Malignancy arising at the ampulla of Vater is not uncommon and adenocarcinoma accounts for most of these malignancies. Neuroendocrine tumours of the ampulla of Vater have been reported, mostly in small series.1
Travis and colleagues proposed a three grade scheme for pulmonary neuroendocrine tumours with substantial reproducibility, including low grade typical carcinoid, intermediate grade atypical carcinoid, and high grade categories of LCNEC and small cell carcinoma.3
Extrapulmonary LCNEC is a highly aggressive neoplasm resembling its pulmonary counterpart both histologically and in its highly malignant behaviour.2
Our case is unique because glandular differentiation in addition to the typical light microscopic and immunohistochemical features of ampullary LCNEC has not been reported previously.
Neuroendocrine tumours with a mixed histological pattern have been reported in pulmonary and extrapulmonary locations.4–6
These neoplasms have been referred to in various terms as combined or mixed tumours. Adenocarcinoid tumours, which histologically contain both ductal and neuroendocrine differentiation, most commonly occur in the appendix.4
Five isolated reports of adenocarcinoid tumours of the periampullary region have been described in the literature.5
However, none of the carcinoid components in previous reports met the diagnostic criteria of LCNEC. We believe that the absence of immunoperoxidase staining for carcinoembryonic antigen and the lack of mucin production in our case mean that this neoplasm should be classified as a LCNEC with glandular differentiation. Ruffini and associates analysed 1158 resected lung tumours and found that 19 (1.6%) had a combined small cell carcinoma/LCNEC plus a non-neuroendocrine carcinoma.6
They showed that patients in the combined group have a poor prognosis and that survival rates are similar to those seen in pure small cell carcinoma. It appears that ampullary LCNEC follows a similar pattern. As in our case, despite the presence of glandular differentiation, LCNEC of the ampulla of Vater is a high grade malignancy with a dismal prognosis.
Take home messages
- We present a rare case of large cell neuroendocrine carcinoma of the ampulla of Vater with glandular differentiation
- Divergent differentiation was also present in the metastatic lymph nodes but was absent after relapse, along with the loss of CD117 overexpression
- Large cell neuroendocrine carcinomas appear to be highly aggressive tumours, with early metastases and a fatal outcome
“Glandular differentiation in addition to the typical light microscopic and immunohistochemical features of ampullary large cell neuroendocrine carcinoma has not been reported previously.”
The intimate arrangement between the two differentiated cell types raises a question of the histogenesis of these tumours. Results from a molecular study suggest that both the carcinoid and glandular components of a mixed tumour share a common multipotential stem cell origin.7
It is noteworthy that Ruffini et al
reported that the metastatic lymph nodes showed pure histology, rather than the mixed tumour type.6
In our present patient, the two components coexisted in the metastatic foci as an intricate admixture with a transition zone. There are three possible mechanisms of metastasis, namely: (1) the common precursors undergo metastasis to the lymph nodes, where the progenitor tumour cells multiply and differentiate as the primary tumour; (2) both cell types of the primary tumour possess the ability to metastasise; and (3) tumour cells of the glandular component are passively carried with the LCNEC cells to the vascular bed of metastatic sites. The common origin theory is more compatible with the intermixing of the two components within the primary tumour and metastases.
Recently, it was shown that KIT was overexpressed in 55–60% of pulmonary LCNEC tumour cells.8,9
This protein, the product of the c-kit protooncogene, is a transmembrane tyrosine kinase receptor that regulates the normal development of different cell lines and also promotes tumour cell proliferation and blocks apoptosis in some haemopoietic disorders and solid malignancies. Loss of CD117 overexpression after chemotherapy is often seen in small cell lung carcinoma.9
One possible explanation is that chemotherapy induces the selection of CD117 negative neoplastic clones in relapsing disease. Our case showed loss of both CD117 overexpression and glandular differentiation in the metastatic lesions after chemotherapy. It remains unclear whether this is a cause and effect association, or whether it arises from the selected tumour cells having an undifferentiated pattern and more aggressive behaviour.
In conclusion, we present a case of LCNEC of the ampulla of Vater with glandular differentiation. Divergent differentiation was also present in the metastatic lymph nodes but was absent after relapse, along with the loss of CD117 overexpression.