A Sister Mary Joseph’s nodule in fallopian tube cancer: exploring the metastatic pathway through gene expression profiling—a case report

Abstract

Background

A Sister Mary Joseph’s nodule is an umbilical metastasis from an intra-abdominal or pelvic malignancy, associated with a poor prognosis. Three possible metastatic pathways for Sister Mary Joseph’s nodule have been postulated: hematogenous spread, lymphatic dissemination, and direct invasion. However, detailed analyses of these metastatic pathways, particularly those involving gene expression profiling, are lacking in literature. We investigated the metastatic patterns of Sister Mary Joseph’s nodule by performing RNA microarray analysis of the primary tumor and each metastatic site in a case of fallopian tube cancer presenting with Sister Mary Joseph’s nodule and inguinal lymph node metastases.

Case presentation

A 48-year-old Japanese woman presented with swelling in an inguinal lymph node. Positron emission tomography-computed tomography imaging revealed multiple lymph node metastases, right ovarian tumor, umbilical metastasis, and peritoneal dissemination. The patient underwent a laparoscopic right adnexal resection, left inguinal lymph node biopsy, and umbilical resection. Pathological examination confirmed the diagnosis of primary high-grade serous carcinoma of the right fallopian tube. Metastatic high-grade serous carcinoma was identified in the lymph nodes and umbilical tissue. Tumor tissue samples were collected from the primary lesion, umbilical metastasis, and inguinal lymph node metastasis for RNA microarray analysis. The results showed that genes involved in cell adhesion, migration, and stromal remodeling associated with the metastatic processes were more highly expressed in both inguinal lymph node metastasis and Sister Mary Joseph’s nodule than in the primary lesion. Interestingly, distinct differences in gene expression profiles were observed between umbilical and lymph node metastases, suggesting different metastatic mechanisms.

Conclusion

Our findings suggest differences in the RNA expression patterns between Sister Mary Joseph’s nodule and lymph node metastases in fallopian tube cancer, indicating the possibility of distinct metastatic mechanisms. Further examination of similar cases and longitudinal studies are necessary to elucidate the metastatic patterns of Sister Mary Joseph’s nodule. This case highlights the potential value of molecular profiling for understanding the complex metastatic processes in gynecological malignancies.

Background

Sister Mary Joseph’s nodules (SMJNs) are umbilical metastases arising from intra-abdominal or pelvic malignancies and are generally associated with poor prognosis [1]. They are often among the most visible indicators of advanced malignancy, signaling widespread metastatic disease at the time of presentation. SMJNs are relatively rare, occurring in approximately 1–3% of intra-abdominal and pelvic cancers. Among these, ovarian cancer is the second most common cause after gastric cancer, accounting for 14–42% of SMJN cases [2–4].

The umbilicus is a susceptible site for metastasis because of its anatomical proximity to the peritoneum, gastrointestinal tract, and pelvic organs [5]. Three primary pathways of SMJN development have been proposed, including: direct invasion of the peritoneum, lymphatic dissemination, and hematogenous spread [6]. The umbilicus has superficial and deep lymphatic networks that communicate with the axillary, inguinal, deep femoral, para-aortic lymph nodes, and bladder, making lymphatic spread a plausible mechanism. In addition, the fetal umbilical vasculature may provide potential routes for hematogenous dissemination. During fetal life, the umbilical vein supplies oxygenated blood from the placenta to the liver via the ductus venosus, whereas the umbilical arteries transport deoxygenated blood from the internal iliac arteries to the placenta. Postnatally, these vessels regress to form the ligamentum teres and medial umbilical ligaments. The persistence of this vascular architecture has been hypothesized to rarely facilitate hematogenous metastasis [7].

Gene expression profiling is a powerful tool in oncology research, enabling the identification of molecular pathways involved in tumor development, progression, and metastasis. By comparing gene expression patterns between primary and metastatic tumors, it is possible to gain insights into the mechanisms underlying cancer dissemination and identify potential therapeutic targets [8, 9]. However, no studies have investigated the metastatic pathways of SMJN using gene expression profiling techniques. Herein, we report a rare case of fallopian tube cancer with both SMJN and inguinal lymph node metastasis. RNA microarray analysis was performed to explore the potential mechanisms of metastases through transcriptional profiling.

