The Spontaneous Regression of Primary Gastrointestinal Malignancies: An Observational Review

The spontaneous regression or remission (SR) of cancer, often described as the partial or complete disappearance of a malignant tumor in the absence of all medical treatment and therapy, is a well-documented phenomenon. With efforts ongoing to establish cancer treatments that limit undesirable outcomes and adverse effects, these uncommon occurrences of SR carry significant implications for novel therapies and warrant further investigation. While several case studies have reported instances of SR in gastrointestinal (GI) malignancies, a comprehensive review of previous manifestations of SR in the GI tract remains lacking. The inclusion criteria for the rare phenomenon are also in need of an appropriate update that takes recent scientific advancements and emerging new medical technologies into account. Our analysis of 390 cases of SR in the GI tract focuses primarily on neoplasms of the hepatobiliary system and proposes an updated version of the older inclusion criteria for spontaneous regression.


Introduction And Background
In 2021 alone, 372,470 new cases of primary gastrointestinal (GI) cancer were reported worldwide, and approximately 124,348 deaths occurred as a result, comprising 19.6% and 20.4% of total new cancer cases and deaths, respectively [1]. Nonetheless, with the introduction of various novel diagnostic, therapeutic, and antineoplastic modalities, the mortality rates of GI cancers have declined significantly over the past several years [2]. These new modalities have led to a greater understanding of the pathogenesis of cancer and of achieving remission. Spontaneous regression (SR) is defined as the complete or partial disappearance of a primary and/or disseminated lesion of a histologically diagnosed metastatic disease in the absence of any medical treatment or therapy known to have antitumor effects. Spontaneous regression has been found to occur throughout the entire body, including the GI tract [3]. But it is not equivalent to a cure, as cancer may reappear or spread elsewhere in the body. The frequency of spontaneous regression varies based on the type of cancer, as it is most commonly reported in renal cell carcinoma, melanoma, and neuroblastoma [3][4][5].
Occurring at a rate of about one out of every 60,000 to 100,000 cases of all cancers, these extremely rare occurrences of SR have the potential to serve as an instructive in vivo model of biological tumor regulation and control [6].
A number of putative mechanisms have been proposed for the observed spontaneous disappearance of malignancies, including inflammation, apoptosis, ischemia, and immunological responses [7]. Other mechanisms proposed to cause SR include epigenetic modifications, hormonal responses, oncogenes, tumor suppressors, cytokines and growth factors, and psychological mechanisms. Unfortunately, several of these postulated mechanisms are based on association and speculation alone, with the exact mechanistic modalities surrounding the SR of GI cancer yet to be elucidated. Regardless, an immunological anti-tumoral response of a patient's body to specific malignancies is among the most prevalently described mechanistic hypotheses for the observed spontaneous disappearance of neoplasms. Since the very inception of the term, spontaneous regression has historically been speculated to be a dynamic interplay of immunological antitumor responses. In 1956, Everson and Cole defined the criterion for SR as the partial or complete disappearance of a malignant tumor in the absence of all treatment or in the presence of therapy that is considered inadequate to exert a significant influence on neoplastic disease. At that time, they theorized that the phenomenon must be an opportunistic by-product of an activated immune response. Cases of SR linked to infections have significantly influenced the discovery of several different anticancer therapies that facilitate the targeting of cancer cells by the host's immune system. For example, immune checkpoint inhibitors have revolutionized modern cancer treatment by targeting inhibitory receptors (e.g., PD-1, CTLA-4, LAG-3), ligands (e.g., PD-L1) expressed on T cells, antigen-presenting cells, and tumor cells, which result in an anti-tumor response by stimulating the host immune system.
Focusing chiefly on malignancies of primary GI origin, this observational review of the literature hopes to bring further attention to the phenomenon of SR while also identifying some potential mechanisms that have been purported to contribute to this largely unreported phenomenon. Secondarily, this comprehensive review aims to introduce a revised and up-to-date version of the older inclusion criteria for SR throughout the body. This updated criterion has been modified in a way that takes into account recent scientific advancements and emerging new medical technologies, with the intent that it will also be easy to follow for physicians and clinical researchers alike. Finally, this study seeks to broaden the scope of how SR is perceived by clinicians and members of the medical community by encouraging a holistic view of the exceptionally rare phenomenon as a dynamic interplay of various modalities.

