Case Report Open Access
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World J Gastrointest Oncol. Dec 15, 2022; 14(12): 2404-2414
Published online Dec 15, 2022. doi: 10.4251/wjgo.v14.i12.2404
Edema of limbs as the primary symptom of gastric signet-ring cell carcinoma: A case report and literature review
Bei Wang, Ling-Li Dong, Gui-Fen Shen, Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Jing Chen, Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Ying Wang, Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
ORCID number: Gui-Fen Shen (0000-0002-3040-4482).
Author contributions: Wang B wrote the manuscript; Chen J and Wang Y diagnosed and treated the patient; Dong LL collected associated references; Shen GF commented on the manuscript and all authors discussed the results, read and approved the manuscript.
Supported by The National Nature Science Foundation of China, No. 81900363.
Informed consent statement: Informed written consent was obtained from the patient for the publication of this report and any accompanying images.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
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Corresponding author: Gui-Fen Shen, MD, PhD, Doctor, Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, Hubei Province, China.
Received: August 26, 2022
Peer-review started: August 26, 2022
First decision: September 8, 2022
Revised: September 17, 2022
Accepted: November 28, 2022
Article in press: November 28, 2022
Published online: December 15, 2022
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Metastatic skin cancers are relatively rare dermatological malignancies. They usually present as nodules, erythematous lesions, scar-like lesions or other lesion types. Signet-ring cell carcinoma (SRCC) is an uncommon histological type of gastric cancer that usually behaves aggressively and has a poor prognosis. Skin metastasis may be the first sign of clinically silent visceral cancer or recurrence of an internal malignancy.


Herein we report on the case of a 55-year-old man with edema of a lower extremity as the primary symptom which progressed from local to generalized pitting edema in the year following skin involvement. Pathological evidence from gastroscopic specimens and subcutaneous tissue biopsy showed typical signet-ring cells and gland-like structures. Consistently, immunohistochemical analysis revealed positive pan-cytokeratin expression in tumor cells. A diagnosis of gastric SRCC with skin metastasis was established. Moreover, lymphoscintigraphy showed an obvious accumulation of radiotracer on the anterior and posterior sides of the right leg which indicated lymphedema. We reviewed the relevant literature on subcutaneous metastases of gastric SRCC.


This rare case emphasizes the importance of physical examination as it may help elucidate the etiology of edema.

Key Words: Gastric cancer, Signet-ring cell carcinoma, Skin metastasis, Lymphedema, Prognosis, Case report

Core Tip: Metastatic skin cancers are relatively rare dermatological malignancies. They usually present as nodules, erythematous lesions, scar-like lesions or other lesion types. We report on a case of skin metastases from gastric signet-ring cell carcinoma in which lymphedema of the limbs presented as an initial symptom. This rare case emphasizes the importance of physical examination as it may help elucidate the etiology of edema.


Metastatic skin cancers (MSCs) are relatively rare dermatological malignancies. They constitute 2% of all skin tumors and the reported incidence rates range from 0.7% to 9.0%[1]. MSCs originate most commonly from breast, lung and gastrointestinal tissues and are recognized as having a poor prognosis[1,2]. Furthermore, cutaneous metastases from gastric signet-ring cell carcinoma (SRCC) are uncommon[3]. The clinical presentation of cutaneous metastases from gastric adenocarcinoma is usually single or multiple nodules or erythematous lesions; only 6.4 % to 7.8 % of these cutaneous metastases are the first clinical manifestation[4,5]. Moreover, to the best of our knowledge, there is no report describing edema of the limbs as the primary symptom of MSCs originating from signet-ring cell gastric carcinoma.

The causes of edema vary. Most causes of edema are due to increased capillary filtration overwhelming the normal lymphatic system[6]. Under some conditions, lymphedema occurs when lymph transport capacity is impaired. Lymphedema can be classified into primary and secondary categories[7]. Both primary and secondary forms of lymphedema are often chronic and insidious in nature. Infections such as lymphatic filariasis are a frequent cause of secondary lymphedema in developing countries, whereas in developed countries, a common cause of secondary lymphedema is cancer treatment. Of note, the metastasis or, rarely, direct invasion of active tumor into the lymphatic network can also produce a severe form of lymphedema[8].

