Synchronous Occurrence of Gastric Signet Ring Cell Carcinoma and Pulmonary Fibrosarcoma in 23‐Year‐Old Male Youth

Abstract

ABSTRACT

The synchronous occurrence of epithelial‐derived gastric signet ring cell carcinoma and mesenchymal‐derived pulmonary fibrosarcoma in a single patient is extremely rare in clinical practice. Here, we report the case of a 23‐year‐old man who presented with hematemesis and melena for 6 days. Gastroscopy revealed two irregular small ulcers in the upper‐middle segment of the gastric body. CT imaging demonstrated uneven thickening of the gastric wall along the greater curvature, with local ulcer formation, as well as a small nodule in the left lower lobe of the lung. The patient underwent thoracotomy, and postoperative pathology confirmed signet ring cell carcinoma in the stomach and fibrosarcoma in the lung. The coexisting tumor was diagnosed in one patient although it is unknown whether it is an accidental event or is caused by some underlying mechanism that makes him develop different malignancy in different organs simultaneously. This report serves to alert clinicians to this rare condition.

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Summary

• The synchronous occurrence of gastric signet ring cell carcinoma and pulmonary fibrosarcoma in one patient is extremely rare.
• This case highlights the importance of a comprehensive evaluation of patients with dual malignancies to reveal the underlying mechanisms by which genetic or carcinogenic factors interfere with each other.
• The synchronous occurrence of tumors originating from two different tissues usually manifests as one tumor's symptoms, while the other is often discovered during routine examinations.
• Young patients diagnosed with special types of malignant tumors should undergo evaluation of their genetic alterations, particularly when there is a family history involving immediate relatives.

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Introduction

Epithelial-derived malignancy originating in the stomach is defined as gastric cancer, a heterogeneous disease with an incompletely understood pathogenesis. Signet ring cell cancer, a distinct subtype of gastric cancer, has long been recognized as unique compared to other adenocarcinoma types in terms of cellular morphology, biology, origin, and prognosis [1]. Globally, the current overall incidence of gastric cancer has declined due to advancements in Helicobacter pylori (H. pylori) treatment and early lesions screening; however, there has been a notable increase in the histological subtype dominated by signet ring cell carcinoma [2]. Unlike other adenocarcinomas, signet ring cell carcinoma predominantly affects women and younger individuals, and frequently arises in the mid-stomach. Its etiology remains unclear, and the role of H. pylori in its development remains controversial [2]. Pathologically, this cancer is characterized by the loss of cell–cell adhesion molecules and the accumulation of mucin within the cytoplasm [3]. Despite some reports indicating favorable outcomes in early-stage cases, the overall prognosis remains poor due to the propensity for peritoneal dissemination [4].

Mesenchymal-derived sarcoma is a rare malignancy that predominantly arises from the embryonic mesoderm. Sarcomas are highly heterogeneous, exhibiting variability not only upon the intertumoral but also on the intratumoral level [5]. The specific mechanistic pathways underlying sarcoma development are deficient; however, recent studies have identified telomere shelterin complex defects and mitotic abnormality as key pathogenic factors [6]. Fibrosarcoma is one of the most commonly diagnosed types of sarcoma. Defined by the World Health Organization, fibrosarcoma is a malignant neoplasm composed of fibroblasts with variable collagen production and classically formed herringbone architecture [7]. The sites that fibrosarcoma mostly attacks are the thigh, trunk, and limb, while the origin in the lungs is uncommon. This neoplasm typically presents as a spherical mass, causing symptoms such as swelling, compression, and pain. Diagnosis is based on the presence of atypical spindle-shaped cells with slender nuclei and scant cytoplasm arranged in a fascicular pattern [8]. However, establishing this diagnosis requires ruling out other more common diseases.

Here, we describe such a combination of synchronous gastric signet ring cell carcinoma of epithelial origin and pulmonary fibrosarcoma of mesenchymal origin to help clinician and pathologist to establish the awareness for identifying the coexistence of rare disease.

