http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380317/
Spontaneous regression of pancreatic cancer: Real or a misdiagnosis?
Abstract
Spontaneous
tumor regression has been subject of numerous studies and speculations
for many years. This phenomenon is exceptional, but well reported, in
some types of tumors, but not in pancreatic cancer. Pancreatic cancer
has the worst five-year survival rate of any cancer. Despite numerous
molecular studies and clinical approaches, using several mouse models,
this cancer responds poorly to the existing chemotherapeutic agents and
progress on treatment remains elusive. Although pancreatic cancer tumors
seldom undergo spontaneous regression, and some authors take that with
skepticism, there are some cases reported in the literature. However,
the variability in the description of the reports and technical details
could make this process susceptible to misdiagnosis. Distinguishing
between different types of pancreatic carcinoma should be taken with
caution as they have wide differences in malignant potential. Diseases
such as pancreatic benign tumors, insulinomas, or autoimmune
pancreatitis could be responsible for this misdiagnosis as a pancreatic
cancer. Here we review different cases reported, their clinical
characteristics, and possible mechanisms leading to spontaneous
regression of pancreatic cancer. We also discuss the possibilities of
misdiagnosis.
Keywords: Autoimmune pancreatitis, Insulinoma, Pancreatic cancer, Pancreatic ductal adenocarcinoma, Spo-ntaneous regression
INTRODUCTION
Spontaneous
tumor regression has been the subject of great interest and speculation
for many years. It is an exceptional and well-documented biological
event in some types of tumors, but not in pancreatic cancer.
Pancreatic cancer is a special form of cancer with the worst five-year survival rate of any cancer[1]. Despite numerous molecular studies and clinical approaches, using several mouse models[2], this cancer responds poorly to the existing chemotherapeutic agents and progress on treatment remains elusive[3].
Pancreatic cancer is seldom described as undergoing spontaneous regression, but there are some cases reported in the literature.
In
this review, the historical background, clinical features, and possible
mechanisms are discussed for spontaneous regression of pancreatic
cancer. In addition, we discuss whether it is a real phenomenon or a
misdiagnosis.
Further understanding of this process and
harnessing of the mechanisms involved will have significant diagnostic,
preventative, and therapeutic implications.
HISTORICAL BACKGROUND AND CASES REPORTED FOR PANCREATIC CANCER
Spontaneous
regression of cancer (SRC) is defined as the partial or complete
disappearance of a malignant tumor in the absence of therapy that is
capable of inducing anti-neoplastic effects. Although SRC has often been
questioned, the literature reveals different cases showing this
phenomenon. In 1966, Everson et al[4] published a classical monograph review describing 176 cases of SRC published from 1900 to 1964. In 1990, Challis et al[5]
reported cases from 1900 to 1987, the majority of which occurred in
renal cell carcinoma, choriocarcinoma, neuroblastoma, melanoma, breast
cancer, and leukemia and lymphomas. Later, in 1993, O’Regan et al[6]
agreed that the five most common tumors to undergo spontaneous
regression are renal cell carcinoma, leukemia and lymphoma,
neuroblastoma, carcinoma of breast and melanoma.
In
these three main reviews, only three cases of pancreatic cancer were
cited, and none of them were described in detail. Here, we review the
most important cases of spontaneous regression of pancreatic cancer that
have been reported in the literature. The first reported case was
described in 1934 and published in 1967, describing a patient admitted
to hospital presenting jaundice, severe pain, nausea, chills, and a high
fever[7].
Laparotomy and biopsy confirmed pancreatic carcinoma. The patient’s
recovery spanned two months, after which she could return to work. She
remained in good health, dying seven and a half years later of a
pulmonary embolism. An autopsy did not find any tumors.
The second case was reported in 1973 by Lokich et al[8]
and described a 42-year-old man with progressive diarrhea and weight
loss. An upper image suggested a mass in the head of the pancreas. The
patient underwent total pancreatectomy and microscopic examination
reveled a moderately well differentiated ductal adenocarcinoma arising
in the head of the pancreas. Adenocarcinoma was also found in the body
of the pancreas, but the tail had only pancreatitis with fibrosis.