In this study, we present a case of atypical gastric adenocarcinoma with signet-ring cell morphology which presented with cutaneous lymphedema as the primary symptom.

Chief complaints

A 55-year-old Chinese male first presented with cutaneous edema of the right lower limb, which developed as systemic edema of all limbs over the course of a year (Figure 1).

Figure 1
Figure 1 The 55-year-old male patient with systemic edema. A: The images of fingers and legs of this patient at the initial visit; B: The images of fingers and legs of this patient at 3-mo visit; C: The images of fingers and legs of this patient at 12-mo visit.
History of present illness

In April 2019, the patient developed edema of the right lower limb with an unknown cause. The edema began to spread from the end of the lower extremity to the groin and trunk area. At a local hospital, he was diagnosed with slight renal insufficiency (estimated glomerular filtration rate: 59 mL/min/1.73 m2). Additionally, cardiac insufficiency and hepatic insufficiency was excluded and the patient underwent magnetic resonance imaging of the lower extremity. The results showed obvious swelling of subcutaneous soft tissue in the right thigh, slight edema in the subcutaneous soft tissue of the left thigh and edema of the long and short head of the biceps femoris. One year after skin involvement, the patient presented with newly diagnosed poly-serous effusions (thoracic cavity, abdominal cavity and pericardium).

Personal and family history

The patient had no significant personal history and denied any health issues or genetic problems in his family. There was no obvious weight loss or significant family history.

Physical examination

On admission, the patient’s temperature was 36.0 ℃, heart rate was 91 beats/min, respiratory rate was 20 breaths/min and blood pressure was 143/92 mmHg. No abnormality was found in the heart and the lungs were clear to bilateral auscultation without any wheezes, rales or rhonchi. Furthermore, there was no tenderness or rebound pain in the abdomen. Additionally, there is no sign of associated gastro-intestinal symptoms such as nausea, vomiting, hematemesis or any change in bowel habits. However, he had obvious pitting edema in the right lower limb but not in the left limb. When pressure was applied to the right lower limb, an indentation remained in the soft tissue after the pressure was removed.

Laboratory examinations

The main characteristics of laboratory examinations during the initial 3-mo and 12-mo visits are listed in Table 1. Specifically, the results showed that the patient’s carbohydrate antigen 724 Levels were slightly elevated during the initial (16.41 U/mL, reference value range < 6.9 U/mL), 3-mo (15.51 U/mL) and 12-mo (15.67 U/mL) visit, while serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 Levels were within the normal range. The levels of urea nitrogen (8.97 mmol/L, 12.54 mmol/L, and 12.83 mmol/L for the initial, 3-mo and 12-mo visits, respectively) were slightly elevated. Similarly, creatinine levels (126 μmol/L, 130 μmol/L, and 152 μmol/L for the initial, 3-mo and 12-mo visits, respectively) were also slightly elevated. Kidney function was evaluated as chronic kidney disease (CKD) G3a by calculating the estimated glomerular filtration rate[9]. However, the results were normal for the patient’s kidney, ureter, and bladder on color Doppler ultrasound. Routine urine tests indicated no proteinuria or hematuria. Thyroid function test results were normal.

