Causes of death in patients with extranodal cancer of unknown primary: searching for the primary site
Causes of death in patients with extranodal cancer of unknown primary: searching for the primary site
Matias Riihimäki 0 1 3
Akseli Hemminki 2
Kristina Sundquist 0 3 4
Kari Hemminki 0 1 3
0 Center for Primary Health Care Research, Lund University , Malmö , Sweden
1 Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ) , Heidelberg 69120 , Germany
2 Cancer Gene Therapy Group, Transplantation Laboratory & Department of Pathology, Haartman Institute, University of Helsinki , Helsinki 00290 , Finland
3 Center for Primary Health Care Research, Lund University , Malmö , Sweden
4 Stanford Prevention Research Center, Stanford University School of Medicine , Palo Alto, California , USA
Background: Cancer of unknown primary (CUP) is a fatal cancer, accounting for 3-5% of all diagnosed cancers. Finding the primary site is important for therapeutic choices and we believe that the organ which is designated as the cause of death may give clues about the primary site. Methods: A total of 20,570 patients with CUP were identified from the Swedish Family-Cancer Database. Causes of death - as reported in the death certificate - were investigated, analyzing reported metastatic sites and histological subtypes separately. Survival was compared with metastatic cancer with a known primary tumor. Results: An organ-specific cancer could be identified as a cause of death in approximately 60% of all CUP patients with adenocarcinoma or undifferentiated histology. In adenocarcinoma, lung cancer was the most frequent cause of death (20%), followed by pancreatic cancer (14%), and ovarian cancer (11%). Lung cancer was the most common cause of death in patients with CUP metastases diagnosed in the nervous system (69%), respiratory system (53%), and bone (47%), whereas ovarian cancer was the most common cause of death when CUP was diagnosed in the pelvis (47%) or the peritoneum (32%). In CUP diagnosed in the liver, liver and pancreatic cancers accounted for 26% and 22% of deaths, respectively. Also in squamous cell CUP, lung cancer was the most common cause of death (45%). Conclusions: According to the causes of death, the primary site appeared frequently to be either the organ where CUP metastases were diagnosed or an organ which may be traced through the known metastatic patterns of different cancer types.
Cancer of unknown primary; CUP; Cause of death
Cancer of unknown primary (CUP) is a group of cancers,
frequently cited to account for 3–5% of newly diagnosed
]. Despite its high incidence, very little is known
about this challenging entity of cancers. Most patients with
CUP have a dismal prognosis: survival estimates are often
in the magnitude of a few months [
], although it may be
longer in hospital-based studies with selected populations
]. Especially, CUP with metastases in the liver has a
poor prognosis, with patients only surviving a median of
two months [
]. However, some favorable subsets have
been described, such as neuroendocrine CUP, and CUP
limited to lymph nodes [
]. CUP poses a challenge
for the treating physician, because cancer treatment is
typically planned based on the primary tumor; therefore,
upon detection of a metastasis, a wide diagnostic workup
is initiated to detect the primary site [
recent advances in diagnostic modalities, including
imaging techniques, expression profiling, and
immunohistochemical methods, not all primary tumors are found, and
some cancers remain cancers of unknown primary.
Ultimately, in some cases the primary site may be detected by
autopsy, and is then often situated in the lungs or
gastrointestinal system [
]. However, in some cases no
primary is found, presumably reflecting the immunological
eradication of the original tumor subsequent to shedding
Although being a diverse group of cancers, some clinical
features distinguish CUP [
]. The primary tumor has
often regressed, or may even have disappeared.
