Complete remission following targeted therapy in BRAF V600E: mutant pulmonary lymphangitic carcinomatosis secondary to rectal cancer—a case report

Abstract

Background

Pulmonary lymphangitic carcinomatosis (PLC) secondary to colorectal cancer is an uncommon manifestation, accounting for fewer than 7% of all PLC cases. Because of its nonspecific clinical and radiologic features, it is frequently misdiagnosed as interstitial lung disease or pulmonary infection. The prognosis remains poor, as the majority of patient’s progress rapidly to acute respiratory failure shortly after diagnosis, with a reported median survival ranging from 2.2 to 7 months. To date, only one documented case has demonstrated survival beyond 12 months. Here, we present a patient who survived 19 months, emphasizing the importance of early recognition and the role of molecular-guided therapy in extending survival.

Case presentation

We present a case of PLC secondary to rectal cancer harboring a BRAF V600E mutation that achieved complete response after relapse with triple combination therapy (dabrafenib, trametinib and cetuximab). A 30-year-old Vietnamese woman presented with unresectable rectal carcinoma and multiple lymph node metastases. She was initially treated with FOLFOX plus bevacizumab, achieving a first complete response, followed by FOLFIRI plus bevacizumab. However, she subsequently developed progressive pulmonary lymphangitic carcinomatosis with impending respiratory failure. Given the BRAF V600E mutation, third-line treatment with a BRAF inhibitor and trametinib combined with cetuximab was initiated. This regimen led to rapid symptomatic improvement, with dyspnea resolving within 1 day, and resulted in a second complete remission, specifically of pulmonary lymphangitic carcinomatosis, which was maintained for 4 months. Despite subsequent disease progression, the patient achieved an overall survival of 19 months from the time of diagnosis.

Conclusions

This case demonstrates that triple combination therapy may induce rapid and durable remission in PLC secondary to BRAF-mutated colorectal cancer. It underscores the importance of comprehensive molecular profiling in guiding personalized treatment for rare metastatic manifestations. Moreover, this report highlights the importance of timely, genomics-guided therapeutic decision-making and pragmatic adaptation of targeted strategies in managing aggressive BRAF V600E–mutant colorectal cancer, particularly in clinically complex and resource-constrained settings.

Background

PLC is a rare manifestation of metastatic malignancy, characterized by the diffuse infiltration of tumor cells within the pulmonary lymphatic vessels. Accounting for approximately 6–8% of all pulmonary metastases and PLC is associated with adenocarcinomas of the breast, lung, stomach, pancreas, and prostate [1]. Clinically, PLC causes rapid-onset respiratory symptoms, typically dyspnea and dry cough, and is frequently misdiagnosed as interstitial lung disease or infection due to its nonspecific radiological and clinical features [2], [3]. Prognosis of PLC remains extremely poor, with most patients developing acute respiratory failure at or shortly after diagnosis with a median survival 2.2–7 months from diagnosis, indicating the urgency of early recognition and intervention [3–5].

While colorectal cancer is one of the leading causes of cancer-related mortality worldwide, PLC secondary to colorectal origin accounts for fewer than 7% of all PLC cases [3]. A literature review covering cases from 1980 to the present (2025) identified only 11 patients have been documented in the literature with PLC originating from colon cancer, and even fewer from rectal primaries (Table 1). This uncommon metastatic pattern is poorly understood, and likely underdiagnosed, contributing to delays in commencement of therapy.

Table 1.

Summary of reported cases of PLC in colorectal cancers from 1980 to 2025. Survival time is measured from the diagnosis of PLC to death

