy (dabrafenib and trametinib) plus cetuximab demonstrated promising outcomes, leading to tumor regression and prolonged survival, thereby offering valuable insights for the management of analogous cases.

INTRODUCTION

Colorectal cancer stands as the third most frequently diagnosed and second most fatal cancer globally[1]. Colorectal cancer normally metastasizes to well-vascularized sites, such as the liver and lungs. Despite the rich vascularity and extensive circulatory communication with the surrounding tissues, penile metastasis from tumors is still very rare[2]. The primary tumor of penile metastasis is predominantly located in the bladder, prostate, and other urogenital organs (65%), followed by colorectal cancer (13%)[3]. The occurrence of metastases is frequently observed at the penile base, followed by the shaft and glans. In the majority of cases, the metastasis manifests as a solitary small nodule on the penis[4]. Penile cancer resulting from colorectal cancer often carries a grim prognosis. Literature research indicates that the median survival period following the diagnosis of penile metastasis is typically five months[5]. To address this challenge, interventions such as surgical resection and chemotherapy are employed in various studies. However, the outcomes have demonstrated limited efficacy[6]. In colorectal cancer, the BRAF^V600E mutation is associated with poorly differentiated tumors, serving as a negative prognostic factor[7]. Due to poor response to standard therapies, its mortality rate is nearly twofold that of BRAF wild-type tumors[8]. Clinical studies have demonstrated that the combined treatment regimen of BRAF inhibitor and MEK inhibitor exhibits significant potential in raising the survival rate of patients harboring such mutation[9].

CASE PRESENTATION

Chief complaints

A 49-year-old Chinese male was admitted with a 5-day history of persistent abdominal pain, bloating, and obstipation.

History of present illness

Five days after the onset of periumbilical colic, abdominal distension, and cessation of exhaust and defecation without apparent etiology, the patient sought medical attention at a local hospital. Abdominal computer tomography (CT) examination revealed thickening of the upper sigmoid colon wall, proximal bowel dilatation, and incomplete intestinal obstruction, which was considered a high possibility of colon cancer (Figure 1). The patient was referred to our hospital for treatment after the conservative therapy proved ineffective. The patient underwent a radical colon cancer resection procedure at our hospital. The surgical pathology revealed a poorly differentiated adenocarcinoma of the colon, invading and breaking through the bowel wall, where eleven out of nineteen removed lymph nodes were positive. No cancer was found in the surgical margins on both sides of the intestinal segment. The presence of tumor emboli was detected within numerous blood vessels, while no evident neural invasion was observed. The immunohistochemistry indicated Her-2 (1+), BRAF (+), and a Ki67 proliferative index of 55%. The gene high-throughput sequencing detection showed BRAF^V600E mutation, APC Glu1540 alteration, and microsatellite stability (MSS) status. The disease was staged as T4a N2b M0 stage IIIC.

Figure 1 Computed tomography scans of the patient upon admission: The diseased segment exhibited thickening of the intestinal wall, rough surface texture, and significantly increased enhancement on the enhanced scan. The proximal colon was obstructive dilatation.

According to the Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of colorectal cancer, the patient underwent postoperative adjuvant chemotherapy of 5-FU, 2800 mg/m², 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m²i.v.; irinotecan, 165 mg/m²; oxaliplatin, 85 mg/m²i.v. (FOLFOXIRI) for four cycles. However, subsequent metastases to the liver and mesorectal fascia were observed in the patient on the magnetic resonance imaging (MRI) scans and positron emission tomography-CT (PET-CT). The treatment regimen was subsequently switched on to FOLFOXIRI in combination with bevacizumab for eight cycles. The patient's metastases gradually diminished and his tumor markers returned to normalcy following treatment with this regimen. Consequently, the patient was transitioned to maintenance therapy of capecitabine plus bevacizumab (5 mg/kg). However, after five cycles of maintenance treatment, the patient presented with novel masses at the root of the penis and coronal sulcus. Pathological examination of the coronal sulcus mass revealed morphological similarities to that of the primary colon tumor, suggesting penile metastasis from colon cancer.