Furthermore, patients with CUP typically have metastases, and
the disease is often characterized by resistance to
chemotherapy. CUP often displays biological features, such as
]. Furthermore, some metastasis-related
genes are frequently overexpressed, e.g. c-Myc [
], MMPs [
], and VEGF [
]. In family studies, CUP
could be linked with several other cancers, e.g. liver, lung,
pancreas, and ovaries [
]. Another approach has been to
investigate the etiology of CUP utilizing death certificates
of patients with CUP; indeed cancers of the lung, liver,
pancreas, and ovaries are common causes of death after
diagnosis of CUP [
]. In CUP limited to lymph nodes,
lung cancer is the most common specified cancer in death
certificates, especially in CUP detected in thoracic lymph
nodes, which supports the notion that the primary cancer
originates in the lung [
In the present study, we investigated the causes of death
in extranodal CUP, depending on the location of CUP
metastases at diagnosis. Different histological subtypes
were analyzed separately
(adenocarcinoma/undifferentiated cancer, squamous cell cancer, and melanoma). We
allow that the tumor resulting in CUP diagnosis may in
fact be different from the original primary tumor, since
when CUP is diagnosed, the primary is by definition not
known. However, our hypothesis is that the tumor causing
death may in fact represent the original primary tumor
which could not be originally detected with the available
imaging methods. Nevertheless, the primary may have
persisted and ultimately resulted in death. We assumed
that the known metastatic pathways of primary cancers
also apply to the metastatic spreading of CUP. To dissect
our hypothesis, the survival kinetics of patients with CUP
was compared with the survival of patients with known
The dataset used in this study was obtained from the most
recent update of the Swedish Family-Cancer Database
(FCD), which is a national research database located at the
Center for Primary Health Care Research, Malmö, Sweden.
The FCD contains, e.g., cancer data from the Swedish
Cancer Registry and death statistics from the Cause of
Death Registry [
], and has been used in several
population-based studies on CUP [
]. All cancer
cases diagnosed from 1958 through the end of 2010 are
included. The Swedish Cancer Registry, which is based on
the compulsory notification of cancer cases and the
completeness of cancer registration has been approximated to
be over 90% [
CUP cases were identified by their ICD-codes
(International Classification of Disease), as reported in the
Cancer Register. The Cancer Register has used ICD-7
since 1958, ICD-9 since 1987, ICD-O/2 since 1993, and
ICD-O/3 since 2005. All subsequent versions in the
Cancer Register are also translated to older versions, enabling
comparisons over time. ICD-9 coding, and later versions,
allow identification of the site of CUP metastases. The
Cause of Death Registry used ICD-9 coding between 1987
and 1996, and ICD-10 coding since 1997 [
Accordingly, the follow-up time was 1987 through 2010. SAS
software was used for statistical analyses. Kaplan Meier
plots were generated with PROC LIFETEST (SAS Version
9.3; SAS Institute, Cary, NC).
The locations of CUP metastases were identified by
their ICD-9 code: respiratory system (195.1, 197.0-3),
liver (197.7), peritoneum/retroperitoneum (195.2, 197.6),
nervous system (198.3-4), bone (198.5), pelvis (195.3),
other specified (195.0, 4, 5, 8, 9; 198.0-2, 6–9), and
“unspecific cup/CUP C80” (199). ICD-9 and −10 codes 199 and
C80 correspond to unspecified CUP location, both in the
Cancer Registry and the Cause of Death Registry. Primary
cancer sites were identified by their ICD-7 codes, and
histological subtypes were identified by their WHO/HS/
CANC/24.1 (pad) codes. Previous reports have shown that
adenocarcinoma and undifferentiated histology are similar,
thus these two histological types were analyzed together
]. Unspecified and other histological subtypes than
adenocarcinoma/undifferentiated, squamous cell, and
melanoma were not included in the analyses.
A total of 28,419 CUP patients diagnosed between 1987
and 2010 were identified from the FCD. Of these, 26,811
(93%) died during the study period. Adenocarcinoma
was the most common histology (14,947 cases [55.%]),
followed by undifferentiated (4143 cases [15.5%]),
squamous cell (773 cases [2.9%]), and melanoma (707 cases
[2.6%]). Unspecified histology (5185 cases [19.3%]) and
other specified histological subtypes (1,056 cases [3.9%])
were omitted from analyses.
In Table 1, the underlying causes of death in patients
with CUP (adenocarcinoma/undifferentiated) are displayed,
depending on the location of CUP metastases at diagnosis.