Although
the patient was stabilized with insulin treatment, one year later he
presented with rectal carcinomatosis consistent with adenocarcinoma of
pancreatic cancer. Postoperatively, the patient received a combined
chemotherapeutic program based on 5-fluorouracil (5-FU) and carmustine
or bis-chloroethylnitrosourea, experiencing a gradual regression.
Twenty-six months following onset of therapy treatment, there was no
evidence of tumor recurrence.
The third case[9]
was a male with a two-month history of ulcer pain and diarrhea. At
exploration, he was diagnosed with a large tumor of the pancreatic head,
extending into the liver with involved lymph nodes. The disease was
confirmed by biopsy but no further manipulation was performed. By the
fourth month following surgery, he was asymptomatic. Examined six years
later, the patient remained symptom-free and a gastrointestinal exam
demonstrated healing of the ulcer.
The fourth case,
published in 1974, reported one case in 1962 of a 21-year-old male who
presented with jaundice, anorexia, and fever of three months duration[10].
A liver biopsy was followed by abdominal pain, fever, tachycardia, and a
decrease in blood pressure. Exploratory surgery to repair bile
peritonitis revealed acute cholangitis and pericholangitis. When he was
re-operated on seven weeks later, and was diagnosed
with pancreatic adenocarcinoma. A T tube placed in the common duct
improved symptoms and he made a slow recovery with no recurrence at the
time of reporting. Unfortunately, details on the duration and intensity
of fever or infection over the course of the illness in most of these
cases were not provided.
In 2003, Hoption Cann et al[11]
reported a case of a 50-year-old man with a three-month history of
weight loss, anorexia, and discomfort after meals. By ultrasound and
computed tomography (CT) identified a hypoechoic mass of 6.5 cm × 4 cm ×
4 cm in the body of the pancreas. The posterior CT-guided biopsy was
positive for pancreatic adenocarcinoma (T2N1M0, stage IIIb). A
subsequent CT scan revealed a further 50%-60% increase in tumor volume
and the tumor was considered inoperable. The patient received
chemotherapy based on gemcitabine, mytomycin, and radiotherapy. As
CA19-9 levels increased from 38 to 140 U/mL and the patient’s health
declined, the treatment was considered a failure. Some days later, the
patient developed acute abdominal pain and fever and, after surgery, he
had a perforated duodenal ulcer with contamination of the abdomen.
Recovery was considered doubtful. However 90 d later, the patient’s
recuperation and weight gain were surprisingly rapid, while the CA19-9
level was normal and a positron emission tomography (PET) scan was
negative for any focal disease. An ultrasound, however, confirmed
residual tumor, although it had regressed by approximately 70%. However,
five months later, an elevated CA19-9 and subsequent PET scan confirmed
a relapse. Although the patient was treated with chemotherapy based on
oxaliplatin and 5-FU initially, then gemcitabine, his health
progressively deteriorated and he died one year later, almost two years
following his febrile infection.
Apart from the
infection, the authors suggested other factors could be relevant to this
tumor regression. Some of them are the vegetarian diet based on Chinese
herbs, high-dose vitamin C and other antioxidant vitamins, hydrogen
peroxide, and ginseng, followed by this patient. However, regression
presented in this case appeared mostly to coincide with a prolonged
febrile infection, similar to that often observed in many other cases of
SRC[11,12].
BENIGN TUMORS
Some
special types of pancreatic tumors are considered benign or their
malignant potential is not well determined. Specifically,
solid-pseudopapillary tumors are classified in this category and were
often previously described in the literature as being related to
spontaneous regression.
