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Part I

Cardinal Manifestations
1
Cardinal Manifestations of Cancer
James F. Holland, MD, ScD(hc)

Cancer is a singular word that embraces a vast sibility of adherence, extravasation, and colo- the affected structure or organ. Nearly all the
diversity of diseases that can occur in any organ nization can occur, establishing metastases. In symptoms that can be caused by cancer can also
system throughout the animal kingdom. The the absence of an intervening event, and given be caused more commonly by noncancerous dis-
unique characteristic of cancer is the prolifera- enough time, with few exceptions, the cancer eases. The astute clinician must include cancer in
tion of cells of a type different from, if ever so process, as described, can lead to such anatomic the differential diagnosis of virtually every
slightly, the normal complement of the organism. or functional distortions that death ensues. symptom, albeit a benign disease may usually
The proliferation may be rapid or slow, the accu- The cancer process does not start with a fully explain it. Doctors never diagnose diseases they
mulation of cells may be massive or miniscule. invasive cancer cell. A disorder in molecular don’t think of. Cancers occur at any age. A
The essence of the matter, however, is that aber- instructions for protein synthesis is the common longer life span provides greater opportunity for
rant cells, distinct from the ordinary evolution of precursor lesion, nearly always because of quali- intrinsic organic events or an encounter with
cell types, appear and accumulate. Thus, a cancer tatively or quantitatively aberrant ribonucleic environmental carcinogens, however, and greater
differs from hypertrophy and hyperplasia, which acid (RNA) messages transcribed from nuclear opportunity for initial DNA mutations to be fully
involve normal cells. deoxyribonucleic acid (DNA). This occurs realized as invasive cancers. Thus age is the prin-
A cancer cell does not obey the complex rules because of a mutation of the DNA, or because of cipal risk factor for most, but not all, cancers.
of architecture and function that govern the usual overexpression of particular genes that encode Such common symptoms as sore throat,
placement and behavior of cells within a tissue. for proteins important as catalysts in pathways for runny nose, or a chest cold can sometimes be a
The wondrous coexistence of cells and tissues of stimulating growth, or because of underexpres- result of cancers of pharynx, sinuses, or bronchi,
multiple types that make up the eye, the finger, or sion of genes whose coded proteins control and respectively. Indeed, patients with these cancer
the kidney, for example, each with appropriate inhibit growth. Portions of genes may be lost, diagnoses usually have been treated, often repeat-
anatomic location, all connections intact to fulfill translocated, or amplified. Indeed, entire chromo- edly and for extended periods, for the benign dis-
their appointed tasks, is part of the miracle we somes may be deleted, replicated, or fused in ease because the more formidable diagnosis was
call life. The explanation for this marvelous orga- abnormal ways. All such distortions of DNA can not considered in the differential diagnosis, and
nization is the field of continuing exploration give rise to abnormal or unbalanced RNA mes- thus appropriate observations were not made.
seeking the messages and exquisite controls that sages, leading to qualitative or quantitative differ- Cancer symptoms often seem commonplace,
exist in multicellular organisms. Some believe ences in proteins that result in disordered cellular such as diarrhea, constipation, or mild pain. They
the ultimate explanations will be discovered not function. Sometimes the functional abnormality may often be intermittent, with spontaneous tem-
in science, but in the field of religion. is so extreme as to be lethal, initiating the suicidal porary improvement, a phenomenon that is usu-
Cancer is distinguished from other abnormal mechanism of apoptosis. In other instances, the ally misinterpreted by patients and often by
cellular growths that lead to benign tumors in functional abnormality results in disease. Some physicians as evidence against the diagnosis of
their characteristic independence from the of these diseases display the characteristics of cancer. In fact, recurrent appearance or chronic-
restrictions present in normal tissues. Benign cancer. Mutation, overexpression, and underex- ity of a symptom which in short duration is char-
tumors expand and compress, but do not attack pression of genes can result from a wide spec- acteristic of a common benign disease markedly
or invade adjacent tissues. Accumulated cancer trum of intrinsic and extrinsic causes, with vari- heightens the possibility of an underlying dys-
cells make a tissue that ignores the anatomic bar- ous pathways that lead not to one final common function caused by cancer.
riers of adjacent basement membranes. Through pathway, but by several converging routes to cells Cancers cause their symptoms by a few read-
chemical and mechanical means, the cancer cell with the phenotypic characteristics of cancer. ily understandable mechanisms.
