case presentation - malignant pleural effusion edited

• No greater opportunity, responsibility, or obligation can fall to the lot of a human being than to become a physician. In the care of the suffering, [the physician] needs technical skill, scientific knowledge, and human understanding. . . . Tact, sympathy, and understanding are expected of the physician, for the patient is no mere collection of symptoms, signs, disordered functions, damaged organs, and disturbed emotions. [The patient] is human, fearful, and hopeful, seeking relief, help, and reassurance.

• –Harrison's Principles of Internal Medicine, 1950

Malignant Pleural Effusion

Christian Gallardo, MD

Objectives

• To discuss a case of Pleural effusion and its approach.

• To discuss the approach to Transudative and Exudative Pleural Effusion using the Light’s Criteria.

• To discuss the Diagnosis and Treatment strategies for Malignant Mesothelioma

General Data

• F.E. • 74/M• Las Pinas• Roman Catholic

Chief Complaint

Difficulty of Breathing

History of Present Illness

2 weeksPTA

•Cough, non productive•No Hemoptysis•No Colds•No Fever•No Chest Pain•No DOB•No Orthopnea, No PND•No Consult done•No Medications taken


1 weekPTA

•Still with non productive cough•Chest pain, G4/10•pricking in character, •radiating to the shoulder, < 1 minute, precipitated by breathing

•No Orthopnea, No PND•No Hemoptysis•No swelling of the legs•Consulted •Medications:•Cefixime 200mg BID•Ambroxol 75mg OD


Few HoursPTA

•Persistence of increased severity of chest pain and non productive coughing•Difficulty of Breathing•Fever, One episode, Low Grade (38C)•No chills•No colds

CONSULT

Past Medical History• Hypertension Stage II

• Maintained on Losartan 50mg/tab 1 tab OD• Type 2 DM

• Maintained on Metformin 500mg/ tab 1 tab OD• CAD

• Maintained on Clopidogrel 75mg/tab 1 tab OD

Trimetazidine 35mg 1 tab TID

Simvastatin 40mg OD HS• S/P Coronary Angiogram (7/26/2008) - UPHR• S/P PTCA of LAD (7/26/2008) - UPHR• S/P IABP Insertion R Femoral Artery (7/26/2008) -

UPHR• S/P ORIF Right Forearm (1994) - UPHR• S/P Cholecystectomy (1982) - ?

Family Medical History

• (-) Hypertension• (-) DM• (-) Bronchial Asthma• (-) Heart Disease• (-) Thyroid disease• (-) Blood Dyscrasia• (-) Cancer

Personal and Social History

• (-) Non smoker• (-) Alcoholic beverage drinker• Retired Office Employee

Review of Systems

• General: (+) Weight Loss 20% for 2 months• HEENT: (-) blurring of visions, (-) sorethroat • Gastroenterology: (-) abdominal pain, (-) diarrhea, (-)

constipation, (-) melena, (-) hematochazia• GUT: (-) dysuria, (-) oliguria (-)anuria • Endocrinology: (-) polyuria, polydipsia, polyphagia, • Musculoskeletal: (-) myalgia• Hematology: (-)easy brusability• Neurology: (-) neuropathy, (-)seizures

Physical Examination

• General: • conscious, coherent, not in respiratory distress

• Vital Signs: • BP: 110/70mmHg RR:24 cpm• CR: 101 bpm, regular T: 38. 1 C

• Skin: • Good skin turgor, no rashes, no jaundice

• HEENT: • Anicteric sclera, pink palpebral conjunctivae, no

tonsillopharyngeal congestion, no nasoaural discharge, no cervicolymphadenopathy, JVP at 9 cm

Physical Examination

• Chest and Lung: • Symmetrical chest expansion, no lagging, no

retractions, dull at percussion at left base, decreased breath sounds at left base, decreased tactile and vocal fremitus at left base, fine crackles at left base

• Heart: • Adynamic precordium, normal rate, regular rhythm, PMI at

6th ICS at MCL, normal S1 and S2, (-) S3 and S4, no murmurs.