Case Presentation

A 23-year-old male patient presented to the Second Department of Surgical Oncology at the General Hospital of Ningxia Medical University on November 20, 2022, with a six-day history of intermittent hematemesis and melena. The patient complained that there was no reason for vomiting, with a volume of approximately 200 mL, accompanied by melena. He felt weak, had decreased appetite, and poor sleep but denied having fever, cough, choking, palpitation, dysphasia, or weight loss throughout the course of the illness. He also denied any prior history of hypertension, diabetes, hepatitis, tuberculosis, surgical trauma, or blood transfusion. However, his father died of gastric cancer at the age of 52, although the specific type is unknown.

Physical examination: Inspection observed a flat abdomen without visible gastrointestinal or peristaltic waves. Palpation touched that the abdomen was flat and soft, with tenderness noted in the lower ensiform area and upper left abdomen. No palpable lump, no rebound pain, no muscle tension, and no palpable liver and spleen below the ribs. Murphy's sign was also negative. Percussion elicited no tenderness over the liver, spleen, or kidney regions. Auscultation demonstrated normal bowel sounds with no vascular murmurs. In view of these findings, a digital rectal examination was performed and revealed no abnormalities. Additionally, no enlarged lymph nodes were palpable in the bilateral clavicular regions.

Laboratory Examination

Erythrocyte count was 3.01 × 10⁹/L, hemoglobin level was 94 g/L, while leukocyte and platelets were within normal ranges. Tests for HBV, HCV, HIV, and syphilis were negative. Glucose, lipid profiles, liver, and kidney function were all normal. Tumor markers CEA and CA199 were within the normal scope.

Auxiliary Examination

Endoscopy revealed two ulcerations along the larger curvature of the proximal gastric body, each measuring 0.8–1.5 cm in diameter (data not shown). Abdominal CT demonstrated thickening of the gastric wall along the greater curvature near the fundus, with a lesion protruding into the lumen and forming a local ulcer. The serosa appeared rough and showed marked enhancement after contrast administration, while the adjacent fat tissues were indistinct, and several lymph nodes were observed in the vicinity. A small amount of effusion was detected in the pelvic cavity. Liver, gallbladder, pancreas, spleen, kidneys, bladder, prostate, or seminal vesicle did not detect abnormalities (Figure 1A,B). Chest CT identified an irregular nodule measuring 0.7 × 1.3 cm in the lower lobe of the left lung. The hilum appeared normal, with no enlarged lymph node detected. The mediastinum was centered, and the trachea was unobstructed. The heart shadow was normal, no pleural effusion was observed, and the chest wall showed no abnormalities (Figure 1C). Single-photon emission computed tomography (SPECT) indicated active bone salt metabolism in the right fourth posterior rib, suggesting a high likelihood of bone metastasis.

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Based on the historical data and positive findings, it can be confirmed that there are two lesions, one in the stomach and another in the lungs. However, it remains uncertain whether these lesions are of the same type, and the origin of bone metastasis is also unclear. Considering the patient's young age and the difficulty in distinguishing between primary and secondary lesions, as well as to alleviate the patient's pain, we decided to perform a left exploratory thoracotomy to use a single incision to remove both the gastric and lung lesions simultaneously.

Intraoperative Findings

Through the incision in the left seventh intercostal space, a mass was found in the lower lobe of the left lung, which did not invade the visceral pleura. Another mass was found at the gastric fundus, which invaded the serosal layer of the stomach wall. Consequently, the patient underwent radical gastrectomy and pulmonary wedge resection.

