A 66YearOld Man with Lung Cancer

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A 66-Year-Old Man with Lung Cancer
Eugene G. Martin, Ph.D. Professor of Pathology
Laboratory Medicine

• Based upon LABORATORY MEDICINE CASEBOOK. An
  introduction to clinical reasoning
• Jana Raskova, MD Professor of Pathology
  Laboratory MedicineStephen Shea, MD
  Professor of Pathology Laboratory
  MedicineFrederick Skvara, MD Associate
  Professor of Pathology Laboratory MedicineNagy
  Mikhail, MD Assistant Professor of Pathology
  Laboratory MedicineUMDNJ-Robert Wood Johnson
  Medical SchoolPiscataway, NJ

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D_F_E_E_T

• R F U Y
• R N I F
• S G I R
• G L E T

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Fastest Responders (in seconds)
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History

• 66 year old male brought to the emergency room
  after he was found to be unresponsive at home.
• Blood sugar was 28 mg/dL (Normal 65-110).
• Regained consciousness after administration of
  dextrose.
• Diagnosed 3 months earlier as having diabetes
  mellitus and started on insulin.
• At the time of that diagnosis chest x-ray
  revealed a mass in left lung bronchogenic
  carcinoma
• Treated with three cycles of chemotherapy, the
  last 6 days ago.

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What questions does this history elicit?

• Why the sudden onset of DM?
• How come his glucose suddenly dropped to 28
  mg/dl?
• How big a problem is glucose of 28 mg/dL

• Could the presence of a lung cancer result in DM?
• What does chemotherapy have to do with this
  story?
• Are there other possibilities?
• What do you worry about here?

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Physical findings

• Physical Exam
• Confused and lethargic man.
• BP 150/90 HR 92bpm
• Temperature 98.8 oC
• Respiratory rate 26 per minute
• Decreased breath sounds on the left side
• Marked weakness of both legs
• Puffy appearance of the face

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What questions do the physical findings elicit?

• Does he have a history of hypertension or is the
  combination of hypertension and an elevated HR
  suggestive of something reflexive? Such as?
• What is the meaning of puffy?
• Why is he so weak?

• Should they have done a supine and standing BP?
  Why?

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Questions from the physical

• Does this patient have orthostatic hypotension?
  (Defn A fall in BP 30/20 on standing). Answer
  YES
• One of the consequences of blood loss is an
  inability to maintain blood pressure upon
  standing. One of the physiologic responses is an
  increase in HR.

• What is the significance of determining a supine
  and a standing BP?
• Is the HR 96 bpm significant?

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HEMATOLOGY At Admission
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Peripheral Blood Smear
Patient
Normal

• Normochromic, normocytic anemia.
• Red cell population is decreased in number
• Cell size and shape normal
• Platelets and neutrophils are unremarkable
• None of this information adds anything to the
  automated hematology count shown earlier

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Questions from the Hematology Results

• Does this patient have anemia? If so, what kind?
• What info do you still need?

• Normochromic, normocytic anemia
• Reticulocyte ?
• Hemolytic disease
• Acute blood loss
• Reticulocyte normal
• Malignancy
• Myeloma
• Chronic Disease
• If this patient had a chronic blood loss for more
  than 6 months you would expect a hypochromic,
  microcytic anemia

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Anemia Assessment

• ?Normocytic, normochromic anemia
• Reticulocyte ?
• Hemolytic disease
• Acute blood loss
• Reticulocyte normal
• Malignancy
• Myeloma
• Chronic Disease
• Macrocytosis is seen in
• Megaloblastic anemias ?
• vitamin B12 and folate deficiency
• Some forms of chronic liver disease
• Microcytosis and hypochromia
• Iron deficiency anemia
• Spherocytosis
• Some forms of anemia of chronic disease

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CHEMISTRY
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Why

• What is the significance of the elevated LDH?
• Why is LDH3 relatively low and LDH2 relatively
  high?
• What is the significance of elevations of both
  LDH, GGTP and Alk. Phos.?

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Lactate Dehydrogenase

• Found most everywhere
• Five fractions (isoenzymes)
• LDH-1 is found primarily in heart muscle and RBCs
• LDH-2 - heart, red blood cells, kidney (lesser
  amounts than LDH-1)
• LDH-3 - highest in the lung.
• LDH-4 - highest in the kidney, placenta, and
  pancreas.
• LDH-5 - highest in the liver and skeletal muscle.
  