• Abdomen: • Flat, soft, normoactive bowel sounds, non-tender. Liver

span: 8 cm, Intact Traube’s space, No Organomegaly

• Extremities: • Full pulses, no edema, extremities with full range of motion

Neurological Examination• Oriented to time, person and place, (-) dysmetria• (-) dysdiadochokinesia, can do FTNT, (-) nystagmus• Cranial Nerves:

• I: can smell• II: 2-3mm PERTL, Fundoscopy: (+) ROR, Clear

Media, Distinct Cup borders, CDR: 1:3, AVR: 2:3, No exudates, No Hemorrhage

• III, IV, VI: Full EOM• V: (+) bilateral corneal reflex, good masseter tone• VII: (-) facial asymmetry• VIII: can hear• IX, X: (+) gag Reflex• XI: can equally shrug shoulder• XII: no tongue deviation

Neurological Examination

• (-) Babinski (-) Brudzinski• (-) Nuchal Rigidity

++5/5

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100%

Salient Features• Male • 74 years old• Cough, non productive• Chest Pain, pricking in character• Shortness of Breath• Hypertensive and Diabetic• Known with CAD• Non- Smoker• Chest and Lung:

• Symmetrical chest expansion, no lagging, no retractions, dull at percussion at left base, decreased breath sounds at left base, decreased tactile and vocal fremitus at left base, fine crackles at left base

Differential Diagnosis

Dyspnea

Cardiac

Acute Coronary Syndrome

Congestive Heart Failure

Pulmonary

Pleural Effusion

Pneumonia PTB Maligna

ncy

Pulmo Embolism

Admitting Impression

• Pleural Effusion Probably secondary to • Parapneumonic process• PTB • Malignancy

• HCVD, Congestive Heart Failure NYHC I Secondary to CAD

• S/P AMI• S/P PTCA• DM Type 2

Course in the Wards• VS: 110/70 CR: 104 RR: 23 T: 38.1 • Venoclysis • Diagnostics

• Cardiac Enzymes were not Requested• Therapeutics

• 1. Paracetamol + tramadol (Dolcet)• 2. Salbutamol + Ipratropium Br

(Combivent) q 8 hrs.• 3. Ambroxol 75mg 1 tab OD• 4. Paracetamol 500mg 1 tab q 4 hrs

for fever• 5. Paracetamol 300mg 1 ampule Q4

hrs for fever

1st Hospital Day

CBC

Hematocrit 31

Hemoglobin 113

WBC 14.5

Segmenters 86

Lymphocytes 06

Monocytes 07

Eosinophils 01

Platelet Count 373

Chest Xray CardiomagalyAtheromatous AortaPleural Effusion, Left

Left Lateral Decubitus

Presence of Shifting Density Towards the Dependent Portion of the Right Hemithorax, Suggestive of Pleural Fluid

12 lead ECG Sinus TachycardiaLeft Atrial EnlargementComplete Right Bundle Branch BlockAnterior Wall Myocardial Infarction, Old

Serum Sodium 135 mmol/LSerum Potassium 4.5mmol/LSerum BUN 4.5 mmol/LSerum Creatinine 68 umol/LSGPT 49 U/LCBG 112 mg/dL

Anatomy of Pleura

• The pleura • Serous membrane that covers the lung

parenchyma, the mediastinum, the diaphragm, and the rib cage.

• Visceral pleura • Covers the lung parenchyma, not only

at its points of contact with the chest wall, diaphragm, and mediastinum but also in the inter-lobar fissures.

Light, Richard. Pleural Diseases. 5th Edition. 2007©

Anatomy of Pleura

• Parietal pleura• Lines the inside of the thoracic cavities. • Subdivided

• Costal• Mediastinal• Diaphragmatic

• The visceral and the parietal pleura meet at the lung root.


Anatomy of Pleura

• Pleural fluid• Normally present between the parietal

and the visceral pleura. • Acts as a lubricant and • Allows the visceral pleura covering the

lung to slide along the parietal pleura lining the thoracic cavity during respiratory movements.


Physiology of Pleural Fluid

• It is believed that the fluid that normally enters the pleural space originates in the capillaries in the parietal pleura

• Human beings• Amount of pleural fluid formed daily in a

50-kg individual = approximately 15 mL • The mean lymphatic flow from one

pleural space = 0.40 mL/kg/hour



• Pleural fluid accumulates when the rate of pleural fluid formation exceeds the rate of pleural fluid absorption.

• Normally, there should be a small amount (0.01 mL/kg/hour) of fluid constantly enters the pleural space from the capillaries in the parietal pleura.



