Spontaneous regression of pancreatic cancer with liver metastases

Abstract

Spontaneous cancer regression is a rare event, scarcely reported among gastrointestinal malignancies. Pancreatic adenocarcinoma regression has been documented in five previous cases, none of which included liver metastases, and the mechanism by which this occurs is not known. A 56-year-old woman with history of discoid lupus, homocysteinemia and peripheral vascular disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDA) metastatic to the liver. She received palliative chemotherapy with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) for 6 months, complicated by mucositis, diarrhoea, vomiting and two Clostridium difficile colitis episodes. Cancer initially responded to chemotherapy. However, due to substantial toxicities, she decided to discontinue cytotoxic chemotherapy and focus on palliation alone. Thereafter, CT and carbohydrate antigen (CA) 19-9 showed further response and ultimately complete cancer regression that has persisted for 33 months after cessation of chemotherapy. This is the first report in the English literature showing spontaneous regression of a PDA with liver metastases. Two possible mechanisms are proposed: antitumoral autoimmunity and tumour hypoxia related to vascular disease.

Background

Spontaneous cancer regression is a rare but previously reported event for which the mechanism remains elusive. This unusual event is estimated to occur once in every 60 000–100 000 patients with cancer.¹ Spontaneous cancer regression was defined by Cole and Everson in 1966 as the partial or complete disappearance of a malignant tumour without treatment or in the presence of therapy that is considered inadequate to exert a significant influence on neoplastic disease.² Pancreatic cancer (pancreatic ductal adenocarcinoma (PDA)) is the fourth leading cause of cancer-related death in the USA³ and the seventh leading cause of death worldwide.⁴ Despite recent advances in therapy, only 8% of those diagnosed with PDA will survive 5 years and the majority will succumb to their disease within 2 years.⁵

Spontaneous cancer regression has more often been reported in other malignancies, including neuroblastoma with the highest rate of spontaneous regression⁶ malignant melanoma (MM) (up to 50% of primary tumours) and renal cell carcinoma (RCC) (1% of all cases).^{7 8} These malignancies share an immunogenic environment, which is the leading hypothesis for how cancers may independently regress. Pancreatic cancer, however, is not considered an immunogenic malignancy as evidenced by the relatively low mutation burden and lack of response to immuno-oncology therapies.⁹ Among gastrointestinal tract cancers, there are case series reporting spontaneous regression of colorectal and hepatocellular carcinomas (HCCs).^{10 11}

We here report a case of spontaneous regression of stage IV pancreatic ductal adenocarcinoma (PDA) with liver metastases. Additionally, we review all cases of PDA spontaneous regression previously reported in the English literature and consider mechanisms underlying this rare occurrence.

Case presentation

A 56-year-old woman with history of discoid lupus, homocysteinemia and peripheral vascular disease with extensive surgical history of bypass interventions and thrombectomies was diagnosed with stage IV PDA metastatic to the liver in January 2016. She presented with postprandial left upper quadrant abdominal pain radiating to her back associated with nausea and a 17-pound unintentional weight loss.

Investigations

CT scan of the abdomen and pelvis identified a 2.5 cm pancreatic body/tail mass and multiple liver lesions measuring up to 1 cm. Core liver biopsy revealed adenocarcinoma with immunohistochemical stains compatible with pancreaticobiliary primary (figure 1). Tumour genomic profiling identified the following genomic alterations: KRAS G12D mutation, CDKN2A deletion exons 1–3, CDEKN2B exon one truncation, p53 R273C mutation, microsatellite stable and low mutation burden.

Figure 1.

(A) Poorly differentiated adenocarcinoma infiltrating the liver. Normal liver is present at the top edge of the figure H&E, ×10. (B) H&E, ×20. (C) Stains positive for CK7, (D) focally positive for CK20, ×20  and (E) negative for CDX-2, ×20. The findings are not organ specific, but in the context of a known pancreatic mass are compatible with metastatic pancreatic adenocarcinoma.

Treatment

The patient commenced palliative chemotherapy with FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) in March 2016. Her chemotherapy course was complicated by mucositis, diarrhoea and nausea/vomiting for which she was hospitalised, and chemotherapy doses were reduced. Surveillance CT in June 2016 showed response to treatment in both the pancreas and the liver (figure 2), and her carbohydrate antigen (CA) 19-9 tumour biomarker decreased (figure 3). She was hospitalised several times due to diarrhoea, dehydration, syncope, hypotension and delirium. Her course was also complicated by hospitalisations for Clostridium difficile colitis in June and July 2016. By August 2016, the patient decided against further chemotherapy in favour of a palliative approach to her cancer.

Figure 2.

Contrast-enhanced CT scans of the abdomen showing the evolution of liver lesions with treatment. (A) In March 2016 prior to treatment, the lesions (arrows) are irregular and heterogeneously hypoenhancing centrally with surrounding perilesional hepatic hyperenhancement. (B) In June 2016, the two smaller lesions in the lower image appear to have resolved and the largest lesion near the hepatic dome is more regular and homogeneously hypodense (cyst-like) although perilesional hyperenhancement remains at all sites. (C) In February 2018, all of the lesions appear to have resolved and the perilesional hyperenhancement has decreased.

Figure 3.

Trend in CA 19-9 biomarker overtime with clinical events highlighted. PDA, pancreatic ductal adenocarcinoma.

Outcome and follow-up

The patient has been surveilled with history, physical examination, and CA 19-9 every 3 months, and CT every 3–6 months. Despite withholding chemotherapy, her tumour has continued to regress per imaging (figure 2), her CA 19-9 has normalised and her symptoms resolved to baseline functional status. In August 2017, she underwent left femoral artery bypass complicated by local wound infection. Her cancer has not progressed and has in fact regressed during the 33 months since her last dose of cytotoxic chemotherapy. Written informed consent was obtained from the patient and registered in her electronic medical record for publication of this case report and any accompanying images.