Search Strategy
A literature search across five databases (PubMed, Medline, Google Scholar, Semantic Scholar, and Jstage) was performed employing the following main keywords: gastrointestinal cancer, spontaneous regression, spontaneous remission, spontaneous necrosis, and abscopal effect. A full list of searched keywords is included in Appendix A. The clinical characteristics of each occurrence of SR within the GI pathway and the related long-term outcomes were then extracted. Articles were excluded if any systemic treatment was used or if any treatment directed at the lesion was utilized before the documented regression. All diseases were limited to the GI tract, spanning the oral cavity, esophagus, stomach, liver, bile duct, gallbladder, pancreas, mesenteries, peritoneum, small intestine, colon, and rectum. A manual search of each work's citations was performed, utilizing additional published works listed in the supplementary materials or reference sections of each of the aforementioned studies. No restriction was applied to the date of publication, the form of publication, or the primary language of the publication.

Inclusion Criteria
Only publications that described the true SR of a histologically confirmed GI cancer were included following the inclusion criteria depicted in Figure 1. These criteria are based on the original criteria proposed by Cole, modified to emphasize histological diagnosis, and adapted to fit multiple clinical scenarios (2). These criteria are summarized as follows: (1) Partial or complete disappearance of the primary tumor or secondary metastasis was radiographically or pathologically demonstrated in the absence of systemic therapy; (2) localized therapy to the lesion prior to the observed shrinkage was excluded; and (3) the malignant neoplasm was histologically proven at some point during this course. Patients with primary neoplasms histologically determined to have originated from outside the GI pathway but demonstrating SR were excluded, even if they demonstrated SR of a secondary metastasis within the GI tract. Patients demonstrating regression of an extra-digestive lesion, histologically determined to have arisen in the GI tract, were included regardless of whether the primary GI lesion had also regressed.

FIGURE 1: Clinician guidelines or criteria for reporting spontaneous regression
From a clinician's initial encounter with a patient with a suspected cancerous lesion to the demonstration of tumor shrinkage or disappearance, potential clinical manifestations of spontaneous regression are schematically investigated and shown. Original figure by the authors.

Data Extraction and Analysis
The following information was extracted and recorded from each article: patient age and sex, location and histological typing of the primary tumor, the site of regression, the period of regression or remission, and the etiological mechanism of regression proposed by the author. The demonstrated recurrence of cancer was also noted in some patients. Limited to each author's interpretation and the duration of follow-up included in each study, the period of remission was defined as one of the following, whichever was found to be the longest: (1) the total period of time during which the tumor demonstrated a shrinkage in size, beginning with the date when the tumor's size was found to be at its maximum to the date when the tumor's size was found to be at its minimum, (2) The total period of time between the partial or complete disappearance of cancer and the most recent follow-up date in which the patient continued to show no signs of metastatic spread or recurrence of the malignancy; (3) the total period of time during which the tumor demonstrated a shrinkage in size prior to its resection, from the proposed date when the tumor's size was found to be at its maximum size to the date of the resection. After the tumor was resected, the specimen was pathologically found to have shrunk or disappeared.
Of the 390 cases of SR of GI malignancies reported meeting our criteria, a majority were noted in men (272 cases, 69.7%) compared to women (118 cases, 30.3%   The vast majority of cases of partial or complete regression occurred within the primary tumor (288 cases, 73.8%); nonetheless, multiple cases demonstrated regression of liver metastases (18 cases, 4.6%), lung metastases (37 cases, 9.5%), lymph metastases (15 cases, 3.8%), or other metastases (24 cases, 6.2%). The period of regression (as defined above) varied greatly in these cases, with some cases reporting just a few days of regression and others expressing several years of remission. Cancer recurrence was reported in 24 cases of SR, comprising 6.2% of total cases of SR in the GI pathway (noted with an asterisk "*" in Appendix B).
The authors proposed various putative mechanisms of SR, which are summarized in Table 2.

