Key Clinical Questions
What are the next steps in evaluation and management priorities for patients admitted to the hospital with suspected cancer diagnosis, including carcinoma of unknown primary?
What are the common tests, including molecular tests, utilized for cancer diagnosis and their significance?
What are the key issues to consider before discharging a patient admitted with suspected/new cancer diagnosis?
As an inpatient provider, one must adapt to each individual patient presentation of suspected malignancy, and expedite a workup with the goal of obtaining enough clinical, laboratory, and radiographic data for diagnosis. Most patients that are ill enough to require hospitalization with suspected malignancy present with either complications of their disease, paraneoplastic syndromes, or advanced stage of cancer. While it is important to obtain a comprehensive history and physical exam, every patient should be asked about the following:
Details of symptom duration and chronology leading to admission.
Comorbidities, any previous cancers, premalignant or spontaneously regressing lesions, and/or prior history of chemotherapy or radiation.
Risk factors causing predisposition for certain malignancies such as alcohol, tobacco, drug use, occupations with notable exposures, use of hormone replacement therapy.
Family history of any malignancies.
The next steps in assessment and management can be tailored to the particular patient presentation.
Knowledge of the incidence of common cancer across various age groups may help with the pretest probability when a patient is admitted with a suspected cancer diagnosis. Five cases highlight common presentations of suspected malignancy. These cases provide a diagnostic framework, but cannot be comprehensive due to the variety or patient characteristics and disease presentations.
Important to assess for comorbidities, any previous cancers, premalignant or spontaneously regressing lesions, and/or prior history of chemotherapy or radiation.
It is estimated that there will be more than 1.5 million new cases of cancer diagnosed in the United States in 2015. Breast cancer accounts for 29% of all newly diagnosed cancers in females, and it is the most common noncutaneous malignancy among females in the United States. In 2015, it is estimated that 231,840 women will be diagnosed with breast cancer. Among males, prostate cancer is the most common malignancy and accounts for 26% of new cancer cases in males. In 2015, it is estimated that 220,840 men will be diagnosed with prostate cancer. Lung cancer is second most common cancer among males and females followed by colorectal cancer.
While heart disease is the leading cause of death among all ages, cancer is actually the leading cause of death among adults between ages 40 to 59 and 60 to 79, with lung cancer being the most common among both sexes. It is estimated that approximately 86,380 men and 71,660 women will die of lung cancer in 2015. It should be noted that while pancreatic cancer is not in the top five most common cause of cancer among males (in sequence they include prostate, lung, colon, bladder, and melanoma) or females (in sequence they include breast, lung, colon, uterine, and thyroid), it is the fourth most common cause of death among both males and females, and thus portends a poor prognosis.
While breast cancer is the most common cancer among females and prostate cancer among males, this estimate is based on overall incidence across lifetime, and the probability of specific cancers varies across different age groups. Among adolescents, leukemia is the most common cancer in both boys and girls. Among young adults (20-39 years), the common cancers include breast cancer, cervical cancer, leukemia, lymphoma, lung, colorectal, and central nervous system neoplasms. Among the elderly, besides breast, prostate, lung, and colorectal, other common cancers include ovarian, esophageal, pancreatic, and bladder cancer. The probability of death due to cancer also varies across different age groups and patients admitted to the hospital are likely the ones who have a worse prognosis. Figures 177-1 A and B summarize the top five leading causes of cancer-related deaths across different age groups.
The top five leading causes of cancer-related deaths across various age-groups among males (A) and females (B). (Based on Siegel R, et al. CA Cancer J Clin. 2015;65:5-29.)
Carcinoma of unknown primary or occult primary account for approximately 5% all newly diagnosed cancers. In 2015, it is estimated that there will be 31,510 patients with newly diagnosed cancers from unspecified sites. The incidence of carcinoma of unknown primary has been decreasing over time, partly due to newer diagnostic techniques, but still a primary site is identified in less than one-third of patients who present with an unknown primary. In general, patients with carcinoma of unknown primary have a poor prognosis and identification of the primary tumor can potentially lead to better outcomes.
In this chapter, we will review the evaluation and management of five common clinical presentations including new bone lesions, liver lesions, lymphadenopathy, mediastinal mass, and brain lesion. We will also review commonly used tumor markers, immunohistochemical tests, and molecular profiling. Lastly, the chapter will cover risk stratification and postacute care.
EVALUATION AND MANAGEMENT
CASE 177-1 BONE PAIN
A 57-year-old female presented to the emergency department with worsening lumbar back pain. The back pain started about 8 weeks ago and was felt to be from lifting a heavy box at work. She was initially treated conservatively with a course of nonsteroidal anti-inflammatory drugs and physical therapy, with no improvement in her symptoms. Her review of systems was positive for bony pain, most notably in the lumbar region, and a 10 lb weight loss over 3 months. She had no lower-extremity motor weakness or sensory change, gait instability, sciatica, saddle anesthesia, or urinary/fecal incontinence. She had no prior operations, and her only medication was 0.3 mg Premarin. She did not use alcohol, tobacco, or drugs. Her examination was unremarkable. Laboratory tests were normal except for an alkaline phosphatase of 223 and calcium of 10.4. Imaging with a lumbar spine magnetic resonance imaging (MRI) revealed evidence of multiple lesions concerning for metastatic disease.
Bone metastases are a common complication of advanced disease, and can be a cause of significant morbidity. Roughly 80% of cases with bone metastasis have an underlying diagnosis of breast, lung, prostate, or renal cell carcinoma. However, many types of malignancies can spread to the bone.
For bone metastasis, the cannot-miss diagnoses are spinal cord compression, pathological fracture, and severe hypercalcemia.