History of past illness

The patient had no special history of chronic diseases or infectious diseases.

Personal and family history

The patient denied any familial history of malignancy or genetic predisposition.

Physical examination

The patient presented with abdominal distention accompanied by tenderness upon palpation, while the vital signs were within normal limits.

Laboratory examinations

The tumor marker carbohydrate antigen-125 (CA-125) was slightly elevated on admission (46.8 U/L), followed by fluctuations in CA-125 and CA19-9 levels with the progression of the disease and implementation of the treatment regimen, while the remaining markers maintained at a low level throughout the whole process (Figure 2).

Figure 2 Changes in tumor markers during treatment. AFP: Alpha fetoprotein; CEA: Carcinoembryonic antigen; CA: Carbohydrate antigen.

Imaging examinations

Upon initial admission, the CT scan of the whole abdomen and pelvis revealed thickening of the wall in the upper segment of the sigmoid colon, with a rough surface and a narrow lesion lumen. There were no obvious signs of metastasis in peripheral lymph nodes, liver and mesorectal fascia.

During the treatment with FOLFOXIRI, MRI and PET-CT showed the disease progression: A new nodule in the mesorectal fascia (10 mm × 10 mm) and a suspicious lesion in liver of segment IV/VIII (10 mm × 9 mm) were considered metastatic tumors.

Further diagnostic work-up

In order to further clarify the nature of the penile mass, the patient underwent local surgical resection of three masses located in the coronary sulcus. A histopathological examination of the resected masses revealed a poorly differentiated adenocarcinoma, consistent with his primary colon tumor (Figure 3). The immunohistochemical examination showed positive expression of CDX2, CK20, and SATB2, indicating a colonic origin for the penile mass (Figure 4).

Figure 3 Hematoxylin and eosin staining of colonic mass and penile mass. The penis mass microscopic pathology performance similar to the colonic mass, considering penile metastasis from colon cancer. A: Colonic mass (original magnification × 100); B: Colonic mass (original magnification × 200); C: Penile mass (original magnification × 40); D: Penile mass (original magnification × 100); E: Penile mass (original magnification × 200); F: Penile mass (original magnification × 400).

Figure 4 The immunohistochemical staining results of the penile mass indicated a colonic origin. A: CDX2 (original magnification × 100); B: CK20 (original magnification × 100); C: SATB2 (original magnification × 100).

FINAL DIAGNOSIS

Based on the patient's comprehensive medical history and pertinent diagnostic evaluations, a diagnosis of colon cancer with BRAF^V600E mutation was established, accompanied by multiple metastases in the penis, liver, mesorectum, among other sites.

TREATMENT

After initial treatment with FOLFOXIRI plus bevacizumab, the patient's tumor exhibited inadequate control and subsequently progressed and metastasized. In accordance with the CSCO guidelines for colorectal cancer diagnosis and treatment, the regimen of BRAF/MEK-targeted therapy (dabrafenib and trametinib) combined with cetuximab (dabrafenib, 150 mg twice daily; trametinib, 2 mg once daily; cetuximab 200 mg/m² once biweekly) was devised based on the tumor's BRAF^V600E mutation (Figure 5).

Figure 5 Timeline of the patient's treatment course. SD: Stable disease; FOLFOXIRI: 5-FU, 2800 mg/m², 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m²i.v.; irinotecan, 165 mg/m²; oxaliplatin, 85 mg/m²i.v.

OUTCOME AND FOLLOW-UP

After the treatment of dabrafenib and trametinib plus cetuximab, the patient's serum levels of tumor markers gradually decreased to within the normal range, and all metastatic lesion exhibited varying degrees of shrinkage. Remarkably, the dimensions of the metastatic lesion at the penile base diminished substantially, decreasing from a magnitude of 1.6 cm × 1.9 cm to a mere 0.5 cm × 0.3 cm. Concurrently, the associated symptoms, including dysuria and penile pain during erection, abated progressively. However, five months later, the patient's disease exhibited further progression and there was a significant increase in tumor markers (CA19-9 388 U/mL). Subsequently, the treatment regimen of FOLFOXIRI in combination with bevacizumab was modified once again. Unfortunately, the patient was subsequently lost to follow-up.