• Almost all of this fluid is removed by the lymphatics in the parietal pleura, which have a capacity to remove at least 0.20 mL/kg/hour.

• Note that the capacity of the lymphatics to remove fluid exceeds the normal rate of fluid formation by a factor of 20.


The most common cause of increased pleural fluid formation is increased interstitial fluid in the lung. The amount of edema in the

lung exceeds 5 g/gram of dry lung weight, pleural fluid accumulates, irrespective of

whether the edema is due to high-protein or low-protein fluid


Radiologic Signs• When more fluid accumulates, it spills over into

the posterior costophrenic angle and obliterates that sinus as viewed in the lateral projection.

• The normally sharp posterior costophrenic angle is obliterated by a shallow, homogeneous shadow whose upper surface is meniscus-shaped.


Course in the Wards• Levofloxacin 750mg 1 tablet OD

• Patient’s Meds:• 1. Essentiale Forte 1 Tab TID• 2. Losartan 50mg 1 tab OD• 3. Clopidogrel 75mg 1 tab OD• 4. Digoxin 0.25 mg 1 tab OD• 5. Metformin 500mg 1 tab OD • 6. Simvastatin 40mg 1 tab OD

HS• 7. Vit B Complex 1 Tab OD• 8. Trimetazidine 35mg 1 tab OD

Course in the Wards• 02 saturation: 97%-98% at 2

lpm via nasal cannula• Sputum AFB for 3 collection• Sputum GS/CS

Sputum AFB x 3 Collection Negative for Acid Fast Bacilli

Sputum GS/CS Gram Stain: Pus Cells: < 25/OIFEpithelial: < 25/OIFGram Positive cocci single and PairGram Negative Short Rods: Few

Couse in the Wards

• Levodropropizine (Levopront) 1 tsp TID PO

• Chest UTZ with Mapping

2nd Hospital Day

Chest Mapping Ultrasound Free fluid in both pleural cavities, more in the left. Approximate Volume in 24cc in the right and 818cc in the left

Ultrasound

• Ultrasound is more accurate than plain chest radiography for estimating pleural fluid volume and aids thoracentesis.

• In a series of 320 patients, Yang et al found that pleural effusions with complex septated, complex non-septated, or homogeneously echogenic patterns are always exudates, whereas hypoechoic effusions can be either transudates or exudates.

BTS guidelines for the investigation of a unilateral pleuraleffusion in adults, Thorax 2003;58(Suppl II):ii8–ii17

Course in the Wards• No Difficulty of Breathing, No

chest pain• VS Stable

• Refered to Cardio Service for CP Clearance

• Started on HR (Rimactazid) 300mg 1 Tab OD and Ethambutol 400mg/tab 1 tab BID

• Tramadol tablet was started

3rd Hospital Day

Course in the Wards With Epigastric discomfort after

taking HR (Rimactazid), No Difficulty of Breathing, No Chest Pain

VS Stable

• Post thoracentesis• Tea colored pleural fluid of 850

cc

• Repeat CXR: Pneumothorax L 10%• O2 increased at 5 lpm

4th Hospital Day

Pleural Protein 19.6

Serum Protein 56.7

Pleural LDH 215

Serum LDH 399

SGPT 62

SGOT 23

ALK Phosphtase 178

Albumin 29.5

Globulin 27

A:G 1.08

Conjugated biirubin 1.4

Unconjugated bilirubin 16.7

Repeat CXR Decrease in the Volume of Pleural Effusion on the Left Following Thoracentesis

Marginal Pneumothorax on the Left

Gram Stain Pus Cells: (+1)Red Blood Cells: FewNo Bacterial Organism Seen

Culture and Sensitivity No Growth after 48 hrs

Color Yellowish

Character Hazy

RBC 1894 cells/ CU MM

WBC 256 cells/ CU MM

Differential Count All Lymphocytes seen

Exudative VS Transudative

Transudativ

e

• Systemic factors influencing the formation or absorption of pleural fluid are altered so that pleural fluid accumulates

• Left ventricular failure, ascites, and decreased serum oncotic pressure with hypoproteinemia.