Table 1 Characteristics of laboratory examinations.
Initial visit
3 mo
12 mo
Reference value range
Full blood count
White cell count as × 109/L6.47.553.58(3.5-9.5)
Neutrophils as × 109/L4.515.562.25(1.8-6.3)
Lymphocytes as × 109/L1.31.320.68(1.1-3.2)
Monocytes as × 109/L0.360.50.23(0.1-0.6)
Platelets as × 109/L218223208(125-350)
Hemoglobin in g/L144136157(130-175)
Tumor markers
Carbohydrate antigen 724 in U/mL16.4115.5115.67(< 6.9)
Carbohydrate antigen 199 in U/mL15.8816.844.43(≤ 34)
Carcinoembryonic antigen in ng/mL)2.812.860.78(≤ 5)
Blood biochemical indicators
Alanine aminotransferase in U/L161114(≤ 41)
Aspartate aminotransferase in U/L131315(≤ 41)
Globulin in g/L28.925.519(64-83)
Albumin in g/L38.232.225(35-52)
Creatine kinase in U/L935624(≤ 190)
Lactic dehydrogenase in U/L163156202(135-225)
Urea nitrogen in mmol/L8.9712.5412.83(3.1-8.0)
Creatinine in μmol/L126130152(59-104)
Estimated glomerular filtration rate in mL/min/1.73 m25552.949.5(> 90)
Random blood glucose in mmol/L6.225.396.12(< 11.1)
Serum potassium in mmol/L4.23.883.89(3.5-5.1)
Serum sodium in mmol/L141.5141142(136-145)
Cardiac troponin T in pg/mL2.22.52.7(≤ 34.2)
N terminal pro B type natriuretic peptide in pg/mL534559(< 161)
Fibrinogen in g/L4.315.035.88(2-4)
D-Dimer in μg/mL FEU1.361.057.19(< 0.5)
Other indicators
Antinuclear antibodies1:1001:100Not available(negative)
Immunoglobulin IgG in g/L9.318.579.27(7-16)
Complement C3 in g/L1.461.321.39(0.8-1.8)
Complement C4 in g/L0.670.390.51(0.1-0.4)
Erythrocyte sedimentation rate in mm/h202125(0-15)
High sensitivity C-reactive protein in mg/L5.526.436.83(0-5)
Interleukin 6 in pg/mL2.723.562.98(0.1-2.9)
Tumor necrosis factor α in pg/mL2.072.973.12(0.1-23)
T lymphocyte (CD3 + CD19 -) as /μL830977780(955-2860)
B lymphocyte (CD3 + CD19 -), as /μL628452(90-560)
Antineutrophil cytoplasmic antibodynegativenegativenegative(negative)
Procalcitonin< 0.05< 0.05< 0.05 (< 0.05)
Imaging examinations

No obvious abnormality was found on computed χ-ray tomography of the chest and abdomen. The 18F-fluorodeoxyglucose (FDG) positron emission tomography was performed. No pathological FDG uptake was detected in the liver, spleen, kidneys, gastrointestinal system, or in either the abdominal or pelvic lymph node groups. Moreover, lymphoscintigraphy labeled with 99mTc-DX showed an obvious accumulation of radiotracer in the right leg on both the anterior and posterior sides after 3 and 6 h diffusion (Figure 2), indicating lymph angiodysplasia and lymphedema. Color Doppler ultrasound of the heart and blood vessels of both lower limbs showed no abnormality.

Figure 2
Figure 2 99mTc-DX lymphoscintigraphy. Images were recorded 10 min, 1h, 3h, and 6h after infusion with the 99mTc-DX indicators at both feet. Lymphoscintigraphy showed an obvious accumulation of the radiotracer both the anterior and posterior sides of the right leg.
Pathological and gastrointestinal endoscopic examination

First, the biopsy of the skin on the lower limb revealed infiltration of the suspicious cells with a signet-ring appearance cells and gland-like structures (Figure 3A-C). Biopsy specimens of the lesions showed reactive epithelial changes [pan-cytokeratin (panCK) positive) (Figure 3C). Because the gastrointestinal tract is the most common source of SRCC, a gastrointestinal endoscopic examination (Figure 3D and E) was subsequently performed. The results showed multiple gastric ulcers without solid neoplasm (Figure 3D and E). However, biopsies of both the body and antrum gastric mucosa showed infiltrating signet ring cell type adenocarcinoma (Figure 3F and G), which were very strongly panCK positive (Figure 3H and I) and CEA positive. Additionally, histopathology showed a less differentiated signet cell ring carcinoma with approximately 20% ki-67 positivity. Taken together, gastrointestinal metastasis was confirmed as the source of the signet-ring cells in skin biopsies. Thus, a diagnosis of metastatic SRCC, most likely from the stomach, was made.