insinuates itself between and into the space of the When these cells are limited to the epithelial layer
normal cells, killing them by chemical and phys- above the basement membrane, they are called 1. A tumor mass grows to such size that it
ical means, the grand usurper. Even though the carcinoma-in-situ or intraepithelial neoplasia. partially or completely occludes an essen-
placenta in mammals shows this behavior, there Similar changes probably occur, but are more dif- tial conduit. Classic presentations are
is self-limitation in location and in survival of the ficult to recognize, in the mesenchymal tissues. cancer of the bronchus where partial
placental invasion. Although leukocytes nor- Even cancer cells that do not penetrate the base- bronchial occlusion causes cough, dimin-
mally extravasate and permeate tissues, they do ment membrane, and thus lack one of the cardinal ishes ciliary clearance of secretion, and
not share the other characteristics of cancer. The features of true cancer, represent a long series of sometimes leads to bronchopneumonia.
cancer cell is partially or absolutely insensitive to antecedent molecular abnormalities that eventu- Complete bronchial occlusion leads to
such normal constraints, and may continue its ally lead to this optically recognizable cellular atelectasis and chronic pneumonia. Com-
invasiveness indefinitely. change. Furthermore, these evolving cancer cells promise of the esophageal lumen by
Upon reaching a circulatory conduit, either a are the common, if not the exclusive, precursor of tumor mass or muscular dysfunction
lymphatic or capillary vessel, a process that may invasive cancer, resulting from infiltration causes dyspha-
not be entirely haphazard, cancer cells often pen- In their earliest stages, as proliferating cells gia, which, in its early presentation, is far
etrate the wall as part of their invasive behavior. accumulate, cancers are almost always asymp- too often attributed to benign cause. Gas-
They then may be carried by the lymphatic or tomatic. Cancers cause symptoms as they tric tumors rarely cause complete
venous circulation to remote sites where the pos- advance because of change in normal function of obstruction, but often impair normal gas-
4 SECTION 1 / Cancer Biology

tric motility. This defect may lead to easy ally presents as a mass, and uncommonly ing, although any vaginal bleeding outside
satiety, anorexia, indigestion, and nausea. this results in hypothyroid laboratory val- the normal menstrual cycle is worthy of
Decrease in caliber of the transverse and ues, but rarely in clinical hypothyroidism. suspicion. Contact bleeding during inter-
descending colon, sigmoid or rectum by A sarcoma of the soft tissues usually course is suggestive of cervical ulceration,
tumor mass can lead to change in bowel presents as a palpable mass. Testicular most commonly a result of cancer.
habit, including diminished caliber of cancer ordinarily presents as a mass: the
stools, constipation and/or diarrhea, and testicle may only be slightly larger than its 4. Pain is commonly thought of as a surrogate
bouts of cramps from peristaltic efforts of fellow, but harder and heavier in the for cancer, although this is mistaken. Most
the proximal gut. examiner’s hand. Ovarian cancer may be cancers are initially painless. Pain occurs
detected as an adnexal mass. when a tumor invades, presses on, or
Compromise of the lumen of the common A new lump or mass, or a changing stretches a nerve, or when proximal
bile duct by carcinoma of the head of the one, requires exclusion of cancer based on smooth muscle contracts in an attempt to
pancreas or of the bile duct itself pro- clinical examination, imaging studies, or a bypass an obstructed or dysfunctional dis-
duces obstructive jaundice, not infre- biopsy. Most lipomas, and the self-discov- tal segment of a conduit. Most pains of
quently after minor antecedent digestive ery of the xiphoid, are two types of lumps short duration that disappear are not
complaints. that can usually be dismissed on clinical caused by cancer. Cancer must enter the
Ureteral obstruction by compression grounds. A dominant breast mass or even differential diagnosis, however, when pain
from retroperitoneal masses or bladder a questionable one, requires assessment is recurrent or persistent without ready
tumor leads to hydroureter and hydro- by appropriate imaging, and often by cyto- explanation, or atypical, or present when
nephrosis, often asymptomatic or revealed logic means. A thyroid nodule, an there is no other recognizable cause. New
by vague discomfort in flank or loin, or by enlarged lymph node that is hard, a node pain, not necessarily severe, must be care-
urinary tract infection. Bilateral obstruc- that remains enlarged without infectious fully interpreted. Abdominal pain and
tion leads to uremia with its protean symp- explanation for 2 weeks, a skin mass with skeletal pain distinct from joint symp-
tomatology. Compromise of the urethra as the characteristics of melanoma or carci- tomatology deserve particular attention,
it courses through the prostate causes noma, especially if ulcerated, a new sub- and early rather than late studies to estab-
diminished urinary stream, inadequate cutaneous or abdominal or scrotal mass all lish a cause. Pain in a breast mass does not
bladder emptying, frequency, urgency, require consideration of cancer and appro- exclude its being cancer.
