Cardinal Manifestations of Cancer

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[edit] Cardinal Manifestations of Cancer

Kathryn L. Edmiston

Cancer is the second leading cause of death in the United States and as such is a concern for most patients seeing their primary care physicians (Table 117-1). The magnitude of the cancer problem is likely to increase in the coming decades as the U.S. population ages. At the beginning of the twentieth century fewer than 10% of Americans were over the age of 55. By 1989 this figure had doubled, and it is expected to increase through the year 2030. The risk of developing cancer increases dramatically with age. The age distribution of cancer deaths is shown in Fig. 117-1.^[1] Because patients frequently visit their primary care physician for routine health maintenance or the evaluation of new symptoms, primary care physicians need to have a thorough knowledge of the clinical signs and symptoms associated with cancer and the initial evaluation of the patient who is suspected of having cancer.

Figure 117-1 Distribution of cancer deaths in the United States by age.

Table 117-1 Estimated Incidence and Mortality of Common Cancers in the United States in 2000

[edit] ASYMPTOMATIC PATIENTS

Patients may be diagnosed with cancer before symptoms occur or may come to medical attention because of symptoms resulting from their cancer. For most types of cancer, diagnosis in the early stages of disease before symptoms have occurred is critical. Treatment of early stage lung cancer may be cured, whereas advanced lung cancer is never curable even with aggressive treatment. This creates a particular dilemma for the primary care physician. How can cancer be diagnosed in its earliest and potentially curable stages before the patient has developed any symptoms? A thorough risk assessment during a routine visit and the appropriate use of cancer screening tests may lead to the diagnosis of cancer in the asymptomatic patient.

A thorough risk assessment can easily be accomplished during the medical interview. Risk assessment should include a history of habits such as smoking and alcohol use, occupational and other environmental exposures, diet, and family history. Cancers associated with specific risks are shown in Table 117-2. Once a patient is found to be at risk, what interventions are necessary? First, and most important, the patient should be counseled regarding the elimination of cancer-causing behaviors. Patients who smoke should be advised of the increased frequency of lung cancer and other cancers of the aerodigestive tract, as well as the risk of cardiovascular and peripheral vascular disease. It is estimated that 90% of all lung cancers are directly caused by tobacco use. Patients who wish to discontinue smoking should be provided with smoking cessation tools (see Chapter 57 ).

Table 117-2 Risk Factors Associated With Common Primary Cancers

Early intervention to prevent the development of cancer may be warranted for patients with certain types of risk. For example, patients with familial adenomatous polyposis are almost certain to develop colon cancer by age 50 if left untreated. Prophylactic colectomy is recommended for prevention. Similarly, patients at high risk for breast cancer may wish to consider tamoxifen for chemoprevention,^[2] genetic screening, or even prophylactic bilateral mastectomy in selected cases.

Finally, careful evaluation of organ systems at risk should be performed during the routine physical examination. Patients with heavy sun exposure or a family history of melanoma should have a thorough skin examination. A thorough inspection and manual examination of the oral cavity in patients with a history of tobacco and alcohol use may detect premalignant lesions or potentially curable invasive carcinomas of the oral cavity. The breasts should be carefully examined, particularly in women over the age of 50 or any woman with a family history of breast cancer.

Cancers that are frequently detected by screening are listed in Table 117-3. A number of cancer screening tools such as mammography,^[3] prostate specific antigen,^[4] and sigmoidoscopy^[5] are recommended by the American Cancer Society for the early detection of cancer.

Table 117-3 Cancers Frequently Detected by Screening Tests

[edit] SYMPTOMATIC PATIENTS

Symptoms of cancer may be vague and nonspecific, such as weight loss, fatigue, and malaise. Specific symptoms may occur because of physiologic or mechanical effects of the primary tumor or metastases at distant sites.

Weight loss occurs commonly at the time of diagnosis in many patients with advanced cancer. Although a wide constellation of gastrointestinal symptoms are common in patients with cancer, decreased caloric intake may not be sufficient to explain weight loss. An aggressive search for an undiagnosed cancer is probably not warranted in most patients with unexplained weight loss as their only symptom until changes in dietary intake, depression, and stresses at work or in family have been assessed. Patients at high risk for cancer, such as smokers or those with additional symptoms, should undergo further evaluation without delay.

Pain is the most feared symptom resulting from cancer. Pain occurs at some time during the clinical course of most cancer patients and may be a result of the treatment or the underlying malignancy. The characteristics of cancer pain originating from different sites are listed in Table 117-4. Although chronic pain affects nearly all patients with advanced cancer it usually can be adequately controlled as described in Box 117-1.

