A 66YearOld Man with Lung Cancer

1
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

2
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.

3
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?

4
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

5
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?

6
Questions from the physical

• Does this patient have orthostatic hypotension?
  (Defn A fall in BP gt 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?

7
Cushing Syndrome

• SYMPTOMS
• Acne or superficial skin infections
• Backache
• Buffalo hump (a collection of fat between the
  shoulders)
• Central obesity with protruding abdomen and thin
  extremities
• Hair growth on the face
• Headache
• Impotence (men)
• Menstrual cycle stops (women)
• Mental changes
• Moon face (round, red, and full)
• Purple marks called striations on the skin of the
  abdomen, thighs, and breasts
• Thin skin with easy bruising
• Weakness
• Weight gain (unintentional)
• Bone pain or tenderness
• Fatigue
• High blood pressure
• Muscle atrophy

• Excess secretion of hormone cortisol Cushing
  syndrome
• Also caused by
• Tumor of the pituitary gland or adrenal gland
• Tumor elsewhere in the body
• Long-term use of anti-inflammatory medicines
  called corticosteroids
• TYPICAL LAB TESTS
• WBC elevated
• Glucose elevated
• Potassium low
• FOLLOW-UP
• Is it the pituitary or something else? Check
  the feedback loop

8
HEMATOLOGY At Admission
9
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

10
Question 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

11
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

12
CHEMISTRY
13
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.?

14
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 lt LDH Type 2
• LDH Type 5 lt LDH Type 4
• Abnormal
• LDH Type 1 gt LDH Type 2
• Myocardial Infarction
• Hemolytic Anemia
• Pernicious Anemia
• Renal infarction
• LDH Type 5 gt LDH Type 4
• Liver disease

15
Liver enzymes and cancer

• ? LDH seen in 50 of patients with cancer
• ? 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.

16
Additional Studies
Arterial Blood Gases
Electrolytes
17
The primary acid-base disturbance is

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

18
Learning Response

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

19
Diagnosis of Acid-Base Disorders
20
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

21
Presentation of Lung Cancer

• Usually recognized late in its natural history
  tumor can often grow a long time before symptoms
• Of 100 newly identified lung cancers, 80 will be
  inoperable at presentation
• 5 year mortality 85-90

22
Presenting Symptoms
23
Metastatic spread of lung cancer

• 1/3 present with symptoms resulting from distant
  metastases
• Most common sites
• Bones
• Liver ? Liver Function Tests rarely are abnormal
  until metastases are large

• Adrenal glands and
• Intra-abdominal lymph nodes
• Brain and spinal cord
• Lymph nodes and
• Skin.

24
What is a Paraneoplastic Syndrome?

• DEFINITION Clinical syndrome involving
  non-metastatic, systemic effects that accompany
  malignant disease.
• Collections of symptoms that result from
  substances produced by the tumor.
• Substances include Hormones or other
  biologically active products produced by the
  tumor.
• Actions
• Activate hormone secretion
• Blockade the effect of hormones.
• Autoimmunity
• Immune-complex production, and
• Immune suppression..
• Symptoms may be endocrine, neuromuscular,
  cardiovascular, cutaneous, hematologic, GI, renal
  or misc.

25
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?

26
Adrenal Gland

• What can happen?
• Adrenals themselves malfunction ? a change in
  hormone secretion (Adrenal Hyperplasia)
• Feedback loop has been altered (e.g. ?? ACTH ? ?
  Cortisol production)
• A tumor mimics either one of the releasing
  factors ? altered production

• Medulla of adrenal gland secretes
• Epinephrine
• ? HR, ? BP, ? Cardiac Output
• ? Blood glucose levels
• Cortex of adrenal gland secretes
• Cortisol (Glucocorticoids)
• Aldosterone ?
• Electrolyte control (? Na,? K Cl-) ? ? BP
  control
• Androgens
• Testosterone (Virilization)

27
Hypothalamic Pituitary Axis
28
What studies would you order? Why?

• ACTH too high ? ? cortisol secretion
• Body fat redistribution ? Moon facies
• Excessive fat at top of back Buffalo hump
• Muscles loose their bulk ? weakness
• ? BP , weakens bones (osteoporosis), diminished
  resistance to infection
• ? Kidney stones, ? diabetes, mental disturbances
  (depression hallucination)
• Testing in AM PM Ordinarily, diurnal rthymn
  high in AM, falls in PM. Not here! Loss of
  control
• ? Aldosterone ? Na retention, K secretion

29
HEMATOLOGY
Death due to septic shock on day 9 (15 days after
the last cycle of chemotherapy
30
AUTOPSY FINDINGS
31
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

