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Clinico-Pathological Conference September 9, 2008 12 Noon, Mountcastle Auditorium PreClinical Teaching Building Questions: (1) What is the most likely cause of the neck, abdominal, and lung lesions? (2) If the lesions are malignant, what is the most likely site of origin? (3) What types of malignancies often present with metastatic disease of clinically unclear origin? Delirium in the Setting of Metastatic Cancer (present in 20-86% of cases; reversible in ~50%) Metabolic Abnormalities hypercalcemia hyperglycemia hyponatremia/hypernatremia uremia hepatic failure others Hypoxia Medications opiates benzodiazepines corticosteroids many others Infections Brain/Leptomeningeal Metastases Bowel/Bladder Obstruction Others Delirium in the Setting of Metastatic Cancer (present in 20-86% of cases; reversible in ~50%) Metabolic Abnormalities hypercalcemia hyperglycemia hyponatremia/hypernatremia uremia hepatic failure others Ca2+ = 11.0 mg/dL (8.5-10.5 mg/dL) Hypoxia ionized Ca2+ = 1.41 mM (1.12–1.32 mM) PTH = 13 ng/L (10-65 ng/L) Medications opiates benzodiazepines corticosteroids many others Infections Brain/Leptomeningeal Metastases Bowel/Bladder Obstruction Others Hypercalcemia of Malignancy Incidence: 10% of cancer cases more common with squamous cell carcinoma of the lung, breast cancer, and multiple myeloma usually recognized late and managed poorly Pathophysiology: PTHrP other factors associated with bone metastases (RANKL, TGFa, TNF, IL-1, others) osteoclastic bone resorption often aggravated by renal insufficiency Presentation: nausea, anorexia, constipation, dehydration, polyuria, apathy, fatigue progression to obtundation and death Treatment: extracellular fluid volume expansion calciuresis bisphosphonates calcitonin, gallium nitrate, others Common Oncologic Conditions Requiring Urgent Evaluation and Intervention Spinal epidural cord compression Brain/leptomeningeal mestastases with intracranial edema Hypercalcemia Leukostasis Vascular obstruction (eg. superior vena cava syndrome) Intestinal obstruction Urinary obstruction Tracheal obstruction Others Common Oncologic Conditions Requiring Urgent Evaluation and Intervention Spinal epidural cord compression Brain/leptomeningeal mestastases with intracranial edema Hypercalcemia Leukostasis Vascular obstruction (eg. superior vena cava syndrome) Intestinal obstruction Urinary obstruction Tracheal obstruction Others Work-up of a Suspected Metastatic Cancer Initial evaluation history and physical examination Questions for consultant complete blood count specialist: serum electrolytes (i) Does this woman have a cancer? serum liver enzymes/bilirubin (ii) Is it curable? serum creatinine (iii) Is it treatable to prolong life or serum calcium improve quality-of-life? urinalysis (iv) Can she tolerate treatment? chest radiograph stool hemoccult evaluation symptom-directed endoscopy *PET or PET-CT scan for glucose uptake serum cancer biomarkers (AFP, b-HCG, PSA, CA125, CEA) Biopsy fine needle aspiration (FNA) or core needle biopsy most accessible site consult pathologist for adequacy of specimens and need for immunohistochemisty/molecular biology assessment Work-up of a Suspected Metastatic Cancer Initial evaluation history and physical examination complete blood count- anemia, leukocytosis serum electrolytes-hyponatremia serum liver enzymes/bilirubin serum creatinine serum calcium-hypercalcemia urinalysis chest radiograph/CT/MR-right kidney mass; liver, lung, bone, stool hemoccult evaluation lymph node, muscle lesions symptom-directed endoscopy *PET or PET-CT scan for glucose uptake serum cancer biomarkers-elevated CEA Biopsy fine needle aspiration (FNA) or core needle biopsy most accessible site consult pathologist for adequacy of specimens and need for immunohistochemisty/molecular biology assessment Carcinoembryonic Antigen (CEA) Glycoprotein involved in cell adhesion encoded by member of the immunoglobulin gene superfamily (the carcinoembryonic antigen family consists of some 29 genes) First identified in 1965 by Phil Gold and Samuel O. Freedman