Table 117-4 Characteristics of Cancer Pain

Trousseau first described superficial migratory thrombophlebitis associated with gastrointestinal malignancies in 1865. Since that time it has been noted that a hypercoagulable state is frequently associated with a diagnosis of cancer. Patients with advanced cancer are clearly at increased risk for the development of deep venous thrombosis (DVT). In 1951 Ackerman suggested that DVT may be the presenting problem of patients with undiagnosed cancer. This continues to be debated. About 70% of patients with DVT have an identifiable risk factor for thrombosis such as bed rest, recent surgery, or varicosities. The risk of occult malignancy in this group is less than 5%. In patients with idiopathic DVT the incidence of undiagnosed cancer is 30% to 35%. Many patients with idiopathic DVT who are concurrently diagnosed with cancer after an extensive screening evaluation (abdominal ultrasonography, abdominal computed tomography [CT], and upper gastrointestinal endoscopy) are found to actually have symptoms of the primary cancer. The appropriate evaluation for patients with idiopathic DVT should be a complete history and physical examination, complete blood count and differential, serum lactic dehydrogenase (LDH), chest x-ray, and evaluation of any additional signs or symptoms consistent with a diagnosis of malignancy.^[6]

[edit] PHYSICAL EXAMINATION

[edit] Skin

A thorough inspection of the skin is useful for detecting skin cancer. The incidence of malignant melanoma has increased dramatically over the last 6 decades. The principal risk factor is sun exposure. The prognosis for patients with deeply invasive primary lesions or regional or distant metastases is grim, so early detection is paramount. Pigmented skin lesions should be examined for size, color, shape, and symmetry. Guidelines for assessing hyperpigmented skin lesions (the ABCD acronym) and the characteristics of suspicious lesions are described in Chapter 87 . Patients with suspicious lesions should be promptly referred to a dermatologist or plastic surgeon for excisional biopsy (see Chapter 87 ).

[edit] Oral Cavity

A careful inspection and manual examination of the oral cavity should be a routine part of the physical examination, particularly in patients over the age of 40 who use tobacco and alcohol. Tobacco and alcohol are the principal etiologic factors in these cancers. About 90% of oral cancers occur in regions easily visualized during the routine physical examination. Premalignant lesions such as leukoplakia and erythroplakia may also be detected and treated early. Leukoplakia appears as thick, white hyperkeratotic plaque most commonly on the buccal mucosa, dorsal tongue, and alveolar ridge. Although considered a premalignant lesion, there is a low frequency of transformation to invasive cancer. Erythroplakia appears as an erythematous granular lesion most commonly on the floor of the mouth, ventral tongue, and soft palate. About 60% to 85% of patients with erythroplakia have early invasive squamous cell cancer at biopsy. Patients with the above diagnoses should be advised to stop smoking and drinking alcohol and should continue under routine surveillance. Vitamin A derivatives may help prevent the subsequent development of second primary tumors of the head and neck in patients previously treated for squamous carcinoma of the oral cavity. See Chapter 183 for further information.

[edit] Lymphadenopathy

Inflammatory adenopathy, congenital abnormalities, and neoplasia are all broad categories that need to be considered when evaluating cervical adenopathy. In the pediatric population, inflammatory and congenital lesions are the most common cause of neck masses. In young adults the frequency of neoplasia, especially lymphoma, increases but it is still less common than inflammatory adenopathy. In contrast, 50% of patients over the age of 40 with an enlarged asymmetric neck mass are diagnosed with carcinoma or lymphoma (see Chapter 183 ). If a careful head and neck examination fails to reveal any abnormalities, a fine-needle aspiration biopsy can usually be performed as an outpatient procedure. Special stains may be necessary to determine the precise nature of the abnormality. If the cytology is consistent with a diagnosis of lymphoma, an excisional biopsy may be required for more precise diagnosis.

Axillary adenopathy is a frequently encountered abnormality in clinical practice and most often is due to benign processes. Large, multiple, matted or enlarging lymph nodes should be biopsied. Supraclavicular adenopathy is almost always of pathologic significance and requires further evaluation. Lung cancer is the most common cancer to metastasize to supraclavicular lymph nodes, and a chest x-ray should be obtained promptly. A Virchow's node in the left supraclavicular fossa may represent involvement from a gastrointestinal cancer.