In 2008, Nakahara et al[13]
described a 18-year-old healthy woman who was admitted to hospital for
evaluation of a pancreatic mass. A solid-pseudopapillary tumor was
suspected from the findings of diagnostic images, and surgery was
recommended. However, the patient refused surgery and a later
ultrasound-guided transcutaneous biopsy revealed proliferation of
tumoral cells with small nuclei showing a pseudopapillary arrangement.
periodic acid-Schiff positive granules and alpha-1-antitrypsin positive
cells were proven, which led to confirmed diagnosis of pseudopapillary
pancreatic tumor. The maximum diameter of the tumor gradually decreased
over 10 years from 45 mm to 15 mm. This was the first report describing
marked spontaneous shrinkage of this particular type of pancreatic
tumor. The authors did not report details of whether the patient took
any medication, antioxidant agent, or vitamins.
In this
case, the authors showed histological findings and CT images suggesting
that the shrinkage of the tumor may be attributable to continued
degenerative change, including minor hemorrhage, necrosis, and
absorption as the tumor was classified hypovascular.
In 2010, Suzuki et al[14]
described a 13-year-old boy showing a demarcated hypovascular round
mass of 50 mm in diameter in the head of the pancreas, presenting
abdominal pain, nauseas, and elevated serum amylase and serum lipase. CT
demonstrated a partially enhanced encapsulated tumoral mass with cystic
components and calcification, without evidence of invasion to the
surrounding organs, which was diagnosed as solid pseudopapillary tumor
(SPT) and treated for acute pancreatitis. Six weeks later, the mass had
decreased to 43 mm in diameter, and nine weeks after admission,
concentrations of tumor markers, such as alpha-fetoprotein,
carcinoembryonic antigen, carbohydrate antigen-199, and elastase-I, were
not elevated, although the level of neuron-specific enolase (NSE) was
slightly increased. Follow-up included routine laboratory tests and CT
demonstrated that the size of the tumor slowly decreased to
non-measurable size. After 4 years, the patient’s NSE level was within
the normal range. The authors presented CT images indicating that the
tumor was highly likely to be SPT, based on the typical CT finding of a
tumor bulging from the contour of the pancreas with eggshell-like
calcification, the existence of both solid and cystic components with
hypovascularity, and the patient’s age. The rapid shrinkage of the tumor
may be attributable to continued degenerative changes, including minor
hemorrhage due to trauma, necrosis, and absorption. The authors did not
report the administration of any medication or different agents to the
patient. The authors suggest spontaneous tumor shrinkage, although they
were unable to obtain pathology for the tumor and are conscious that
there have been reports of recurrence and metastasis that developed more
than 10 years after tumor resection in this type of neoplasm.
Considering
all of the cases reported above, we can distinguish a wide variation in
the description of the data presented. The first cases reported, until
1980, do not show images or acute laboratory test results that could
verify the real entity of spontaneous regression of pancreatic
carcinoma. In some cases, they do not specify the type of pancreatic
tumor or give details about the biopsy, making it difficult to determine
if it would be classified as a different entity, based in current
diagnostic criteria.
However, considering the
difference in the availability of medical technology more than 30 years
ago compared with the present, this data should be taken with caution,
and it is difficult to conclude whether these cases would be considered
as genuine spontaneous regression of pancreatic adenocarcinoma today or
would be considered as misdiagnoses.
The most recent
cases, published since 2000, are more accurate in the presentation of
images and blood test values, although they also show variability.
Finally,
the most recent report concludes a diagnosis of SPT and not
adenocarcinoma of pancreas. All of these data show that there are no
recent cases reported of spontaneous regression of adenocarcinoma of the
pancreas, unlike pseudopapillary tumors, which represent 1% of primary
pancreatic tumors and are characterized by low malignant potential[13,14].
Some
other types of pancreatic tumors with spontaneous regression, rather
than adenocarcinomas and peudopapillary tumors, have been described. The
most common neuroendocrine tumor with spontaneous regression is an
insulinoma.
Insulinoma is a rare endocrine tumor
developed from pancreatic beta cells. Eighty-seven percent are benign
tumors, seven percent belong to multiendocrine neoplasia syndrome, and
only six percent are considered malignant, as defined by the presence of
metastasis[15].