DISCUSSION

The liver, peritoneum, lung, and bone are the most frequently observed metastatic sites in colorectal cancer. Nevertheless, there have been reports of less common sites such as the pancreas, ovary, brain, and even the oral cavity[10]. Metastasis of colorectal cancer to distant organs is often indicative of advanced tumor progression and carries a poor prognosis. After the source of metastasis is identified through immunohistochemical examination, local resection of metastatic lesions followed by systemic chemotherapy is commonly employed as a standard treatment[11].

The occurrence of penile metastasis from colorectal cancer is exceedingly rare in clinical practice, and the incidence rates differ significantly between colon cancer and rectal cancer. In reported cases of penile metastasis from colorectal cancer, the proportion of rectal cancer is significantly higher than that of colon cancer[12]. The precise mechanism underlying the metastasis of colorectal cancer to the penis remains elusive, with potential routes including retrograde venous spread, retrograde lymphatic spread, arterial spread and direct extension[13,14]. In particular, the retrograde venous spread is the most widely accepted among them. The modes of dissemination may encompass a diverse array of mechanisms. Different from the colon cancer, the low rectal cancer can drain from the middle and inferior rectal vein to the internal iliac vein. Through retrograde venous cell migration, tumor cells can be transferred to the internal pudendal vein and the dorsal penile vein system, resulting in penile metastasis of rectal cancer. However, colon cancer commonly drains via the superior and inferior mesenteric veins before eventually entering the portal vein system, thereby bypassing the penile vascular system, which necessitates further exploration of the specific route of penile metastasis in colon cancer[15,16]. Given the postoperative histopathological findings in our case, which indicated the presence of numerous vascular tumor emboli and metastatic cancer in peri-intestinal lymph nodes, it is plausible to suggest that retrograde lymphatic spread may have been one of the pathways for penile metastasis of colon cancer in this particular case[12,17]. However, the precise mechanism underlying penile metastasis remains to be further elucidated.

The most prevalent manifestations of penile metastases encompass penile pain and tenderness, the presence of a nodular mass on the penis, and the occurrence of malignant priapism[8,17]. In our case, in addition to pain during urination, we observed an intensely tender mass at the base of the patient's penis, which aligns with the characteristic symptoms associated with penile metastases. When penile metastases occur, the majority of patients exhibit concomitant metastases to other anatomical sites, including the liver, lung, and peritoneum[18]. The prognosis associated with penile metastases is generally unfavorable, characterized by a mean survival duration of merely nine months. Its treatment methods include surgical resection, radiation therapy, and chemotherapy. The surgical resection procedure involves the excision of the local mass and complete penectomy. The latter may significantly impact the social-psychological state and daily life of the patients. However, it may also enable patients to obtain greater benefits and longer survival[19]. Therefore, the choice of treatment for penile metastasis remains controversial. In addition to surgical intervention, appropriate chemotherapy and targeted therapy play a pivotal role in effectively managing micro-metastasis, suppressing tumor recurrence, and significantly prolonging patient survival. In the case we reported, the therapy of cetuximab, dabrafenib and trametinib exhibited satisfactory efficacy.