Case presentation

A 48-year-old Japanese woman (height, 157.8 cm; weight, 47.2 kg; body mass index (BMI), 19.0 kg/m²), gravida 2 para 1, with no significant medical history, presented with a chief complaint of left inguinal lymph node swelling. In her family history, her father was diagnosed with thyroid cancer in his 70s and her mother with gastric cancer at 70 years of age. She initially visited a local clinic where positron emission tomography-computed tomography (PET-CT) revealed multiple lymph node metastases, a right ovarian tumor, umbilical metastasis, and peritoneal dissemination (Fig. 1). Malignant lymphoma was initially suspected; thus, the patient was referred to our hospital. On physical examination, a firm, nontender, mobile lymph node measuring approximately 2 cm was palpated in the left inguinal region. The umbilicus showed a firm subcutaneous nodule approximately 1 cm in diameter without overlying skin ulceration or discharge.

Fig. 1.

Positron emission tomography-computed tomography findings. Positron emission tomography-computed tomography revealing (a) para-aortic lymph node uptake (maximum standardized uptake value of 17.8) (arrowhead), (b) umbilical uptake (maximum standardized uptake value of 9.1) (arrowhead), (c) right ovarian tumor uptake (maximum standardized uptake value of 12.8) (arrowhead), and (d) inguinal lymph node uptake (maximum standardized uptake value of 17.8) (arrowhead), suggesting multiple lymph node metastases and umbilical involvement

Biopsy of the inguinal lymph nodes revealed a high-grade serous carcinoma. She was referred to our department with a suspected primary tumor in the right ovary. Laparoscopic right adnexectomy, a left inguinal lymph node biopsy, and umbilical resection were performed for diagnosis. Histopathological examination confirmed a high-grade serous carcinoma originating from the right fallopian tube. Metastases consistent with the primary tumor were identified in both the umbilicus and inguinal lymph nodes (Fig. 2). The disease was classified as International Federation of Gynecology and Obstetrics stage IVB fallopian tube carcinoma.

Fig. 2.

Macroscopic and microscopic findings using hematoxylin and eosin staining. (a, b) Macroscopic view of the resected umbilicus. The tumor did not invade beyond the fascia (arrowhead), making direct spread from peritoneal dissemination unlikely. (c, d) High-grade serous carcinoma observed beneath the epidermis (hematoxylin and eosin staining, 40× and 200× magnification). (e) Intra-abdominal laparoscopic image showing an enlarged right ovarian tumor (~4 cm). Abbreviations: Ut., uterus; Rt. OVT, right ovary and fallopian tube. (f) Macroscopic appearance of the resected right adnexa, showing solid components within the ovarian mass. (g, h) Hematoxylin and eosin staining of the primary lesion (40× and 200×), confirming high-grade serous carcinoma. (i) Macroscopic view of the resected inguinal lymph node. (j, k) Hematoxylin and eosin staining of the lymph node (40× and 200×), consistent with metastatic high-grade serous carcinoma of tubal origin

The patient received three cycles of neoadjuvant chemotherapy with carboplatin and paclitaxel (the TC regimen), which resulted in tumor shrinkage. Interval debulking surgery, including total abdominal hysterectomy, left adnexectomy, and partial omentectomy, was performed. Postoperatively, myChoice^® CDx testing (Myriad Genetics, Inc., Salt Lake City, UT, USA) showed a homologous recombination deficiency with a genomic instability score of 48 and negative tumor BRCA mutation. The patient received TC combined with bevacizumab as adjuvant therapy, and maintenance therapy with bevacizumab and olaparib was planned. The patient tolerated the treatment well, with no significant complications reported during or after chemotherapy or surgery. At the latest follow-up, the patient remained on maintenance therapy with bevacizumab and olaparib, and was clinically stable with no evidence of disease progression.

