What is Cancer?

The simplest living component of the human body are it's individual living cells. There are many types of cells within the adult body, but they all arose from a single fertilized egg cell implanted in the womb. This cell was "pleuri-potential", meaning it contained all the information necessary to construct a new human body. Astoundingly, every single body cell (except the sperm and egg cells) retains the total amount ("complement") of information to construct a duplicate person! This information is carried by the tiny "genes" in each cell, which are themselves compacted into a substance called "DNA" which forms the 48 chromosomes within every human cell. Normally, much of the genetic information is "masked" within cells as they divide and develop ("differentiate") from previous cells.

Only the information needed to perform their specified function is readily available. This accounts for why cells specialize to become brain, bone, cartilage, muscle and fat cells, for example. Cells themselves are arranged into network structures called "tissues", such as heart tissue, lung tissue, eye tissue and kidney tissue. The blood is a circulating tissue. Furthermore, various tissues can be further combined to form "organs" like the brain, pancreas and larynx (voicebox). Moreover, at a higher level, organs can be integrated into "organ systems" such as the respiratory, digestive, nervous, and reproductive systems. Thus increasing levels of complexity and sophistication are seen as the human develops, but every part of the body can be defined by it's cellular components.

The cells comprising a fledgling human grow very rapidly in the womb, in early childhood, and through puberty. In adulthood, new cells are only formed to replace those which have died from injury, old age or disease. The division of cells to produce new ones is under tight control by the "genes" within each cell. and if they become damaged, the cell may start dividing out of control. Cancer starts in a single cell which has become abnormal. This cells produces millions, and eventually billions, of copies of itself. The copies are called "clones". These clones fail to function as normal esophagus tissue, but instead divert resources from healthy cells to fuel their own growth. When there are about 1 billion cells, they form a clump, or "tumor" 1/2 inch across. A "tumor" merely means a swelling, it can be caused by infection, inflammation, cancer or whatever. If a tumor only grows in it's local area (even very large) but does not have the capacity to spread to distant body areas, it is called "benign" and is not cancer. If, however, the tumor has this ability to spread, it is called "malignant" and this is cancer.

The actual process of spread is called "metastasis", and can occur to any area of the body. It is this ability to spread that makes cancer so dangerous. Patients rarely succumb to the growing tumors themselves. Rather, cancer most commonly kills by causing anemia (lowered red blood cell count), infection (due to a lowered white blood cell count), and bleeding (due to lowered blood platelet count). We also see interference with normal organ functioning, and a general debility arising from malnutrition, dehydration, and multiple metabolic disturbances. While modern medicine can extend the lifespans of most cancer patients by partially correcting these disturbances, only completely eliminating the "malignant clone" of cancerous cells from body will cure the disease. What is Cancer of Unknown Origin?
Every cancer initially arises from somewhere. Usually, the location where the first cells turns malignant ( "transforms") to start a cancer is obvious, since an enlarging tumor becomes apparent there . The location where a cancer first starts is called the "primary site". The cancer then spreads into adjacent tissues by "local extension", that is direct growth from the primary site. An example is a bone tumor extending into the muscle and fat surrounding the bone. Next, the cancer commonly spread into the "lymphatic system" which is comprised of a network of tiny "lymph channels" which drain the tissue fluid with bathes body cells with oxygen and nutrients [there is not a blood vessel connecting to every cell; instead the blood fluid ("plasma") seeps out of the smallest blood cells to supply groups of cells and absorb their waste products, and this fluid is collected by the lymphatic system]. The lymph channels carry their fluid to normally pea-sized "lymph nodes", which are packed with white blood cells.

These lymph nodes tend to occur in clusters, called "glands". They purify the plasma, killing bacteria and trapping cancer cells. When they detect something foreign in the plasma, such as a germ, allergen or cancer cell, these lymph glands swell up ("lymphadenopathy"). As an example, there are about 400 lymph nodes in the neck region and people often note swollen "glands" in their neck with a strep throat. Ultimately, the lymph glands interconnect via lymph channels, and all of the lymph fluid eventually drains back (into the "left thoracic duct" nearby the heart) to rejoin the bloodstream. The point of all this is that cancer can spread from the primary site to local lymph glands ("lymphogenous dissemination") causing them to swell, and then to more distant lymph glands. The lymph glands closest to the primary tumor are called "first eschelon" nodes, and more distant ones are called "secondary nodes" and named by their anatomical location.

Cancer can also spread ("metastasize") from the primary site via the bloodstream, since individuals cancer cells can be sucked ("embolized") into local small blood vessels ("capillaries"). This process is called "hematogenous dissemination", and can spread the cancer to ANY living area of the body. This is basically "seeding" of the cancer to fertile areas where "metastatic tumors" (as distinguished from the initial "primary site") can flourish. Certain areas of the body seem more "receptive" to trapping cancer cells from the bloodstream and promoting their growth. These areas are those that have good blood supply and complex loose fibrous networks that trap cells, such as the lungs, liver, bones, brain and skin. In fact, these environments may prove more hospitable for tumor cell growth than the primary site, resulting in a larger "metastatic tumor burden" (bulk) than the size of the initial tumor! Thus, the more obvious appearance of the cancer may well be to the site(s) of spread, rather than the area it started in. All cancers are described by where they putatively started, and the areas that they have spread to ("involved").

However, in a minority of cancer patients (5 to 10%) not only is the site of spread more evident than the "primary site", but the site of origin is not apparent at all! This is called "Cancer of Unknown Primary", (or "Unknown Origin" or "Occult Carcinoma") and represents a serious dilemma for treatment. Sometimes the "primary site" can be intuited with great accuracy. An example is when the lymph nodes in the armpit ("axilla") only are involved with cancer in a woman with high risk for breast cancer-- the likely origin of the cancer is in the breast on that side of the body, even if nothing shows up on physical exam or mammogram of that breast. On the other hand, sometimes the origin may be very perplexing and nearly impossible to discern, such as when a single lump of non-skin cancer arises on the torso, and could have arisen from any number of inapparent areas. Then the cause ("etiology") of cancer is unknown, and may either become apparent over time, be deduced from medical inquiry, or may never be known. As will be seen, many cancers which are originally classified as "Unknown Origin" will ultimately "declare themselves" with careful investigation, but about 20% will remain unsolved.

