Peritoneal carcinomatosis in metastatic Non-Small Cell Lung Cancer: review of the literature.

Introduction
Lung cancer (LC) is among the most prevalent malignancies globally and represents the leading cause of cancer-related mortality. In the United States, the estimated numbers of new LC cases and related deaths in 2025 are 226,650 and 124,730, respectively [1]. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all LC cases and is well known for its propensity to metastasize to the brain, bones, adrenal glands, and liver. Peritoneal carcinomatosis (PC) is an infrequent yet increasingly recognized site of metastasis in advanced NSCLC. PC represents a disseminated form of malignancy that typically arises from intra-abdominal primary tumors, such as ovarian, colorectal, and gastric cancers. Its occurrence in NSCLC, a malignancy primarily affecting the thoracic cavity, has historically been regarded as exceedingly rare. Nonetheless, recent advancements in imaging technologies, longer survival rates due to improved systemic treatments, and molecular profiling have contributed to an increased recognition of atypical metastatic patterns, including peritoneal spread, in NSCLC patients [2–4]. Clinical incidence of PC in NSCLC remains low, typically ranging between 1 and 2% based on imaging and symptomatic presentation [5, 6]. However, autopsy studies have revealed a higher prevalence, with peritoneal involvement observed in approximately 5% of patients who die from NSCLC [7]. The adenocarcinoma subtype appears to be most frequently associated with peritoneal dissemination, likely due to its aggressive phenotype and greater tendency for extrapulmonary metastasis [8]. Recent advancements in systemic therapies, particularly targeted therapies and immune checkpoint inhibitors (ICIs), have significantly extended survival in patients with advanced NSCLC. This prolongation of life may allow for the emergence of atypical metastatic patterns, including peritoneal spread, which may have previously gone undetected due to shorter survival times [9, 10]. Isolated peritoneal metastases have also been described, particularly in NSCLC harboring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements [11, 12]. The underlying mechanisms for peritoneal metastasis from a primary lung tumor may include hematogenous dissemination via systemic circulation [13], lymphatic spread through diaphragmatic channels [14], or, less commonly, transcoelomic seeding potentially facilitated by invasive procedures [15]. Despite its rarity, PC in NSCLC is associated with a poor prognosis and represents a diagnostic and therapeutic challenge that warrants increased clinical awareness [16–28].

Pathogenesis
The development of PC in NSCLC is a rare event and remains poorly understood. Several mechanisms have been proposed to explain the dissemination of tumor cells from the primary lung site to the peritoneal cavity. Hematogenous spread via systemic circulation is considered the most plausible route, particularly in the context of widespread metastatic disease, allowing tumor emboli to seed the peritoneum through mesenteric or omental vasculature [5]. Lymphatic dissemination may also contribute, especially in cases where extensive mediastinal or retroperitoneal lymph node involvement disrupts lymphatic drainage and facilitates retrograde peritoneal spread [29]. Another hypothesis involves transdiaphragmatic migration of malignant cells via diaphragmatic lymphatic stomata, a mechanism observed in ovarian and gastric cancers, although its relevance in pulmonary malignancies remains speculative [30]. Molecular and histopathologic subtypes of NSCLC may also influence the likelihood of peritoneal involvement. Lung adenocarcinomas, particularly those with micropapillary or solid patterns, show a greater propensity for aggressive and extrapulmonary spread, including to the peritoneum [31]. Moreover, epithelial–mesenchymal transition (EMT), a key process in tumor cell invasion and metastasis, has been implicated in enhancing peritoneal dissemination through increased cellular motility and detachment from the primary tumor mass [32]. Recent studies have also implicated the role of integrins, matrix metalloproteinases, and chemokine signaling in promoting the adhesion and survival of neoplastic cells within the peritoneal microenvironment [33]. Although uncommon, PC may represent a distinct metastatic phenotype within NSCLC, particularly in patients with prolonged survival following systemic therapy or with specific oncogenic drivers such as EGFR mutations, which are associated with atypical patterns of dissemination [10]. Available evidence regarding the genomic landscape of PC arising from NSCLC remains scarce. In a next-generation sequencing (NGS) analysis, Nassereddine et al. [34] reported molecular