The
diagnosis of insulinoma is established by demonstrating inappropriately
high serum insulin concentrations during a spontaneous or induced
episode of hypoglycemia. Imaging techniques are then used to localize
the tumor[16]. In 2008, Groselj et al[17]
described a 64-year-old patient presenting with paroxysmal episodes.
Electroencephalography finding suggested metabolic encephalopathy and
laboratory tests showed hypoglycemia, and high insulin and C-peptide.
Finally, ultrasonography and gagnetic resonance imaging (MRI) confirmed
an insulinoma in the head of the pancreas. The authors pointed out that
the patient had a spontaneous recovery of the pancreatic tumor.
The
overall survival rate of patients with benign insulinoma do not differ
from that expected in the general population, and a misdiagnosis could
be a reasonable justification for reporting SRC, even if it is not
considered a malignant phenotype. Malignant insulinomas are rare, and
patients have prolonged survival, even in the presence of liver or lymph
node metastasis. It has been reported that some patients with malignant
insulinoma who developed metastatic disease 4 years to 12 years after
initial diagnosis, remained alive for up to 25 years[18].
This better outcome compared to the acinar or ductal adenocarcinoma
could be a reason for a misdiagnosis, or it could also be reported as a
spontaneous regression of pancreatic cancer.
AUTOIMMUNE PANCREATITIS MIMICKING PANCREATIC CANCER
Autoimmune pancreatitis (AIP) was described by Sarles et al[19] in 1961 and then proposed by Yoshida et al[20]
in 1995 as a type of chronic pancreatitis occurring secondary to an
autoimmune process, which may cause permanent structural and functional
damage of the pancreas.
AIP represents approximately 6% of the patients with chronic pancreatitis[21,22]
and is a heterogeneous manifestation associated with elevated serum
levels of the immunoglobulin G subtype 4 (IgG4), which decreases with
corticosteroid therapy. The most common site of extrapancreatic
involvement is the bile duct, where distal biliary or mass-forming AIP
mimics pancreatic cancer and proximal biliary involvement[23].
Recently, two types of AIP have been described, type 1 (or
lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic duct
centric pancreatitis or granulocyte epithelial lesion). Although
clinically these two entities have comparable presentations, they differ
significantly in their demography, serological characteristics, other
organ involvement, and relapse rate[24].
While
type 1 is associated with elevation of nonspecific autoantibodies and
serum IgG4 levels, type 2 does not have definitive serologic autoimmune
markers. In addition, high serum IgG4 may also be found in patients with
pancreatic cancer[25], and tumoral markers such as CA19-9, SPAN-1, and DUPAN-2 may also be elevated in patients with AIP[26].
These findings can make the diagnosis of AIP confusing. AIP, in
contrast to other benign chronic pancreatic diseases, can be cured with
immunosuppressant drugs[27]; therefore, the differentiation of AIP from pancreatic cancer is of particular interest in clinical practice[28]. Two studies have also pointed out the possibility that some patients with AIP may develop pancreatic cancer[29,30],
and this contributes to increasing misdiagnosis. However, the
synchronous presence of adenocarcinoma and AIP can not be excluded, as
some cases have been reported[31] and pancreatic cancer can develop after histologically confirmed AIP diagnosis[32].
Attempting to establish applicable diagnostic guidelines, the Japan Pancreas Society[33], the Korean Society[34], and more recently American criteria by Chari et al[24]
in the Mayo Clinic at the Honolulu consensus proposed specific criteria
to distinguished the two histological types of AIP and pancreatic
cancer. The five important diagnostic criteria include imaging,
histology, serology, other organ involvement and response to therapy,
leading to an improvement in the diagnostic yield for AIP and avoidance
of misdiagnosis of pancreatic cancer[35]. Nevertheless, several cases have been reported that suspect pancreatic cancer rather than AIP[36-38].