Approach if malignancy involves skeletal metastases
History should include assessment of cancer risk factors. As breast cancer is one of the top differentials in a females presenting with bone metastasis, clinicians should ask questions pertaining to breast cancer risk including date of last mammogram, prior abnormal mammograms or breast biopsies, family history of breast or ovarian cancer, parity, age at menopause, and whether any use of hormone replacement therapy.
A comprehensive physical exam should specifically include a breast exam, axillary lymph nodes (LNs), and in males a prostate exam including inguinal lymph nodes. Laboratory studies should include CBC with differential, metabolic panel, hepatic panel, lactic dehydrogenase, vitamin D level, serum protein electrophoresis, and serum-free light chains. If the patient is male over 40 years of age, prostate specific antigen (PSA) should be measured. The utility of other tumor markers is generally nonspecific, and therefore not helpful in the diagnostic workup. Specific radiographic studies should be performed for painful lesions and/or lesions in weight-bearing areas to rule out pathological fracture.
Imaging may reveal osteolytic or osteoblastic (sclerotic) lesions, or a mix of both. Plain films require 30% to 50% of bone mineral loss in order to visualize. Bone scan or computed tomography (CT) scan will identify bony metastasis, pathological fractures, and primary source of malignancy. Osteoblastic lesions are characterized by new bone formation and are best detected with the use of a nuclear medicine scan, such as a radionuclide bone scan. However, osteolytic lesions destroy normal bone and can be missed by bone scans. Osteolytic lesions, such as the ones seen in multiple myeloma, are often best picked up by skeletal survey (bone x-ray) or CT scans.
Differential if malignancy involves skeletal metastases
It is important to note that most types of cancer produce both osteolytic and osteoblastic lesions. However, there are specific tumor types that have a predilection for a certain presentation (see Figure 177-2).
Differential diagnosis according to type of bone lesion.
In Case 177-1, the highest malignancy on the differential would be breast cancer given her history of hormone replacement therapy, gender, age, and nulliparity. Therefore, a mammogram and breast ultrasound should be performed. In premenopausal female, particularly those with dense breasts, breast MRI should be considered if needed.
A biopsy is necessary to determine the histology and the site of origin of the cancer. Often, the oncology consult and interventionalist can assist with institution specific protocols and choosing the ideal site of biopsy. The general principles of choosing an optimal site for biopsy include:
Choose the least invasive and safest modality of biopsy
Core biopsy is preferred over fine needle aspirate
Ensure there is an ability to get an adequate sample for further testing
Depending on institution and reagents used, a bone biopsy is less optimal due to the procedure of decalcification, which can alter DNA quality for subsequent molecular testing.
Management priorities in cases such as the one described above focus on pain relief and ruling out the “cannot-miss” diagnoses. In the case of painful bony metastasis, IV analgesics are often needed for immediate and effective pain relief in addition to adjuvant medications such as acetaminophen and NSAIDs.
The cannot-miss diagnoses are spinal cord compression, pathological fracture, and severe hypercalcemia. See Table 177-1 for management of these conditions, or refer to Oncology Emergencies, Chapter 176 for additional details. Early diagnosis and intervention leads to decreased morbidity in this patient population.
TABLE 177-1Cannot-Miss Diagnosis in Patient Presenting with Persistent Back Pain ||Download (.pdf) TABLE 177-1 Cannot-Miss Diagnosis in Patient Presenting with Persistent Back Pain
|Diagnosis ||Presentation ||Evaluation ||Management |
|Spinal cord compression ||Progressive pain, worse when supine, proximal leg weakness, sensory changes or bowel/bladder incontinence ||MRI for cord compression, CT myelography: used when MRI not available or accessible || |
IV Dexamethasone 10 mg followed by 4 mg IV q 6 h.
STAT neurosurgical and radiation oncology consultations.
|Pathological fracture ||Localized musculoskeletal pain, persistent despite NSAIDS and/or narcotics ||x-Ray followed by CT scan if suspicion is high enough || |
Pain relief, orthopedic and radiation oncology consultation for treatment and possible prophylactic fixation.
Consideration of bisphosphonate (eg, zoledronic acid, pamidronate).
Consideration of kyphoplasty or vertebroplasty for painful fractures.
|Hypercalcemia ||Confusion/altered mental status, fatigue, hypovolemia, abdominal pain, constipation, symptoms of nephrolithiasis ||PTH, PTHrP, 1,25-Dihydroxyvitamin D || |
Normal saline to promote calciuresis.
Bisphosophate with zolendronic acid or pamidronate.
Consideration of calcitonin (2-8 U/kg SC every 6-12 h).
CASE 177-2 LIVER METASTASIS
A 63-year-old male presents to the hospital with a 25 lb unintentional weight loss over the last 2 months, polydipsia, nocturia, right upper quadrant (RUQ) pain, pruritis, and jaundice. He had not sought medical attention previously, but his daughter brought him to the hospital because of his “yellowish hue.” Review of systems was positive for the above, as well as fatigue and loss of appetite.
He had no prior surgical history, and was on no other medications. He had been a lifelong smoker with 40+ pack years, and consumed 4 to 5 alcoholic drinks per night, but no history of drug use. Past medical history is significant for alcohol related pancreatitis, chronic obstructive pulmonary disease (COPD), and gastroesophageal reflux disease (GERD), but no known inflammatory bowel disease (IBD), hepatitis B/C/NASH, or Barrett’s esophagus. There was no family history of liver disease or cancer.
Exam: Notable for scleral icterus, jaundice, multiple excoriations of the skin, and midepigastric tenderness on deep palpation, but no murphy’s sign or subcutaneous nodules in the para-umbilical area.
