Hi again ravibattula-ga,
My condolences on your difficult diagnosis. As usual, the following
is not a substitute for medical advice or direct examination and
Having an unknown primary is very difficult to treat, as I'm sure you
know, primarily because treatment regimens are aimed at specific tumor
types. As a bit of an aside, in terms of finding out what the primary
tumor is, a relatively recent modality for detection of tumors is PET
(Positron Emission Tomography).
PET is a nuclear medicine study where a type of sugar is tagged with a
radionuclide. Metabolically active cells preferentially consume sugar
and therefore accumulate radionuclide. PET images these cells and
therefore gives (roughly, not taking various artifacts into
consideration) a map of metabolic activity in the body. It is more
sensitive for detection of cancers than CT alone. Here is a very
compelling case, similar to your case, where PET made a significant
difference in diagnosis and management for a patient with liver
metastases from a primary tumor of unknown origin:
Here is a brief description of a group who examined multiple studies
looking at PET's utility in identifying unknown primary tumors:
The overall sensitivity in this study was 87%, meaning that 87% of
unknown primary tumors were identified. By comparison, CT is about
40% sensitive for detecting unknown primary tumors. Most of the
tumors identified by CT are ovarian.
Dr. Gutzeit, et al., recently published a paper looking at the utility
of PET-CT for detection of tumors of unknown primary. This is a new
modality that combines PET and CT (using a single machine). This was
initially done to provide higher quality PET images, but can also give
anatomic imaging information via CT for better localization of PET
information. Here's their abstract and the reference:
"PURPOSE: To retrospectively evaluate fused positron emission
tomography (PET)/computed tomography (CT) in depicting the primary
lesion in cancer of an unknown primary tumor, compared with PET, CT,
and PET and CT side-by-side evaluation. MATERIALS AND METHODS:
Institutional review board approval and informed consent were
obtained. Forty-five patients (26 men and 19 women) with metastatic
cervical adenopathy (n = 18) or extracervical metastases (n = 27) of
unknown primary tumor were included. The mean age of the patients was
57 years (range, 29-95 years). PET/CT imaging was performed in all
patients 1 hour after administration of 350 MBq of fluorodeoxyglucose
with a whole-body field of view. Contrast agents were administered
orally and intravenously in all patients to ensure diagnostic CT data.
PET/CT data sets were evaluated for the primary tumor, and imaging
results were compared with those of CT, PET, and PET and CT
side-by-side evaluation. Differences in diagnostic performance were
assessed by using the McNemar test with Bonferroni correction, which
accounts for multiple comparisons. RESULTS: PET/CT depicted the
primary tumor in 15 (33%) of 45 patients. In 30 (67%) patients, the
primary tumor site remained occult (P > .05). PET and CT side-by-side
evaluation depicted 13 (29%) of 45 tumors (P > .05). PET alone
revealed the primary tumor in 11 (24%) of 45 patients (P > .05), while
CT alone helped in the correct diagnosis in eight (18%) of 45 patients
(P > .05). There were no significant differences between the
diagnostic accuracies of PET/CT and the other imaging modalities.
CONCLUSION: PET/CT was able to depict more primary tumors, though not
significantly, than either of the other imaging modalities, but larger
patient cohorts are required to finally judge its value for revealing
the primary tumor site."
Gutzeit A. Antoch G. Kuhl H. Egelhof T. Fischer M. Hauth E. Goehde S.
Bockisch A. Debatin J. Freudenberg L. Unknown primary tumors:
detection with dual-modality PET/CT--initial experience. [Journal
Article] Radiology. 234(1):227-34, 2005 Jan.
A reprint can be requested from Dr. Gutzeit:
Please note too that the eMedicine article does not include a good
discussion of PET or PET-CT.
Unknown primary tumors (UPT), aka Cancers of Unknown Primary (CUP),
comprise about 2-4% of all cancers according to one source (see NIH
site below) and 5-15% according to the eMedicine site below.