Exudative

•Pleural surfaces or the capillaries in the location where the fluid originates are altered such that fluid accumulates•Pleural malignancy, para-pneumonic effusions, and pulmonary embolism


Patient with Abnormal Chest Xray

Suspected Pleural fluid

Blunting of Costophrenic angle

Lateral Decubitus Chest Radiograph,

Chest CT, Ultrasound

Fluid Thickness >

10mm

Yes

Algorithm 2

No

Observe

Pleural Effusion Unlikely


Algorithm for distinguishing transudative

from exudative pleural effusions

Yes

Suspected Pleural fluid

Diagnostic ThoracentesisAny of the following met?PF/ Serum Protein >0.5PLDH/Serum LDH >0.6

Pleural LDH > 2/3rd Upper Normal LimitYes

Probable Exudate

CHF or Cirrhosis?

NoExudate

Apperance of Pleural Fluid; Glucose of Pleural Fluid; Cytology and Differential Count; Plerual Fluid Marker for TB

Yes

Serum Fluid

Gradient >3.1

No

Transudate

Treat CHF or

Nephrosis


Algorithm for distinguishing transudative

from exudative pleural effusions

Pleural Fluid Protein Patient’s Values

Light’s Criteria

Pleural Protein / Serum Protein

19.6 0.34

56.7

Pleural LDH /Serum LDH

215 0.53

399

Pleural LDH > 2/3rd the upper limits of N serum LDH

215(N: 313 -618)

215< 412

Is the Light’s Criteria for diagnosing an Exudative

Pleural Effusion Fulfilled ? Transudative

Pleural Effusion

Light’s Criteria• Light criteria have an overall diagnostic

accuracy of 93% but commonly misclassify effusions (approximate diagnostic accuracy, 65%) when any 1 of the 3 criteria has a value near its cutoff point.

• Light criteria can be effectively used to categorize effusions as exudates because they are associated with the increased permeability of pleural membranes or the breakdown of intrapleural cells, allowing high–molecular weight constituents to concentrate in the pleural space.

Heffner, J and Klein, J. Recent Advances in the Diagnosis and Management of Malignant Pleural

Effusion, Mayo Clin Proctocol, 2008;83(2):235-250

Light’s Criteria

• For many years, a pleural fluid protein level of 3.0 g/dL was used to separate transudates from exudates, with exudative pleural effusions characterized by a protein level above 3.0 g/dL (13,14).

• Light's criteria identified 98% of the exudates correctly, but they were less accurate in identifying transudates, misclassifying 19 of 112 (17%)


Pleural Fluid Findings Suggestiveof Malignant Pleural Effusion (MPE)


Why Transudative?

• Malignant pleural effusions were transudative in 1.5% of malignant mesotheliomas, 6.8% of metastatic diseases, and 11.1% of paramalignant effusions. Cytological examination of pleural fluid in patients with unexplained transudative effusion is essential to rule out malignant processes.

Gonlugur, T., Gonlugur, M. Transudates in Malignancy: Still a Role for Pleural Fluid: Ann Acad Med Singapore 2008;37:760-3

Why Transudative?

• Transudative malignant effusions are generally due to early stages of mediastinal node involvement, atelectasis, or concomitant congestive heart failure.

Gonlugur, T., Gonlugur, M. Transudates in Malignancy: Still a Role for Pleural Fluid: Ann Acad Med Singapore 2008;37:760-3

Gross Apperance of Pleural Fluid

• Most transudative and many exudative pleural effusions • Clear, straw colored, nonviscid, and

odorless• Blood tinged

• Pleural fluid RBC count is between 5,000 and 10,000/mm3

• Turbid pleural fluid• increased cellular content or increased

lipid content

The appearance of the pleural fluid and any odour should be noted. [C]

A pleural fluid haematocrit is helpful in the diagnosis of haemothorax.



Gross Appearance of Pleural Effusion

• Turbid pleural fluid that clears with centrifugation • Pleural infection

• Turbidity persists after centrifugation, • Chylothorax or a pseudochylothorax

• Chocolate sauce or anchovy paste • Amebiasis with a hepatopleural fistula

• High viscosity • Suggestive of malignant mesothelioma;

2nd to an elevated pleural fluid hyaluronic acid level


RBC Count

• Bloody• Hematocrit should be obtained on the

fluid• Hct > 1%

• Malignant pleural disease, • Pulmonary embolus• Traumatically induced pleural

effusion • Hct >50% of that of the peripheral blood

• Hemothorax - consider performing a tube thoracostomy


WBC Count

• Pleural fluid WBC count is of limited diagnostic use.