Discussion
This systematic review includes the presentation of 390 cases reported in 346 scientific papers, journals, case studies, and published books. These publications were generated over the past 95 years. Interestingly, 325 cases were published in the modern era, defined as cases published in the past 30 years. Following the review of these articles, multiple common factors were revealed, including a tendency for SR to occur in patients over the age of 55 (297 patients, 76.2%), patients of the male sex (272 patients, 69.7%), and patients with primary liver tumors (209 patients, 53.6%) or secondary liver metastases (18 patients, 4.6%). The clinical features and proposed mechanisms surrounding these cases of SR within the GI pathway, along with the location and duration of remission, are documented in Appendix B. Patients within this cohort of reported cases displayed varied periods of stability, ranging from just a few days of observed partial tumor regression to several years of cancer remission, up to 20 years cancer-free.

Mechanisms of Spontaneous Regression
Historically, SR has been speculated to occur in the setting of a prolonged febrile illness due to viral or bacterial infection; nonetheless, only a fraction of cases of SR (35 patients, or 5.1%) have been attributed to a hyperthermic state and infection [8]. In cases of SR occurring during times of acute febrile infections, immune cell infiltrations and signaling cascades are postulated to lead to tumor cell death and cancer tissue necrosis via the release of interleukins, tumor necrosis factors, and interferons (specifically IL-2, IL-6, and IL-8) [9][10][11][12][13][14][15][16][17]. Viral infections notably induce the production of interferons, which are capable of their own immunomodulatory effects involving macrophages, B-cells, and monocytes, alongside the induction of IL-2 receptors in some cancers [6][7][8]. Most recently, tumor regression has been reported after COVID-19 vaccination and infection with its wide-ranging pro-inflammatory effects on the host immune system [18][19][20][21][22][23].
Enhanced antitumoral immunogenicity is proposed to play a profound role in the involution of several GI cancers. In fact, examples displaying the correlation between SR and the elimination of immunodisruptive factors (e.g., medications, viral infection, checkpoint proteins) are perhaps the best evidence supporting the involvement of immunological mechanisms in the achieved SR of GI cancer [24,25]. Tumors have also occasionally been found to regress following systemic or localized treatment for some other disease process. For example, certain localized therapies have been observed to cause tumor regression of both the target lesion and any untreated tumors [26]. Described as the "abscopal effect," this phenomenon is purportedly mediated by a systemic anti-tumor response that follows after receiving radiation therapy for a metastatic lesion or an entirely separate neoplasm. Overall, more than half of the reported cases of SR within the GI tract have been attributed to immunological processes (202 cases, 51.8%), with authors also suggesting the involvement of endocrine factors (four cases, 1.0%) and inflammatory responses (14 cases, 3.6%).
Ischemic models of regression are also proposed to play a key role in the dynamic interplay of antitumoral mechanisms described in the SR of cancer. Tumor cells require an ample supply of blood, so limiting their blood supply and perfusion could intuitively starve the cells to death [27][28][29]. Consequently, systemic and tumoral hypoperfusion (30 cases, 7.7%), rapid and unpredictable growth (14 cases, 3.6%), anti-angiogenic factors (three cases, 0.8%), and vascular compromise (26 cases, 6.7%) are all theorized to lead to the SR of GI cancer [30][31][32][33][34]. For example, there are multiple cases of SR described as following profound systemic hypoperfusion associated with hemodialysis, surgical invasion, or GI hemorrhage [30][31][32][33][34]. Several reviewed cases of SR (44 patients, 11.3%) have been specifically attributed to diagnostic biopsy procedures alongside tumor ablation and angiographic techniques [3,7,35]. In addition to impairing the adequate delivery of essential nutrients and oxygenation to the remaining (AL3) malignant tissue, these procedures are known to set forth a landslide of tumor-derived antigens into circulation, thus acting as a therapeutic vaccine [4,36].
While endocrinologic mechanisms are largely considered to play a secondary role in the course of tumor regulation, notable hormonal changes are considered possible antecedents to SR [37]. In a case describing a presumed appendiceal neuroendocrine tumor (NET) during pregnancy, Sewpaul et al. observed rapid regression following the patient's completion of her pregnancy, suggesting that the pregnancy did not worsen the course of the disease but instead may have contributed to tumor regression [38]. Additional influences on the endocrine system by psychological events, such as trauma and stress, suggest that a patient's psychological status might also influence the course of tumor development. In a case study detailing the SR of one patient's recurrent oral squamous cell carcinoma (OSCC), Oya et al. describe how the 73-year-old patient was unable to understand the state of his recurrent cancer following cerebral infarction and dementia and postulate how this "unconsciousness" functioned as a preferable psychological condition for tumoral regression [39].