Here is a nice summary of the condition from eMedicine:
"Tumor of unknown origin is a distinct clinicopathological entity
defined as the presence of a metastatic cancer without a known primary
site of origin. This entity can be diagnosed only if the histology of
the tumor is not consistent with the known tumors of the organ from
which the biopsy was taken.
This entity is a diagnostic dilemma and a therapeutic challenge. It
creates anxiety among not only patients and their families but also
physicians, who feel uncomfortable informing patients that they have
an advanced disease of unknown origin."
The National Cancer Institute summarizes the current thought on the
types of tumors CUP could likely represent:
"The majority of CUP are adenocarcinomas or undifferentiated tumors;
less commonly, squamous cell carcinoma, melanoma, sarcoma, and
neuroendocrine tumors can also present with a primary site of origin
that cannot be determined. In approximately 15% to 25% of patients the
primary site cannot be identified even at postmortem examination."
And further in the article:
"The distribution of primary sites that are likely to result in CUP
contrasts with the distribution of major primary adenocarcinomas as
reported in the Surveillance, Epidemiology, and End Results data. Most
large studies have shown that carcinoma of the lung and pancreas are
the most common primary carcinomas that initially present as CUP.
Other common malignancies such as colorectal, breast, and prostate
cancers infrequently present as CUP.[7-10]"
The above NCI site has a good deal of additional peer-reviewed
information regarding CUP, along with multiple references for more
The following site also has a good deal of information on CUP/UPT,
with a more patient oriented focus:
The above site includes information on alternative therapies.
The NIH Cancer site sums up the current thinking on treatment for CUP as follows:
"CUP is a term that refers to many different cancers. For that reason,
treatment depends on where the cancer is found, what the cancer cells
look like under a microscope, and the patient?s age and overall
physical condition. No method is standard, but chemotherapy, radiation
therapy, hormone therapy, and surgery may be used alone or in
combination to treat patients who have CUP. Even when the cancer is
unlikely to be cured, treatment may help the patient live longer or
improve the patient?s quality of life. However, the potential side
effects of the treatment must be considered along with the potential
eMedicine has an excellent frequently updated article on CUP. Their
site includes details on current treatment options, which I'll talk
One group in Japan tried using two chemotherapy agents (Paclitaxel and
Cisplatin) to treat a group of patients with unfavorable types of CUP.
Here are their results:
"Of the 37 patients, 31 had adenocarcinoma subtypes. The overall
response rate of 26 patients with measurable lesions was 42% [95%
confidence interval (CI) 23?61%]. Stable disease was seen in six
patients and progressive disease in nine. Median time to progression
was 4 months (95% CI 1.3?6.8). Median overall survival was 11 months
(95% CI 8.3?13.5). The major toxicities were neuropathy and
neutropenia. Grade 4 neutropenia occurred in 10 patients, but febrile
neutropenia was seen in four."
The free full text of this article is available:
Treatment of true CUP, where the primary tumor or tumor type is never
identified, is largely based on educated guessing about the primary
tumor type, based on the type of presentation (age, gender, secondary
symptoms, etc.). This approach is somewhat limited in that these
tumors are by their very nature atypical - they metastasize very early
and likely behave atypically from other primary cancers of the same
A recent article gives a good overview of the current means by which
this "educated guessing" takes place, going through the various
presentations that can be encountered and treatment options for each.
Mintzer DM. Warhol M. Martin AM. Greene G. Cancer of unknown primary:
changing approaches. A multidisciplinary case presentation from the
Joan Karnell cancer center of pennsylvania hospital. [Case Reports.
Clinical Conference. Journal Article] Oncologist. 9(3):330-8, 2004.