Labs: T Bili of 8.1, D Bili of 6.0, glucose of 360, AG 16, 2+ bilirubin in urinalysis.
Imaging: RUQ US—Large hypoechoic mass measuring 2.8 × 4.4 cm within the head of the pancreas, resulting in dilatation of the common bile duct to 10 mm. Extensive intrahepatic biliary ductal dilatation, with multiple liver lesions concerning for metastatic disease.
The key step in the assessment of one or more liver lesions suspected to be malignant is to determine whether or not it is a primary liver or biliary tumor, versus a metastatic lesion from a cancer outside of the liver. Of note, it is much more common (18-40 ×) for liver lesions to represent metastatic disease rather than primary liver neoplasms.
Differential if suspected malignancy involves liver metastases
Nearly all metastatic solid malignancies have been reported to present with liver disease; however, the most common cancers are as follows:
GI—pancreas, colon, esophageal, gastric, neuroendocrine
GU (renal cell cancer, bladder, adrenal)
GYN (ovary, endometrial)
Even though the incidence is lower, a primary liver etiology must also be on the differential. There are three main categories of aggressive invasive carcinomas originating in the liver: hepatocellular carcinoma (HCC), cholangiocarcinoma, and gallbladder carcinoma.
Approach if suspected malignancy involves liver metastases
A complete physical exam should be performed, including digital rectal exam and guaiac fecal occult blood test for both sexes.
Laboratory studies include CBC with differential, with specific attention to platelet count (surrogate for portal venous hypertension), chemistry panel, serum levels of direct and indirect bilirubin, aspartate aminotransferase, alanine transaminatse, alkaline phosphatase, prothrombin time, international normalized ratio (INR), albumin, Ca, lactate dehydrogenase (LDH), and albumin. Tumor marker levels of carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA 19-9) should be sent if pancreatic biliary tract, or colon primary are suspected, and alpha-fetoprotein (AFP) if HCC is suspected. In a patient with known liver disease such as hepatitis C, a rising AFP is highly suggestive of HCC.
Further evaluation with imaging is usually needed. For patients with liver nodules on ultrasound, such as the patient presentation above, National Comprehensive Cancer Network guidelines recommend evaluation with a multiphase contrast-enhanced CT or MRI. A high-quality triple phase CT scan with intravenous and oral contrast medium provides an excellent assessment of disease extent in the liver, as well as elsewhere in the abdominal cavity. The three phases of the study allow for differentiation of metastatic lesions by their vascular nature. Colorectal, gastric, and lung metastases tend to be hypovascular lesions, and are best detected on portal venous phase contrast-enhanced images; renal cell carcinoma, melanoma, neuroendocrine, thyroid, and sarcoma are hypervascular, and enhance to a greater degree than normal liver parenchyma on arterial phase imaging.
Imaging can also be very useful in determining whether or not a biopsy is needed. The most common primary liver neoplasm in the United States is hepatocellular carcinoma, which appears as a hypodense mass on CT. Often, the HCC lesion receives direct blood flow from the hepatic artery, which lends it to having arterial hypervascularity on imaging in comparison to the liver parenchyma, which is fed by the portal vein. Again, a multiphase (unenhanced, arterial phase, portal venous phase, and delayed venous phase) helical CT or dynamic contrast-enhanced MRI can be very suggestive of HCC. The characteristic finding is intense arterial update followed by contrast washout in the delayed venous phase. It is important to review the images with experts in abdominal radiology, because if there is a classical enhancement pattern for HCC, one can forego a biopsy.
Besides imaging of the abdomen, a chest CT is also recommended to search of a primary and/or other evidence of metastatic disease.
If there is no evidence of a primary lesion, or if there is a suspected primary pancreatic mass such as in the case above, endoscopic evaluation can be useful for biopsy given that tissue must be obtained to complete the diagnostic workup. This may include endoscopic ultrasound, esophagodenoscopy, and/or colonoscopy. For women, a mammogram and breast ultrasound is also indicated in the search for the primary.
If there is concern for biliary obstruction in a patient presenting with jaundice and elevated bilirubin as in the case above, a gastroenterology consultation for consideration of MRCP or ERCP with biliary stenting should be strongly considered. For principles of obtaining a biopsy, see Case 177-1.
Management priorities in cases such as the one described above focus on identifying any evidence of biliary obstruction and identification of the underlying malignancy as outlined in Table 177-2. Refer to Chapter 158 (Biliary Disease: Jaundice, Obstruction, and Acute Cholangitis) for additional information.
TABLE 177-2Management Priorities in Patient Presenting with Liver Lesions ||Download (.pdf) TABLE 177-2 Management Priorities in Patient Presenting with Liver Lesions
|Diagnosis ||Presentation ||Evaluation ||Management |
|Biliary obstruction || |
Often painless jaundice, dark urine, and light-colored stools
Fever, tachycardia, and possible hypotension if there is superimposed cholangitis
Labs including CBC with differential, chemistry panel including liver function tests, bilirubin, coags. Blood cultures if febrile
Right upper quadrant ultrasound or abdominal CT scan as mentioned above often can identify the biliary obstruction
If negative, consult gastroenterology for consideration of MRCP or ERCP
Urgent gastroenterology consultation for consideration of biliary stent to alleviate the obstruction
Broad-spectrum antibiotics and IVF if febrile with concern of superimposed cholangitis
In the case above, the patient had evidence of biliary obstruction and underwent successful biliary stenting with a subsequent decrease in the bilirubin levels. The pancreatic mass was biopsied and was found to be consistent with adenocarcinoma. Treatment in these cases depends on the tumor type, performance status, and overall patient preference. Often, systemic chemotherapy is the treatment of choice. Surgery is rarely an option, however there are exceptions—colorectal cancer, sarcomas, neuroendocrine (to palliate tumor-related pain or hormonal symptoms)—where a multidisciplinary team is assembled and surgery is considered.
