- Case report
- Open Access
Alpha-fetoprotein (AFP) as tumor marker in a patient with urothelial cancer with exceptional response to anti-PD-1 therapy and an escape lesion mimic
- Johannes C. Melms†1, 2,
- Rohit Thummalapalli†2,
- Kristin Shaw3,
- Huihui Ye3,
- Leo Tsai4,
- Rupal S. Bhatt1 and
- Benjamin Izar1, 2, 5, 6Email authorView ORCID ID profile
© The Author(s). 2018
- Received: 17 April 2018
- Accepted: 10 August 2018
- Published: 12 September 2018
The development of a new lesion in a patient with a complete remission to anti-PD-1 therapy is highly concerning for a drug resistant escape lesion. Here, we present a case of a 62-year-old patient with chemotherapy-resistant metastatic urothelial cancer who had a complete remission to pembrolizumab. The patient’s disease burden tracked closely to serum levels of alpha-fetoprotein (AFP) expressed by the tumor and served as an accurate tumor marker. Surveillance imaging revealed a solitary growing pulmonary nodule mimicking an escape lesion in the absence of an increase in AFP levels. Biopsy of this lesion revealed a benign intraparenchymal lymph node with no evidence of metastatic carcinoma. This case indicates that in some patients, biomarkers aberrantly expressed by their tumors, such as AFP in this patient, may be used as a tumor marker for response to anti-PD-1 therapy and emphasizes the importance of confirming potential escape lesions by pathologic examination.
Immune checkpoint blockade (ICB), including anti-PD-1/PD-L1 and anti-CTLA-4 therapy, revolutionized the treatment landscape of several cancers, including urothelial cancer . While some patients experience deep and durable responses, the majority of patients have either intrinsic or acquired resistance . Progressive disease is most frequently discovered by enlarging or new lesions on cross-sectional imaging, however, there is a broad differential for nodules, particularly in the lung, including infection and inflammation . Determining the etiology of lung nodules is therefore important, as it may affect medical and potentially curative surgical management in the context of oligometastatic disease. Tumor markers are helpful in some cancers and can help guiding therapies, for example, CA125 in ovarian cancer. However, no such tumor markers are available in most cancers. Here, we describe a case of a patient with metastatic, chemotherapy-resistant urothelial carcinoma with a complete response to treatment with anti-PD-1 monotherapy. The patient’s tumor aberrantly expressed alpha-fetoprotein (AFP), which served as a serum tumor marker that tracked very closely with disease burden. Following a complete resection, the patient developed an isolated, slowly growing lung nodule. Although there was no concomitant increase in AFP, the patient underwent resection of the lesion, which revealed a benign intraparenchymal lymph node, but no malignant disease.
Immune checkpoint blockade has revolutionized therapy for several different cancer types, however, drug resistance remains a major challenge for the majority of patients . Unfortunately, the majority of patients experience either disease growth or development of new metastatic lesions that escape immunity. It is clinically important to obtain histopathologic confirmation of true progression, as compared to so-called pseudo-progression , where lesions grow due to influx of immune cells and increase of biomass on radiographic imaging. Proper identification of new lesions could dictate treatment decisions. In addition to pseudo-progression, one has to distinguish other reasons for new lesions, in particular in the lung, such as infections or inflammation .
We report a case of a urothelial cancer patient with complete response to immune checkpoint blockade who developed an apparent escape lesion. The patient’s disease tracked very closely to serum AFP levels, and the strong expression of AFP on the tumor itself supported the tumor as the primary source. AFP is a tumor marker used for screening for hepatocellular carcinoma (HCC)  and was the reason that it was checked in this patient with chronic hepatitis B. AFP-producing urothelial tumors are extremely rare . In the case presented here, AFP levels were helpful as a serum tumor marker that correlated tightly with the disease burden observed by clinical examination and cross-sectional imaging. Interestingly, the patient developed what appeared to be a pulmonary escape lesion, but without concomitant elevation in AFP. To determine the nature of the lung lesion, the patient underwent resection and histopathological examination, which revealed the presence of a benign intraparenchymal lymph node that mimicked an escape lesion. This highlights the need for definitive diagnosis of patients with isolated presumed escape lesions to guide proper management, and in this patient, the fact that absent AFP elevation was a good indicator for the non-malignant nature of the lesion. Furthermore, we suspect that in addition to being a mere marker of disease burden, it is also possible that AFP peptides may have served as an epitope linked to the deep response following anti-PD-1 therapy. In line with this hypothesis, a recent report in HCC identified an AFP-peptide (AFP-158)-specific T cell receptor (TCR) that promotes dramatic activity in in vitro and in vivo tumor models  and the development of AFP-targeted chimeric antigen receptor therapy is underway .
In summary, we present a case of deep response to anti-PD-1 therapy with a tumor that strongly expressed AFP, which served as a reliable tumor marker and possibly as immunogenic antigen. The case also highlights the need for biopsy and careful pathologic examination of apparent escape lesions to guide proper clinical management.
We thank Paul Vanderlaan for support with interpreted pathology specimens and helpful comments for the manuscript. We thank the patient and his family for agreeing to report this case.
B.I. was supported by the Ludwig Center for Cancer Research at Harvard, NIH/NCI grant K08-CA222663, the SITC-BMS Fellowship for Translational Immunotherapy, and the Dana-Farber Cancer Institute Barr Award for Translational Cancer Research.
BI and RSB took clinical care of this patient. KS and HY provided pathology figures and interpreted pathology specimens. LT provided interpreted CT scan images and provided a selection thereof shown in this manuscript. JCM, RT, BI wrote the manuscript with input from all authors. All authors read and approved the final manuscript.
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