This article is available for free from this page:
Table 4 of the above article lists the scenarios with the greatest
potential for long-term survival:
"Axillary nodal adenocarcinoma
Unrecognized extragonadal germ cell tumors
Squamous cell cancer involving cervical lymph nodes
Poorly differentiated neuroendocrine carcinoma"
Patients with these so-called "therapy responsive subtypes" of CUP
have the greatest chance at long term survival, which I would include
in the "90% recovery" that you specify. The authors of the above
paper give a somewhat more hopeful view than that held in the past,
particularly because of improved molecular and radiological methods
that help guide the educated guessing portion of the diagnosis, which
then leads to more appropriate treatment and improved survival. Here
is their comment in this regard:
"The scenario of cancer of unknown primary where a lesion was
recognized as cancer but not otherwise discernible as carcinoma,
lymphoma, sarcoma, or melanoma is all but gone. While a few cases may
still defy categorization, the use of immunoperoxidase staining for
keratins, vimentin, and common leukocyte antigen, as well as the
availability of molecular genetic assays for immunoglobulin and T-cell
receptor rearrangements has allowed categorization of most of these
entities to at least a broad group of tumors, helping to focus workup
Additional information on gathering information to narrow the primary
tumor type to help identify therapy responsive subtypes in CUP can be
found in these articles:
Hillen HF. Unknown primary tumours. Postgrad Med J. 2000
Free full text available:
Dennis JL, Hvidsten TR, Wit EC, Komorowski J, Bell AK, Downie I,
Mooney J, Verbeke C, Bellamy C, Keith WN, Oien KA. Markers of
adenocarcinoma characteristic of the site of origin: development of a
diagnostic algorithm. Clin Cancer Res. 2005 May 15;11(10):3766-72.
Full text is not freely available, but a full text reprint can be
requested from Karen Oein (the Principle Investigator):
Based on their algorithm, 88% of these tumors were correctly
classified, which may lead to improved therapy and survival.
While the previous discussion described the patients with the best
chance of greater than 90% recover, or for that matter any significant
response to therapy, it is likely of at least psychological benefit to
know of someone who has survived for a significant period of time.
There is a case report in the literature describing just such an
"An 18-year-old male presented in 1979 with a gastrinoma of unknown
primary origin. Massive upper-digestive haemorrhage led to total
gastrectomy, at which histology evidenced liver metastases, confirmed
9 months later at reoperation for an intestinal occlusion.
Postoperative morphological evidence of liver metastases was
repeatedly negative using abdominal ultrasound and computerized
tomography (CT) scans and magnetic resonance imaging (MRI), but a
recent somatostatin-receptor-specific scintigraphy (Octreoscan) was
positive only in the liver area. Twenty-two years after diagnosis, the
primary tumour has not been identified, the patient leads a normal
life, and his circulating gastrin levels, although still elevated at
317?550 pg/ml (normal < 127 pg/ml), have fallen over recent years from
> 1000 pg/ml. We discuss the relevance of the described prognostic
Webb SM, Mones J. Twenty-two years' survival of metastatic gastrinoma
evidenced recently by somatostatin-receptor-specific scintigraphy.
Eur J Gastroenterol Hepatol. 2002 Mar;14(3):333-6.
The article is not freely available, but you may request a reprint from Dr. MonÚs:
One paper from Ireland looked at CUP with liver metastases found an
almost universally bleak outcome:
"AIM: The objectives of this study were to identify prognostic
features for patients with hepatic metastases and unknown primary
neoplasms (UPN), determine the common primary tumours, assess the
value of diagnostic tests in finding these tumours, and evaluate the
impact of therapy and knowledge of the primary tumour on patient
survival. MATERIALS AND METHODS: Eighty-eight patients with UPN and
liver biopsy proven hepatic metastases over a 10-year period were
reviewed (M:F, 58:30; age range 27-91 years, median 64.5 years).
Histopathology, diagnostic investigations and success at identifying
the primary neoplasm were recorded. In addition, in 70 patients with
adenocarcinoma histology (M:F, 48:22; age range 27-91 years, median 65
years), treatment and survival data from the date of biopsy were
recorded. RESULTS: The histological spectrum included adenocarcinoma
in 70, neuroendocrine in four, squamous cell carcinoma in four, small
cell carcinoma in four, carcinoid in two, hepatoma in one and three
others. Extensive investigation identified a primary neoplasm in 16/88
patients (18%) including colorectal in six, gastric in two, lung in
four, oesophageal in two, prostate in one and carcinoid in one. In the
adenocarcinoma group survival data were available for 62/70 patients.