abnormalities involving nine genes, TP53, KRAS, STK11, BRAF, EGFR, DDR2, ERBB4, SMAD4, and CTNNB1, with at least one alteration detected in nearly 89% of adenocarcinoma cases. Among these, TP53 emerged as the most frequently affected gene, present in more than half of tumors, and often co-occurring with additional mutations, including those in KRAS, STK11, BRAF, SMAD4, CTNNB1, and other pathways. Consistent with its established role as a major oncogenic driver in NSCLC, KRAS represented the second most commonly mutated gene. Notably, the predominance of alterations in TP53, KRAS, and STK11 aligns with mutational patterns typically associated with tobacco exposure. A recurrent non-V600E BRAF variant, specifically D594G, has been described in both pulmonary and colorectal malignancies. This mutation is linked to impaired protein activity, suggesting that conventional BRAF inhibitors are unlikely to provide therapeutic benefit. However, emerging evidence indicates that tumors harboring D594 alterations may coexist with RAS pathway mutations and could potentially demonstrate sensitivity to MEK inhibition. A particularly unusual acquired LMNA–NTRK1 fusion was reported following osimertinib resistance in a case, where entrectinib was introduced together with an EGFR-TKI rechallenge strategy [35]. Broader cohort analyses by Abbate et al. [27] and Nassereddine et al. [34] reported frequent co-mutations involving TP53, KRAS, and STK11 in patients experiencing aggressive clinical trajectories, although these studies did not specifically establish molecular predictors of peritoneal tropism. Taken together, these observations suggest that oncogenic drivers, particularly EGFR and BRAF, may influence not only therapeutic susceptibility but also metastatic behavior, potentially predisposing to peritoneal dissemination. Although targeted therapies often produced only temporary benefit, the available evidence supports the hypothesis that distinct molecular subsets of NSCLC may follow atypical metastatic routes, warranting confirmation in larger genomically annotated cohorts. In addition, three tumors exhibited high PD-L1 expression levels (>50%), a feature that would currently support eligibility for immune checkpoint inhibitor (ICI) therapy [34]. A recent systematic review further supported the evidence that PC in NSCLC is overwhelmingly associated with adenocarcinoma histology [35]. Only one documented case of squamous cell carcinoma (SCC) with confirmed PC was identified, originating from a retrospective report by Patil et al. [28]. Importantly, no reports of large-cell, adenosquamous, or pleomorphic carcinoma were found within the available literature. The predominance of adenocarcinoma in this setting likely reflects its recognized biological tendency to disseminate via hematogenous routes and invade serosal surfaces. Several case reports have further demonstrated that PC may represent the first or even sole manifestation of metastatic relapse, sometimes emerging despite previous systemic disease control [35, 36]. Nevertheless, the mechanisms capable of explaining the origin of PC in NSCLC remain incompletely understood and are likely multifactorial [13].

Clinical manifestations and diagnosis
Clinically, symptoms of peritoneal metastasis in NSCLC are often subtle but may range from asymptomatic to severely debilitating, with significant impairment in performance status (PS), including nausea, vomiting, anorexia with weight loss and fatigue, abdominal discomfort or distension, and, in some cases, overt ascites. These symptoms are frequently misattributed to treatment-related side effects or unrelated gastrointestinal pathology, delaying diagnosis [37] and worsening an already poor prognosis. Ascitic fluid cytology may help confirm the diagnosis, although sensitivity is limited. Importantly, peritoneal involvement is typically a marker of advanced-stage disease and portends a poor prognosis, with median survival durations ranging from 3 to 6 months in historical cohorts [38, 39]. However, this paradigm is beginning to shift in select patients with targetable genomic alterations or robust responses to immunotherapy. The early diagnosis of PC in NSCLC remains clinically challenging due to its low incidence, frequently nonspecific symptoms, and frequent occurrence in the setting of disseminated metastatic disease [6]. Contrast-enhanced computed tomography (CT) is the first-line imaging modality, often revealing indirect signs such as peritoneal thickening, nodularity, omental caking, or ascites [40, 41]. However, CT has limited sensitivity for detecting small-volume or early peritoneal disease [42]. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) may improve diagnostic accuracy by identifying hypermetabolic peritoneal lesions, particularly in the absence of widespread disease or in patients with unexplained abdominal symptoms [10, 43, 44]. Nevertheless, microscopic or low-metabolic disease may still elude detection. Diagnostic paracentesis with cytologic analysis of ascitic fluid can support the diagnosis, although sensitivity varies widely (50–70%) and is influenced by tumor burden and the presence of mucin-producing tumors [11, 34, 35, 45–48]. From a diagnostic standpoint, immunohistochemistry (IHC) played a central role in confirming lung origin in peritoneal lesions. Across studies, pulmonary markers such as TTF-1 and CK7 were consistently expressed, whereas gastrointestinal lineage markers including CK20 and CDX2 remained negative. This immunophenotypic profile proved particularly useful in cytology-based diagnoses where tissue sampling was limited. More recently, molecular testing has been successfully applied to ascitic-derived specimens, including cell blocks and cytospin preparations. In several reports, NGS enabled detection of actionable alterations (EGFR, BRAF, NTRK), supporting both diagnostic attribution and individualized treatment selection [49]. Nonetheless, cases such as that of Ohta et al. highlight that conventional cytology combined with IHC remains a practical diagnostic strategy when comprehensive molecular profiling is not accessible [35]. When cytologic results are inconclusive, laparoscopic peritoneal biopsy remains the gold standard, enabling direct visualization, targeted sampling, and histopathologic confirmation [50]. Timely identification of PC in NSCLC is critical, as it has important implications for staging, therapeutic planning, and prognostic stratification.

Prognosis and treatment
Several clinical and biological factors have been identified as prognostic determinants in this setting. Poor PS (ECOG ≥ 2), the presence of malignant ascites, and extensive peritoneal tumor burden are among the strongest predictors of reduced overall survival, reflecting advanced disease and limited tolerance to systemic therapy [6]. Prognosis is further worsened by concomitant extra-peritoneal metastases, particularly hepatic and multiple visceral involvement, suggesting widespread hematogenous spread [16, 51]. From a molecular perspective, patients harboring actionable oncogenic drivers may experience relatively improved outcomes due to the availability of effective targeted therapies, whereas driver-negative tumors typically follow a more aggressive course [25, 26, 34, 35]. In addition, laboratory markers of systemic inflammation and malnutrition, including hypoalbuminemia and elevated neutrophil-to-lymphocyte ratio (NLR), have been correlated with poorer survival [6, 34, 35]. The treatment of PC in NSCLC remains largely palliative, as peritoneal involvement typically reflects an advanced stage of disease with limited curative options. There is currently no consensus standard for the treatment of peritoneal metastases in NSCLC and systemic therapy constitutes the cornerstone of management (Table 1). Overall, lung cancers presenting with PC appear to share a similar spectrum of driver alterations with other advanced NSCLC cases. Nevertheless, comprehensive molecular profiling together with PD-L1 immunohistochemical assessment remains essential to optimize therapeutic decision-making in this rare clinical context. Chemotherapy remains a first-line option for patients lacking actionable genomic targets and with preserved PS [52], although response rates in the presence of PC are often suboptimal due to poor peritoneal drug penetration and overall aggressive disease behavior [6]. Platinum-based doublets, most often carboplatin plus pemetrexed, were commonly administered, sometimes in combination with immune checkpoint blockade (e.g., pembrolizumab) or anti-angiogenic therapy (e.g., bevacizumab) [52–55]. However, once PC becomes established, prognosis appears particularly unfavorable. Rapid progression despite multi-agent chemotherapy and subsequent docetaxel was reported by Ohta et al. [35]. Bazine et al. documented disease stabilization exceeding four months with chemotherapy plus VEGF inhibition [21]. Long-term survival outcomes have also been reported in highly selected patients. Sibio et al. [56] described survival of 25–36 months in two individuals treated with cytoreductive surgery followed by systemic chemotherapy for isolated peritoneal metastases. By contrast, report by Tanriverdi et al. [19] emphasize the limited benefit of single-agent approaches such as docetaxel or pembrolizumab in patients with rapidly progressive disease and significant tumor burden. Overall, these findings reinforce the importance of early molecular assessment and prompt initiation of appropriate systemic therapy before substantial deterioration in PS. In patients harboring actionable mutations such as EGFR mutations or ALK