CASE 177-3 LYMPHADENOPATHY
A 56-year-old immunocompetent male presents to the hospital with painless “lumps” in his neck. In addition, he had been having difficulty breathing, dysphasia, and an altered voice for the past several days. Review of systems was negative for fevers, weight loss, or night sweats. He had not had any sore throat or viral illness recently. He took Ibuprofen, but his symptoms remained unchanged. He had no prior surgical history, and was on no other medications. He had been a lifelong smoker (2 packs/d) with a 60+ pack year history, and consumes 1 to 2 alcoholic drinks on a nightly basis, but had no history of drug use.
On examination, temperature was 98.1, blood pressure (BP) 130/85, heart rate (HR) 105 bpm. Notably, there were nontender, fixed lymph nodes measuring 1 to 3 cm in the cervical chain, bilaterally. The rest of the physical exam was unremarkable. Plain films of the chest and neck showed no evidence of tracheal deviation, foreign body, or extrinsic compression. ENT was called urgently since the symptoms were concerning for an upper airway obstruction.
Approach if suspected malignancy involves lymphadenopathy
Lymphadenopathy is defined as enlargement of lymph nodes, and is generally considered pathologic if >1 cm in adults, although this varies by lymph node basin involved. Unfortunately, there is not a clear definition of size for lymph nodes to be suspected of having a malignant etiology. There are data to suggest that an LN > 2 cm or an abnormal chest x-ray (CXR) increases the positive predictive value of the node being malignant, whereas recent ENT symptoms increases the negative predictive value. Other features suggestive of malignancy include progression over weeks to months, painless/nontender, matted or “hard,” located in the supraclavicular, cervical/scalene, or isolated in the axillary region, or symptoms such as dysphagia/voice changes or B-type symptoms (fever, weight loss of >10%, and night sweats).
History is essential, and should include a thorough evaluation for any infectious or autoimmune signs or symptoms considering those, as opposed to malignancy, are the most common etiologies in a patient presenting with lymphadenopathy. Additional questions to determine the probability of an underlying malignancy include: any prior malignancy, HPV status, HIV/HHV8, history of organ transplant and EBV exposure, history of H. pylori, and use of tobacco and alcohol.
A complete physical exam should be performed. Further assessment (eg, ENT exam of tongue, buccal mucosa, gums, palate, full skin exam, evaluation of liver/spleen, breast exam) becomes necessary depending on the lymphatic region involved.
Basic laboratory studies include CBC with differential, chemistry panel, liver function tests, B-HCG if patient is of reproductive age, and LDH. If there is concern for infectious, autoimmune, or granulomatous conditions, testing for EBV/CMV/HIV/viral panel/Toxo/Brucella/ANA/anti-ds DNA/ACE level is indicated.
Imaging techniques to aid in the determination as to whether an LN is malignant can begin with an ultrasound. The long axis (L)/short axis (S), or L/S ratio is a highly sensitive and specific test to differentiate between a benign or malignant LN. Over 95% of enlarged cervical nodes identified on US with an L/S ratio of greater than 2 are correctly diagnosed as benign. Similarly, patients with a rounder shape and L/S ratio of less than 2 are consistent with metastatic disease 95% of the time.
As long as there are no contraindications, additional imaging with CT scans and IV contrast is generally the next step in evaluating underlying malignancy. Given the high cost, use of positron emission tomography (PET) or PET-CT is generally limited to patients with neck lymphadenopathy suggestive of squamous-cell carcinoma or diffuse lymphadenopathy consistent with an aggressive lymphoma. Aside from those indications, the usefulness of PET-CT is less well defined, and should be discussed in consultation with oncology colleagues.
Differential of suspected malignancy with lymphadenopathy
The differential and the workup would vary according to the specific lymph node region involved (outlined in Figure 177-3):
Cervical LN: Highest on the differential is head and neck cancer, workup includes PET/CT, pan-endoscopy with laryngoscopy, staging bilateral tonsillectomies, and bronchoscopy, and biopsy for immunohistochemistry (IHC).
Supraclavicular LN: Highest on the differential is abdominal primary (however, lung, head and neck, breast, ovary, and prostate can metastasize to supraclavicular LN), workup includes CT of neck/chest/abdomen and pelvis, endoscopy with EGD and colonoscopy, and biopsy for IHC.
Isolated axillary LN: Highest on the differential in females is breast cancer, workup includes mammogram, breast US, and biopsy for IHC.
Inguinal LN: Highest on the differential is squamous cell of cervix/anus, workup includes CT of neck/chest/abdomen and biopsy for IHC.
Differential of lymphadenopathy by lymph node region. (Adapted, with permission, from Mescher AL. Junqueira’s Basic Histology: Text and Atlas, 14th ed. New York, NY: McGraw-Hill Education; 2016. Fig. 14-1.)
As noted above, it is important to rule out infection, autoimmune disorders, reactive causes, granulomatous diseases, etc. For the next steps in assessing a patient with lymphadenopathy, multiple factors must be considered, such as location of enlarged LN (see Figure 177-3), size, duration, and likelihood of malignancy when deciding what and how to attempt a diagnostic biopsy. In general, biopsy should be considered for LNs that are persistent (>4 weeks, or despite antibiotic treatment), hard, and fixed/matted.