No	Author (Year)	Patient (Gender, Age)	Primary Cancer	Initial Symptoms	Chemotherapy Regimen	Survival Time	Cause of Death
1	Phillips (1981)[13]	Male, 34	Colon cancer	Dry cough and dyspnea	None	< 0.5 month	Respiratory failure
3	Shimura et al. (1994)[14]	Female, 52	Colon cancer	Productive cough, dyspnea	Not specified	5 months	Respiratory failure
4	Thomas et al. (2008)[15]	Female, 31	Colon cancer	Dry cough and dyspnea	FOLFOX4 (oxaliplatin + leucovorin + 5-fluorouracil)	0.5 months	Respiratory failure
5	Otsubo et al. (2011)[16]	Female, 26	Sigmoid colon cancer	Dry cough + Dyspnea	Carboplatin + Paclitaxel	1 month	Respiratory failure
6	Jinnur et al. (2016)[17]	Male, 66	Colon cancer	Chronic cough	Leucovorin, 5-Fluorouracil and Irinotecan	Not specified	Not specified
7	Del Rosario et al. (2016)[18]	Not specified	Colon cancer	Dyspnea, cardiac tamponade, pleural effusion	Bevacizumab + Cetuximab	12 months	Not specified
8	Wang et al. (2019)[19]	Male, 66	Colon cancer	Nonproductive cough	Cetuximab	< 1 months	Respiratory failure
9	Our reported case	Female, 30	Rectal cancer	Dyspnea	FOLFOX6 + Bevacizumab; FOLFIRI + Bevacizumab; Dabrafenib + Trametinib + Cetuximab	19 months	Respiratory failure

In this report, we present a rare case of PLC secondary to rectal cancer in a patient who achieved complete clinical and radiologic response following the administration of targeted therapy guided by genetic profiling.

Case presentation

In July 2023, a 30-year-old Vietnamese woman presented with a history of asthma was admitted with respiratory failure, following a 2-week history of progressively worsening diffuse abdominal pain, hematochezia, dry cough, and dyspnea. Physical examination revealed several palpable, hard, painless left supraclavicular lymph nodes. The patient appeared visibly distressed and tachypneic, with a respiratory rate of 28 breaths per minute. Her oxygen saturation on room air was 92%, which improved to 96% with supplemental oxygen via nasal cannula.

Excisional biopsy of cervical lymph node revealed metastatic adenocarcinoma (Fig. 1A, B). Colonoscopy also revealed a circumferential tumor on the lower rectum, and showed a moderately differentiated adenocarcinoma consistent with finding on cervical lymph node biopsy (Fig. 1C, D). Chest CT scan suggested bronchial wall thickening, thickening of peribronchial vascular interstitial tissue, interlobular septal thickening and ground-glass opacities in both lungs (Fig. 2A). PET/CT scan showed a rectal tumor at the corresponding position on the colonoscopy with high FDG-uptake (SUV max of 11.1) and multiple FDG-avid lesions in the lungs, cervical lymph nodes, mediastinal lymph nodes and abdominal lymph nodes (SUV max of 9.4) (Fig. 2C). The patient was diagnosed with metastatic rectal cancer.

Fig. 1.

A, B Histopathology of a cervical lymph node showing metastatic adenocarcinoma, with the normal nodal architecture effaced by tumor cells (H&E, original magnifications × 5 and × 100). C, D Histopathology of the rectal tumor showing a moderately differentiated adenocarcinoma with irregular tubules, intraluminal necrosis, and a desmoplastic stroma, adjacent to benign colonic glands (H&E, original magnifications × 50 and × 100)

Fig. 2.

Chest CT scan and PET/CT before and after first-line therapy with FOLFOX plus bevacizumab. A Presence of bronchial wall thickening, thickening of the peribronchovascular interstitium (orange arrows), interlobular septal thickening (red arrows) and ground glass (yellow arrow) in both lungs during initial admission; B following six cycles of first-line therapy, a complete response at the lung was achieved; C PET/CT revealed multiple FDG-avid lung lesions, bilateral supraclavicular lymph nodes (yellow arrow), mediastinal lymph nodes (red arrow), and abdominal lymph nodes (orange arrow); D complete response was achieved at both the primary tumor and other targeted lesions on PET/CT

Tumor profiling of the primary tumor identified a BRAF V600E mutation, initially detected by immunohistochemistry (IHC) and subsequently confirmed using the StripAssay method. The tumor was negative for HER2 expression, demonstrated microsatellite stability (MSS), and showed no detectable KRAS or NRAS mutations by StripAssay. Next-generation sequencing was not performed because of cost considerations.