Spontaneous Regression in Cancers of Specific Pathohistology
Hepatocellular carcinoma: While testicular germ cell tumors, neuroblastomas, and renal carcinomas are conventionally the most frequent types of histologically diagnosed tumors presenting this phenomenon, several recent studies report an increasing incidence of SR within the GI pathway, particularly in primary hepatic lesions [6,40]. Correspondingly, we found that HCC was by far the most frequently observed type of cancer within the GI pathway to have undergone SR, with 199 total cases reported in the literature from 1982 to 2021. The reviewed cases proposed several mechanisms surrounding the involution of HCC, primarily citing ischemic and immunological antitumoral models of regression.
To prevent a barrage of immune responses to innocuous materials while still enabling immunity to pathogens, the complex cellular, functional, and molecular modeling of the liver allows for a dynamic, multifaceted approach to immune surveillance that incorporates the tolerogenic organ's inherently immunosuppressive microenvironment and its distinct hepatic regulatory pathways [41]. It is possible that any manipulation of this multipronged system, such as through the abatement of the tolerogenic characteristics of hepatic APCs or the enhancement of effector lymphocyte function, could potentially have the desired effect of increased anti-tumor activity and tumor regression [42].
Interestingly, several of the changes associated with the SR of the poorly prognosed tumor can also be observed following transarterial chemoembolization (TACE) treatment, thus suggesting that the SR of HCC should, to some degree, involve ischemic processes [43]. Regression of HCC has also been linked to rapid tumor infiltration, in which the notably hypervascular tumor grows more rapidly than its blood supply, leading to local or centralized ischemia, intratumoral bleeding, and hemorrhagic necrosis of the lesion [44]. These distinct immunologic and vascular attributes of the liver combine to form a tumoral environment wherein an intrahepatic malignancy is uniquely positioned to respond to immune and ischemic changes compared to tumors of other organs of the GI tract. Otherwise, abstinence from alcohol, persistent fever, withdrawal from androgens, blood transfusions, and the use of herbal medicines have also been described as leading to the SR of primary hepatic lesions.
Primary oral and gastrointestinal lymphoma: Cases detailing the SR of primary oral and GI lymphomas were observed to span the entirety of the alimentary canal, from several primary extranodal lymphomas of the oral cavity to four cases of rectal lymphoma that regressed spontaneously. Regarding the spontaneous regression of aggressive NHLs of the digestive tract, several cases have been reported demonstrating the spontaneous involution of lymphoma following improved immunological status, particularly in HIVinfected patients receiving antiretroviral therapy [27][28][29][30][31][32].
While SR is an exceptionally rare occurrence in aggressive lymphomas, such as DLBCL and ALCL, it can occur relatively frequently in low-grade lymphomas such as follicular lymphomas (FLs) and mucosaassociated lymphoid tissue (MALT) lymphomas. Generally, well-or moderately-differentiated forms of cancer are considered low immunogenic tumors due to their limited mutational load and concomitant limited neoantigen expression. In a retrospective analysis of 209 cases of NHL from 1965 until 1978, Gattiker et al. reported the occurrence of SR in 18 out of 140 (12.9%) cases of nodular type malignant lymphoma and 2 out of 69 (2.9%) cases of diffuse type malignant lymphoma [45]. The relationship between gastric mucosaassociated lymphoid tissue (MALT) lymphoma and H. pylori is very well established, and low-grade gastric MALT lymphomas are known to regress following the bacteria's eradication [46]. This reversible reactivity of low-grade MALT lymphomas to H. pylori infection is a clearly documented phenomenon; hence, cases detailing the regression of low-grade MALT lymphomas involving H. pylori eradication through the use of eradication therapy were excluded from the scope of this careful review.
Pancreatic ductal adenocarcinoma: With only a few cases reported in the literature, pancreatic tumors are seldom known to undergo SR, leaving clinicians skeptical of this lethal tumor's ability to truly demonstrate involution when left untreated. Despite numerous molecular and immunological approaches, pancreatic cancer is typically poorly responsive to existing chemotherapeutic and immunological antineoplastic agents. This lack of response to immunotherapies is largely due to cancer's low mutational burden and tendency to favor an immunosuppressive microenvironment characterized by self-isolating dense desmoplastic tissue and an exceptionally low number of infiltrating T cells [47,48]. In a recently published article investigating the possibility of misdiagnosis leading to a presumptive finding of SR in pancreatic cancer, Herreros-Villaneuva et al. emphasized how different types of pancreatic carcinomas must be cautiously distinguished from otherwise benign tumors, insulinomas, and immunoglobulin G4 (IgG4)-associated autoimmune pancreatitis during the process of recording SR [49]. Regardless, four additional cases of pancreatic ductal adenocarcinoma (PDAC) have since been published, citing various multifactorial models of SR, including acute pancreatitis and bacterial or fungal infection in the vicinity of the pancreatic tumor, leading to improved immunogenic tumor presentation [48,[50][51][52].
Colorectal cancer: Like pancreatic cancer, colorectal cancer has long been considered poorly immunogenic, largely based on indirect data from epidemiological studies on the lack of SR in colorectal cancer [53,54]. This lack of immunogenicity in this cancer can be attributed to the failure of tumor-infiltrating lymphocytes to demonstrate substantial lytic activity against cancer cells, as demonstrated in in vitro models [55,56]. While colorectal cancer constitutes more than 15% of all malignancies, it represents less than 2% of all tumors to demonstrate SR [57]. Still, several other rare forms of GI cancer, including Merkel cell-like small cell carcinoma of the parotid gland and multiple gastroenteropancreatic neuroendocrine tumors (GEP-NETs) of the stomach, bile duct, and pancreas, were observed to spontaneously regress.