The origin of a cancer may be inapparent for several reasons. Firstly, a cancer is not generally detectable with any of our radiology procedures until it is at least 1 cm. in diameter (about 1 billion cells), but it may have spread to a more fertile area for growth before getting this large at the "primary site"-- and thus go unnoticed there. Also, the original cancer site may have outstripped it's blood supply, and died, but managed to "seed" the bloodstream before disappearing in it's primary site. Likewise, immune processes (white blood cells) may have successfully detected and destroyed the cancer when it was small at the primary site, but (unfortunately) not before it had managed to metastasize to an area where the immune system is less effective (i.e. brain or bone). Another possibility is that the whole of the primary cancer "shed" away into the lymph system and bloodstream, simply leaving no remaining cancer cells in it's orginal area. Sometimes the original site of the cancer simply dies ("apoptosis") from genetic instability or other unknown reasons. Finally, there may be tissues in the body in the wrong places (called "ectopic tissues") which resemble normal tissue counterparts, but become cancerous. Thus, tissue resembling the thyroid may be found in the ovary, or resembling bone may be found in the lung. If these abnormal areas become cancerous (as they are prone to do) then we may fruitlessly search the normal area of that tissue (i.e. thyroid or bone) for the primary site-- but there is none to be found. Thus, we can understand why a Cancer of Unknown Primary may or may not eventually have it's area of origin discovered, and also that if we successfully treat the area(s) of metastasis, we may in fact have no cancer cells remaining in the body.

What are the Types of Unknown Primary?

There are basically 4 types of cancer found when a tumor of unknown origin is analyzed, and many subtypes. As we will see, the specific subtype gives important clues as to the origin of the cancer. The basic types of cancer derive from their "normal tissue counterparts"-- that is what usually normal type of cell "transformed" to become cancerous . Again, their are many specialized types of cells in the body and every single one has the potential to turn cancerous, and spread anywhere in the body. However, the 4 types usually identified in cancer of unknown primary are these:

Squamous Cell Carcinoma: Carcinoma means cancer, and "squamous cells" are the lining cells of the body. They make up the skin, lining of the mouth and tongue, anus and vagina. They look like "fried eggs" under the light microscope, with the "yolk" representing the central "nucleus" which contains the genes, and the enclosing edge being the "membrane" which encases and protects the cell. Squamous cells are very resistant to irritation and abrasion, and divide quickly to heal injuries. Thus, cuts and burns in the mouth heal more quickly than any other body tissues. Owing to this resilience of squamous cells, other types of cells, when chronically irritated (as from tobacco smoke) may actually try to turn into squamous cells, a process called "dedifferentiation". Thus many cases of lung cancer (40%) attributed to smoking are of the squamous type. In general, pure squamous cell cancer tends to grow large in it's local area before under- going distant spread, and so is a less common cause for cancer of unknown primary than the other types listed below.

Adenocarcinoma: This is a cancer arising from the cells in the body which form glands, and these are extensively located throughout the lungs, breasts, digestive, urinary and reproductive systems. Any tissue that must stay moist and forms mucous or other fluids has cells which can turn to adenocarcinoma. About 40% of lung cancers, 40% of esophagus cancers, virtually all breast, stomach, pancreas, prostate and uterus cancers are adenocarcinoma. The cells tend to gather to form glands under the microscope, and cancer is deter- mined by a rapid rate of cell division, irregular and dark appearing nuclei, and too many glands trying to form in too small an area of tissue. Adenocarcinoma has more propensity for early spread to distant organs than the squamous cell variety. We usually "grade" the cancer using Roman numerals from I to III, with "grade I" looking very much like the normal tissue and tending to be indolent, and "grade III" looking very malignant under the microscope and tending to be aggressive. "Grade II" looks and tends to act intermediate in behavior. It is also common for "grade I" to be referred to as "well-differentiated", "grade II" to be called "moderately differentiated" and "grade III" to be "poorly differentiated" adenocarcinoma. However, more than one grade may be present in a tumor, in which case it is called "mixed grade". It is also possible for adenocarcinoma to be mixed with squamous cells. If the squamous "component" is malignant, it is called "adenosquamous", and if it is benign, it is called an "acanthoma".

Poorly Differentiated Carinoma or Adenocarcinoma warrants a special category since it is then a lot harder to tell where the cancer arose from, and this is a common cause for cancer of unknown primary. Recall that the more differentiated a cancer is, the more closely it resembles normal tissue, and the more benignly it will behave. In fact, the aggressiveness of "cancer" is on a spectrum, with some tumors (such as pancreas adenocarcinoma) tending to be highly dangerous, and others (like basal cell cancer of the lip) are quite unlikely to be deadly-- even if treatment is delayed. Again, the most aggressive cancers tend to be those which are "poorly differentiated"; they look very little like any normal tissue in the body. The way we normally determine where a cancer has arisen is twofold-- first we look at where the obvious primary tumor is (which we can't easily ascertain in cancer of unknown origin) and then we examine a selection of cells ("biopsy") from the tumor (to see what type of pre-existing normal tissue it arose from. When the cancer is relatively "well differentiated", it is fairly easy for the pathologist to determine what type of normal cell it arose from. Also, it is somewhat more likely for well-differentiated cancers to grow large in their initial area, making the source obvious. On the other hand, "poorly differentiated" can- cers may be so unlike any normal body tissue that even an expert pathologist cannot tell what type of cell it is--- only that it means the criteria for cancer! (i.e. rapid division, irregular nuclei, irregular borders and invasion of nearby normal tissues). Thus, a pathologist may not even be able to tell whether the cancer is squamous cell carcinoma or adenocarcinoma (or of any other type) by looking at it under his classically most important tool-- the light microscope. Then other (newer) types of studies will be necessary to categorize the origin of the cancer.