Figure 3
Figure 3 The immunohistochemistry and gastric endoscopy. A: H&E histological samples of the skin tissue on the right lower limb, 10 ×; B: H&E histological samples of the skin tissue on the right lower limb, 20 ×; C: Histological samples of the skin tissue on the right lower limb stained for panCK, 20 ×; D: Images of gastric endoscopy: Gastric body; E: Images of gastric endoscopy: Gastric antrum; F: H&E histological samples of the mucosa in gastric body, 10 ×; G: Gastric antrum, 20 ×; H: Histological samples of the mucosa in gastric body stained for panCK, 20 ×; I: Gastric antrum, 20 ×. Note the abundant signet-ring cells (black arrows) (B) and (G). H&E: Hematoxylin and eosin; panCK: Pan-cytokeratin.

Gastric SRCC with skin metastases.


Surgical intervention is not possible for advanced or metastatic gastric cancer. First-line systemic therapy regimens with 2 cytotoxic drugs are preferred for these patients[10]. The preferred regimens for first-line systemic therapy includes fluoropyrimidine (fluorouracil or capecitabine) combined with either oxaliplatin or cisplatin (category 2B)[10]. Given the renal insufficiency in this patient, oxaliplatin or cisplatin was not suitable[11]. Thus, from August 21 to September 2, 2019, the patient received a combination of chemotherapy with tegafur (a prodrug of 5-fluorouracil, 60 mg/PO/bid), and paclitaxel (second-line systemic therapy; 100 mg/iv/QW). Over the next 5 mo, he received another five cycles of chemotherapy.


At the 3-mo visit, his limb edema had worsened. By the 12-mo visit, edema had spread from the lower limbs to the entire body (Figure 1), and the patient presented with newly diagnosed polyserous effusions (thoracic cavity, abdominal cavity and pericardium). After 6 mo of treatment, the patient declined further chemotherapy and received palliative diuretic therapy.


This report describes a rare case in which cutaneous metastasis led to the detection of gastric SRCC. Additionally, this gastric SRCC primarily presented as lymphedema of the limbs after the subcutaneous metastases. The typical sites for metastasis of gastric cancer are the liver, peritoneal cavity and regional lymph nodes[12]. The incidence rate of cutaneous metastasis from gastric SRCC is less than 2%; however, when present, the median survival time is 6.5 mo. Common cutaneous manifestations of gastric SRCC include single or multiple red, violet or hyperpigmented asymptomatic nodules, or more rarely, as cellulitis-like or erysipelas-like erythematous plaques[12]. However, our report presents a case of a patient with gastric SRCC who developed carcinomatous lymphangitis, which is very rare in clinical practice.

Skin metastases from internal tumors are uncommon in clinical practice. In women, the most common origin of skin metastases is adenocarcinoma of the breast, whereas squamous cell carcinoma of the lung is the most common in men. Skin metastases in patients with gastric SRCC are extremely rare. The largest series of patients with skin metastases came from a study by Lookingbill et al[3] with a total of 4020 patients. Current information about skin metastases from cancer of the stomach comes from the publication of small series or case reports. The first thorough review of a cutaneous metastases from gastric cancer was performed in 2014 by Cesaretti et al[13] and included 72 reported patients with cutaneous lesions at various locations on the body surface. However, to the best of our knowledge, skin metastases from gastric SRCC as the first manifestation have not yet been reviewed.