Strengths and Limitations
While prior retrospective analyses have investigated the incidence of SR for specific cancers and its occurrence within the individual organs of digestion, an observational study of this scope, broadly examining all prior cases of SR throughout the entire GI pathway, has never been published to date. This first-of-its-kind study systematically and thoroughly extracts and organizes information from an array of 390 individual cases of SR within the GI pathway. Although the majority of reports were restricted to the English literature, cases in other languages, including Spanish, Chinese, German, and Japanese, are included in this broad review in order to better demonstrate the global incidence of the otherwise rare phenomenon. Putative mechanisms for SR, including immunological, ischemic, and idiopathic modalities, are also explored and discussed in a detailed manner with the hopes of aiding in an understanding of SR as a dynamic interplay of complex and interconnected antitumoral responses.
In general, SR remains a poorly understood and somewhat vaguely defined phenomenon. Our review has multiple limitations. Recognizing true SR as a host response to specific tumors may continue to be obscured by bias in how the regression is reported. In addition to the possible underreporting of cases of SR by certain physicians, there is also a significant amount of variability in how SR is defined. Distinguishing SR from abscopal effects and tumor regression instigated by eradication therapy remains highly subjective and may result in the misreporting of true spontaneous antitumoral host responses to specific cancers. Overall, the literature is quite heterogeneous, and not every case study reported the duration of follow-up or the duration of remission in a similar manner as would be expected in a retrospective review of this kind.

Conclusions
SR is an extremely rare occurrence. Nonetheless, certain recurrent patterns in cases of SR, as demonstrated in this review, deserve ample consideration. To better study SR in the future, there must be an emphasis on standardizing how SR is reported. A well-defined registry would also be helpful. Ultimately, this broadly encompassing yet focused assessment is meant to bring attention to the phenomenon of SR and perhaps aid in the investigative efforts in the burgeoning field of immunotherapies.   Oct;42 (7):1536-9.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.