[edit] Breast Mass

The breast examination is a complex and difficult part of the routine physical examination because of the wide variability in normal anatomy. The breast is a composite of fat and glandular tissue that changes throughout the menstrual cycle. These changes are typically referred to as fibrocystic change and should not be considered abnormal. However, any discrete palpable mass in the breast requires further evaluation. Although mammography is a useful screening test for breast cancer, it should not be used alone in the diagnosis of a palpable breast mass. A normal mammogram particularly in a young, premenopausal woman does not definitively exclude the diagnosis of cancer.

The differential diagnosis of a palpable breast mass includes fibroadenoma, benign cyst, and carcinoma. See Chapter 43 for a detailed presentation of breast diseases.

Signs on physical examination that require urgent evaluation are redness, warmth, and tenderness of the breast. There may or may not be a palpable mass in the breast. Although a biopsy is required to confirm the diagnosis, these may be signs of inflammatory breast cancer and prompt staging and treatment are indicated.

[edit] Chest

A chest x-ray is the most important diagnostic test in a patient with pulmonary complaints. Pleural effusions may result from inflammatory, cardiovascular, and neoplastic disorders. Thoracentesis obtains fluid that may yield a precise diagnosis. Fluid should be analyzed for LDH and protein content, cell count and differential, culture, pH, and cytology. The characteristics of a malignant pleural effusion are listed inBox 117-2. Malignant pleural effusions occur most commonly in patients with lung and breast cancer. A chylous effusion with high lipid content occurs most commonly from lymphomatous involvement of lymph nodes in the retroperitoneum and mediastinum.

A solitary pulmonary nodule (SPN) is an opacity seen on chest x-ray measuring less than 4 cm and completely surrounded by lung parenchyma. It is a common incidental finding that requires further evaluation. The purpose of further diagnostic evaluation is to distinguish malignant neoplasms that are potentially curable with surgery from benign lesions and incurable malignant lesions. If the patient has had prior chest x-rays, these should be obtained for comparison with the most recent examination. If the SPN has been present and unchanged over 2 years, it is probably benign and a subsequent chest x-ray should be obtained to ensure stability. If previous chest x-rays are not available, further study is warranted. Fluoroscopy may be useful for clarifying subtle or questionable abnormalities on chest x-ray. For larger lesions or when the fluoroscopy is equivocal, CT scanning is the most useful diagnostic test. Lesions with benign appearing calcifications or CT-detectable fat in a well-circumscribed pulmonary nodule are probably benign and do not require further evaluation. The presence of enlarged mediastinal or hilar lymph nodes or multiple nodules is more likely to occur with malignant disease. See Chapter 81 for a presentation of neoplasms of the lung.

[edit] Abdomen

Unexplained ascites, hepatomegaly, or a palpable abdominal mass may all suggest the presence of an intraabdominal malignancy. Ascites in a middle-aged woman is a common presentation for ovarian cancer. The first step in evaluating such a patient is a pelvic examination to assess the presence of an adnexal mass. Additional studies should include transvaginal ultrasound or an abdominal CT scan to assess the extent of disease and a blood test for CA 125. CA 125 is a marker for ovarian cancer and is elevated in 80% of patients with ovarian cancer.

When the pelvic examination is normal, and for men with unexplained ascites, paracentesis should be performed. Malignant ascites typically is bloody, with malignant cells seen on cytologic analysis.

Hepatomegaly can occur as a result of benign infiltrative disease of the liver or involvement of the liver by tumor. Involvement of the liver by metastasis is far more common than the occurrence of primary hepatocellular carcinoma. Lung, colon, and breast cancer frequently metastasize to the liver, and a prior history of these cancers should raise the clinical suspicion of metastatic liver disease in a patient with hepatomegaly. A CT scan provides the most diagnostic information in evaluating hepatomegaly. If lesions consistent with metastatic or primary liver cancer are seen, a biopsy may be required to establish the precise diagnosis (see Chapter 105 ).

A palpable abdominal mass should be evaluated by a CT scan to determine its origin and relation to normal intraabdominal organs. A tumor mass in the abdomen may be a primary or metastatic focus of disease. Further evaluation and biopsy depend on the location and radiographic appearance of the mass. A mass arising from the large bowel may be further evaluated with colonoscopy (see Chapter 105 ). Upper gastrointestinal endoscopy may be indicated for upper abdominal masses or those that may be of pancreatic origin. A percutaneous fine-needle aspiration biopsy under CT or ultrasound guidance is the procedure of choice for diagnosing a renal mass.