Other Poorly Differentiated Cancers: While the above mentioned cancers are by far the most common (over 80% of malignancies) there are MANY other subtypes of cancer arising from the specialized cells of the body. Examples include Sarcoma (from structural or soft tissue-- muscle, fat, cartilage, sinew or bone cells), Lymphoma (from white blood cells and immune cells), Germ Cell Cancers (from sperm or egg cells), Melanoma (from pigment cells) and Neuroendocrine Cancers (from brain, nerve, and hormone making tissues). Some areas of the body have specialized types of glandular cells, such as the "transitional" cells of the bladder and the "follicular" and "medullary" cells of the thyroid. Any of these types of cells may look so cancerous that their origin cannot be easily determined. If the cancer failed to thrive in it's initial area, but managed to spread elsewhere, then we have a cancer of unknown origin.

How Common Is Cancer of Unknown Origin?

Initially, there are about 75,000 cases of cancer of unknown primary site each year in the United States, and in 15,000 cases per year the primary site is never identified.

What are the Symptoms and Signs of Cancer of Unknown Primary?

A "symptom" is something that the patient feels, such as headache or fatigue, while a "sign" is something that can be measure by the doctor, such as fever or weight loss. We noted above 4 types of cancer of unknown primary which are distinguished by the pathologist using a light microscope. Each of 4 types has its own particular "presentations"-- that is how it first appears to the physician:

Adenocarcinoma that is "well" or "moderately" differentiated is the commonest (~60%) subtype of cancer in patients with an unknown primary. These patients are usually over 60 years old, and have spread ("metastasis") to multiple areas of the body. The commonest areas are lung, liver, bone and brain. Given the widespread nature of the cancer when it is first detected, and the presumed incurability of the cancer, there is reluctance on the part of physicians to perform extensive tests to determine where the cancer arose from, and thus it remains an "unknown primary" during the patient's lifetime in 80% of cases!

However, if a thorough search is made, either while the patient is alive or after their death (with an autopsy), the "primary site" can be identified in ~75% of patients. Since the cancer typically spreads to so many body areas, there are a myriad of signs and symptoms that the patient may first notice. These include new bone pain from spread to bone (usually spine, pelvic, upper arm, thigh bones and skull, called the "proximal body"-- as opposed to the areas below the elbow and knee, called the "distal extremities"). If the intestinal system is involved, the first signs can be nausea, vomiting, and bowel movement changes presaging a bowel ob- struction by tumor. Liver involvement is shown by dull aching pain in the right upper abdomen (as tumors grow in the liver and stretch it's nerve-rich "capsule") as well as easy bruising, fatigue, skin "spiders" [angiomata], palm redness, yellow eye-white ("scleral icterus") and skin ("jaundice"), itching, and swelling of the whole body ("anasarca")-- ALL signs of progressive liver failure. Usually a person requires only about 10% remaining normal liver to stay alive. Involvement of lung is seen as shortness of breath, wheezing as tumor blocks the lung tubes ("bronchi"), coughing up blood ("hemoptysis") as the tumor invades into blood vessels, and infection ("pneumonia") as the tumor blocks bronchi and traps foul bacteria in them. It is not uncommon for pneumonia to be a first sign, and after the pneumonia "clears" on antibiotics, a remaining "mass" is seen on a chest X-ray-- which proves to be cancer. Brain metastasis manifests as headache (as the brain lining [dura] stretches-- the brain itself feels no pain), visual blurring (as the "cranial nerves" controlling eye movement are stretched), loss of strength in the opposite side of the body (similar to stroke), changes in sensation ("pares- thesias"), poor coordination, short-term memory and judgement lapses. Another area of nervous system invovement is "epidural spinal cord compression", which means the tumor has spread to the spine and is pressing upon the spinal cord. This results in progressive paralysis and loss of sensation under the tumor area which will be permanent unless prompt treatment is obtained (discussed later).

There are some specific presentations of Adenocarcinoma worth mentioning, as their site of origin is often elucidated by past physician experience. The first is if a woman has swollen lymph glands in an armpit ("axilla") but no demonstrable tumor in the breast on that side-- treating such a woman as having "stage II" can- cer of the breast can (with irradiation) can give a 70% survival rate at 10 years if the cancer has not spread elsewhere. If it has, these woman are treated similarly to other metastatic breast cancer patients. The second is if a man has metastatic cancer to bone but no where else-- prostate cancer is strongly suspected. Even if nothing is found on prostate exam or biopsy, hormonal therapy for a metastatic prostate cancer may slow the disease and increase lifespan. The third scenario is when a woman has "peritoneal carcinomatosis"-- that is diffuse spread of the cancerous cells along the inner linings of the abdomen and pelvis. In this case, ovarian cancer is the most likely diagnosis and specific chemotherapy for ovarian cancer (platinum and taxol) may extend lifespan.

The most common origins, however, for adenocarcinoma of unknown primary are from the "aerodigestive tract"-- lung, liver, pancreas, colon and stomach. The chances for prostate, breast, and ovary cancer are actually rare in these patients. Some other origins, especially when lymph nodes are seeded by adenocarinoma, are discussed below under "squamous cell carcinoma".