rearrangements, targeted therapies (e.g., osimertinib, alectinib) have demonstrated efficacy even in cases with peritoneal involvement, offering improved disease control and symptom relief [36, 49, 57–65]. Similarly, ICIs such as anti-PD-1/PD-L1 agents may provide clinical benefit, particularly in patients with high PD-L1 expression, although data specific to PC subgroups are limited [53–55]. However, a retrospective analysis by Aarnink et al. [66] showed that pleural or peritoneal involvement was associated with reduced efficacy of immunotherapy alone, regardless of treatment line or PD-L1 status. Supportive care measures, including paracentesis for symptomatic ascites and nutritional support, play a critical role in improving quality of life [67]. Experimental therapeutic strategies, such as intraperitoneal immunotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC), have been proposed but remain investigational in thoracic oncology. Preclinical evidence suggests that modulation of the tumor microenvironment and peritoneal immune surveillance may play a role in the metastatic process and represent novel therapeutic targets [68]. Intraperitoneal chemotherapy and cytoreductive surgery (CRS) with HIPEC, standard in selected gastrointestinal and ovarian cancers, are not routinely indicated in NSCLC due to the diffuse nature of metastases and lack of supporting evidence [56, 69–72]. Given the poor prognosis associated with PC in NSCLC, treatment decisions should be individualized, taking into account molecular profile, overall disease burden, symptomatology, and patient preferences [5].

Discussion
Recent advancements in imaging technologies, longer survival rates due to improved oncological systemic treatments, and molecular profiling have contributed to an increased detection of atypical metastatic patterns, including peritoneal spread, in NSCLC patients. However, the pathogenesis of PC remains incompletely understood. Not occasionally, Patil et al. identified a significant association with malignant pleural effusion, implying a potential dissemination route possibly involving serosal communication [28]. In their series, up to 29% of patients presented with concomitant pleural involvement, which represented the most frequent synchronous site. Despite this finding, the correlation alone does not fully elucidate the underlying pathogenesis, as the majority of PC cases occur without any pleural disease. Reported survival in PC is still dismal, with a median of a few months. These data are consistent with the study by Niu et al., which demonstrated that non-classical metastatic sites in NSCLC are associated with poorer prognosis [51]. Despite this, therapeutic interventions beyond supportive care remain infrequent and only 27% of patients underwent either first-line or palliative chemotherapy, and merely 7% received surgical treatment. While these low rates may reflect the frequently poor PS of this patient population, they also raise the concern that potentially beneficial therapeutic options may be underutilized. Notably, LC, including those with unusual presentations like PC, may harbor actionable genomic alterations amenable to next-generation targeted therapies. However, the genomic landscape of PC in LC remains largely undefined. Isolated reports have identified oncogenic driver mutations such as EGFR and KRAS mutations, ALK and ROS1 rearrangements, and, less commonly, MET mutations. Conversely, ICIs, which have demonstrated substantial efficacy in selected NSCLC subpopulations, appear to be considerably less effective in patients with PC [66]. Favorable prognostic indicators in this setting may include younger age, female sex, and a non-smoking history [25, 27]. Finally, given the rarity of PC in NSCLC, there are no established guidelines for its diagnosis or management. There is a critical need for prospective data, standardized diagnostic criteria, and the inclusion of peritoneal involvement in clinical trial stratification. Molecular profiling and liquid biopsy may also enhance early detection and guide therapy selection in the future. Understanding the biological behavior of this atypical metastatic route may shed light on broader mechanisms of tumor dissemination and resistance.

Conclusion
Although rare, PC in NSCLC reflects an aggressive disease subset. Early diagnosis through imaging, molecular testing, and multidisciplinary assessment is critical. Targeted therapies and ICIs have opened new avenues of treatment, but the overall prognosis remains poor. Intraperitoneal chemotherapy remains experimental and is not a standard treatment in NSCLC. Further clinical researches are essential to enhance understanding of tumor biology and may help identify high-risk patients, develop tailored interventions, and improve outcomes for this unique patient population.