Postoperative Pathology

The stomach specimen revealed a 2 × 2 × 3 cm³ ulcerative mass located in the lesser curvature of the stomach, with a grayish-white color and a solid and tough texture, which had invaded the entire layer of the gastric wall (Figure 2A). Microscopic examination proved the presence of signet ring cell carcinoma mixed with a small amount of poorly differentiated adenocarcinoma. No lymphatic metastases were found in the perigastric, lesser curvature, right side of the cardia, left side of the stomach, and lower esophagus (Figure 2B). Immunohistochemical analysis demonstrated HER2 (2+), MLH1 (+), MSH6 (+), MSH2 (−), PMS2 (+), and a Ki-67 proliferation index of 60% (Figure 2C,D). Therefore, the pTNM staging was classified as T4aN0Mx. Fluorescence in situ hybridization (FISH) gene expression analysis revealed negative HER2 signals and wild-type PIK3CA. The lung specimen exhibited a 1 cm solid mass with a grayish-white and grayish-yellow appearance, characterized by a soft yet tenacious texture and well-defined margins. Microscopic examination proved the diagnosis of fibrosarcoma, featuring poorly differentiated malignant tumor tissue with areas of necrosis, some spindle-shaped cells arranged in a longitudinal pattern, and abundant blood supply in the stroma (Figure 3A,B). Immunohistochemistry results showed CD34 (−), Vimentin (+), CKpan (−), a Ki-67 proliferation index of 70%, and SOX-10 (−) (Figure 3C,D).

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Differential Diagnosis

This case of gastric signet ring cell carcinoma needs to be differentiated from peptic ulcer as both gastroscopy and macroscopic specimens showed ulcerative lesions. Ulcers caused by peptic ulcers are typically circular in shape, small in size, and have well-defined edges. In contrast, the ulcer in this case is relatively large, hard, and infiltrates the entire gastric wall. Visually, it should initially be considered malignant. Furthermore, postoperative histopathological analysis demonstrated that signet ring cells are dominant, with few components of poorly differentiated adenocarcinoma, leading to a histological classification of signet ring cell carcinoma. Meanwhile, no pathological features indicative of gastric lymphoma, leiomyoma, or others were observed, allowing them to be excluded from the diagnosis.

The left lower lobe fibrosarcoma needs to be differentiated from peripheral lung cancer. Peripheral lung cancer often presents imaging manifestations such as spiculation and lobulation signs. Importantly, cancer is a malignant tumor originating from epithelial tissue, whereas sarcoma arises from mesenchymal tissue. Pathologically, cancer typically forms nests, while sarcomas are more dispersed. In this case, the tumor's pathological morphology lacked cancer nests or glandular structures and instead was composed of spindle-shaped cells with significant heterogeneity, accompanied by necrosis and blood vessels, suggesting a mesenchymal origin. Additionally, lung nodules need to be distinguished from tuberculoma, which typically affects the upper lobes and histologically includes caseous necrosis, multinucleated giant cells, and lymphocytes. Postoperative pathology in this case did not reveal these characteristics, enabling tuberculosis to be excluded. More importantly, fibrosarcoma is often diagnosed by exclusion, requiring differentiation from other soft tissue tumors. For instance, rhabdomyosarcoma exhibits, under the microscope, long spindle-shaped rhabdomyoblasts with abundant cytoplasm that stains red, along with small round cells featuring sparse cytoplasm and deeply stained nuclei. Leiomyosarcoma's tumor cells appear densely packed, displaying spindle or oval shapes with variable sizes and forms. Mitotic figures are visible, and the eosinophilic cytoplasmic content presents a fibrous texture. The nuclei are rounded with blunt ends, and the tumor cells are arranged in a crisscross pattern longitudinally and transversely. Liposarcoma reveals adipocytes with lipid vacuoles in the cytoplasm that compress the deeply stained and atypical nuclei, creating pressure artifacts. Vascular sarcoma forms structures resembling vascular lumens or fissures of varying sizes and shapes. Malignant fibrous histiocytoma consists of fibroblast-like cells that may include chronic inflammatory cell infiltration. Radially arranged fibroblasts hold diagnostic significance. In this case, based on morphological characteristics and the negativity of markers such as CK, SOX-10, and CD34, epithelial, neural, and vascular tumors have been ruled out. The only positive marker was Vimentin. Although Vimentin lacks specificity, in cases where other origins are excluded and Vimentin shows strong positivity, fibrosarcoma remains the most likely diagnosis.