Poorly Differentiated Cancers (including Adenocarcinoma which was listed separately above) comprise about 30% of total patients; of this 30% about 10% have poorly differentiated adenocarcinoma. The most common origins for this are lung, breast, colon and prostate cancer. The other 20% have a wide variety of other possible cancers. These include sarcoma, lymphoma, kidney, neuroen- docrine, germ cell and melanoma cancers. The most common sites and signs of organ spread are often similar to (1) above. However, there are some crucial differences in evaluating these patients, since we are less certain of even the basic subtype of cancer without further tests. Poorly differentiated cancer are more likely to spread to distant lymph glands, to the upper portion of the chest separating the lungs ( "mediastinum") and to the area along the front portion of the spinal column ("retroperitoneum"). Spread to the mediastinum can show as large "masses" there on Chest X-ray. These can compress the lung bronchi and lead to shortness of breath, the esophagus and lead to difficulty swallowing, as the blood flow back from the upper body, leading to well as facial and arm swelling. Also, vocal cord paralysis can result for a mediastinal mass compress- ing the nerves to the voicebox ("larynx"). Spread to the retroperitoneum can show as back pain, swelling in the lower body from pressure on the large vein (inferior vena cava) returning blood to the heart, and kidney problems from compression of those organs. Poorly differentiated cancer patients tend to be younger than those with well-differentiated cancers, and tolerate treatment better. Moreover, some of the subtypes (i.e. lymphoma and germ cell cancers) have good chance for total cure even when they are widespread ("disseminated") through the body.

They require particular "regimens" of chemotherapy to treat them, and giving this chemotherapy is obviously predicated upon identifying them! Thus, oncologists consider it more important to identify the primary site and specific subtype in patients with poorly differentiated cancers, and have a less fatalistic outlook for many of them than for the other types. This is in spite of the fact that without any treatment, poorly differentiated cancers spread and kill more quickly (see below) than their well differentiated counterparts.

Squamous Cell Carcinoma represents only about 5% of patients with cancer of unknown primary; we had previously said that squamous cancers tend to grow large in their area of origin prior to distant spread. The locations for squamous cell carcinoma tend to be more distinctive, which also accounts for their lesser percentage in making up cancers of unknown origin. If a squamous cell cancer has become widespread through the body, the most likely origin is lung. Also, breast adenocarcinoma in women can undergo "squamous metaplasia" which means that it transforms its appearance to look like squamous cell carcinoma.

More commonly, squamous cell carcinoma is found in a group of lymph nodes in a particular area of the body. The lymph nodes in the upper neck are called the "cervical" nodes (cervical also means neck) and many primary cancers of the head and neck area "drain" to these nodes. Thus, if an thorough search is done (by an otolaryngologist- an "Ears, Nose and Throat" doctor) for the origin of the cancer, it is found in 40% of cases. Usual sites of the primary when upper neck lymph nodes have squamous cell carcinoma are the nasopharyx (area of the uppermost throat behind the nose), tonsils, base of the tongue, and pyriform sinus (a soft tissue recess at the junction of the pharynx and larynx). These sites are often "blind biopsied" (meaning tissue samples are taken of them) during "endoscopy" (flexible light tube visualization) by the otolaryngologist, and this may show the primary site even if no "gross" (visible with the naked eye) tumor is identified. If lymph nodes are found in the lower neck, the source is usually from a lung cancer (recall that 40% of lung cancers are squamous cell carcino- ma) and the same goes for lymph nodes in the area above the collarbone (the "supraclavicular nodes". If the cancerous nodes are found in the left supraclavi- cular area, this is called "Virchow's node" and shows a likely origin in the abdo- minal area, while left armpit nodes ("Irishe's node) are probably from the eso- phagus or anal cancers when involved with squamous cell carcinoma-- or the squamous metaplasia of breast adenocarcinoma mentioned above. Lymph node swelling in the belly button ("umbilical") area is called "Sister Mary Joseph" nodes, and is most likely from ovarian, cervical or vaginal cancer (all pelvic). Of course any of the above nodes may be involved with adenocarcinoma, which is from the same original area but of different cell type. Spread to groin lymph node areas is usually from penile, vaginal, or anal squamous cancer or melanoma.

With any of the above types, as the cancer grows, it depletes the body of nutrients and interferes with normal metabolism. In most patients with advancing cancer, we see weight loss (defined medically as a greater than 10% loss of body weight in 6 months). Also common are Night Sweats (from cancer getting into the bone marrow), Anemia (from lowered red blood cell count), Infections and Fever (from lowered white blood count) and easy bruising and prolonged bleeding time (from lowered platelet count). Nearly universal is a sense of fatigue, and mental depression is also seen. Occult cancer can mimic most any other disease known.

How is Cancer of Unknown Origin Detected and Evaluated?

If a patient comes in with general signs of symptoms of cancer, the extent of the doctor's evaluation will depend upon the general condition and wishes of the patient and family members. Cynically speaking, it may also depend upon how much their Managed Care Organization (HMO) is willing to pay. There is indisputably a big difference between a young mother coming in with some lymph nodes involved with adenocarcinoma in one armpit only, versus a ninety year old patient with Alzheimer's disease and cancer riddling their body. In the past, doctors considered cancer of unknown primary site an almost universally fatal disease, but newer evaluation and treatment methods have determined this to be false. Some bleak statistics for survival in cancer of unknown origin (below) are based upon the past practice of just letting patients pass away, in the belief that nothing could be done. On the other hand, sometimes in truth nothing positive can be done, excepting making the patient comfortble, and invasive, painful and expensive evaluations are unwarranted-- or even cruel. In general, a test should only be ordered if its results may change the treatment. If a patient is to be evaluated for treatment of a cancer of unknown primary site, the following are commonly done:

Full Physical Examination is the least expensive test, and may determine the origin of the cancer. Obviously, if it is not looked for, it probably won't be found. Today's doctors tend to be less skilled in physical examination than the "old school", since with laboratory and radiologic scanning technology many things can now be discovered that previously went unnoticed at physical exam. This has unfortunately led to a complacency about physical exam; less attention is paid to it (compared to when it was really the only diagnostic tool!). The doctor asks about the medical history, fatigue, night sweats and recent weight loss. An exam including digital rectal exam, with the doctor's gloved finger, is imperative. The doctor tests the retained stool on his examining glove for occult blood, which is indicative of many bowel cancers. This test detects prostate enlargement in men, which can indicate either "benign prostatic hypertrophy" ("BPH"), or prostate cancer. For women, it is appropriate to do a full pelvic exam, looking for gyneco- logical cancers. The exam will logically be directed by whether the patient has a localized symptom, such as enlarged glands ("lymph nodes"), or general signs of possible cancer such as fatigue and weight loss only. Checking lymph nodes is of particular value in well or moderately differentiated adenocarcinoma and squamous cell carcinoma. Cancer tends to spread to these glands, and they enlarge ("lymphadenopathy"). Note, however, just having gland enlargement does not prove cancer is causing it, as many infective or inflammatory processes can also cause enlargement. The physician also does a thourough abdominal exam to look for masses or organ swelling (especially in the liver) which may represent cancer spread, and listens for altered bowel sounds which may mean impending obstruction. The lungs are listened to ("auscultated") for wheezing or fluid accumulation-- telltale signs of pneumonia or tumor blocking bronchi. The head and neck are carefully checked, and a "neurological" exam is done looking for changes in strength or sensation, poor coordination, visual, hearing, balance, judgement and memory. Finally, the whole skin surface, nail beds and joints should ideally be checked for metastasis, skin cancer and clues to metabolism.

Laboratory Tests include standard Complete Blood Count ("CBC") that checks red blood cell count, white blood cells count, and platelets. A blood "smear" or "differential"is made and the shape of the blood cells are viewed microscopically. This is the way that particular types of white blood cells are identified. The basic types are lymphocytes (30%), neutrophils (60%), Eosinophils (5%), Monocytes (3%) and Basophils (1%). Signs of infection include multi-segmented areas in the neutrophils, increased percentage of lymphocytes, or "toxic granulation" particles in these cells. Signs of cancer include anemia, which may be of the "iron deficiency" (microcytic--"small red cell") type, normal cell size but too few of them, or large red blood type ("megaloblastic") similar to that seen in vitamin B12 or folate deficiency. The "reticulocyte" count tells how many new red blood cells are being formed by the bone marrow. Also, the actual number or white cells per cubic milliliter of blood is often above or below the normal value (4,000 - 10,000) with cancer. Platelet count is usually low (<150,000) accounting for problems of easy bruising or spontaneous bleeding.

Blood Serum Chemistry Panel ("SMA") which tells blood sodium, potassium, bicarbonate, glucose, cholesterol, and liver and kidney function. Also it tests for calcium, phosphorus and uric acid which may be abnormal, and gives clues if the cancer has gone to bone (by the "alkaline phosphatase" enzyme released from destroyed bone). In more advanced cancer, blood calcium may be high ("hypercalcemia"). Tests of blood clotting ability are PT, PTT, Fibrinogen and Bleeding time. These are especially important if a major surgery is being considered. Many cancers directly or indirectly disturb blood clotting (coagulation) and sometimes reversing these disturbances can extend lifespan. A urinalysis ("UA") tells about infection, blood, sugar or protein in the urine.

Specialized Blood Tests are especially important in poorly differentiated cancers where we have not determined the specific type. These are the "tumor markers" which are characteristically produced by particular cancers. These include:

A. Carcino-Embryonic Antigen ("CEA") for bowel cancers, which is a protein produced by the cancer itself. Unfortunately, it is not specific for the exact type of bowel cancer, nor even always for the presence of cancer at all! However, it is useful to detect recurrence after treatment (if it was elevated before treatment went down with the treatment).

B. CA-125 is commonly elevated in ovarian cancers and those that have spread to the "peritoneum"-- the inner lining membrane of the pelvis and abdomen.

C. Beta-HCG and Alpha Fetoprotein ("AFP") can be high in germ-cell cancers from the ovaries, testicles, or at other locations in the body. AFP is also elevated in many liver cancers.

D. Prostate Specific Antigen ("PSA") is fairly specific for prostate cancer in men and is a routine test in any man older than age 50. E. Amylase and Lipase, and CA-15 are commonly high in pancreas cancer.

Radiology Tests will be determined by the suspected location of the primary, since there are so many of them and they are so expensive it is not feasible to do them all! Also, the "yield" (usefullness) of these tests is fairly limited, since they do not usually detect tumors smaller than 1 cm. (1 billion cells). On the other hand, if lots of tumor is visible in several organs, finding it elsewhere doesn't surprise us and rarely changes therapy (except perhaps for symptom relief). The most routine test is the plain Chest X-ray, to detect large tumors in the lungs, fluid buildup ("effusions") and pneumonia. If tumor origin in the lung is suspected, or spread there is important for therapy, CT scan of the Chest ("thorax") can detect tumor missed on plain X-ray. If CT scan is done for Abdomen or Pelvis, it can also show whether large tumors ("masses") are or enlarged lymph nodes are present.

CT scan with contrast means injecting some "radio-opaque" material into an arm vein, this helps to highlight blood vessels around the tumor and make the scan easier to read. Insist upon "omnipaque" or equivalent contrast, which is more expensive but also more comfortable and less likely to cause an allergic reaction or kidney damage. If something suspicious is seen on a CT scan, the radiologist can often do (a pre-planned) fine-needle sampling of an abnormality to prove or disprove cancer spread there. This procedure is done in the radiology department under local anesthesia, and is ~85% accurate for determining whether cancer has spread to that spot or not. The main risks from fine-needle sampling ("biopsy") of a lung lesion (abnormality) is collapse of the lung, which causes the patient marked shortness of breath. The risk of lung collapse approaches 20% depending upon how experienced the radiologist is. If the lung does collapse, a "chest tube" will need to be placed through a hole made in the chest wall, and suction applied to re-expand the lung. This usually only required an overnight hospital stay, afterwhich the chest-tube is removed. Fine Needle biopsy can also be done for a liver abnormality to "rule-out" cancer there. The main risk of this procedure is excessive bleeding from the liver, if this happens the patient may need emergency surgery to stem to bleeding. Bone can also be fine-needle biopsied, but it is often inconclusive and a larger ("open") surgery is needed to get a bigger sample to tell if cancer is present. The brain may be biopsied by "stereotactic" techniques; a neurosurgeon uses a fine needle coordinated in three dimensions to sample a brain lesion under local anesthesia. This might be done after a brain CT scan or MRI (below) detected a tumor there.