Sixteen of 62 patients received active treatment with either surgery,
chemotherapy, radiotherapy or a combination protocol. Forty-six of 62
patients received palliative care alone. Median survival for the
adenocarcinoma group overall was 49 days. The median survival for
treated patients (49 days) versus untreated patients (52 days) was not
significantly different (P=0.128). Patients <65 years were more likely
to receive active treatment than those >65 years (P=0.006). Age with a
hazard ratio (HR) of 1.01 (P=0.178), active treatment
(HR=0.65;P=0.194), knowledge of the primary neoplasm (HR=0.60;P=0.213)
and male gender (HR=0.88;P=0.642) had no significant effect on
survival. CONCLUSION: Although hepatic metastases are associated with
poor prognosis, it is essential that a liver biopsy be performed to
obtain a histological diagnosis. Adenocarcinoma metastases carry a
dismal prognosis, and no prognostic factors, including knowledge of
the primary tumour, are significant for patient survival. Extensive
investigation is not warranted in patients with adenocarcinoma liver
I should point out that a median survival of, for example, 49 days in
the treated patients means that half of the patients survived longer
and some may have survived to the end of the studies followup period.
Because CUP is such a heterogeneous mix of diseases, it's hard to
predict who will respond and be in the small group of patients who
respond to therapy. This is why the methods discussed earlier are
important to determine who should be treated.
Hogan BA, Thornton FJ, Brannigan M, Browne TJ, Pender S, O'Kelly P,
Lyon SM, Lee MJ. Hepatic metastases from an unknown primary neoplasm
(UPN): survival, prognostic indicators and value of extensive
investigations. Clin Radiol. 2002 Dec;57(12):1073-7.
A second paper confirms the poor outcome of patients with CUP
metastatic to the liver:
"Carboplatin plus paclitaxel combination chemotherapy is effective in
patients with predominantly nodal/pleural metastases of unknown
primary carcinoma and in women with peritoneal carcinomatosis.
However, in patients with liver, bone, or multiple organ involvement,
the combination offers limited benefit. The investigation of novel
treatment approaches is highly warranted for this group of patients."
Briasoulis E, Kalofonos H, Bafaloukos D, Samantas E, Fountzilas G,
Xiros N, Skarlos D, Christodoulou C, Kosmidis P, Pavlidis N.
Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II
Hellenic Cooperative Oncology Group Study. J Clin Oncol. 2000
Both of these articles are a few years old, and this is a rapidly
progressing field, so I wouldn't take either of these as the final
word on the subject. That being said, the latest treatment
recommendations typically arise from clinical trials investigating
various treatment options (see below).
No alternative therapies have been proven to be effective, which
doesn't mean that they don't work. Here is a site (mentioned above)
that discusses alternative and complimentary therapies for cancer
patients. These are not particularly specific to CUP, but are likely
to be beneficial. There is an increasing amount of data to support
that one's mental state can have an effect on survival, although this
area is research is still developing.
The prognosis of CUP is improving, but is still poor for patients with
CUP metastatic to the liver. The latest treatment options are being
tested for efficacy and toxicity in various clinical trials. Any
future successful treatment regimen is highly likely to originate from
a successful clinical trial. While a therapy is undergoing a clinical
trial, one can't tell if it is effective or not, but the thought of
many patients is that it can't do any harm to try something. One of
the problems is that it's also unknown if some therapy may actually
cause more harm than good, which is why clinical trials are conducted.
That being said, a lot of thought and review goes into the design of
clinical trials to avoid treatment regimens likely to be more harmful
Here is a link to a continuously updated page from the National Cancer
Institute, listing all of the current clinical trials in the country
for patients around the world with CUP:
There are currently 13 trials running, the first 5 are the most
relevant to CUP. Details of each of these trials, along with contact
information, can be found at the above link. Select a study, click
the check box, and then click on "Display Selected Studies."
I hope this information was useful. I wish you the best in the
management and treatment of this difficult condition. Please feel
free to request any clarification.
Search Terms used alone and in combination via Google and the
Ovid/PubMed medical database. Additional references were gleaned from
various bibliographies of papers found using the above resources.