Testing for fecal occult blood is recommended as part of the routine physical examination for patients over the age of 40. Those patients who are found to have occult blood in the stool or iron-deficiency anemia may have an occult gastrointestinal malignancy. Further evaluation should be guided by the presence of any associated symptoms (see Chapter 105 for a detailed presentation of GI neoplasms).

[edit] Prostate

Prostate cancer is the most common cancer affecting men in the United States. The American Cancer Society estimated that there would be 180,400 new cases of prostate cancer diagnosed in the United States in 2000. Enlargement of the prostate is part of the normal aging process and often results in symptoms of frequency, urgency, and hesitancy. It is often very difficult to distinguish on clinical criteria alone whether symptoms are due to benign prostatic hypertrophy or cancer. Patients who are symptomatic, even if the digital rectal examination (DRE) is normal, should probably be evaluated with the following tests.

Patients with prostate cancer may be asymptomatic or have symptoms similar to those in patients with benign disease. Asymptomatic patients may come to attention because of palpable findings on DRE such as diffuse enlargement or focal, well-localized nodules. Any hard area or discrete nodule detected on routine DRE should arouse suspicion for carcinoma. Transrectal ultrasound (TRUS) and determination of the prostate specific antigen (PSA) add significantly to the information obtained during the DRE. The diagnostic workup for prostate cancer is presented in detail in Chapter 152 .

[edit] Testis

Testicular cancer is the most common malignancy occurring in young men between ages 20 and 35. The only identifiable risk factor for testicular cancer is cryptorchid testis. There is an eleven-fold to fifty-fold increased risk in the undescended testis compared with the frequency in normally located organs. Orchiopexy does not decrease this risk but may allow for earlier diagnosis.

Since the diagnosis of testicular cancer is frequently delayed and often misdiagnosed, young men are now being instructed in testicular self-examination as a means of improving early diagnosis of testicular cancer. The differential diagnosis of a testicular mass is shown in Table 117-5 and includes acute and chronic epididymitis, varicocele, hydrocele, and inguinal hernia.

Table 117-5 Differential Diagnosis of a Testicular Mass

Transscrotal ultrasound is a useful diagnostic tool in the evaluation of a testicular mass. Patients who are found to have a solid mass should be referred for inguinal orchiectomy (see Chapter 155 ).

[edit] DIAGNOSIS

Symptomatic or asymptomatic patients may have a variety of findings consistent with a diagnosis of cancer. Although patients may be suspected of having cancer based on abnormal physical findings or radiographic studies, a diagnosis of cancer always requires a biopsy. A biopsy may confirm the diagnosis of malignancy and may provide important prognostic information. Biopsy material may be obtained in a variety of ways depending on the site.

A fine-needle aspiration biopsy can be accomplished with a minimum of morbidity in the outpatient department. Material is sent to the pathology lab for cytologic evaluation. This is a particularly useful procedure for evaluating palpable masses in the breast and enlarged palpable lymph nodes. Needle aspiration biopsy guided by ultrasound or CT can be used to biopsy abnormalities in a variety of sites including breast, thyroid, and essentially all abdominal and pelvic organs except bowel and bladder. Incisional or excisional biopsy or a more extensive procedure may be necessary to obtain tissue for diagnosis if the fine-needle aspiration biopsy is nondiagnostic or if additional material is thought to be necessary for a complete histologic evaluation.

The pathologist plays an essential role in evaluating the patient with a suspected diagnosis of cancer. The patient's age, symptoms, physical findings, suspected diagnosis, and the site of the biopsy should all be communicated to the pathologist before the procedure to be certain that an optimal specimen is obtained, handled, and fixed in a manner that maximizes diagnostic accuracy. The pathologist has a variety of tools that are used to establish a precise diagnosis of cancer. Immunohistochemical markers may help to distinguish a carcinoma from a sarcoma or a lymphoma. Additional special stains may be necessary to reach a precise diagnosis or to identify a primary site when it is not clinically evident.

Once a diagnosis of cancer has been established, further studies may be needed to determine the extent of the disease and the precise stage of the cancer even if the patient is otherwise healthy. All patients should have a complete history and physical examination. Laboratory evaluation should include a complete blood count and differential and blood tests to screen for kidney, liver, and bone disease. Any abnormalities in the history, physical examination, or laboratory studies that may be due to cancer require further diagnostic evaluation. Even if all of the above studies are normal, selected radiographic studies may be required based on the natural history and usual pattern of metastases from the specific primary site. For example, all patients with cancer do not require a head CT unless there are symptoms, abnormalities in the neurologic examination, or if cancer from the patient's primary site frequently involves the brain.