An electronic literature search was conducted using Medline (PubMed) and Google Scholar databases in August 2022 with the terms “gastric SRCC and cutaneous metastases”. The data of publication ranged from 1989 to 2022. There were a total of 30 studies, of which 5 lacked main information; thus, we present a review of 25 studies on cutaneous metastases from gastric signet-ring cell adenocarcinoma (Table 2). The 25 studies included 17 male and 8 female patients with an average age of approximately 58.0-years-old. Although reliable allocation of a skin metastasis to the original tumor is not possible, some preferential associations are obvious. Previous data showed that gastrointestinal and colorectal tumors mainly develop distant skin metastases in the abdomen[14]. In our review, the locations of skin metastases from gastric signet-ring cell adenocarcinoma included the abdomen (10/26, 40.0%), face (7/25, 28.0%), head (5/25, 20.0%), neck (6/25, 24.0%), back (8/25, 32.0%), chest (3/25, 12.0%), armpits (1/25, 4.0%), groin (2/25, 8.0%), arms (3/25, 12.0%) and limbs (3/25, 12.0%). Only one patient presented with initial symptoms and without any local or general clinical symptoms[15]. In all cases, only seven patients presented with weight loss and gastrointestinal symptoms (such as vomiting, loss of appetite, dyspepsia or abdominal pain)[16,17] as the first manifestation. For the cutaneous manifestations, seven patients presented with skin lesions[18-20] (scar-like or other types of lesions), nine patients with nodules[21] and five with erythema. Ours is a rare case, not only due to dramatic skin metastasis as the first presenting sign but also because the patient presented with obvious edema of the lower limbs. In addition, the prognosis of skin metastases from gastric signet cell carcinoma is poor. In all 25 cases reviewed, only 4 patients survived. Most patients died a few weeks (mean 6.1 wk) later after skin involvement[16]. Currently, the patient in our case is alive, but also has advanced symptoms (systemic edema in all limbs) (Figure 1).

Table 2 Gastric signet ring cell adenocarcinoma.
Sites of skin involvement
Initial present symptoms
1Male/67Nodular lesions on his eyelid, cheeks, scalp, and backWeight loss of 8 kg within 1 moNot availableDOD 3 mo after skinXELOX chemotherapy (oxaliplatin and capecitabine)[23]
2Male/69On forehead, back, neck, and armsDysphagia from eating and multiple cutaneous nodulesNot availableDOD 1 mo after skinSurgery[24]
3Female/53On abdomen and thighsLivedo reticularisNot availableDOD 7 mo after skinChemoradiation[25]
4Female/72Skin infiltration in the lower limbs, abdomen, and root of the upper limbsLymphangitisStage IIIa DOD 5 mo after skinAdjuvant chemotherapy with capecitabine + oxaliplatin[26]
5Female/75On the abdomenIndurated scarlike lesions on the epigastric areaStage IIIa (T4aN1M0)DOD 3 mo after skinChemotherapy (5-fluorouracil, infusional folinic acid, and oxaliplatin)[27]
6Female/57On the abdomenWith growing lesions on skinStage IIIa (T3N2M0)Not availableAdjuvant chemotherapy [infusional folinic acid + 5-fluorouracil] and radiotherapy, a second round of chemotherapy[20]
7Female/45On head and the backThe cutaneous metastases disappearedSurvivalChemotherapy with S-1 (Tegafur) plus cisplatin [28]
8Male/52Armpits, axillae, groin, and neck foldsProgressive dermal, mucosal, and perianal lesions, weight lossT3N2M1Not availableN/A[18]
9Male/21Cutaneous nodule on his chestCutaneous noduleStage IVSurvivalChemotherapy with oxaliplatin (day 1) and S-1[29]
10Male/85A lesion of the right occipital scalpAbdominal pain, malaiseT4N1M0DOD 5 mo after skinNot available[30]
11Male/35Cutaneous nodules on the upper chest, abdomen and left scapular regionWithout any local or general clinical symptomsNot availableNot availableNot available[15]
12Male/76Skin ulcer on right hypochondriumHematemesis, weight loss and loss of appetiteT4N2M0DOD 1 mo after skinChemotherapy with irinotecan and oxaliplatin[16]
13Female/50Large erythematous plaque on the left side of the neck; and an erythematous lesion in the perineal regionBowel habit and weight lossNot availableDOD 0.5 mo after skinNot available[31]
14Male/59Painless nodule of the left flankPainless nodule of the left flankNot availableDOD 0.5 mo after skinMetastatic infiltration of a 32-yr-old surgical scar[32]
15Male/50The umbilical areaWith a single asymptomatic skin lesionNot availableNot availableNot available[19]
16Male/69Asymptomatic indurated scar-like lesionAsymptomatic indurated scar-like lesionStage IVDOD 10 mo after skinChemotherapy with cisplatin, Taxotere, and xeloda[33]
17Female/71Limited cyan erythema on the right side of the middle and lower abdomenAbdominal skinNot availableDOD 12 mo after skinChemotherapy (unknown medication)[34]
18Male/48Bracelet bracelet ("tripe palm"); and hyperkeratosis of fingersSkin edema with pigmentationNot availableDOD 36 mo after skinChemotherapy with cisplatin, 5-fluorouracil and folic acid[35]
19Male/44Multiple cutaneous eruptions on face and neckVomiting and weight lossNot availableN/ANot available[17]
20Male/51Abdominal and backWithout any symptomNot availableDOD 2 mo after skinSurgery[36]
21Male/67Diffuse erythematous and warm induration over his right cheek and neckDyspepsiaStage IVDOD 0.75 mo after skinRadiotherapy[37]
22Male/55Lower part of face and neckWith multiple itchy nodulesNot availableDOD 7~8 mo after skinNot available[21]
23Female/58Right inguinal erythema with itchingWith chylothoraxNot availableDOD 4 mo after skinNot available[38]
24Male/44On the face, trunk, and upper extremitiesMultiple cutaneous nodulesStage IVSurvivalChemotherapy with an oxaliplatin-based regimen and denosumab[39]
25Male/68Right chin region and on the left foreheadErythematous skin lesion, nodular skin lesionT4N0M0Not availableSurgical treatment[40]