• Relative amounts of a particular isoenzyme of LDH
  in the blood can provide diagnostic clues.

• Normal
• LDH Type 1
• LDH Type 5
• Abnormal
• LDH Type 1 LDH Type 2
• Myocardial Infarction
• Hemolytic Anemia
• Pernicious Anemia
• Renal infarction
• LDH Type 5 LDH Type 4
• Liver disease

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Liver enzymes and cancer

• ? LDH seen in 50 of patients with CA
• ? GGTP is also commonly seen in patients with
  cancers WITH or WITHOUT liver mets.
• ? Alk. Phos. Also commonly seen in patients with
  cancers WITH or WITHOUT liver mets.
• If biliary obstruction by tumor ? ? serum
  bilirubin and a MUCH greater ? in alk. Phos.

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Additional Studies
Arterial Blood Gases
Electrolytes
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The primary acid-base disturbance is

• Respiratory acidosis
• Metabolic Alkalosis
• Metabolic Acidosis
• Respiratory alkalosis

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Learning Response

• ANSWER The primary disturbance is a partly
  compensated metabolic alkalosis
• ? pH - alkalosis
• ? HCO3
• ? PCO2
• Total CO2

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Diagnosis of Acid-Base Disorders
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Vomiting

• Acid-losing alkalosis (Metabolic alkalosis)
• The gastric mucosa produces HCl by carbonic
  anhydrase mediated conversion of H2CO3 ? HCO3-
  and H
• Gastric HCl is lost in vomiting
• H is continually being lost. H2CO3 is
  continually being consumed
• CO2 component ? because the HCO3- that is
  released when HCl is produced remains in the
  blood stream and gets broken down
• Because H2CO3 is decreased the lungs tend to
  retain CO2 to compensate generally not
  sufficient to prevent an increase in the usual
  201 ratio of HCO3- to H2CO3

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What is a Paraneoplastic Syndrome

• Clinical syndromes involving non-metastatic
  systemic effects that accompany malignant
  disease.
• Collections of symptoms that result from
  substances produced by the tumor which occur
  remote from the tumor itself.
• Symptoms may be endocrine, neuromuscular,
  cardiovascular, cutaneous, hematologic, GI, renal
  or misc.

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Clinical Course

• Patients glycemia stabilized
• Electrolyte abnormalities were corrected by
  appropriate replacement therapy
• MRI of brain was normal.
• Why did they do this?
• Additional studies ordered
• What would make sense?

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Hypothalamic Pituitary Axis
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Patients with tumors that secrete ACTH or
ACTH-like

• Hypokalemic nephropathy
• Urinary potassium leakage of more than 20 mEq per
  24 hrs.
• Occurs in 50 of individuals with ACTH-secreting
  tumors of the lung.

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What studies would you order? Why?
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HEMATOLOGY
Death due to septic shock on day 9 (15 days after
the last cycle of chemotherapy
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AUTOPSY FINDINGS
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Bone Marrow findings

• Normal bone marrow biopsy
• Cellularity is normal with adequate numbers of
  fat cells and a heterocellular hematopoietic cell
  population
• Bone marrow at autopsy (15 days post
  chemotherapy)
• Marked hypocellularity
• No evidence of tumor is present

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Liver

• Note edge of tumor nodule with infiltration by
  clumps of tumor cells between adjacent hepatic
  cords.
• Tumor cells spindle shaped consistent with small
  cell CA of the lung

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Chest x-Ray

• Left Lung Mass Primary lung CA
• Possible adjacent pneumonia

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Histopathology Lung Mass

• HE x12
• Sheets of darkly staining cells, areas of
  necrosis and fibrosis.
• No glandular or squamous differentiation is
  apparent
• HE x50 Small Cell CA
• Small cells with little cytoplasm
• Nuclei are oval and spindle-shaped and mitoses
  are frequent
• Focus of necrosis present

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CT Abdomen

• Bilateral adrenal hyperplasia
• Right gland appears larger than left at this level

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Case Summary

• Final Diagnosis
• Small Cell CA of lung
• Post chemotherapeutic sepsis
• Ectopic ACTH production by Small Cell CA
• ? hyperglycemia and Diabetes Mellitus
• ? bilateral adrenal hyperplasia
• Hyperaldosteronism documented
• ? Electrolyte abnormalities

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Small Cell CA

• Strongly associated with a history of cigarette
  smoking
• Only 1 occur in non-smokers.
• Originates in central or hilar area of the lung
• Metasizes early and widely
• Initial response to chemotherapy or radiation is
  good

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QUESTIONS
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Why the sudden onset of DM?