Magnetic Resonance Imaging ("MRI") uses magnetism instead of ionizing radiation and is excellent for showing enlarged lymph nodes and spread into fat or muscle. It can also be given with intravenous contrast ("gadolinium") to highlight the blood vessels and areas of tumor spread, which characteristically have some swelling ("edema") around them well shown by MRI. However, it is about three times as expensive as CT scan (~$1000) and isn't routine. Another non-invasive test is Ultrasound, it uses sound waves to detect tumors and fluid but is not very specific. It is very dependent on the person doing the test, unlike CT scan or MRI. A Bone Scan will often "light up" if cancer has spread to bone, this is used very commonly for suspected breast, prostate, kidney and lung cancers. However, it can also "light up" ("enhance") from trauma or infection. A newer test called a "Positron Emission Tomography" ("PET") scan can help scan the entire body to look for tumor spread, especially when combined with an MRI. It can also be used distinguish dead ("necrotic") tissue from active tumor. If a test will not change the intended therapy depending upon it's result, in general it will not help the patient and should not be ordered .

Biopsy (sampling the cancer) is the most important test in diagnosing any cancer! For cancer of unknown primary site, the easiest and safest metastasis is usually biopsied, such as spread to the skin or a superficial lymph node. As above, needle biopsies of from tumors on deep organs can often be done under CT scan guidance, by the radiologist in their department using a local anesthetic to numb the skin where the needle is put through. Another method to biopsy the "aero-digestive tract" (head and neck, lungs and bowel) is to use a flexible tube ("endoscope") with an internal light source to guide it. Patients are given mild ("twilight") anesthesia (usually with demerol and valium) and the endoscope is guided to the suspicious area. It has a "cutting scissors" on its end so biopsy samples can be taken. For suspected prostate cancer, a "biospy gun" is inserted into the man's rectum (under ultrasound guidance) and multiple samples taken. Stereotactic (3 dimensional) needle samplings ("aspirations") can be done from brain or breast tumors. For gynecological cancers, Pap smears showing a representation of cells from the uterus, cervix and vagina are collected and a full scraping of the uterus ("dilatation and cur- ettage" or "D&C") may be done under general anesthesia. To adequately examine the pelvis those with suspected female cancers, and "exam under anesthesia" ("EUA") may be done by a gynecological oncologist-- a doctor specializing in female cancers. "Washings" of cells from the bladder, lungs or stomach (or drawn out by a needle from peritoneal cavity) can then be sent for "cytology" to look for any malignant cells. If the above methods are incon- clusive in diagnosing whether a tumor seen on scans is malignant, an "open" surgical procedure under general anesthesia may be required. All of the above are meant to get some tissue sample for the pathologist to confirm whether a cancer exists at all. With unknown primary, the next step is determining the type.

Re-Examination of the Biopsy Material is the most important step in determining the origin of the a of cancer with an unknown primary site. To give proper treatment, we must known exactly what we are dealing with. Then we can use the established guidelines for therapy for that particular cancer. With adequate investigation, we can determine the primary site in over 80% of those with an initially unidentified origin. As metioned, there are basically four initial diagnosis using the light microscope (differentiated adenocarcinoma, undiffer- entiated adenocarcinoma, undifferentiated carcinoma, squamous cell carcino- ma). There can be disagreement between pathologists, called "discordance" (averaging 30%) between pathologists looking at the same specimen! There can also be mixtures of types and grades of cancer within specimens. A truly expert pathologist review is the most important diagnositic test in cancer of unknown origin . An expert can derive subtle clues about the structure (called the "archetecture") of the the cancer to determine its origin. When this is not possible by the light microscope alone, other methods are used. These now include "special stains" ("immunostaining") to examine the cells, examples:

Squamous Cell Carcinoma Is "positive" (stains with) "Epithelial" stains including "cytokeratin" and EMA "epithelial membrane antigen".

Adenocarcinoma is positive with various stains depending upon its origin.

A. For breast cancer, we expect positive epithelial stains (above) as well as possible "estrogen receptor" ("ER") and "progesterone receptor" ("PR").
B. For prostate cancer, we expect postive epithelial stains and "PSA"
C. For bowel cancers, we often see staining for intracellular "mucin".

Neuroendocrine tumors like small cell lung cancer, carcinoid, and islet cell tumors of the pancreas commonly stain with "neuron specific enolase" and "chromografin", as well as Epithelial stains.

Melanoma stains with "S-100", "vimentin", and often with "HMB-45" . It is important to note that some melanomas have no pigment ("amelanotic").

Lymphoma commonly stains with "common leukocyte antigen" and "EMA".

Germ Cell Tumors can stain with Epithelial stains, "HCG", and "AFP".

Sarcomas of fat, bone, sinews and cartilage stain with "Vimentin", those of skeletal muscle origin (rhabdomyosarcoma) stain with "Desmin", and those of blood vessel linings (angiosarcoma) stain with "Factor VIII antigen".
It is crucial to note that some stains are more "specific" than others-- for instance the Epithelial stains are seen with many tumors, but help obviate ("rule out") sarcoma, while PSA is very specific for prostate cancer. New stains are being developed every month; "batteries" of multiple staining tests are more specific than individual tests, and also more sensitive (likely to detect something).

Electron Microscopy is an extremely valuable tool in identifying a cancer of unknown primary site. This is particularly helpful in poorly differentiated cancers, but is a specialized test used only if the above tests are inconclusive. Electron Microscopy can tell between poorly differentiated carcinomas, sarcomas and lymphomas, and identify melanomas and neuroendocrine cancers. This is done by looking for "characteristic ultrastructures" in these cancers:

A. Squamous Cell Carcinoma-- identified by finding "cytokeratin filaments" and "desmosomes" within the cytoplasm (cellular fluid), and intracellular bridges.
B. Adenocarcinoma-- "microvilli" (small projections) on the cell surfaces.
C. Sarcoma-- ultrastructural (extremely small) muscle, fat, cartilage fibers.
D. Lymphoma-- Features of white blood cell "lineage" (family classification).
E. Melanoma-- "premelanosome" particles in the cellular fluid.
F.Neuroendocrine tumors-- "neurosecretory granules" in the cellular fluid.