In the review by Cesaretti et al[13] in 2014, 80% of the patients received a management approach ranging from local excision to chemotherapy or chemoradiation therapy to treat their cutaneous metastases. In our review, 16 patients were treated with chemotherapy (11/16), chemoradiation therapy (1/16), surgery (3/16), or radiotherapy (1/16). Chemotherapy is the first choice for the treatment of advanced gastric signet-ring cell adenocarcinoma. In particular, chemotherapy regimens 5-fu/fa/oxaliplatin (5-fluorouracil, folinic acid, and oxaliplatin) and S-1 (tegafur plus cisplatin) were preferred in our review of cutaneous metastases after gastric signet-ring cell adenocarcinoma.

Because carcinomas generally spread preferentially via the lymphatic route and gastrointestinal tumors are known to spread to lymph nodes or lymph-vessels, in this case, it is hypothesized that an aggressive clone of signet cell gastric carcinoma metastasized to the lymph-vessels and then, by making a blockage of lymph-vessels, appeared in the dermis of the skin as an apparently primary skin edema or lymphedema. Lymphedema is a clinical condition characterized by an increased volume of subcutaneous soft tissues due to impairment of the lymphatic system. Lower limb edema is a very common symptom; the most common underlying mechanisms include venous and lymphatic disease, volume overload, increased capillary permeability and decreased oncotic pressure. The most commonly associated diseases are deep vein thrombosis and chronic venous insufficiency, heart failure, hepatic or renal failure hypoproteinemia, idiopathic cyclic edema and drug-induced edema. Lymphedema induced by gastric SRCC is rare and has not been previously reported.

Additionally, the patient’s kidney function was evaluated as CKD G3a by calculating the estimated glomerular filtration rate. Renal dysfunction is classified into nonuremic and uremic stages. Patients with non-uremic renal failure (NURF) are defined as having impaired renal function, but are dependent on their own kidneys. The reason is currently unknown. Recently, owing to the increase in the aged population and the incidence of diabetes mellitus, the number of patients with gastric cancer associated with NURF have been increasing[22]. Whether gastric cancer itself or other factors led to the NURF in this patient remains unclear.


We report on a case of skin metastases from gastric SRCC in which lymphedema of the limbs presented as an initial symptom. This case emphasizes the importance of excluding malignancy from the differential diagnosis of edema. Thus, a careful clinical physical examination must be performed on patients with edema to ensure that no information is missing and to obtain further clinical data which could pave the way for further studies.


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