in human colon cancer tissue extracts Serum from individuals with colorectal, gastric, pancreatic, lung, hepatocellular, and breast carcinomas, or with medullary thyroid carcinoma, often have higher levels of CEA than healthy individuals Serum CEA testing best used for monitoring cancer recurrences after surgical resection Serum CEA levels are also elevated in smokers, in preneoplastic conditions (eg. colonic polyps), and in non-cancerous conditions such as ulcerative colitis, pancreatitis, and cirrhosis Cancer of Uncertain Primary Origin Primary site of origin is never found for some 2-6% of adults with metastatic cancer (the site of origin is still not evident in 15-25% even at post-mortem examination) Clinical clues: pattern of spread presence of serum biomarkers Most are adenocarcinomas (~60%; lung cancer, etc.) others include: poorly differentiated carcinoma (20-30%), squamous cell carcinoma (5-10%), neuroendocrine carcinoma (1-5%), others Median survival ranges from 11 weeks to 11 months with an overall 5-year survival rate ~11% Pathological Findings from Biopsy of Suspected Metastatic Cancer Epithelial cancer (carcinoma) Lymphoma Thyroid cancer Melanoma Sarcoma Germ cell cancer Non-malignant diagnosis Gene Expression Profiling as an Aid to the Diagnosis of Carcinoma of Uncertain Primary Origin* classification scheme able to predict site of origin in 90% of cases *Su AI et al. Cancer Res. 61: 7388-93 (2001) “Physiological Staging”: Does the patient have any medical problems/conditions that might affect the choice of treatment if she has cancer? Systemic Chemotherapy heart disease- could be exacerbated by anthracyclenes lung disease- could be further complicated by bleomycin kidney diseases- could increase the risk of renal failure from cisplatin neuromuscular diseases- could be worsened by exposure to microtubule-targeted antibiotics uncontrolled infection- could be worsened by any chemotherapy drug that lowers white blood cell counts Radiation Therapy anatomic abnormalities- eg. a horseshoe kidney connective tissue diseases- abnormal scarring/response to damage from ionizing radiation previous radiation therapy to nearby tissues- reduces tolerance to further radiation “Physiological Staging”: Does the patient have any medical problems/conditions that might affect the choice of treatment if he has cancer? Systemic Chemotherapy heart disease- could be exacerbated by anthracyclenes lung disease- could be further complicated by bleomycin kidney diseases- could increase the risk of renal failure from cisplatin neuromuscular diseases- could be worsened by exposure to microtubule-targeted antibiotics uncontrolled infection- could be worsened by any chemotherapy drug that lowers white blood cell counts Radiation Therapy anatomic abnormalities- eg. a horseshoe kidney connective tissue diseases- abnormal scarring/response to damage from ionizing radiation previous radiation therapy to nearby tissues- reduces tolerance to further radiation Clinico-Pathological Conference September 9, 2008 12 Noon, Mountcastle Auditorium PreClinical Teaching Building Questions: (1) What is the most likely cause of the neck, abdominal, and lung lesions? Cancer, but I would like to have had a pathologist examine biopsy cells or tissues. (2) If the lesions are malignant, what is the most likely site of origin? Imaging studies suggest kidney cancer, but renal cell carcinoma typically does not produce CEA. My guess would be renal pelvis cancer (mucinous cancer, adenocarcinoma, transitional cell carcinoma) or lung cancer. However, again, I would like to have had a pathologist examine a biopsy. (3) What types of malignancies often present with metastatic disease of clinically unclear origin? Adenocarcinomas; however, almost any type of cancer can present this way. Clinical goal is to find treatable cancers. For Additional Information/Further Reading Glover KY et al. Carcinoma of Unknown Primary. In Abeloff’s Clinical Oncology, 4th Edition, Abeloff, M.D., Armitage, J.O., Niederhuber, J.E., Kastan, M.B., and McKenna, W.G. (Eds.), Elsevier Inc., Philadelphia, PA (2008).