While Electron Microscopy is usefull, it may still fail to distinguish squamous cell carcinoma from adenocarcinoma in the most poorly differentiated cases. Genetic Analysis of chromosomal and (on a finer level) gene abnormalities is the most rapidly advancing way to identify particular cancers. We have discovered that cancer is basically a disease of the genes, where specific ones (termed oncogenes") are inappropriately turned on, or others ("suppressor genes") are inappropriately turned off-- leading to the uncontrolled cell division we call cancer.

Long lists of gene abnormalities ("mutations") associated with various cancers are appearing in the literature, and have been best studied in leukemias, lymphomas, esophagus and lung cancers. We can look for normal chromosome patterns by doing a "Karyotype"-- it costs several hundreds of dollars and shows if the cells have the normal 48 chromosomes (46 general "autosomes" and 2 sex chromosomes). This will tell whether there are breaks in the chromosomes, and whether a piece of one has become glued onto another ("translocation"). Examples include the "Philadelphia Chromosome" (translocation between #9 and #22) seen with chronic myelogenous leukemia and some acute lymphocytic leukemias. Finding other translocations such as between chromosome #8 and #14 is proof of lymphoma when other immunoglobulin "surface protein markers" are present. This is important in cancer of unknown type since lymphoma is often a very treatable disease. On a finer level, we can look at the actual genes for evidence of oncogenes and suppressor genes, examples include the p-53 suppressor inactivation, and c-MYC, RAS, BCA-1 seen in many breast cancer. This method of identification is not yet specific and is still in its infancy, however.

Despite all of the above technology, often the best way to diagnose the origin of a cancer of unknown primary site is by having an astute, experienced pathologist review the biopsy slides under the light microscope in conjunction with a "clinical correlation"-- that is consideration of the patient's particular "presentation" of signs and symptoms. The expert pathologists opinion may be bases upon "gut feeling" as well as concrete information, and this is what makes pathology an art as well as a clinical science! Confident pathologists are not bashful about sending their slides (and opinion) to another pathologist for confirmation or contradiction.

Miscellaneous Tests may be ordered to see how well the patient will tolerate a major surgery. An Electrocardiogram ( "EKG") is standard before any surgery, to see if there is recent heart damage. Further heart studies may include a "Thallium Scan" combined with a treadmill test to see how well the heart muscle is getting oxygen, and if any portions of it have died in a prior heart attack. "Echocardiogram" is basically a very fancy way of listening to the heart using ultrasound instead of a stethoscope, when combined with "Doppler" flow imaging it tells about condition of the heart valves (whether there is any backflow or leakage -- "regurgitation" or "incompentcy"). Lung ("pumonary function") tests including the Forced Expiratory Volume ("FEV") and "Vital Capacity" tell how well the lungs are taking in new air and forcing out used air. An "Arterial Blood Gas" is a blood sample taken out of an artery (usually in the wrist) and analyzed for oxygen and carbon dioxide content, to see how well the oxygen being drawn into the lungs is passing into the blood. Again, every test ordered should have a justification, and should be able to change the planned therapy depending upon its result.

What is the Survival from Cancer of Unknown Origin?

This depends upon many factors, including what type of cancer is present, the age and condition of the patient, the extent of the cancer, and the treatment selected. The "textbook" numbers for surivals are artificially low since many patients are elderly, have other severe medical conditions, and are not treated aggressively. In looking at the below numbers, it is important to remember that many patients do much better:

Adenocarcinoma, Well or Moderately Differentiated-- Long term survival averages 15%, and average survival is 6 months.

Poorly Differentiated Carcinoma: Long term survival averages 10%, and average survival is just 2 months (without aggressive therapy).

Squamous Cell Carcinoma: Long term survival averages 30%, and the average survival is 18 months.

The above numbers, based upon historical averages, are frankly bleak, and help explain while so many physicians have a nihilistic attitude toward cancer of unknown primary site. However, many patients who do not have extensive cancer, or who have a treatable subtype, are alive and well 10 or 20 years after diagnosis! There are lots of patients in whom a fatalistic view of their chances for prolonged survival is just not justified, and who will live out normal lifespans if their cancer is properly treated. In general, survivals for patients with cancers of unknown primary site have been increasing, and this is not fairly reflected in the above abysmal statistics. Furthermore, many patients live many years with a diagnosis of "incurable cancer".

Treatment of Cancer of Unknown Primary Site

In contrast to other cancer topics, the bulk of important information for cancer of unknown primary site is not the treatment, but the discovery of what type of cancer we are actually dealing with. As mentioned, in over 80% of cases careful exam and evaluation can elucidate the particular subtype of cancer and the original site it arose from. Once we known what the patient actually has, we can treat using the guidelines established for the cancer, including its Latest Effective Treatment. There are some classical cases of unknown primary that, when treated as though the site were known, lead to prolonged survivals for many patients, and even some cures:

A. Women with Armpit ( "Axillary") lymph node metastasis only may be treated as local breast cancer (Stage II), and if there are more distant sites of spread than as metastatic breast cancer (Stage IV). If the breast on the same side (ipsilateral) is removed with a modified radical mastectomy, an "occult" (too small to be seen by physical exam or scans) breast cancer is seen in about 60% of patients. The patient probably get chemotherapy as appropriate for breast cancer (see related CancerAnswers Transcript) and possibly Radiation Therapy. If the cancer has spread to other locations, hormonal therapy will be used.

B. Men over 50 years old with cancer metastatic to bone should be strongly suspected of having prostate cancer, and hormonal therapy can provide symptom relief and possibly prolong life, as related in that CancerAnswers Transcript.