Outcome and Follow-Up

The patient recovered very well after surgery and subsequently received SOX standard chemotherapy (oxaliplatin 180 mg ivd d1; tegafur, gimeracil, and oteracil potassium capsules 50 mg po bid d1–14; 21d/cycle) for a cycle to eliminate residual tumor cells and control metastatic foci. After discharge, the patient continued taking oral tegafur, gemcitabine, and oteracil potassium capsules. A 1-year follow-up positron emission tomography/computed tomography (PET/CT) showed no new tumor growth, and the bone lesion was also stable. During the follow-up period, the patient survives and participates in social activities normally.

Discussion

The concepts of synchronous and metachronous tumors were first introduced by Warren in 1932. A synchronous tumor refers to the concurrent or sequential occurrence of two tumors, detected either simultaneously or within a six-month period, exhibiting different histological characteristics in the same or different organs and tissues within an individual. In contrast, metachronous or asynchronous tumors are defined by the timing of detection, occurring at longer intervals, often years apart [9, 10]. Our case presents an individual simultaneously diagnosed with gastric cancer and pulmonary fibrosarcoma, which should be classified as synchronous tumors. Only a few literatures reported the synchronous occurrence of such tumors. In the context of the digestive tract, as a subtype of gastric adenocarcinoma, gastric signet ring cell carcinoma has only been documented in a limited number of studies to coexist with neuroendocrine tumors or stromal tumors in one location, or with renal cancer in a different organ [11–13].

The novelty of our case is not only the different organ, but also the different origin. Our patient presented with upper gastrointestinal symptoms and, during routine screening, a concurrent lung mass was discovered. This patient underwent a comprehensive physical examination and received detailed postoperative pathology results. This confirmed the presence of very rare synchronous tumors, including signet ring cell carcinoma in the stomach and sarcoma in the lung. The simultaneous discovery of an epithelial tumor and a stromal tumor raises a question of whether this is coincidental or has an underlying association.

To clarify its molecular mechanism, we first analyzed the detections in gastric cancer. Immunohistochemistry found the positive HER2 expression, but FISH results were negative. When immunohistochemistry shows a result of 2+, FISH should be considered the gold standard. Given the negative FISH result, the pathogenesis of gastric cancer in this patient might not be driven by HER2. Besides, despite mismatch repair (MMR) proteins being mostly preserved, the negative expression of MSH2 attracted our attention. It has been reported that gastric signet ring cell carcinoma more frequently exhibits low or stable microsatellite instability (MSI), while high MSI is less common [14]. MMR proteins function as repair tools for maintaining genome stability. When MMR deficiency leads to the gradual accumulation of DNA mutations in microsatellite regions, MSI can form and potentially progress to cancer [15]. Furthermore, the patient exhibited wild-type PIK3CA, suggesting that activation of the PI3K/AKT signaling pathway was not significant. Although our case has limited positive biomarkers, which may not fully clarify the genetic background, it still highlights the unique characteristics of signet ring cell carcinoma and underscores the importance of MSI in this patient.