Overall, of all specified cancer causes of death, lung cancer
was the most common (20%), followed by pancreatic
cancer (14%), and ovarian cancer (11%). Substantial
differences could be noted in causes of death between different
CUP sites. The most common specific CUP location was
the liver. Of all specified cancer causes of death, the most
common for CUP of liver were cancer of liver (26%),
pancreas (22%), colorectum (13%), and biliary system (13%).
In CUP of the peritoneum, the causes of death were
different: ovarian cancer (32%), pancreatic cancer (16%), and
CUP = Cancer of unknown primary. C80/199 = CUP with unspecified location. The most common cause of death is bolded.
In the present study, we investigated causes of death in
CUP patients. Distinct patterns could be seen in the
causes of death depending on the location of CUP
metastases at diagnosis. Overall, lung cancer was the
most common cause of death when the initial site of
CUP (adenocarcinoma/undifferentiated) was the nervous
system (69%), respiratory system (53%), or bone (47%).
On the other hand, ovarian cancer was a common cause
after diagnosis of CUP in the pelvis (47%) and peritoneum
(32%). We suggest that the cause of death, as determined
in the death certificate, at least for some CUP patients
point to the origin of primary tumor. For CUP diagnosed
in the respiratory system lung and mediastinal cancers
accounted for 79% of specified cancer deaths and survival
curves were identical with primary metastatic lung cancer,
which is compatible with the notion that the primary was
a lung cancer that evaded detection during diagnostic
workup. Similarly, for CUP located in the liver at diagnosis
liver/pancreas/biliary system deaths accounted for 61% of
all specific cancer deaths and survival kinetics were
identical with metastatic liver cancer. Lung cancer deaths in
patients whose CUP was located in the nervous system and
bone is consistent with known metastatic pathways, as are
ovarian cancer deaths with CUP locations of the
peritoneum and pelvis. Thus we suggest that CUP location at
diagnosis should direct a careful search of the primary to
the likely sites defined here. This also has implications
with regard to therapeutic choices.
Many of the patterns seen may be attributed to the
known metastatic pathways [
]. For example, ovarian
cancer frequently metastasizes within the pelvis and the
peritoneum. Pancreatic cancer frequently metastasizes to
the liver. Lung cancer often metastasizes within the
respiratory organs, or to the nervous system and bone. Kidney
cancer (included in “urinary system”) is also known to
metastasize to the skeletal system. Considering the high
incidence of bone metastases among breast and
prostate cancer patients , it may be surprising to note
that breast and prostate cancer are relatively uncommon
causes of death in patients with CUP of bone, compared
with lung cancer. There may be many reasons for this
finding. The development of bone metastases is
influenced by how long the patient lives with the tumor [
and the primary tumor should be detected during that
time. Also, because breast and prostate cancer are
relatively easily detected by mammography and PSA tests, is
seems reasonable to assume that many such tumors
should be correctly diagnosed, and therefore not noted as
CUP. Our results rely heavily on the accuracy of death
certificates in Sweden. Generally, cause of death
coding in Sweden is considered to be reliable, especially
if the underlying cause of death is cancer [
Most cancer deaths occur in hospitals, and regardless
of the location of death regulations specify that the
issuer of the death certificate was either involved in
the treatment of the patient, or profoundly educated
themselves with the medical record. In unclear cases
autopsy has been traditionally employed. Either way,
the issuer of the death certificate has intimate knowledge
of the patient’s medical history including the different
phases of the malignancy.