When considering a biopsy, the principals discussed in Case 177-1 apply here as well. However, with lymphadenopathy and any concern for lymphoma, an excisional biopsy is ideal to preserve architecture for an accurate diagnosis. Biopsy sites that have the highest yield include the supraclavicular and axillary, whereas the inguinal LNs have the lowest yield and are most often reactive.
Management priorities in cases such as the one described above focus on identifying any evidence of upper airway obstruction as a result of a head and neck primary, which is a life-threatening emergency that requires immediate diagnosis. Involve specialists such as ENT or anesthesia urgently to ensure airway is patent; if any concerns exist, the goal should focus on airway management with steroids, epinephrine, consideration of heliox, or even intubation if patient does not improve.
Other considerations for patients with diffuse lymphadenopathy concerning for an aggressive lymphoma is evaluation for tumor lysis syndrome. Often tumor lysis syndrome occurs after the start of treatment, but can occur spontaneously with aggressive cell turnover causing lysis and release of K, P, nucleic acids, which can lead to renal and cardiac complications. Key labs to evaluate for tumor lysis syndrome include uric acid, K, P, Ca, and Cr. Management focuses on aggressive hydration, treating hyperkalemia, hyperphosphatemia, symptomatic hypocalcemia, and elevated uric acid. Elevated uric acid can be managed with either allopurinol, which inhibits xanthine oxidase to decrease uric acid production, or Rasburicase in severe cases, which breaks down existing uric acid (see Chapter 176 [Oncologic Emergencies] for additional information).
CASE 177-4 MEDIASTINAL MASS
A 35-year-old male presents to the hospital with a history of feeling “congested” for several weeks. He also notes progressive shortness of breath with exertion and fatigue. He was treated initially with a 7-day course of antibiotics, and his symptoms improved slightly but have not resolved. In addition, he has noted progressive head/neck/arm swelling. The review of systems was negative. Specifically, he has no fevers, weight loss, night sweats, cough, or hemoptysis. He had no prior operations and was on no other medications. He did not use alcohol, tobacco, or drugs. There was no family history of malignancy.
On examination, temperature was 98.2, BP 120/71, HR 110 bpm. Notably, there was evidence of facial edema, upper extremity edema, distended veins over the chest wall, and a positive Pemberton’s sign (worsening of his respiratory symptoms, cyanosis, and facial congestion after he elevated his arms in the air). The rest of the physical exam was unremarkable. Plain films of the chest and neck showed a widened mediastinum with concern for a large mediastinal mass.
Approach if suspected malignancy involves mediastinal mass
Mediastinal masses can be malignant or benign, and generally form in the membranous portion between the lungs where the heart, large arteries/veins, trachea and bronchi, and esophagus reside. This area is separated anatomically into the anterior, middle, and posterior mediastinum. Most patients with mediastinal masses are asymptomatic, however patients can present, such as in the example above, with symptoms related to extrinsic compression on the vessels, nerves, esophagus, or airways.
A comprehensive history is important, including an evaluation for any prior radiation, chemotherapy, and chemical exposure (asbestos/silica/diesel exhaust, etc), and a thorough physical exam should be performed.
Labs include β-HCG, AFP for men followed by testicular US if markers if elevated, PTH if parathyroid adenoma is suspected, and antiacetylcholine receptor antibodies if there is concern for thymic tumor with myasthenia gravis.
Initial imaging with a CXR is appropriate. Once a mediastinal mass is identified, or if suspicion remains despite a negative CXR, a CT scan with contrast is necessary, unless the use of contrast is contraindicated. CT scanning is the most appropriate and valuable imaging modality for evaluating mediastinal masses.
The differential diagnosis for mediastinal masses is broad and largely based on age, symptoms, and anatomic location of the tumor. The initial step is to identify which compartment (anterior, middle, or posterior) the tumor is located, thus narrowing the differential, as summarized in Table 177-3.
TABLE 177-3Common Etiology of the Mediastinal Mass ||Download (.pdf) TABLE 177-3 Common Etiology of the Mediastinal Mass
|Anterior Mediastinum ||Middle Mediastinum ||Posterior Mediastinum |
Thymoma or thymic cyst
Teratoma/germ cell tumor
Metastatic disease to LN
Granulomatous involvement of LN
Bronchogenic cyst or tumor
The most common etiologies of an anterior mediastinal mass is a thymic mass (70% are benign, 30% are malignant) or a lymphoma (Hodgkin’s or Non-Hodgkin’s lymphoma/NHL). Others include germ cell tumors, thyroid masses, goiter, aneurysm, metastatic carcinoma, parathyroid adenoma, lipoma, or a hernia. The pneumonic 5Ts (Thymus tumor, Thyroid tumor, Teratoma, Terrible lymphoma, and Thoracic aorta aneurysm) is often used to remember the differential diagnosis of anterior mediastinal mass.
The most common etiology of a middle mediastinal mass is a lymphoma (Hodgkin’s or NHL) or an enlargement of the lymph nodes as a result of malignancy or granulomatous disease. Others include vascular abnormalities such as aortic dissection or aneurysm, vascular masses, or benign growths from respiratory mucosa or pericardium, known as a bronchogenic or pericardial cysts.
The most common etiology of a posterior mediastinal mass is a neurogenic tumor (nerve sheath, ganglion cell, paraganglionic tumors) or a cyst. Others include meningocele, an extension of the meninges through an opening in the spine as a result of a congenital defect, esophageal abnormalities such as acalasia, hernia, or malignancy, cysts, or areas of bone marrow expansion used for extramedullary hematopoiesis.