One week after admission, her respiratory status continued to deteriorate. Empirical treatment with corticosteroids, broad-spectrum antibiotics, antifungal, and antiviral agents was initiated. However, there was no clinical or radiological improvement, the patient's ECOG performance status declined to 3. PLC was highly suspected.

We immediately initiated first-line treatment with FOLFOX plus bevacizumab, which led to gradual improvement of her dyspnea. Surprisingly, PET/CT demonstrated a first complete response after six cycles of treatment, with complete remission of the primary rectal tumor, pulmonary lymphangitic carcinomatosis, and all other target lesions according to RECIST v1.1 criteria (Fig. 2B, D). The patient subsequently transitioned to maintenance therapy with capecitabine and bevacizumab after completing 12 cycles of FOLFOX plus bevacizumab. Eight months after initiation of first-line therapy, in March 2024, isolated recurrence of pulmonary lymphangitic carcinomatosis was observed, while all other lesions remained in complete remission. At the time, the patient’s only symptom was a persistent dry cough and second-line therapy with FOLFIRI and bevacizumab was administered. Approximately 6 months later, in September 2024, the patient presented to the emergency department with severe dyspnea. Chest CT scan demonstrated peribronchovascular interstitial thickening and interlobular septal thickening (Fig. 3A). A presumptive diagnosis of pneumonia or asthma exacerbation was considered. Her respiratory distress worsened severely, and ECOG performance status went down to 3 within a week. Oxygen saturation dropped to below 90% despite supplemental oxygen. The patient was diagnosed with recurrent PLC.

Fig. 3.

Chest CT scan of recurrent PLC and after initiation of triple targeted therapy: A recurrent PLC with peribronchovascular interstitial thickening (orange arrow) and interlobular septal thickening (red arrows) was shown on chest CT scan in September 2024; B lesions were no longer visible suggesting a complete response in November 2024

Current evidence at that time supported the approval of doublet targeted therapy with encorafenib plus cetuximab for the treatment of BRAF V600E-mutated colorectal cancers in the non-first-line setting [6]. Due to the lack of alternative therapies, and because it was the only available option at that time, the patient was offered off-label treatment with cetuximab, dabrafenib, and trametinib, based on limited evidences [7–9].

The patient demonstrated a remarkable improvement shortly after therapy. She was able to breathe comfortably without supplemental oxygen, with oxygen saturation levels improving from 88% on room air to 96% within 24 h. Her respiratory rate decreased from 28 to 18 breaths per minute, and she reported significant relief from dyspnea. Clinically, she showed a marked improvement in vital signs and overall condition, allowing for safe discharge on day 3 of hospitalization.

After starting third-line therapy in September 2024, imaging performed in November 2024 demonstrated complete resolution of lung metastases, with all other lesions remaining in remission, representing a second remission (Fig. 3B). The aggressive triple therapy may have several adverse effects. The cetuximab-induced grade I–II rash persisted throughout the entire course of drug administration in our case and was relieved by local application of ointment containing glucocorticoids and topical lotion. Four months later, in January 2025, recurrent pulmonary metastases were identified, accompanied by new-onset pericardial effusion, indicating subsequent disease progression (Fig. 4A, B). The patient subsequently elected to transition to hospice care and passed away in February 2025, resulting in a final overall survival of 19 months from diagnosis (Fig. 5).

Fig. 4.

Chest CT scan obtained 4 months after triple targeted therapy: recurrent and new lung lesions (A—red arrows) and pericardial effusions (B—orange arrow)

Fig. 5.