The BRAF^V600E mutation occurs in roughly 8%-12% patients with metastatic colorectal cancer (mCRC), which represents a poor response to most systemic therapies and a worse prognosis[20]. BRAF controls cellular survival, replication and differentiation by encoding serine/threonine protein kinase, which plays a critical role in the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. When the V600E mutation occurs, BRAF kinase activity is enhanced by insertion of a negatively charged residue near the phosphorylation site in the catalytic domain, followed by phosphorylation of MEK1 and MEK2, activating ERK1 and ERK2. This process phosphorylates a variety of cell substrates involved in cell proliferation and inhibition of cell apoptosis, promoting tumor survival, growth and metastasis[21-23]. Unlike mCRC with microsatellite instability, which can benefit from immune checkpoint inhibitors such as pembrolizumab and ipilimumab + nivolumab, the mainstream treatment for mCRC with BRAF^V600E mutation and MSS is still surgical resection followed by chemotherapy. Chemotherapy regimens include CAPEOX, mFOLFOX6, FOLFIRI or FOLFOXIRI combined with the anti-vascular endothelial growth factor monoclonal antibody bevacizumab. When the tumor recurred or metastasized further, BRAF and MEK inhibitors (dabrafenib and trametinib) in combination with the anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab) may serve as a good option[23,24]. In contrast, single-agent BRAF inhibitors, such as dabrafenib and encorafenib, have demonstrated efficacy in BRAF^V600E-mutated melanoma, thyroid cancer, and small cell lung cancer. However, they have exhibited limited therapeutic benefits in metastatic colon cancer with BRAF^V600E mutation[25]. In addition, the combination of BRAF inhibitor and EGFR antibodies, such as dabrafenib + panitumumab and encorafenib + cetuximab, has demonstrated favorable outcomes in terms of both anti-tumor efficacy and overall survival[26,27]. In a clinical trial, the efficacy of dual BRAF and MEK inhibition was assessed using dabrafenib in combination with trametinib, excluding the EGFR inhibitor, among a cohort of 43 patients. Among them, five patients (12%) exhibited a positive response to the treatment regimen, with a median progression-free survival of 3.5 months. Notably, one patient achieved a complete response, maintaining the response for a duration of 36 months[28]. The lack of efficacy of single-agent BRAF inhibitor therapy in BRAF^V600E mutation mCRC is due to the suppression of ERK-dependent negative feedback mediators that restrict the MAPK pathway. This may lead to the induction of RAS activity as well as the activation of RAS kinase, which generates RAF dimers that bypass activation of MAPK signaling pathway, thereby attenuating the antitumor effect. EGFR antibodies exert their best anti-tumor effect by inhibiting this process in combination with BRAF and MEK inhibitors[21,22]. When EGFR monoclonal antibodies are introduced, such as cetuximab in combination with dabrafenib, trametinib, and panitumumab, the patients' recovery rate reaches 21%, with a median progression-free survival of 4.2 months[23].

Cases of penile metastasis from colon cancer are infrequent, and several factors contribute to this rarity. The dismal prognosis associated with metastatic penile cancer often leads to a short survival period for patients, making it challenging to track certain cases. Moreover, the scarcity of this medical condition may cause surgeons to overlook its occurrence and fail to document it adequately. Additionally, patients might refrain from seeking medical attention due to symptoms such as penile pain, erectile dysfunction, or the presence of foreign objects protruding from the penis surface in order to preserve their dignity. Furthermore, reported cases also underscore instances of chemotherapy-induced penile pain and side effects like rash, which can potentially mask early signs of penile metastasis during treatment. These various factors collectively account for potential missed diagnoses.

In this case, we employed targeted mutations to modify the chemotherapy regimen, leading to rapid reduction of metastatic lesions and obviating the need for penile resection, thereby preserving the patient's quality of life. This approach not only maintained physiological function and psychological well-being but also significantly improved prognosis across multiple dimensions. Targeted therapy effectively prolonged survival period. Therefore, when penile metastasis is detected, our preferred treatment strategy would focus on preserving the penile function rather than resorting to resection, reflecting our compassionate care for the patient. These considerations enhanced patient compliance with medical advice and adherence to the treatment regimen. Taking the impact of psychosocial factors on patients' treatment into consideration proves to be highly significant and should not be underestimated.

CONCLUSION

In summary, since penile metastasis is a rare occurrence primarily originating from genitourinary organs, and colon cancer rarely serve as the primary source, further investigation into its specific mechanisms and appropriate treatment options for penile metastasis originating from colon cancer is required. The presence of BRAF^V600E mutation in colorectal cancer often indicates a poor prognosis, therefore developing a targeted therapy for this specific mutation is highly important. Relevant targeted therapies on colon cancer with BRAF^V600E mutation in our case effectively impeded tumor progression and extended patient survival, which can serve as a valuable reference for analogous cases.

ACKNOWLEDGEMENTS

The authors would like to thank the patient and his families for their support and cooperation.