Although the diagnosis may be convincing based on the history and imaging, a tissue guided biopsy is normally the next step, however there are exceptions to this rule. For example, if imaging is suggestive of a thymoma, a biopsy is not necessary. It is important to consult with your surgical team and oncologists to determine if a biopsy is the next step, and what procedure is indicated.
Depending on the case scenario, a surgical biopsy may be preferred to FNA or core biopsies, in order to ensure the specimen has adequate architecture and quantity to make a diagnosis.
Often, for masses in the anterior and middle mediastinum, a diagnosis can be made with a biopsy via mediastinoscopy or anterior mediastinotomy. Alternative procedures that can achieve an adequate biopsy sample, depending on location of the mass, include endoscopic transesophageal or endobronchial ultrasound-guided biopsy, or video-assisted thoracoscopy, so it is important to organize a multidisciplinary team in these cases to determine the next step in evaluation.
As discussed above, in cases where mediastinal masses are causing symptoms, it is generally related to extrinsic compression on the vessels, nerves, esophagus, or airways, which can cause Horner syndrome, superior vena cava (SVC) syndrome, a pleural or pericardial effusion (possible tamponade), or phrenic nerve involvement. It is important to recognize these complications and manage them appropriately and in a timely fashion (see Chapter 176 [Oncologic Emergencies] for additional information).
CASE 177-5 BRAIN LESION
A 55-year-old right-handed female presented to the emergency department with complaints of word-finding difficulty for the past couple days. No weakness or sensory deficit. No falls. No aura like symptoms. No fever or chills. No history of seizures. She denied any trouble swallowing or hoarseness in voice. She denied any pain, changes in bowel/bladder pattern, SOB, chest pain. No nausea/vomiting. Besides the symptoms mentioned above, review of systems was positive for dull headaches, particularly on coughing for the past couple weeks.
Past medical history significant for hypercholesterolemia and gastro-esophageal reflux disease. No known history of malignancy or radiation exposure. Family history positive of coronary artery disease on paternal side. Excellent performance status (KPS = 90).
Examination was remarkable for slurred speech. No cranial nerve deficit noted. No sensory or motor weakness. Labs did not reveal any hematological or metabolic abnormality. She underwent a CT scan of the brain which revealed a 1.4 cm lesion in the left frontal lobe suggestive of brain metastasis. She was started on decadron and admitted to the inpatient hospitalist service for further workup and management.
While brain metastasis usually present later in the course of malignancy, in about 10% of patients brain metastasis is the presenting feature of malignancy. The key step in the assessment is to distinguish brain metastasis from primary brain malignancy and other nonmalignant causes.
Differential if suspected malignancy involves brain metastases
While any malignancy can potentially cause brain metastasis, the common malignancies associated with brain metastasis include:
In general, majority of metastasis occur in the supratentorial region, usually in the vascular border and gray-white matter junction, but cerebellar metastasis can also occur.
Approach if suspected malignancy involves brain metastases
While clinical features from brain metastasis can mimic other neurological conditions, presence of headache that increases with cough or bending (brain metastasis raise intracranial pressure), acute onset of focal neurological deficit in a patient with known history of malignancy, should raise the possibility of brain metastasis. A complete physical exam should be performed, including a breast and axillary exam specifically in females (to evaluate for breast lump and axillary lymphadenopathy). Laboratory studies include CBC with differential, chemistry panel, and relevant tumor markers (to help with differential diagnosis of malignancy).
While patients may have had brain metastasis diagnosed by CT scan, a dedicated MRI with contrast is usually required to (a) delineate the specific lesion better and (b) identify other sites of brain metastasis, particularly in the posterior fossa. Multiple brain metastases usually indicate spread from other sites as opposed to primary brain malignancy. Brain metastasis from renal cell carcinoma, melanoma, and choriocarcinoma usually tend to be hemorrhagic with tendency to bleed, as opposed to metastasis from other solid tumors, and therefore, anticoagulation should be considered in caution in patients with these malignancies.
Besides MRI with contrast, if brain metastasis is suspected (as opposed to primary brain malignancy), then obtaining restaging CT scans is often helpful in identifying the potential primary site of tumor origin. In particular lung cancer should be high on the differential, and if needed PET scan should be considered. If breast cancer is suspected, then mammogram and/or breast ultrasound (breast MRI in premenopausal women with dense breasts) should be considered.
While brain biopsies can be technically challenging, whenever possible a brain biopsy should be obtained in a patient presenting with brain metastasis, particularly solitary brain metastasis without any systemic evidence of disease. The biopsy can help distinguish between primary brain malignancy, metastasis, or nonmalignant cause, such as infection, and can also help narrow down the primary site of tumor origin.
Sometimes, resection of a solitary brain lesion is preferred to a biopsy as it can be both diagnostic and therapeutic. Accordingly, neurosurgery should be consulted early in the admission of a patient admitted for brain metastasis.
Questions related to prognosis often come up in such admissions. A graded prognostic index called recursive partitioning analysis (RPA) can be helpful in this scenario. Class 1 RPA refers to young patients (<65 years) with good KPS (>70) and no/controlled systemic disease, while class 3 RPA includes patients with poor KPS (<70), and class 2 includes those who do not fall in class 1 or 3. Patients with class 1 RPA have a better prognosis as compared to those with class 3 (median 7.1 vs 2.3 months). However, the prognosis is also dependent on site of primary malignancy (in general patients with breast cancer do better than those with lung cancer), and the RPA score has been modified as diagnosis-specific graded prognostic index (DS-GPA) to account for the type of malignancy.
Management priorities in cases such as the one described above should focus on distinguishing brain metastasis from other diagnostic possibilities and identification of the primary site of malignancy, as outlined in Table 177-4.