Notifications of cancer to the Swedish Cancer Registry
require two separate reports, one by a clinician and the
other by a pathologist. CUP is reported if no primary
tumor is found after adequate diagnostic work-up. If a
primary site is found later, CUP diagnosis may be changed
to the true primary [
]. Death registration is a completely
independent process through the Causes of Death
Register. The data are reported by a medically qualified death
registrar who is usually well aware of the clinical course of
the disease because for over 90% of cancer deaths
examination at hospital prior to death was the basis on which the
death certificate was issued [
]. CUP offers a unique
opportunity to monitor the sequence of events from the
hidden primaries to fatal organ metastases because death
certificates give the site of organ metastasis as the cause of
death even if histopathology indicates CUP. This practice
deviates from that of any other cancer for which the
primary cancer is given as the cause of death. Autopsy data
are not used to change CUP diagnosis and nor would they
be helpful because autopsy rates in Sweden have steadily
declined, from 25% in 1987 to 7% in 2010 (women), and
from 33% to 16% (men) [
]. Furthermore, the rate is
lower in cancer patients and elderly. Previous family
studies have shown that the cause of death in patients
with CUP often is the same that is diagnosed in a family
Two classic theories are often used to explain the
metastatic process: the seed and soil hypothesis, and the
anatomical/mechanical hypothesis [
]. The seed and
soil hypothesis stipulates that the interaction between
the tumor cell (“seed”) and the target organ (“soil”) is
important for the development of metastases. This theory
partly explains why some malignancies tend to
metastasize to the same organ where the tumor originated, or to
selected target organs, e.g. breast cancer to the other
breast or to the brain, while prostate cancer is often
multifocal locally or metastatic to the bone. Also, the
anatomical/mechanical hypothesis has shown merit in explaining
metastatic patterns, and can be presumed to be important
in CUP. Due to the portal venous system, it is natural that
the primary cancer in CUP of liver may often be found
within the gastro-intestinal system. In nodal CUP,
anatomical factors may also play an important role
]. In CUP of lymph nodes in the head, neck, or
thoracic region, the most common cause of death was
lung cancer, whereas in axillary lymph node CUP, it was
breast cancer. Although the present results imply that a
primary tumor may be found in patients with CUP, it is
important to remember that initiating excessive diagnostic
maneuvers is not necessarily the best strategy for these
Although the primary site in CUP may be explained
through the metastatic patterns of common cancers, some
evidence points out that the primary tumor in CUP might
in fact reside in the same organ as CUP, or even be the
primary tumor itself. Different explanations supporting
this view have been presented in previous studies. If the
CUP in fact is the primary cancer, the tumor may have
undergone massive phenotypical changes, seeming to be
metastatic tissue, whereby it is not diagnosed as a primary
]. Alternatively, if the hidden primary tumor in
CUP has resided in the same organ as the metastasis,
it may have regressed to an undetectable size, or even
have been eradicated by immune surveillance [
In practice, this has manifested in two ways in previous
epidemiological research: 1) the cause of death in many
patients with CUP may frequently be scored as cancer of
the same organ where CUP was detected [
], and 2)
that CUP confers an increased risk of a second cancer
diagnosis at some locations, including the lung, ovaries,
and kidney, all of them common primary sites for
We have investigated the causes of death in patients with
CUP with the aim to explore the origins of this challenging
disease. In approximately 60% of CUP patients, an
organspecific tumor was listed as the underlying cause of death,
lung cancer being the most common. When CUP was
localized to the nervous system, respiratory system and bone,
the primaries should be preferentially searched in the lung.
In medicine, therapy follows diagnosis and thus even if
primaries are not found, the aforementioned biological
notions have relevance for selecting a therapy for each
patient. When CUP is diagnosed in the peritoneum or
pelvis., even in the primary site cannot be identified, the
initiation therapy targeting ovarian cancer could be considered
]. Although we provide some insight to the conundrum
CUP, further etiological research is motivated. Many
patients with CUP are however elderly, and one must weigh
the possible harmful effects of a prolonged diagnostic
workup in these patients, especially if therapy is unlikely to
result from a more accurate diagnosis [
]. However, in
modern oncology, an increasing number of options are
available to oncologists and thus the possibility of optimal
diagnosis should not be overlooked, as some effective
therapies can be administered with low toxicity.
This study was approved by the ethical committee at
Lund University, Sweden.
The authors declare that they have no competing interests.
KS provided the data. MR and KH designed the study. MR, AH, KS, and KH
interpreted the results. MR drafted the manuscript. All authors helped write
and critically reviewed the manuscript. All authors read and approved the
This work was supported by the German Cancer Aid. The funding sources
had no role in the design or interpretation of the study.
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