Timeline of diagnosis, treatment interventions and clinical outcomes

Discussion

Lymphangitic carcinomatosis (LC) is a rare and often underdiagnosed condition in cancer patients. Klimek et al.’s systematic review cites PLC prevalences of 4–8%, and that PLC is the first manifestation of the underlying cancer in 1% of patients [3]. PLC diagnosis ideally requires histopathological confirmation via lung biopsy, but this may not always be feasible, especially if the patient's condition is poor. In such cases, diagnosis is often made based on characteristic radiological findings on high-resolution CT (HRCT), such as thickening of interlobular septa and peribronchovascular interstitium, combined with FDG PET/CT which shows increased tracer uptake correlating with the tumor burden [11]. This combined radiologic approach integrated with clinical presentation and disease course is commonly used in clinical practice when biopsy is not feasible or poses significant risk [12]. In our case, where clinical condition is poor, this non-invasive diagnostic approach based on HRCT and PET/CT findings alongside clinical judgment is appropriate and recognized. The pathophysiology of PLC presents unique therapeutic hurdles compared to more common hematogenous metastases. The lymphatic vessels, acting as conduits for tumor cell dissemination, allow for widespread and often insidious infiltration throughout the pulmonary parenchyma. This diffusion complicates local therapies, including radiation and challenges the ability of systemically administered chemotherapy to be adequately distributed to target lesions. PLC often presents with a constellation of symptoms, including dyspnea, cough, and hypoxemia that significantly impair quality of life and limit functional capacity.

In colorectal cancer, the nonspecific presentation of PLC often leads to delays in initiating treatment. Most cases are only identified at the stage of severe respiratory failure, with patients typically dying within 1 month of hospitalization and less than 6 months since the first presentation of respiratory symptoms (Table 1). Reported cases consistently present with persistent dry cough and progressive dyspnea, which eventually lead to respiratory failure. Therefore, clinicians should maintain a high index of suspicion for PLC and promptly evaluate any patient with a history of cancer who presents with unexplained respiratory symptoms.

In the previously reported cases, the duration from onset of respiratory symptoms to death is generally very short. Only one documented case has achieved a survival time of more than 12 months from diagnosis of PLC (Table 1). Our patient survived a total of 19 months, underscoring the clinical effectiveness of a genomics-guided, off-label targeted treatment strategy and highlighting the novelty of implementing a locally adapted precision-medicine approach in a resource-limited setting, which may contribute to extended survival in similar cases.

The presence of a BRAF V600E mutation in this case provides a critical molecular rationale for the observed response. The BRAF V600E mutation, found in approximately 8–12% of metastatic CRCs, leads to constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and is consistently associated with aggressive clinical behavior [20]. In the present case, the coexistence of a BRAF V600E mutation and pulmonary lymphangitic carcinomatosis represents a rare and clinically aggressive disease presentation that may partially account for the unfavorable clinical outcome. However, a direct biological or clinical association between BRAF V600E mutations and the development of pulmonary lymphangitic carcinomatosis has not been established.

Our case aligns with existing literature demonstrating the efficacy of BRAF-targeted therapies in BRAF V600E-mutated metastatic CRCs, exemplified by the BEACON CRC trial [6]. However, off-label combinations, such as dabrafenib and trametinib, have been investigated as therapeutic alternatives due to their clinical effects in several selected cases. In Vietnam, encorafenib was not available at the time of treatment due to regulatory approval status and economic constraints, which precluded its routine clinical use. Consequently, the combination of dabrafenib, trametinib, and cetuximab was selected as a rational, locally accessible alternative to enable timely initiation of targeted therapy in this patient with BRAF V600E–mutant colorectal cancer.

While the BEACON trial did not specifically analyze outcomes in patients with PLC, it is implied that the addition of cetuximab may enhance the efficacy of BRAF inhibition by overcoming compensatory EGFR activation. The complete response observed in our patient further supports this notion. However, it is important to acknowledge that the potential benefits of cetuximab may be context dependent. BRAF V600E mutations activate the MAPK pathway, promoting tumor growth. While BRAF inhibitors such as dabrafenib or encorafenib directly target this mutation, resistance often develops due to feedback mechanisms that upregulate EGFR signaling. Cetuximab, an anti-EGFR monoclonal antibody, can block this compensatory feedback, enhancing the overall antitumor efficacy [21, 22]. This synergy may be particularly relevant in the context of PLC, where the immune microenvironment within the pulmonary lymphatic vessels may play a critical factor to determine treatment response.