TABLE 177-4Management Priority for a Patient Presenting with Brain Lesion ||Download (.pdf) TABLE 177-4 Management Priority for a Patient Presenting with Brain Lesion
|Diagnosis ||Presentation ||Evaluation ||Management |
|Brain lesion ||Headache that increases with cough or bending, focal neurological deficit || |
MRI brain with contrast.
Staging scans to identify primary site.
Mammogram and/or breast ultrasound if breast cancer suspected.
In certain instances, surgical resection is preferred as it can be diagnostic and therapeutic.
Avoid anticoagulation in hemorrhagic brain metastasis (usually melanoma, renal cell carcinoma, and choriocarcinoma.)
In the case above, the patient had an MRI brain which demonstrated a left frontal enhancing circumscribed lesion measuring 1.5 cm in greatest dimension. No evidence of any other lesion. The patient underwent surgical resection of the brain lesion which demonstrated metastatic adenocarcinoma, ER/PR negative, HER2 positive, TTF-1 negative. Staging CT scans revealed no radiological evidence of disease. Mammogram and breast ultrasound revealed a 1.3 cm lesion in the left outer quadrant. Breast sore biopsy revealed adenocarcinoma, ER/PR negative, HER2 positive, with histological features similar to the brain metastasis. The patient was referred to a medical oncologist and was started on systemic anti-HER2 based therapy.
Generally, patients with suspected malignancy do not require hospital admission, and most can be treated as outpatients with an expedited workup. Exceptions include patients with rapidly progressive disease that need urgent chemotherapy (eg, small cell carcinoma, lymphoma), oncological emergencies, or other medical concerns that require urgent evaluation and intervention, such as the following:
Acute complications of malignancy, for example perforation, bleeding, or fistula
Biliary or bowel obstruction
High-grade esophageal obstruction with inability to manage oral secretions or maintain hydration
Protracted vomiting, inability to maintain hydration or nutrition
The tumor marker name is a bit of a misnomer, as tumor markers are not specific to malignancy and may be present in benign conditions or falsely elevated with liver disease or renal failure, and therefore need to be interpreted with caution. Tumor markers are not 100% sensitive and negative tumor markers cannot rule out the possibility of malignancy. Similarly tumor markers are not 100% specific and positive tumor markers cannot replace a histological diagnosis.
The diagnostic utility of tumor markers is predominantly as an adjunctive test to aid in evaluating patients hospitalized with a clinical presentation of suspected advanced malignancy and should largely be confined to cases where a certain primary is favored (see Table 177-5). For example, a high or rising PSA, a marker of prostate cancer, is helpful in a male patient over 40 years of age with suspected malignancy presenting with osteoblastic metastases. The markers of a germ cell tumor, such as β-HCG and AFP, can be helpful in males presenting with midline masses. Similarly, in a patient with known liver disease, a rising AFP can be suggestive of hepatocellular carcinoma. Common tumor markers and the associated malignancies are outlined in Table 177-5.
TABLE 177-5Common Tumor Markers Associated with Solid Tumors ||Download (.pdf) TABLE 177-5 Common Tumor Markers Associated with Solid Tumors
|Tumor Marker ||Tumor Type |
|CEA ||Colon adenocarcinoma, hepatocellular |
|CA 19-9 ||Pancreatic, biliary tract |
|NSE ||Neuroendocrine tumors, small cell lung cancer (SCLC), carcinoid |
|CA 15.3, CA 27.29 ||Breast cancer |
|CA 125 ||Ovarian cancer |
|PSA ||Prostate cancer |
|AFP ||Hepatocellular carcinoma, germ cell tumor |
|β-HCG ||Germ cell tumor, gestational trophoblastic disease |
IMMUNOHISTOCHEMISTRY AND TISSUE DIAGNOSIS
Tissue diagnosis remains the goal-standard test in cases of suspected malignancy. The general principle is to acquire enough tissue to allow for diagnosis, accurately stage the patient, and perform the necessary molecular testing, including genomic testing for targetable mutations.
A core or excisional biopsy is preferred, considering fine needle aspiration often results in insufficient tissue and loss of the detailed histology needed for diagnosis. Inadequate tissue limits the number of special studies that can be done on the sample, and therefore can have major implications for treatment (see Table 177-6 for examples of cancers with known targetable mutations and FDA approved treatments), or even necessitate a second biopsy. Often, determining the site to biopsy is a multidisciplinary discussion with radiology, the oncology consult, and interventional radiology or surgery.
TABLE 177-6List of Specific Genomic Alterations and Matched Targeted Therapy ||Download (.pdf) TABLE 177-6 List of Specific Genomic Alterations and Matched Targeted Therapy
The key to diagnosis is immunohistochemical classification, as it is reliable, inexpensive, and generally available. Cytokeratins (CKs), proteins in the intermediate filament protein family, in epithelial cells are particularly useful in the diagnosis of malignancy. Expression of these cytokeratins is often specific to tissue or organ, and can aid in correctly identifying the origin of the tumor. CK 7 generally involves tissue from the lung, ovary, endometrium, or breast, whereas CK 20 is usually expressed in the colon or Merkel cells. The combination of CK 7 and CK 20, either both present or both absent, also proves to be useful in identifying a primary site (see Figure 177-4). Once cytokeratin profiling by CK 7 and CK 20 have narrowed the possible tumor origin, additional IHC can also be informative. For example, certain cancers have specific profiles.