Then, we analyzed pulmonary sarcoma. In our case, pulmonary fibrosarcoma was diagnosed through radiographic, histopathological, and immunohistochemistical examinations. Imaging demonstrated atypical masses; histological examination revealed highly malignant tumor cells with narrow, longitudinal, staggered, and diffuse arrangements. The vimentin marker confirmed the mesenchymal origin [16], and the high Ki-67 index correlated with malignant behavior. A case report describes a soft tissue mucinous fibrosarcoma containing scattered spindle and stellate cells, which also showed positive staining for vimentin and negative staining for CD31, CK, S-100, P63, and HHF-35 [17]. This suggests that the morphology, along with the positive mesenchymal expression in these spindle-shaped fibrous cells, likely originates from a sarcoma of fibrous tissue. Studies have demonstrated that both signet ring cell carcinoma and sarcoma may possess immunosuppressive microenvironments. Recent research analyzed signet ring cell carcinoma from an immune microenvironment perspective using single-cell RNA sequencing and found that CD4⁺/CD8⁺ T immunocytes were largely inactive, reflecting its immunosuppressive nature [18]. Sarcomas are generally considered less immunogenic compared to other tumors and also display an immunosuppressive tumor microenvironment [19]. A proteomics study characterized canine fibrosarcoma with matched muscle, adipose, and connective tissue using liquid chromatography/mass spectrometry and identified CD68⁺ macrophages in over 90% of tumor tissues, with these immune-related changes showing high homogeneous [20]. Reports examined that CD68⁺ macrophages, CD4⁺/CD8⁺ lymphocytes, and complement C3 infiltration in the fibrosarcoma's stroma would be reduced by the addition of the inflammation-associated long pentraxin 3; the role was considered as the modulation of fibrosarcoma's immune inflammatory infiltrates [21]. Signet ring cell cancer, as other literature reported, had its MSI status associated with the increase of CD3⁺ tumor-infiltrating lymphocytes [22]. This indicates the link between immune modulation and MSI. Based on these circumstantial evidences, we attempt to explain the relationship among MSI, immune cells, signet ring cell carcinoma, and sarcoma. In our case, a deficiency of MSH2 was detected, prompting us to consider the possibility of immune cell infiltration associated with MSI in this patient. Intrinsically, MSI-high tumors exhibit abundant immune cell infiltration, which differentiates their sensitivity to immune checkpoint inhibitors compared to microsatellite stable (MSS) tumors [23]. Although our patient displayed only a low degree of MSI, this still indicates that immune dysfunction may be a concurrent event in signet ring cell carcinoma and fibrosarcoma.

Another factor to consider is that the patient's father was also a victim of gastric cancer; however, unfortunately, we are unable to trace the family history due to the limitations in medical documentation at that time. This patient himself was diagnosed with two tumors accompanied by bone metastasis at a very young age. Thus, we must take into account the possibility of a genetic background and genetic defects that may accumulate in one body due to multigene mutations with genetic susceptibility as the cause of developing various forms of cancer [24]. Hereditary diffuse gastric cancer is an autosomal susceptibility condition caused by a germline mutation in the CDH1 gene, which encodes the E-cadherin protein. This type of cancer typically presents as signet ring cell carcinoma that always affects young populations [25]. Our patient has this hereditary condition, though it is not yet clear whether there is a genetic mutation. Additionally, no biopsy was performed to determine the source of the bone metastasis, but the patient's bone lesions remained stable after chemotherapy, so special intervention should not be imposed. Another hypothesis is that single carcinogenic factors may interact with two tissues, especially neighboring ones. Under a certain genetic background, gene mutations could trigger the development of tumors with different histological types in different organs.

Therefore, we speculate that this synchronous tumor likely has an inherent correlation rather than being an accidental phenomenon. Certainly, our case has some limitations. Due to economic pressure and clinical considerations, genetic testing was not performed on the smaller lung tumor after its complete resection, CDH1 germline mutations were not detected, and bone metastasis was not suitable for biopsy, leaving its origin unclear. Anyway, this case still inspires our thinking on this synchronous tumor and is worth reporting.

Author Contributions

Meng Zhu: conceptualization, writing – original draft, writing – review and editing. Jingwei Ma: conceptualization, data curation, resources. Ning Zhang: investigation, methodology, visualization. Tao Li: supervision, validation.

Acknowledgments

We thank the General Hospital of Ningxia Medical University for providing high-quality medical resources.

Consent

Written informed consent was obtained from the patient to publish this report for scientific purposes while keeping their identity confidential, in accordance with the journal's patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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