Gallbladder cancer is a rare but highly malignant cancer, which is often diagnosed at a metastatic stage due to its asymptomatic manifestation. [2] Adenocarcinoma is the most common histologic variant of gallbladder cancer, comprising 90% of cases; further classification into subtypes notes adenocarcinoma NOS as the most common subtype (68% of all cases) with adenocarcinoma with neuroendocrine features comprising only 2% of cases. [3] Here we present a unique case of metastatic gallbladder adenocarcinoma with neuroendocrine features with initial presentation as a left neck mass identified as metastasis to the thyroid gland.

A comprehensive literature review revealed only three other reports of gallbladder carcinoma with thyroid metastases (Table 1). [10,11,12] Mean age of this cohort is 59 (range 48-74), younger than those with adenocarcinoma of the gallbladder (mean age 72) [2]. All previously reported cases occurred in females, with our patient is the only reported male. Interestingly, it has been suggested that estrogen may play a role in gallbladder cancer and metastases of cancers in general to the thyroid as the prevalence of both entities is higher in women; [13,14,15] however, these data are controversial. The unique pattern of metastasis to the thyroid in this small subset may suggest that certain histologic subtypes have a predilection for the thyroid gland. However, the cases presented here represent a varied histology and grade: moderate to poorly differentiated adenocarcinoma (2), moderately differentiated squamous cell carcinoma (1) and poorly differentiated adenocarcinoma with neuroendocrine features (1; Table 1). Likewise, there is an absence of a pattern of other metastatic sites between these patients, with previously reported patients have had greater number of metastatic sites at the time of diagnosis of the thyroid metastasis: distant spread to the lung, axillary nodes, cervical nodes, and mediastinal nodes (Table 1). Our patient had only one other site of metastatic involvement upon diagnosis, pathologically identified as connective tissue of the neck. While this may represent a replaced lymph node, all other sampled lymph nodes were negative, and no other nodes were noted on PET-CT; the apparent liver lesion was identified as an extension of the gallbladder and not a metastasis. With disease progression, metastatic disease in our patient became widespread, involving the adrenals, liver and truncal and limb subcutaneous fat. The variability within these cases regarding histology and metastatic spread causes difficulty in effectively predicting the biology and behavior of these lesions.

Due to the rarity of gallbladder cancer presenting with a metastasis to the thyroid, and the extent of disease at the time of diagnosis, treatments have included surgical resection of both the gallbladder and the thyroid, adjuvant chemotherapy and radiation therapy (Table 1); however, survival was reportedly short, only 4 and 7 months (Butte and Kurniali, respectively). Due to the lack of obvious lymph node involvement in our patient, surgical resection and adjuvant chemotherapy were offered and, within a few months, the patient was classified with no evidence of disease. However, within a month of the completion of traditional chemotherapy and initiation of surveillance only, other metastatic lesions manifested, suggesting an aggressive biology. While a rare tumor protocol utilizing immunotherapy was available, the lack of insurance coverage precluded initiation for five months, during which time the disease progressed. Once the rare tumor protocol was initiated, the disease stabilized; however, the underlying disease had progressed and the patient expired at 19 months post-diagnosis.

While resection is still the curative option for gallbladder cancer, this strategy is limited as most patients present with metastatic disease [16,17]. Due to the rarity of this disease, especially in the cases reviewed here, and the nature of this unusual presentation, traditional chemotherapy has not been shown to be effective. However, more recently, as the biology of gallbladder metastases has been more thoroughly investigated [19] and genetic analysis of tumors has promoted the development of additional therapeutic strategies such as targeted immunotherapy, as was noted in our patient, there is promise of controlling the progression of disease [18]. Thus, there is an essential role for bioanalysis for all rare tumors and early employment of targeted therapies to optimize patient care and influence outcomes.