RNA microarray analysis

Tumor tissues were collected from the primary site (right fallopian tube) and from the umbilical and inguinal lymph node metastases. Total RNA was extracted using the RNeasy^® Plus Mini Kit (Qiagen, Hilden, Germany, cat. no. 74136). RNA quality was assessed using an Agilent RNA 6000 Nano Kit (Agilent Technologies, Santa Clara, CA, USA; cat. no. 5067-1511) and an Agilent 2100 Bioanalyzer (Agilent Technologies; cat. no. G2939BA).

A microarray analysis was performed as follows. A total of 250 ng RNA was processed into complementary RNA and subsequently into biotin-labeled single-stranded DNA using the GeneChip WT PLUS Reagent Kit (Thermo Fisher Scientific, Waltham, MA, USA; cat. no. 902280). A sample comprising 2.3 μg of single-stranded DNA was hybridized to the Clariom^™ S Array, human (Thermo Fisher Scientific, cat. no. 902926) using the GeneChip^™ Hybridization, Wash, and Stain Kit (Thermo Fisher Scientific, cat. no. 900720) in the GeneChip^® Hybridization Oven 645 (Affymetrix, cat. no. 00-0331). Arrays were stained and washed using the GeneChip^® Fluidics Station 450 (Affymetrix, cat. no. 00-0079), and scanned with the GeneChip^® Scanner 3000 7G (Affymetrix, cat. no. 00-0210).

Scanned data were automatically saved as CEL files, which were analyzed using Transcriptome Analysis Console software version 4.0 (Thermo Fisher Scientific) to generate expression data and visualization. For gene ontology (GO) enrichment analysis, we selected differentially expressed genes with a fold change greater than four. Enriched GO terms were extracted using a significance threshold of p < 0.05. The results shown in Fig. 3 include the top ten enriched pathways based on p-value ranking.

Fig. 3.

Results of RNA microarray analysis. (a) Gene ontology terms enriched in the umbilical metastasis compared with the primary tumor. (b) Gene ontology terms enriched in the lymph node metastasis compared with the primary tumor. SMJN, Sister Mary Joseph’s nodule

Functional enrichment analysis was conducted using ClusterProfiler version 3.18.0, an R package for functional profiling of genes and gene clusters (R version 4.0.3) [10]. GO enrichment analysis revealed the upregulation of genes involved in key metastatic processes, including cell adhesion, migration, and stromal remodeling, in both umbilical and inguinal lymph node metastases compared with the primary tumor (Fig. 3). Although certain expression patterns were shared between the two metastatic sites, distinct differences were observed, suggesting site-specific molecular mechanisms (Tables 1 and 2).

Table 1.

Genes upregulated only in the umbilical metastasis compared with the primary tumor

EGFR, epidermal growth factor receptor; Wnt, wingless-related integration site; EMT, epithelial-mesenchymal transition; SMJN, Sister Mary Joseph’s nodule

Table 2.

Genes upregulated only in the inguinal lymph node metastasis compared with the primary tumor

BMP, bone morphogenic protein; Wnt, wingless-related integration site; EMT, epithelial-mesenchymal transition; SMJN, Sister Mary Joseph’s nodule

Discussion

SMJNs are distinctive clinical manifestations of metastatic disease from intra-abdominal or pelvic malignancies and are associated with poor prognosis [11]. Ovarian and other gynecologic cancers are among the most frequent sources of SMJNs in women [2, 3, 11].

The diagnosis typically involves visual inspection and palpation, followed by imaging and histopathological confirmation [12]. Differential diagnoses include benign conditions such as umbilical hernia and pyogenic granuloma, necessitating biopsy for confirmation [13, 14]. In the present case, umbilical resection was performed for diagnosis.

