Spontaneous regression of metastatic cancer cells in the lymph node: a case report

Spontaneous regression of a malignant tumor is the phenomenon of disappearance of cancer cells without any treatment [1, 2]. Even though this event seems to be rare, it has been observed for thousands of years [3]. Spontaneous regressions are known to be related to acute infections, vaccine therapy, surgical removal of the malignant tumor and the taking of herbal medicines [4]. And these phenomena are more common in pediatric embryonal tumors, and breast and skin cancers [4].

Of note, the immunological characteristics of these tumors have drawn attention to the main underlying mechanisms of spontaneous regression. Previous studies on spontaneous regression have involved investigations of various immunologic markers for natural killer cells, macrophages and dendritic cells, that could be involved in enhanced tumor targeting immune responses [5, 6]. However, there has not been a comprehensive immunological overview comparing lymph node metastasis and spontaneously regressed metastasis in the lymph nodes of the same patient. We think it is very important because the immune cell profiles are quite variable between individual hosts, depending upon age [7], hormonal status [8–10], environmental cues [11], nutrition [12] and even bio-behavior [13].

Thus, we conducted an immunological study in one patient with buccal cancer (squamous cell carcinoma), in which spontaneous regression of metastatic lymphadenopathy was confirmed by surgical pathology. We expect that our study will contribute to the understanding of the underlying mechanisms of spontaneous regression of solid cancers, and hopefully, the findings will suggest new immunological methods of preventing or treating cancer or corresponding lymph node metastasis.

The purpose of this case report is to compare the differences of the immune cell profiles between the lymph node harboring malignant tumor cells and the tumor-regressed lymph node in the same patient, which possibly occurred through the rare process of spontaneous regression. Even though the results could not provide direct evidence of the underlying mechanisms of the spontaneous regression of the malignant tumor, our findings may have clinical significance in that the immune cell profiles according to the different disease status in the lymph nodes were analyzed in the same patient. Because the individual had quite a variable range of immune cell populations, we believe our data from the single patient may reflect the change of immunity related to tumor regression more accurately.

There was a time gap of 4 years 6 months between the initial and salvage surgery of neck lymph nodes. The pathology of the salvage surgery revealed total tumor regression and no viable tumor cells in the lymph nodes dissected. Thus, transition between tumor and non-tumor area was not observed in the specimens, suggesting that tumor cells arriving at the lymph nodes previously may undergo total cell-death process due to immunological events or unknown etiology. Of note, the tumor-regressed lymph node was located in the contralateral lower neck, which was not exposed to any treatments, such as surgery or radiation.

A previous study on the immune response in cervical intra-epithelial neoplasia with and without spontaneous regression reported that CD8(+), CD4(+)/CD25(+) cell ratios and CD138(+) plasma cells were independent predictors of tumor regression [14]. However, the study did not evaluate the spatial and temporal changes of the immune profiles in the patients. Meanwhile, our study clearly showed a feature of low Treg and high NK cells in the tumor-regressed lymph node in the same background of immunity.

There have been many reports supporting the involvement of Treg and NK cells in cancer remission. Treg cells are well known to play a major role in tumor-driven immune evasion [15–17]. Thus, there is a high chance that Treg cells can also exert their effects on tumor colonization and growth in the metastatic lymph node. Reciprocally, a decrease of Treg cells was one of the hallmarks of tumor regression in our study. NK cells are a subset of cytotoxic cells, important to the maintenance of innate immunity [18], and they seem to be a main effector cell for inducing tumor regression. Taken together, the interaction between Treg and NK cells may be an important phenomenon in spontaneous tumor regression [19].

However, the differences of immune cell profiles in our study were not able to be translated into a cause-effect relationship and the dynamics of tumor regression. For instance, a huge number of macrophages might infiltrate into tissues following malignant tumor cell death. Dendritic cells could accumulate around a regressed tumor, just after cell antigens had been exposed outside after cell death. Thus, we have to be very cautious about the interpretation of these results. Nevertheless, our study illustrated that Treg and NK cells were the main differences among various immune cell populations in the tumor-regressed lymph node, suggesting that they could modify the tumor microenvironment to suppress tumor growth and enhance self-arrest of the tumor.

We describe a case of spontaneous malignant tumor regression in a metastatic lymph node, and through immunohistochemical analysis of the tumor-regressed lymph node, reveal the key features of a lower recruitment of Treg cells and a high infiltration of NK cells in this case of spontaneous regression. Thus, we think that Treg and NK cells may play a key role in tumor regression, and additionally, the modulation of Treg cells, as part of the group of NK cells, may be a good therapeutic method to control lymph node metastasis. We believe our findings should be validated through a large cohort and in-depth mechanistic study.

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