The patient's 4-month complete response to dabrafenib, trametinib, and cetuximab in BRAF V600E-mutated rectal cancer with PLC reflects both the potential and limitations of targeted therapy in this high-risk setting. There are some factors limiting response durability in this case. First, tumors with MSS exhibit lower immunogenicity and reduced immune infiltration compared to MSI-H counterparts, limiting the durability of targeted therapies. MSI-H status also correlates with prolonged responses due to enhanced immune activation [23]. Emerging evidence from trials combining BRAF/MEK inhibitors with anti-PD-1 agents demonstrates improved durability [24, 25]. The lack of immune checkpoint blockade combination here may explain shorter response [26]. Second, the patient received the regimen as a later-line therapy, which may reduce its efficacy. First-line studies (e.g., BREAKWATER trial) show longer median response durations (13.9 months) with encorafenib, cetuximab and chemotherapy, suggesting prior treatments may exhaust therapeutic efficacy [22]. Third, resistance mechanisms may have developed, as PIK3CA mutations activate parallel survival pathways, potentially reducing the duration of therapeutic response [9]. In addition, subclonal populations with intrinsic resistance to BRAF/MEK inhibition likely contributed to early progression [27]. This study highlights the necessity for personalized, multi-modal treatment strategies in BRAF-mutated PLC, as therapeutic responses tend to be transient, underscoring the need for relevant and adaptive therapeutic options. The integration of genomic profiling, biomarker analysis, and targeted therapies holds promise for improving outcomes in patients with PLC and other aggressive form of CRCs.

Because the patient passed away before a formal interview could be conducted, the perspective below reflects observations recalled by the treating team rather than direct quotations from the patient or her family. At the time of admission, the patient presented in critical condition. The medical team discussed the aggressive nature of the disease and the limited availability of standard therapeutic options. An individualized treatment strategy, including off-label therapy, was proposed. The potential benefits and risks were explained, and the patient agreed to proceed. During treatment, her clinical status improved and symptoms became more manageable. She was able to maintain independence in daily activities for longer than initially anticipated. With subsequent disease progression, goals of care were re-evaluated. In view of her overall condition and the lack of additional effective therapies, the focus of care shifted to hospice management, prioritizing comfort and quality of life.

Conclusions

PLC can be a rare metastatic manifestation of colorectal cancer and may mimic common pulmonary conditions. Oncologists should maintain suspicion for PLC when patients with colorectal malignancy present with unexplained respiratory symptoms. This case is remarkable for the rapid and dramatic response achieved through precision medicine. Detecting the BRAF V600E mutation enabled targeted therapy, combining BRAF/MEK inhibitors and with anti-EGFR agents, which significantly improved outcomes in a condition that usually responds poorly to conventional treatments and has a poor prognosis.

Limitations

This report is subject to several important limitations. As a single-case observation, it provides hypothesis-generating insights but does not allow causal inference or generalizability. The diagnosis of pulmonary lymphangitic carcinomatosis was based on clinical and radiologic findings without histopathological confirmation, as lung biopsy was contraindicated in the setting of clinical instability; therefore, diagnostic certainty, although high, cannot be absolute.

In addition, comprehensive molecular profiling was limited. Serial biomarker assessment and circulating tumor DNA (ctDNA) analyses were not performed, precluding evaluation of clonal dynamics, molecular evolution, and mechanisms of acquired resistance. Finally, data were collected retrospectively, and no prospectively defined patient-reported outcome measures were available, limiting systematic assessment of symptom burden and quality-of-life trajectories during treatment.

Author contributions

TTDT participated in the conceptualization, investigation, and analysis, and was a major contributor to the manuscript writing. TTTH participated in the investigation, analysis, and writing the manuscript. HLN participated in investigations. DTN participated in the investigation and wrote the manuscript. TDQ participated in conceptualization, investigation and validation. TPV participated in investigation and validation. KNV participated in analysis and validation. VDL participated in validation. HGY participated in review and validation. SHV participated in conceptualization, manuscript writing, and review and editing. All authors have read and approved the final manuscript.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

The study was approved by the Ethics Committee in Biomedical Research of Vinmec International General Hospital Joint Stock Company—VinUniversity (approval number: 61/2026/CN/HĐĐĐ VMEC). Written informed consent was obtained from the patient for participation of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interest

We declare no conflict of interest.