Discussion

Spontaneous regression of pancreatic cancer is a very rare event with only five cases reported in the English literature (table 1). As early as 1967, Shapiro¹² reported on complete recovery and autopsy findings with no trace of cancer in a patient with initial diagnosis of inoperable pancreatic carcinoma after exploratory laparotomy and biopsy confirmed diagnosis. In 1971, Eidemiller and colleagues reported on a case of pancreatic cancer with hepatic extension deemed inoperable.¹³ Despite the absence of antineoplastic therapy, the cancer did not progress. In 1974, Tchertkoff et al described an inoperable pancreatic carcinoma that spontaneously regressed following a febrile episode. They suggested an immune reaction to peritonitis triggered this response.¹⁴

Table 1.

Previous cases of pancreatic cancer spontaneous regression reported in the English literature

Author	Year	Sex	Age	Stage	Histology	Proposed mechanism of regression
Shapiro12	1967	F	–	NA	Adenocarcinoma	NA
Eidemiller et al 13	1971	M	–	NA	NA	NA
Tchertkoff et al 14	1974	M	21	NA	Adenocarcinoma	Bacterial infection
Cann et al 15	2004	M	50	III	Adenocarcinoma	Acute febrile response, alternative therapies: Chinese herbs, high-dose vitamin C
Chin et al 16	2017	M	77	IIA	NA	Leucocyte activation, fever, allergenic and hormonal influences

NA, not available.

Immune surveillance was also postulated by Cann et al ¹⁵ who reported on a case of spontaneous regression of locally advanced stage III PDA. This patient was initially treated with gemcitabine and radiation therapy without response. Two months after cessation of therapy, the patient suffered a perforated duodenal ulcer complicated by peritonitis. His CA 19-9 thereafter normalised, and PET-CT was without evidence of cancer activity for 6 months. The authors suggested that innate immunity stimulated by peritumoral infection provoked tumour leucocyte infiltration. This case is similar to our’s in that regression continued following initial response to chemotherapy.

Most recently, Min and colleagues¹⁶ described a case in which a patient with suspected localised pancreatic head PDA underwent carotid endarterectomy as part of his preoperative evaluation, which was in turn complicated by non-ST elevation myocardial infarction (MI). Surgery was postponed, and ultimately CA 19-9 and CT normalised without intervention. An immune mechanism stimulated by the fever and leukocytosis accompanying the MI was proposed.

To our knowledge, the case reported here is the first case of spontaneous regression of metastatic PDA. We hypothesise two principal mechanisms underlying spontaneous regression of this tumour: protective antitumoral immunogenicity and angiogenic effects on the tumour microenvironment.

Protective antitumoral immunogenicity

Three features may have contributed to enhanced antitumoral immunogenicity in this patient. First, she suffered two bouts of C. difficile colitis. In MM, previous studies have suggested that cross-reactivity with pathogenic antigens may lead to molecular mimicry and heightened immunogenicity. Cross-reactivity against melanoma-associated antigens has been exploited in the development of melanoma cancer vaccines.^{7 17–19} Here, either cross-reactivity to antigen-specific targets or generalised immune reaction may have been stimulated by the concurrent infection.^{20 21}

In HCCs, spontaneous tumour regression has been associated with tumour leucocyte infiltration after pyogenic infections associated with elevated interleukin (IL)-18 levels,²² which augments cell-mediated immunity by infiltrating T lymphocytes and natural killers cells.^{23 24} An association between pyogenic infection and spontaneous regression has also been described in haematological malignancies.²⁵

Second, our patient carries a diagnosis of discoid lupus. The presence of autoimmune disease has also been associated with metastatic cancer regression. Melichar and colleagues²⁶ observed that RCC with lung metastases regressed following a flare of psoriasis with psoriatic arthritis. Third, our patient had a history of severe peripheral vascular disease associated with hyperhomocysteinemia. Elevated homocysteine levels are known to stimulate leucocyte recruitment by upregulation of chemoattractant molecules and IL expression.²⁷

Angiogenic effects on the tumour microenvironment

Pancreatic cancer is uniquely characterised by a dense desmoplastic stroma that impairs vascular access to the tumour. The archetypal PDA microenvironment is notably immunosuppressive and hypoxic, characterised by the presence of pancreatic stellate cells and proliferating myofibroblasts that secrete abundant extracellular matrix proteins during tumorigenesis.²⁸ In RCC, vascular interruption of tumour perfusion has been associated with cancer regression. For example, unintentional interruption of tumour blood supply while performing a percutaneous biopsy and prophylactic use of thrombotic agents to prevent postprocedural haemorrhage have both been linked with RCC regression.²⁹ Chronic vascular disease in our patient and her tendency towards thrombi formation may have augmented the already hypoxic environment and thereby reduced nutrient supply to the tumour.

Other mechanisms

Additional mechanisms proposed for spontaneous cancer regression include the abscopal effect of radiation therapy, idiopathic tumour hypoxia, cessation of alcohol consumption and use of herbal medications such as Phellinus linteus, androgen withdrawal and vitamin K administration.¹¹

Learning points.

• Rare cases of spontaneous cancer regression in the absence of antineoplastic therapy have been reported.

• Both autoimmunity and antitumour immunogenicity are mechanisms proposed for this rare finding.

• Vascular disease contributing to antiangiogenic effects may also contribute to spontaneous pancreatic ductal adenocarcinoma (PDA) regression.

• A better understanding of these mechanisms may be used to develop novel treatment approaches for metastatic PDA.