Direct invasion via peritoneal dissemination is the most common metastatic route [6]. Although hematogenous and lymphatic spread have also been proposed, these are less common because of the lack of regional lymph nodes around the umbilicus and the rarity of isolated umbilical blood-borne metastasis. Lymphatic or hematogenous dissemination may be responsible in cases without peritoneal involvement, as observed in our patient. One hypothesis suggests that tumor burden may alter lymphatic flow and reroute it toward the superficial lymphatic vessels, facilitating its spread to the umbilicus [15].

Although previous reports have suggested lymphatic spread [6], our RNA microarray analysis showed distinct gene expression profiles between umbilical and lymph node metastases, suggesting that SMJN may not always share the same route. A major limitation of our study is that it was based on a single case. Therefore, it remains unclear whether our findings represent typical SMJN profiles. Accumulation of further cases and longitudinal sampling is required. Molecular profiling could eventually help identify novel factors involved in SMJN development and inform future treatment strategies. Our results demonstrate the upregulation of metastasis-related gene sets, such as those involved in cell adhesion and stromal remodeling, in both umbilical and lymph node metastases. However, the distinct gene expression profiles observed between these two sites suggest that SMJN may be involved in a metastatic pathway other than lymphatic dissemination. Considering the lack of peritoneal dissemination adjacent to the umbilicus, and the absence of histological lymphovascular invasion, hematogenous spread remains a plausible hypothesis, although definitive conclusions cannot be drawn from a single case. To further elucidate the mechanisms underlying SMJN formation, future research should focus not only on increasing the number of cases but also on complementary approaches. These include: (1) longitudinal sampling from a single patient prior to the appearance of SMJN, although this is clinically challenging; (2) transcriptomic analyses of SMJN in cases without evident lymph node involvement; and (3) comparative studies across different cancer types to identify shared gene expression signatures in SMJN and lymph node metastases. Ultimately, in vitro validation using functional assays such as gene knockout models is essential for confirming the causal roles of candidate genes in the metastatic process.

Case summary

We report a rare case of fallopian tube carcinoma presenting with both umbilical and inguinal lymph node metastases. Gene expression profiling revealed distinct differences between the primary tumor, umbilical metastasis, and lymph node metastasis, suggesting the possibility of different metastatic mechanisms. This case highlights the potential value of molecular profiling in understanding the complex metastatic behavior of gynecologic malignancies.

Conclusion

We report a rare case of fallopian tube carcinoma with both umbilical and inguinal lymph node metastases in which RNA microarray analysis was performed on primary and metastatic tumors. Our findings suggest that SMJNs may arise via a pathway different from that of lymph node metastasis, as reflected in their distinct gene expression profiles.

Further studies involving additional cases and time-course samples are necessary to elucidate the mechanisms underlying SMJN formation. Molecular profiling may improve our understanding of SMJN pathogenesis and guide the development of new treatment approaches for gynecological cancers with unusual metastatic patterns.

Abbreviations

SMJN

Sister Mary Joseph’s nodule

PET-CT

Positron emission tomography-computed tomography

TC

Carboplatin, paclitaxel chemotherapy

GO

Gene ontology

Author contributions

TU carried out the data curation, visualization, and investigation, and drafted the manuscript. YM conceived the study, participated in its design and coordination, and helped to draft the manuscript. HNa participated in the formal analysis, data curation, and visualization. AI participated in the formal analysis and visualization. HNi participated in the formal analysis, data curation, and visualization. KN contributed to the writing and editing of the manuscript. IK contributed to the writing and editing of the manuscript. SM contributed to the writing and editing of the manuscript. TH contributed to the writing and editing of the manuscript. KB conceived the study, participated in its design and coordination, helped to draft the manuscript, and acquired funding. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The microarray dataset supporting the conclusions of this article is available in the NCBI Gene Expression Omnibus under accession no. GSE297669.

Declarations

Ethics approval and consent to participate

The patient provided written informed consent to participate in this case study. The study was approved by the local committee on the use of gynecological cancer samples for experimental studies of the Hiroshima University (IRB file no. E2020-2190).

Consent for publication

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

Competing interests

Not applicable.