Complete staging evaluation is essential for further management. Most solid tumors are staged by the TNM classification and grouped in stages 1 to 4 as described in Box 117-3. Unique TNM classifications exist for each primary site.^[7] The stage at diagnosis often determines the appropriate treatment modality. Patients with localized disease may require only local therapy such as radiation or surgery, whereas patients with disseminated disease may be considered for systemic therapy. Second, the stage at diagnosis has a major impact on prognosis. Patients with localized disease may be curable, in contrast to most patients with disseminated cancer in whom the disease may be treatable but not curable. Finally, it is essential that patients enrolled in clinical trials be uniformly staged so that the results are generally valid.

[edit] Carcinoma of Unknown Primary Site

Most patients with metastatic cancer have a clinically obvious primary site where the tumor began. However, approximately 5% of patients with metastatic cancer have a clinically occult primary site despite a complete history, physical examination, routine laboratory studies, and a chest x-ray. Myriad extensive diagnostic testing can be undertaken in an attempt to identify the primary site, but this is generally futile because a primary site is not identified.^[8] Moreover, specific identification of the primary site usually does not have a major impact on the subsequent outcome. Efforts should be directed at identifying treatable tumors such as the lymphomas, hormonally responsive malignancies such as breast and prostate carcinomas, germ cell tumors, and small cell carcinoma of the lung.

Some situations need special consideration.^[9] Poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site describes a subset of patients who may have a favorable response rate to cisplatin-based combination chemotherapy. The most favorable responses occur in young patients with a limited number of metastases located in the retroperitoneum or peripheral lymph nodes. About 30% of these patients are disease-free after treatment, and prolonged complete remissions may be achieved.

Adenocarcinoma in an axillary node in an otherwise asymptomatic woman should be treated as an occult breast primary. Immunohistochemical stains for estrogen and progesterone on the biopsy specimen may provide corroborative evidence of a breast primary. Mammography may be useful in identifying an occult breast cancer, but a normal mammogram does not rule out the possibility of a breast primary. Women who have adenocarcinoma of unknown primary only in an axillary lymph node should undergo breast surgery and axillary dissection and receive adjuvant therapy similar to that for patients with stage 2 breast cancer. In contrast to other patients with adenocarcinoma of unknown primary, the prognosis is good with approximately 65% 5-year disease-free survival.

Patients with upper or midcervical lymphadenopathy secondary to squamous cell carcinoma should be evaluated for a head and neck primary. This should include a chest x-ray and endoscopic evaluation of the whole upper aerodigestive tract. If no primary is identified, aggressive combined modality therapy with radiation therapy and neck dissection should be prescribed in the same dosage and fields as in patients with a known head and neck primary. With this approach the 5-year survival is 30% to 50%.

Occult prostate cancer should be searched for in men with osteoblastic metastases involving the axial and appendicular skeleton, since patients with diffuse metastatic prostate cancer are likely to benefit from hormonal therapy. In a male patient with diffuse osteoblastic metastases and adenocarcinoma on biopsy, an elevated serum PSA or immunohistochemical staining of the biopsy specimen for PSA is sufficient to initiate treatment for metastatic prostate carcinoma.

[edit] The Multidisciplinary Approach

Once the diagnosis of cancer is established, it should be communicated and explained to the patient. It is always helpful to have a family member or significant other present during this discussion. A thorough explanation of the treatment plan, potential complications, and expected outcome is essential.

Although many specialists are frequently involved in caring for the patient with cancer, the primary care physician is a vital part of the multidisciplinary team. Patients often look to their primary provider to help them understand the complicated aspects of their cancer management. Subspecialists also appreciate the unique perspective of the primary care physician for assessing the impact of other chronic diseases on future care. The primary care physician should continue to counsel the patient and family even after the diagnosis of cancer is established.

When the diagnosis of cancer is made, referral to the appropriate subspecialist is often necessary. This may include a medical oncologist, radiation oncologist, and surgical oncologist. Nurses, social workers, physical therapists, enterostomal therapists, occupational therapists, and clergy are also important members of the health care team.

[edit] FUTURE DIRECTIONS

Clinical research is being done to improve the care of patients with most solid tumors. Patients who are referred to tertiary care cancer centers are often candidates for participation in clinical research trials either through cooperative groups or pharmaceutical companies. Patients should be encouraged to participate in clinical trials to obtain the best possible care for their cancer and to help develop new and innovative cancer treatments for the future.

[edit] REFERENCES