C. Women with cancer spread along the lining of the abdomen and pelvis, that is the "peritoneum", should be suspected of having ovarian cancer, they can be treated and occasionally cured by using chemotherapy with Platinum and Taxol.

D. Patients with Squamous Cell Cancer in the upper neck ( "cervical") lymph nodes are suspected of having a "head and neck" primary, especially if they have been long time users of alcohol and tobacco. With bulky disease (over 2 centimeters) in the neck a surgical "dissection" is performed to remove the cancer, and all patients will get radiation therapy. Up to 40% of patients will have the primary site discovered, it others it is presumably annihilated the the radiation therapy. The question is how far to extend the field of irradiation, since it may arise from as high up as the nasopharynx (behind the nose) or as low as the subglottis (under the vocal cords) When the commonest areas for origin of head and neck cancer are treated aggressively , survival at 5 years averages about 50%.

E. Patients with Squamous Cell OR Adenocarcinoma in the lower neck lymph nodes ( "lower jugular") or those above the collarbones ("supraclavicular") often have the lung as the site of cancer origin. Since lung cancer is an aggressive disease, these patients do not do as well with local therapy to the lymph nodes as those with cancer arising from the head and neck. Just treating the involved lymph nodes leads to about 15% 5 year survival, so this may justify doing something to treat the presumed occult site in the lung. This would be chemotherapy (we can not irradiate the entire lung with high enough doses to kill cancer without fatally injuring the patient). Giving the agents 5-FU and Cisplatinum) commonly used for lung cancer does apparently raise the survival of these patients to about 25- 30% at 5 years, and so is reasonable for the patient in otherwise good health who wishes aggressive therapy.

F. Patients with cancer spread to Groin lymph nodes usually have an origin in the anal or genital areas. If these patients have the groin lymph nodes removed, and radiation is given afterward to the groin and pelvis (which includes the anal area) over 30% of these patients will still be alive at 5 years.

Remember than the above survivals are actually better than they may appear, since many patients are elderly or sick with other "co-morbid" conditions (i.e. heart or kidney problems) and so actually die of something other than cancer within 5 years. When the pathologic studies identify a particular cancer (i.e. germ cell cancer, lymphoma, sarcoma) then appropriate therapy can be given. However, sometimes it happens that we are just unable to identify the type and origin of an undifferentiated cancer. In these cases it is important to look at the age, work and habits of the patient, as well as their family history of cancers. Very poorly differentiated cancers often originate from the lung, and may be treatable with chemotherapy similar to that used for Small Cell lung cancer. Also, breast cancer may take on squamous characteristics as it spreads, but still be treatable as a breast primary (with chemotherapy and hormones). Some patients will have there entire "workup" unrevealing ("negative") but still want treatment for a cancer of unknown origin. Besides the local treatment (i.e. surgery and/or irradiation) to remove the site of spread, we can give patients who tolerate it chemotherapy.

[Note-- doctors don't commonly treat the local site of spread when it is to bone without symptoms, since this is not shown to improve survival].

Chemotherapy has been featured in several large studies based upon giving Platinum to patients with cancer of unknown origin. Especially well known was a study at Vanderbuilt University Medical Center where 220 patients were treated with chemotherapy. Various "regimens" were used including mixtures of Cisplatin, Adriamycin, Vinblastine, Bleomycin or Etoposide. A "Complete Response" (no detectable tumor remaining) was seen in 26% of patients with Cisplatin based therapy, while an additional 36% had a "Partial Response" (some resolution of tumor, or at least no further growth). Thirty two of the patients (16%) were apparently cured by the chemotherapy, having no detectable disease over 5 years later. If patients went over 24 months without signs of cancer return, the chance for cure was over 90%. Other series of patients have shown even higher survival at 5 years (i.e. >40%) and of patients who get a "Complete Response", about 70% live 10 years. So, chemotherapy is an important option for patients with a cancer of undetermined origin. It is recommended (from results at M.D. Anderson Cancer Center, Vanderbuilt, Europe) that patients get a regimen that contains Platinum and Etoposide, and possibly other drugs as "combination chemotherapy".

It is important to note that the usual chemotherapy given is the standard 6 monthly cycles; there is not current evidence that longer treatment with "Maintainance" chemotherapy further improves survival (but it certainly increases side-effects). In general, patients with the site of unknown primary in lymph nodes, retroperitoneum, and pelvis do best, and up to 45% percent of those with lymph node disease only are still alive at 5 years in collected series. If spread is to the lung, liver or brain, survival is less but many of these patients can still have substantial and prolonged quality of life with palliative (symptom relieving) treatment. CancerAnswers has an In-Depth Transcript on Symptom Relief and Chemotherapy available through our Web Site.

Conclusion

The most important factor for cancer of unknown origin is doing a thorough investigation to classify the type of cancer and determine the origin, so that appropriate treatment can be given. Even for those in whom no "primary site" can be found, modern chemotherapy battles the disease in most patients and will cure an increasing minority. Some luckier patients will be found to have an aggressive lymphoma or germ cell cancer that can usually be cured with appropriate chemotherapy. However, survivals have been increasing for all patients using modern irradiation and chemotherapy, and do not justify the "give up" attitude that even many physicians have held until recently. New investigations into substances that block tumor blood vessel growth ("angiostatin and endostatin") may soon be curing bulky tumors that we now cannot properly treat. The patient who wishes to be aggressive should make sure this is communicated to their oncologist, and that their doctor is up to date on the recent advances in identifying and treating this disease. In general, the current prospects for patients with cancer of unknown primary site are better now than ever before, and improving for both longevity and quality of life.

This is the full transcript, offered freely in the spirit of internet sharing, of CancerAnswers' report on Cancer of an Unknown Origin. Much more, including latest additional treatments for Cancer of Unknown Origin can be found on our order page. Thank you for using CancerAnswers as your information resource.