Breast: Estrogen (ER) and Progesterone Receptor (PR) +, HER2 +, Mammaglobin +
Lung Adenocarcinoma: TTF-1 +, NapsinA +
Lung Squamous Cell Carcinoma: P63 +, CK5/6 +
Lung Small Cell Carcinoma: TTF-1 +, Synaptophysin +
Prostate: Prostate Specific Antigen +, Prostate Acid Phosphatase (PAP) +
Melanoma: S100 +, Vimentin +, Melan-A +
Neuroendocrine: Chromogranin +, Synaptophysin +, CD56 +
Hepatocellular: Alpha-fetoprotein (AFP) +, HepPar-1 +
Germ cell: HCG +, AFP +, Oct4 Transcription Factor +, PAP +
Immunohistochemical features of common cancers. (Adapted, with permission, from Varadhachary GR, Abbruzzese JL, Lenzi R. Diagnostic strategies for unknown primary cancer. Cancer. 2004;100:1776-1785.)
In oncology, molecular profiling of the tumor is being increasingly utilized to select specific marched targeted therapies as outlined in Table 177-6. For example, breast cancer is no longer considered one disease and it is a routine practice to obtain the status of ER (estrogen receptor) and HER2 (Human Epidermal Growth Factor Receptor 2) to select specific targeted therapy. Similarly, lung cancer is divided by presence/absence of EGFR mutation, ALK fusion, and there are a few others in development. The key is to detect an actionable alteration that could guide therapy and potentially lead to better outcomes.
In addition, molecular profiling may have diagnostic benefit and could be considered in the workup of a patient with suspected malignancy in which the primary cannot be established. The tissue-of-origin molecular profiling assays take advantage of the fact that there are specific gene expression profiles, depending on the site of origin of the tumor. They can identify a probable primary site of origin up to 70% to 98% of the time. Historically, these cases of “cancer of unknown primary” represent 5% of all newly diagnosed patients with solid malignancies each year, and have a poor prognosis (approximately 9 months when treated with empiric chemotherapy). With tissue-of-origin molecular profiling and site-specific directed chemotherapy, or targeted therapy, this increased to 12.5 months in one study performed at Sarah Cannon Research Institute, which is a promising for the future investigation into the use of this tool. However, as of this publication, as the clinical utility of gene signature profiling has not been proven, routine gene signature profiling to identify tissue of origin is not routinely recommended as standard of care according to the National Comprehensive Cancer Network.
The discharge planning process must ensure that the patient’s care needs can be met once they leave the acute hospital setting. Following a hospitalization for a suspected malignancy, many patients require ongoing medical care, the details of which will be unique to each patient presentation. If any drains or catheters were placed during the hospitalization, it is important to ensure the patient is aware of the follow-up plan, has services scheduled or knows how to care for the drain or catheter, knows if they are safe to shower or bathe, and knows how to check for signs of infection.
Often a biopsy will be performed in the hospital, or scheduled on discharge. If the biopsy will be after discharge, consider notifying the patient to stop taking aspirin and NSAIDS 7 days before the procedure if appropriate, fast after midnight the day night before, and arrange a caregiver to drive them home and stay with them following the biopsy. Whether the biopsy is inpatient or outpatient, if results are not available it is helpful to set expectations and explain that the pathologist needs to process the sample, which can take 7 to 10 days or longer. Ensure the patient has a contact name/number in case they are not notified of any results within that timeframe.
Importantly, a quarter of patients become clinically depressed after a diagnosis of cancer, while others can suffer from extreme stress or anxiety. It is helpful to tell patients the signs and symptoms of these conditions, and encourage them to reach out to others such as their provider team after discharge, friends, family, and support groups (American Cancer Society programs may be offered in the area—1-800-227-2345). Early intervention with palliative care follow-up, focusing on psychological and physical symptoms, should be considered in certain circumstances, as there are adequate data to show a quality of life and possible survival benefit in patients with advanced disease. The Center to Advance Palliative Care and the American Cancer Society states “palliative care is appropriate at any age and at any stage in a serious illness, and can be provided together with curative treatment.” Try to provide encouragement and instill that adequate sleep, eating, light exercise, and a daily schedule can be ways of ensuring they stay mentally and physically healthy to optimize the chances of success during cancer management.
DISCHARGE CHECKLIST FOR DISORDER
If a biopsy occurred in the hospital, patient is aware of how to care for the site and has follow-up if required (eg, to remove stitches).
Any necessary home medical equipment (oxygen, nebulizer, walker, etc) has been scheduled for delivery, and the patient has been provided education to ensure proper and safe use.
Medications and management of side effects (eg, pain medication causes constipation so laxative use should be addressed) have been reviewed.
Patient is aware of what to expect, and has a provider name/number to contact if he/she experiences any fever, infection, severe pain, bleeding, or other concerning symptoms.
All follow-up tests and appointments have been scheduled, and patient is aware of date, location, and time of each, and can arrange necessary transportation to these visits.
The patient or family have been asked if they require any documentation to address employment issues or family medical leave.
et al. Lymphadenopathy and malignancy. Am Fam Physician. 2012;66:2103–2110.
et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute. J Clin Oncol
DL. Approach to the patient with cancer. In: Kasper
et al, eds. Harrison’s Principles of Internal Medicine, 19th ed. New York, NY: McGraw-Hill Education, 2015:467–475.
et al. Utility of serum tumor markers as an aid in the differential diagnosis of patients with clinical suspicion of cancer and in patients with cancer of unknown primary site. Tumour Biol
et al. Imaging of liver metastases: MRI. Cancer Imaging
et al. Cancer statistics, 2015. CA Cancer J Clin
et al. Carcinoma of unknown primary site. N Engl J Med
et al. Application of a prediction rule to select which patients presenting with lymphadenopathy should undergo a lymph node biopsy. Medicine (Baltimore).