In 2005, Ozden et al[39]
described a 58-year-old woman with jaundice referred for pancreatic
head carcinoma and diagnosed by MRI. By laparotomy, a pancreatic head
mass involving the mesocolon, pancreatic body, and tail was found.
Pancreatic biopsies revealed cholecystitis and pancreatitis with
lymphoplasmacytic infiltration. Two months after the surgery there was
no parenchymal lesion on MRI. Serum immunoglobulin G, G4, and E levels
were increased.
The authors report this as a
spontaneous regression of a pancreatic head mass and biliary obstruction
because of autoimmune pancreatitis. In this and other cases of a
patient with autoimmune pancreatitis that were initially misdiagnosed as
pancreatic cancer, the response to steroid therapy could appear to be a
spontaneous resolution of a malignant pancreatic tumor. Patients
operated on for pancreatic adenocarcinoma could represent a false
spontaneous regression of pancreatic cancer instead of lack of
malignancy.
MECHANISMS LEADING TO SPONTANEOUS REGRESSION
Most
of the SRC cases reported do not provide a discussion regarding
possible explanatory mechanisms. In pancreatic cancer reports, only the
most recent publications show data in detail (images and laboratory
test) and finally suggest some possible biological mechanisms leading to
the spontaneous regression.
The prevalent hypotheses
regarding mechanisms leading to spontaneous regression include the
immunological response in the host as the most important factor[40-43].
Other mechanisms causing spontaneous regression include increased
apoptosis and necrosis, epigenetic modifications, hormonal responses,
role of oncogenes and tumoral suppressors, cytokines and growth factors,
and psychological mechanisms (Table (Table1).1). All of these mechanisms were reviewed in 1996 by Papac[44], who specifically described some cancers, but not pancreatic tumors.
Possible mechanisms for spontaneous regression in pancreatic cancer
Today, the activation of these mechanisms in spontaneous regression of cancer occurs infrequently[5,40,45,46]
and remains not well documented in pancreatic cancer. In other related
tumors, like hepatocellular carcinoma, several mechanisms leading to the
spontaneous regression of these tumors have been described, such as
abstinence from alcohol[47], persistent fever[48], withdrawal of androgen[49], blood transfusion[50], massive bleeding[51], and use of herbal medicine[52].
However, in the small number of reported pancreatic cancer cases, no
evidence of clear and specific events was observed during the period of
spontaneous regression.
Renal cell carcinoma accounts
for the largest number of patients with spontaneous regression with
acceptable histology and radiological confirmation[53,54];
therefore, this disease offers the best system to study the
immunological response in spontaneous regression. The increased
incidence of some tumors in immunosuppressed individuals, and regression
following reduction of immunosupressive agents, suggests an important
role for immunological factors[55,56]. Cytokines, interferon, and interleukin 2 (IL-2), IL-6 and IL-8[57,58],
exert antitumor effects. While cytokines could activate T-lymphocytes,
natural killer, lymphocyte-activated killer cells, and tumor
infiltrating lymphocyte cells as a mechanism of action, interferons are
capable of multiple immunomodulatory effects, involving monocytes,
macrophages, and B-cells, as well as induction of IL-2 receptors[59,60].
Regression
often occurs in the setting of febrile illness (bacterial or viral),
other, different, cytokines associated with the host response to
infections could mediate the regression as tumor necrosis factors[61].
Patients diagnosed with pancreatic cancer frequently suffer infections
and all of these cytokines could play an important role in the
spontaneous regression of pancreatic cancer; however, there is no
evidence of this phenomena in the literature. Angiogenesis, as an
essential component of the malignant process, has also been investigated
as a mechanism contributing to regression. Several cytokines are known
to inhibit this process, such as tumor necrosis factor-alpha and
transforming growth factor beta, which could play a role in spontaneous
regression[62].
Regarding hormonal mechanisms that could exert a role in pancreatic
cancer, there is no data suggesting specific effects in spontaneous
regression, although studies should be made because the endocrine
pancreas could be exerting an important role.