32
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

33
Chest x-Ray

• Left Lung Mass Primary lung CA
• Possible adjacent pneumonia

34
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

35
CT Abdomen

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

36
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 documented
• Hypercortisolism -
• Hyperaldosteronism ? Electrolyte abnormalities

37
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

38
QUESTIONS
39
Why the sudden onset of DM?

• Loss of Insulin Production by the Pancreas - Type
  I Diabetes
• Hes old. Its just natural Type II Diabetes
• A substance that either interferes with insulin
  secretion or inhibits cellular responses to
  insulin has been released
• Vitamin B12 deficiency
• Post-chemotherapeutic myelosuppression?

40
Learning Response

• ANSWER 3 -- A substance that either interferes
  with insulin secretion or inhibits cellular
  responses to insulin has been released
• Rapid onset of diabetes requires that insulin
  secretion be turned off, or that cells become
  unresponsive to insulin.
• Type I diabetes with destruction of the pancreas
  is uncommon in a 66 year old
• The onset of Type II diabetes is usually gradual
• Vitamin B12 has nothing to do with sudden
  diabetes
• Myelosuppression by chemotherapeutic agents would
  not effect glucose uptake or utilization by
  insulin.

41
What was the most likely cause for his glucose
suddenly dropped to 28 mg/dl?

• Increased secretion of cortisol
• Insulin administration
• Increased secretion of aldosterone
• Vomiting
• Diarrhea

42
Learning Response

• ANSWER 2 Insulin administration
• Secretion of ACTH ? Stimulation of the adrenal
  cortex and the production of cortisol. Cortisol ?
  ? glycogen stores to be release and increases
  blood glucose levels
• Increased secretion of aldosterone ? ? Na,? K,
  but has little effect on glucose levels
• Prolonged vomiting might cause cortisol to be
  released as a response to stress, which would ?
  glycogen release ? ? blood glucose, but it would
  not lower glucose levels because it would not
  increase insulin levels

43
What is the greatest danger of a sugar of 28?

• Loss of consciousness
• Spontaneous recovery will occur, its not
  dangerous
• Mild delerium
• Death

44
Learning Response

• Answer (4) - Death
• A blood sugar of 28 is a medical emergency.
  Symptoms of an insulin overdose reflect very low
  blood sugar levels and include headache,
  irregular heartbeat, increased heart rate or
  pulse, sweating, tremor, nausea, increased
  hunger, and anxiety. Insulin overdose -gt
  resultant hypoglycemia and its effects on the
  central nervous system can be life threatening
• Hypokalemia, hypophosphatemia and hypomagnesemia
  can develop with excess insulin administration

45
How could the presence of a lung cancer result in
DM?

• The pancreas is one of the principle sites for
  metastases
• Ectopic production of ACTH by small cell
  carcinomas (SCC) leads to cortisol release from
  the adrenals and conversion of glycogen to
  glucose ? diabetes
• The pituitary is often a target of metastases.
  In response the pituitary releases ACTH -gt
  diabetes
• Small cell carcinomas release glucose directly
  from the tumor

46
Learning Response

• Answer (2) - Ectopic production of ACTH by small
  cell carcinomas (SCC) leads to cortisol release
  from the adrenals and conversion of glycogen to
  glucose ? diabetes
• The pancreas is rarely a site for SCC
  metastases
• The pituitary is also an extremely rarely target
  for metastases. The feedback loop is broken
  because exogenous ACTH is released by the tumor
  and overrides the reflex control.
• Small cell carcinomas do not release glucose
  directly from the tumor

47
Most common type of lung cancer associated with
ectopic hormone production is

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

48
Learning Response

• ANSWER (1) The most common type of lung cancer
  associated with ectopic hormone production is a
  small cell carcinoma (10)
• Small cell carcinomas originate from
  neuroendocrine cells of the bronchial epithelium
• Neuroendocrine cells are capable of producing ACTH

49
The most common lung cancer in women and
non-smokers?

• Small cell carcinoma(SCC)
• Adenocarcinoma
• Squamous cell carcinoma
• Large cell carcinoma

50
Learning Response

• Answer (2) Adenocarcinoma
• Adenocarcinoma of the lung is the MOST COMMON
  primary lung cancer in women and non-smokers
• Pulmonary adenocarcinomas are occasionally
  associated with paraneoplastic syndromes, but
  rarely with ACTH secretion!

51
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

52
Learning Response

• Answer (2) Small cell carcinoma of the lung is
  strongly associated with a history 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.