In all three cases in this series, a malignant infradiaphragmatic tumor was diagnosed following an initial finding of left supraclavicular lymph node metastasis during follow-up after surgery for tongue cancer.
Patients with oral squamous cell carcinoma and those with other types of head and neck cancer are at higher risk of a second primary cancer than patients with cancers at most other sites [3]. Mroueh et al. found a second primary cancer in 10% of patients with oral squamous cell carcinoma in their cohort [3], while Min et al. reported that the risk of a second primary oral cancer was higher (standardized incidence ratio 16.25, 95% confidence interval 13.04–20.02) than that of a non-oral second primary cancer (standardized incidence ratio 1.37, 95% confidence interval 1.29–1.45) in Korean patients with cancer in the oral cavity [4]. The highest relative risk for a second primary cancer in the oral cavity was observed in patients with floor of mouth cancer, followed by those with gingival and tongue cancers [3, 4]. In patients with tongue carcinoma, the second primary cancer most frequently occurs in the oropharynx, followed by the esophagus and larynx [3, 4]. In contrast, second primary carcinomas at other sites, such as the intrahepatic bile duct, bladder, and prostate, are rare in patients with tongue carcinoma.
Metastasis of infradiaphragmatic tumors to the left supraclavicular lymph node is also reported to be rare. The incidence of metastasis has been reported to be 3.6% for intrahepatic cholangiocarcinoma [1], 1.4% for bladder carcinoma [5], and approximately 0.3% for prostate carcinoma [6–8].
Metastasis from an infradiaphragmatic tumor to the left supraclavicular lymph node occurs via the rich lymphatic network of the retroperitoneal lymph nodes, cisternae chyli, and the thoracic duct, which drains into the systemic circulation via the left subclavian vein. Infradiaphragmatic tumor metastases to the lymph nodes of the head and neck without lung involvement are considered to occur via the vertebral venous plexus system [9].
Morphologically, the vertebral venous plexus system shows interindividual variability with little or no valves and many branches [10]. Therefore, tumor nests encounter little resistance as they ascend through the vertebral venous plexus when the intra-abdominal or intrathoracic pressure is increased [10], and these tumor nests do not pass through the lung [11].
3.1 Diagnosis
Combined radiological and serological assessments are useful for the diagnosis of primary cancer. CA19-9 and alpha-fetoprotein levels helped make the diagnosis in our first case, as did the PSA level in the second case.18F-FDG‐PET/CT has greatly improved our ability to detect an unknown primary tumor, particularly those in a distant location. However, 18F-FDG PET/CT sometimes fails to reveal organ-localized prostate cancer [12–15]. In our third case, the 18F‐FDG uptake was weak on 18F-FDG-PET/CT. Thus, prostate cancer cannot be ruled out even if the uptake is weak, and careful examinations, such as PSA measurements, should be considered.
3.2 Pathology
In our second case, because of the presence of atypical cells with slight squamous differentiation in the fine-needle aspiration biopsy and the lymph node specimen, the difficulty of obtaining a definitive pathological diagnosis from excisional biopsy of the left supraclavicular lymph node, and the patient’s history of squamous cell carcinoma of the tongue, primary cancer screening was started in the head and neck and lung regions. However, the lymph node metastasis originated from the bladder. The histological presentation of urothelial carcinoma is very similar to that of squamous cell carcinoma [11, 16, 17]. If histopathological examination reveals squamous differentiation in metastatic cervical lymph nodes, it is necessary to include the bladder in the search for the primary cancer site [16, 18]. In this case, GATA3(+) staining of the metastasis to the supraclavicular lymph node revealed that the primary cancer was not squamous cell carcinoma of the tongue but urothelial carcinoma in the bladder. The CK7(+) and CK20(-) phenotypes indicate a high probability of bladder urothelial carcinoma [19]. Combined immunolabeling for CK7 and CK20 often aids in the identification of urothelial bladder cancer; however, these markers have limited sensitivity and specificity [19]. Immunohistochemistry of the transcription factor GATA3, a sensitive and specific diagnostic urinary epithelial marker, has been widely used in the diagnosis of urothelial cancer [19, 20].
3.3 Prognosis
Our first patient opted for palliative care only and survived for 11 months after the diagnosis of lymph node metastasis. There have been some reports of improved survival (for more than 6 years) after successful chemotherapy treatment for metastasis of cholangiocarcinoma to Virchow’s node [21, 22]. Therefore, the prognosis of patients with intrahepatic cholangiocarcinoma and metastasis to the left supraclavicular lymph node is not always poor [21].
The prognosis has been consistently poor in the limited number of case reports on cervical lymph node metastasis from bladder carcinoma [23, 24]. The median survival of patients with metastatic bladder cancer who receive supportive care alone is 4–6 months [18]. Our second patient, who chose palliative care, survived for only 2 months after the diagnosis of left supraclavicular lymph node metastasis. As in previous reports, her prognosis was poor.
Even for patients with advanced-stage prostate adenocarcinoma and metastasis to the head and neck region, survival may be extended by rapid diagnosis and appropriate treatment [25]. Hormonal therapy has been shown to prolong survival, even for patients with metastasis of prostate adenocarcinoma to Virchow’s node [26]. One study found that the average survival time was 25.8 (range 1–101) months for patients with prostate adenocarcinoma and Virchow’s node metastasis and pointed out that the prognoses of these patients was superior to that of patients with metastatic adenocarcinoma with a non-prostatic origin [25]. Our third patient survived for 47 months after the diagnosis of left supraclavicular lymph node metastasis.
The prognosis of malignant infradiaphragmatic tumors after metastasis to Virchow’s node is generally considered to be extremely poor [21]. However, our experience suggests that the prognosis may depend on the characteristics of the tumor and that rapid diagnosis is important for providing appropriate treatment. Enlarged left supraclavicular lymph nodes can be more easily palpated and visually inspected than nodes in other areas of the body. If enlarged left supraclavicular lymph nodes are detected on routine clinical examination, clinicians should request additional assessments such as CT, MRI, ultrasonography and PET/CT to ensure rapid detection and diagnosis of the primary lesion. In addition, biopsy of the enlarged cervical lymph nodes and serological assessments should be conducted to diagnose the primary cancer.
Further accumulation of cases and more detailed studies of malignant infradiaphragmatic tumors with Virchow’s node metastasis are needed.