nocturia, and when severe, obstructive priate diagnostic study. 5. Unexplained weight loss may first indi-
uropathy and uremia. cate an unsuspected cancer, and when
Tumors in the cecum and ascending 3. Ulceration on the skin or on an epithelial combined with grumbling low grade dis-
colon and in the urinary bladder, because surface, can lead to blood loss and occa- comforts, malaise, and fatigue, is a cause
their content is not solid and because of sionally can serve as a portal of infection. for particular scrutiny. A wide variety of
greater luminal diameter, uncommonly Skin ulcerations are commonly ignored other diseases can also cause these com-
cause obstruction, but may distort nor- for weeks or months and are often inter- mon symptoms, but that does not justify
mal function enough to alter bowel or preted as a common injury of unremem- relegating cancer to the bottom of the list
urinary habits. bered origin that did not heal. in seeking a cause. A second complete
history and physical examination after a
2. A mass discovered by palpation or x-ray Bronchial ulceration results in hemopty- short interval is imperative if a diagnosis
may be a presenting finding, as in breast sis, usually blood-tinged sputum, and is not established after initial studies.
carcinoma. Dysfunction from replace- only rarely massive bleeding. Any of the 6. Pleural or pericardial effusion caused by
ment of the substance of a parenchyma- upper alimentary canal cancers can ulcer- cancer can lead to dyspnea and discom-
tous organ by tumor is a subset of mass ate and bleed. Usually the bleeding is fort. Increasing abdominal girth, often
presentation The classic example is pri- slow, intermittent, and silent, leading to with malaise, constipation, and weight
mary or, more commonly, metastatic brain iron-deficiency anemia. Hematemesis or gain, is a cardinal symptom of ascites. In
tumor, which becomes identified by massive melena is uncommon. Carcino- the thorax, bronchogenic carcinoma,
abnormal brain function. Seizure or paral- mas of the cecum and ascending colon mesothelioma, metastatic breast or ovar-
ysis, sensory or coordination abnormality, often present as anemia because of ulcer- ian cancer, and primary carcinoma of
memory defect, and personality change ation and bleeding. “Cranberry” stools serous membranes are the frequent causes
may all be consequences of space occupa- are occasionally reported, but more often, of malignant effusion. Ascites as a pre-
tion. These changes may occur not only symptoms of unexplained anemia are the senting symptom is characteristic of ovar-
because a specific area of the brain is clinical presentation. ian cancer and cancer of the serous mem-
affected, but because of calvaria, owing to Carcinoma of the bladder and carci- branes. Pancreatic cancer, mesothelioma,
intracranial pressure. Similar dysfunction noma of the kidney often present metastatic carcinoma of the liver and sev-
of the spinal cord with distal motor and because of hematuria. Sometimes this is eral nonneoplastic diseases also enter the
sensory phenomena can reflect space fortuitously discovered as a microscopic differential diagnosis.
occupation. Bilateral girdle pain is always or chemical abnormality on routine uri- 7. Invasion of the wall of a hollow viscus
suspicious of spinal cord tumor. nalysis. Clots from renal bleeding can can lead to perforation. Cancer is not sus-
lead to concomitant ureteral colic. pected in most cases when this rare event
Hepatic dysfunction by space occupation Hematuria less often heralds prostate occurs. Pneumothorax from perforation
from primary or metastatic tumor, often cancer, but hematospermia implies of the pleura by a primary or metastatic
with related intrahepatic bile duct com- prostate disease, carcinoma, or benign pulmonary tumor is an uncommon emer-
pression, can present as jaundice. Some- hyperplasia, because carcinoma of the gency. Fistulization of gastric cancer into
times the liver enlarges to enormous size, epididymis and seminal vesicle are the transverse colon leads to vague
causing digestive disorders, discomfort, exceedingly rare. abdominal discomfort, which is misinter-
or pain, and a visible and palpable mass in Endometrial carcinoma most often preted or neglected, and then sudden
the upper abdomen. Thyroid cancer usu- presents as postmenopausal vaginal bleed- onset of diarrhea with prominent gastro-
CHAPTER 1 / Cardinal Manifestations of Cancer 5

colic reflex. Appendiceal cancer, albeit a 10. A few tumors may be manifest first by smoked, heavily imbibed alcohol, or sun
rare tumor, frequently presents as acute paraneoplastic syndromes. Myasthenia worshipped, all are in groups that deserve
appendicitis with peritonitis because of gravis, Raynaud’s syndrome, hyper- special consideration for the particular can-
rupture. Perforation of the colon is more trophic osteoarthropathy and clubbing, cers that occur in them at a higher fre-
frequently caused by diverticulitis than by and refractory anemia may herald thy- quency than normal.