A
mechanism that has received more attention for spontaneous regression in
the literature is the apoptotic process inside the tumor. The
activation of this programmed cell death was proposed as the basis for
spontaneous regression, especially in neuroblastoma[63]
and renal cell carcinoma. Several authors suggest that the neoplastic
cells, in response to different stimuli, such as T-cell mediated
survival signals or cytokine regulation, could undergo apoptosis,
followed by clinical remission.
As several data have
demonstrated, vascular endothelial growth factor receptor blockade leads
to rapid, robust, and progressive regression of tumor vasculature,
increased intratumoral hypoxia, and apoptosis, and reduced tumor
invasiveness and metastasis in pancreatic islet cancer[64].
Thus, this process could also be implicated in tumor regression. This
apoptotic process is driven by oncogenes and tumoral suppressor gene
expression and, although there is no specific, documented examples on
the role of changes in the expression of regulator genes, this
possibility has been cited in leukemia[65] .
The
expression of these oncogenes or tumoral suppressors could be switched
by mutations and by epigenetic mechanisms, leading to apoptosis inside
the tumor. The cited epigenetic changes have been demonstrated in
retinoblastoma tumors[66] by abnormalities in methylation levels[67].
Some authors have suggested that loss of hypermethylation may be
involved in the spontaneous regression of some retinoblastomas, but
there is no confirmed evidence. In addition, repression of telomerase
activity has been proposed as a possible mechanism for regression[68-70].
Some studies showed that patients whose tumors do not show telomerase
activity underwent spontaneous regression, suggesting repression of
telomerase activity as a possible mechanism for regression, although it
has not yet been demonstrated in any type of pancreatic cancer.
Differentiation,
a mechanism by which malignant cells develop a non-malignant phenotype,
has been shown to occur in several types of cancer, such as
retinoblastoma, neuroblastoma, choriocarcinoma, teratocarcinoma, and
leukemias[71,72],
where differentiation is possibly the major factor contributing to
spontaneous regression, but this is still unknown in pancreatic cancer.
Finally, related to the immunological response in tumors, psychological
mechanisms have been proposed as a possible phenomenon in some cancers,
but this is still regarded with skepticism. Although authors have
reported psychological reasons, corroborating biological studies are
lacking[73,74] and are not approved by most investigators.
This
lack of information forces us to conclude that spontaneous regression
in pancreatic cancer is not a well-documented phenomenon, the mechanisms
leading to the regression remains unknown, and only hypotheses can be
made based on some other types of tumors. In recent reports, where the
radiological and histological confirmation of pancreatic disease are
more precise, only an immunological response has been suggested as the
most probable mechanism leading to regression of pancreatic cancer. Most
of the causative factors leading to this phenomenon remain speculative.
In
conclusion, it is very difficult to determine the characteristics of
pancreatic cancer patients who experience spontaneous regression and the
mechanisms leading to such spontaneous regression.
Currently,
the existence of spontaneous regression of pancreatic cancer is a
matter of debate. The small number of cases cited in the literature as a
possible spontaneous regression could represent a nonmalignant disease,
such as AIP or specific pseudopapillary tumor of the pancreas. In the
cases described many years ago, the data presented make it difficult
evaluate the diagnosis because of the lack of advanced images techniques
or laboratory tests to distinguish pancreatic cancer from other
diseases. In addition, many cases are not completely well documented,
the presence of metastasis is questionable, therapy may have played a
role, or the temporary or permanent regression of tumor growth was not
defined.
Therefore, cases of spontaneous regression of
pancreatic cancer described in the literature should be taken caution.
Biological and molecular findings cannot provide a complete explanation
of the underlying mechanisms and accumulation of such cases and further
investigations of regression will contribute to better understanding of
this intriguing phenomenon.
Elucidation of the
mechanism could lead to better understanding and replication of the
process, and to improved therapies for pancreatic cancer treatment.
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