• Septic shock
• Aplastic anemia
• Anemia of chronic disease and lymphopenia
• Vitamin B12 deficiency
• Post-chemotherapeutic myelosuppression?

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Learning Response

• ANSWER 3 -- changes compatible with chronic
  disease and lymphopenia
• CBC shows normochromic, normocytic anemia and
  lymphopenia
• Cells of myelomonocytic origin and platelets are
  within the normal range
• r/o myelosuppression
• r/o a septic state
• Vitamin B12 defic ? macrocytic anemia
• Aplastic anemia is characterized by pancytopenia

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What was the most likely cause for his glucose
suddenly dropped to 28 mg/dl?

• Osmotic diuresis of hyperglycemia
• Hemolyzed blood sample
• Increased production of aldosterone
• Vomiting
• Diarrhea

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Learning Response

• ANSWER 2 Hemolyzed blood sample
• Hemolyzed blood specimens give artificially
  elevated levels of serum K. RBCs split apart.
  High concentration of K intracellular
• All other options (Vomiting, Diarrhea, Inc.
  Aldosterone and Hyperglycemia) lead to a loss of
  K.

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What is the greatest danger of a sugar of 28?

• Extra hepatic biliary obstruction
• Myocardial Infarction
• Muscle Disease
• Malignancy and possible liver involvement

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Learning Response

• Answer (4) The presence of malignancy and
  possible liver involvement
• Extrahepatic biliary obstruc. ? an ? in serum
  bilirubin AND a larger ? in Alk. Phos. than is
  seen here
• This group of enzymes is not helpful in
  differentiating myocardial infarction or muscle
  disease.
• ? total LDH, with a non-specific isoenzyme
  pattern is seen in 50 of patients with
  carcinoma PARTICULARLY in advanced stages.
• An ? in serum GGTP is seen in a variety of
  carcinomas, including lung cancer EVEN in the
  absence of liver metastases.
• Serum Alk. Phos. may be produced by lung neoplasm
  in the absence of liver involvement

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How could the presence of a lung cancer result in
DM?

• Diabetes is likely due to his hypercortisolism
• Hypercortisolism is due to the primary adrenal
  problem
• Ectopic production of ACTH by the tumor
• Electrolyte abnormalities are due to ?
  aldosterone production

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Learning Response

• Answer (2) Hypercortisolism is due to the primary
  adrenal problem
• Ectopic production of ACTH by the tumor -?
  hypercortisolism
• Cortisol inhibits glucose uptake in most tissues
  ? hyperglycemia and DM
• ? ACTH is most likely due to production in the
  lung tumor, not by an enlarged pituitary
• Brain MRI Normal
• Induces bilateral adrenal gland hyperplasia
• Electrolyte abnormalities are typical of
  hyperaldosteronism - ? aldosterone documented

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Most common type of lung cancer associated with
ectopic hormone production is

• Small cell carcinoma
• Adenocarcinoma
• Squamous cell carcinoma
• Large cell carcinoma

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Learning Response

• ANSWER (1) The most common type of lung cancer
  associated with ectopic hormone production is a
  small cell carcinoma
• Small cell carcinomas originate from
  neuroendocrine cells of the bronchial epithelium
• Neuroendocrine cells are capable of producing ACTH

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The most common lung cancer in women and
non-smokers?

• Small cell carcinoma
• Adenocarcinoma
• Squamous cell carcinoma
• Large cell carcinoma

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Learning Response

• Answer (2) Adenocarcinoma
• Adenocarcinoma of the lung is the MOST COMMON
  primary lung cancer in women and non-smokers

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Which is INCORRECT?...

• Small cell carcinoma of the lung most often
  starts in the central or hilar region
• Small cell carcinoma of the lung is usually NOT
  associated with a history of cigarette smoking
• Small cell carcinoma of the lung tends to
  metastasize widely
• Small cell carcinoma of the lung best responds to
  chemotherapy and radiation therapy

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Learning Response

• Answer (2) Small cell carcinoma of the lung is
  strongly associated with a hx. of cigarette
  smoking
• Only 1 of Small Cell Carcinomas occur in
  non-smokers.
• Small cell carcinomas originate in the central
  or hilar region, metastasize early and widely,
  and initially respond well to chemotherapy and/or
  radiation therapy.