colon cancer. Ruptured ectopic preg- moma, myeloma, lung cancer, and hema- Too often by the time cancer is diagnosed,
nancy due to choriocarcinoma has been tologic dyscrasia (and thymoma) respec- it is past the stage of easy curability. It is
reported. Tracheoesophageal fistulization tively. A diligent search must be made for oftern long past the time when the earliest
rarely occurs early in the course of these and other causes. symptoms were rationalized or ignored.
esophageal or bronchogenic carcinomas. 11. Cardinal manifestations may not be asso- Mammography has decreased mortality
8. Fever of unknown origin that persists for ciated with cancers detected by screening from breast cancer, cytology and early
more than 1 week must include cancer as is demonstrated by Pap smears, mam- treatment have diminished cervical cancer
among its possible causes. Hodgkin’s dis- mography, prostate-specific antigen mortality, and other screening programs
ease, other lymphomas, acute leukemia, (PSA) determinations, colonoscopy, portend similar promise by diagnosing
cancer of the kidney, and cancers of the computed tomography (CT) lung scan- cancers before they become symptomatic.
liver are high on the list of neoplasms that ning, and total skin examination. Asymp- Cancer has replaced syphilis as the great
can cause fever. Certain cancers predis- tomatic cancers discovered by these imitator. Many symptomatic patients with
pose to infections because of ulceration, methods are generally far less advanced cancer are still curable with today’s thera-
obstruction, or disordered leukopoiesis. than those that cause symptoms. Occa- pies. However, delay cannot possibly help
9. Occasionally, patients present with symp- sionally, routine chemical or hematologic once an early symptom occurs that eventu-
toms of specific endocrine hyperactivity laboratory data in asymptomatic patients ally proves to be caused by cancer. Inclu-
that turn out to be caused by cancer. suggest cancer or leukemia. Such inci- sion of cancer as a possibility in every dif-
Hyperadrenalism, which sometimes first dental discovery reinforces the proposi- ferential diagnosis can save lives.
manifests as hirsutism, can indicate tion that early in their pathogenesis, can- The present expansion of our horizons by
adrenal cancer. Cushing syndrome can cers are almost always asymptomatic. the fruits of genomics and proteomics
also result from small cell carcinoma of 12. Cancerophobia does not predispose to can- augurs well for earlier identification of
the lung. Hyperparathyroidism may come cer. Depression occurs more frequently cancers. Not only is it reasonable to believe
from parathyroid cancer and can be mim- with carcinoma of the pancreas than with that clinical diagnosis will accelerate, but
icked by ovarian cancer and squamous gastric carcinoma, however, and may be an the use of these two scientific disciplines is
carcinomas. Tumors that secrete thyroid early symptom of pancreatic neoplasia. A likely to alter our understanding of the can-
hormone, estrogens, insulin, glucagon, broad spectrum of diseases, exposures, and cer process as it occurs in humans. It is
aldosterone, epinephrine, or nore- lifestyle behaviors predispose to specific hoped that the consequent impact of this
pinephrine are usually benign tumors of cancers. As examples, patients who have knowledge on cancer prevention and on
the parent endocrine organ, but cancer had inflammatory bowel disease, human cancer therapy will be revolutionary. The
must always be considered. Functional papilloma virus infection of the cervix, or cardinal manifestations of cancer may then
neuroendocrine tumors may secrete sero- hepatitis infection; those with prior radia- become laboratory abnormalities that are
tonin and other vasoactive principles that tion exposure, alkylating agent treatment, instrumentally detectable well before clin-
cause the carcinoid syndrome. or asbestos exposure; and those who have ical presentation.