• Most transudates • Have WBC counts below 1,000/mm3,

• Most exudates • Have WBC counts above 1,000/mm3

• Parapneumonic effusions• Pleural fluid WBC counts above

10,000/mm3


Neutrophils

• Predominate in pleural fluid resulting from acute inflammation as with pneumonia, pancreatitis, pulmonary embolization, subphrenic abscess, and early tuberculosis

• Interleukin (IL-8) appears to be one of the primary chemotaxins for neutrophils in the pleural space

• The significance of neutrophils in an exudative pleural effusion is that they indicate acute inflammation of the pleural surface.


Lymphocytes

• Probably has a malignant disease, tuberculous pleuritis, or a pleural effusion after CABG surgery

• Almost all of the effusions secondary to tuberculosis, but only two thirds of the effusions secondary to malignant disease had predominantly small lymphocytes


Differential cell counts on the pleural fluid

Pleural lymphocytosis is common in malignancy and tuberculosis.


Protein Measurements

• The pleural fluid protein levels • Generally higher in exudative pleural

effusions than in transudative pleural effusions.

• Pleural fluid protein levels • Not useful in separating the various

types of exudative effusions, however, because the protein level in most exudates is elevated to a comparable degree


Glucose Level

• Low pleural fluid glucose level (<60 mg/dL) indicates• Parapneumonic effusion• malignant disease• rheumatoid disease• tuberculous pleuritis

• The lower the pleural fluid glucose level, the more likely that one is dealing with a complicated parapneumonic pleural effusion.


Lactic Acid Dehydrogenase Measurement

• The higher the LDH, the more inflamed the pleural surfaces

• All Effusions with elevated pleural fluid LDH levels • Seen in most malignant effusions


pH Measurements• Transudative PE,

• Pleural fluid pH is usually higher than the simultaneous blood pH• Active transport of bicarbonate from the

blood into the pleural space• Exudative PE

• Pleural fluid pH falls substantially below that of the arterial pH

• If the pleural fluid pH is below 7.0, • Complicated parapneumonic effusion

• Therapeutic thoracentesis or tube thoracostomy


pH

pH should be performed in all non-purulent effusions.[B]

In an infected effusion a pH of <7.2 indicates the need for tube drainage.


Tests for Diagnosing Pleural Tuberculosis

• Adenosine Deaminase Measurement• Higher in tuberculous pleural effusions

than in other exudates • Cutoff level of between 40 and 45 U/L is

used with levels above this being indicative of tuberculosis• The higher the level, the more likely

the patient is to have tuberculosis


Course in the Wards Shortness of Breathness with epigastric

pain VS Stable

Repeat CXR: Pneumothorax 80%

Clopidogrel discontinued

Stat CTT: 400cc drained, blood tinge, (+) fluctuations

O2 at 5 lpm via nasal cannula

Post CTT: Reexpansion of L Lung

ICU Transfer

6th Hospital Day

12 lead ECG Sinus TachycardiaComplete Right Bundle Branch BlockAnterior Wall Myocardial Infaraction, Old

Ultrasound of Abdomen Negative Sonographic Study of the Kidneys, Ureters and Urinary Bladder. Normal sized Prostrate Glands; Negative for Mass

Repeat CXR 80% Pnumothorax

Repeat CXR after 6 hrs Post CTT

Complete Reexpansion of the Left Lung with Resoption of the Pleural Fiud Along the Left Costophrenic Area

Pneumothorax

• Air in the pleural space, that is, air between the lung and the chest wall

• Spontaneous pneumothoraces• Ooccur without antecedent trauma or

other obvious cause• Traumatic pneumothoraces

• Occur from direct or indirect trauma to the chest.

• Iatrogenic pneumothorax• An intended or inadvertent consequence of

a diagnostic or therapeutic maneuver


Complications of Pneumothorax

• The most common complication of thoracentesis is pneumothorax.

• When three different series involving 459 patients are combined, 51 of the patients (11%) developed a pneumothorax and chest tubes were necessary in 9 (2%).

• In a more recent report, the incidence of pneumothorax was 4% in a series of 506 thoracenteses and 2% received a chest tube (18).


Complications of Pneumothorax

• Thoracentesis is probably the third leading cause of iatrogenic pneumothorax. • Incidence: 5%

• Approximately 20% to 50% of those with a pneumothorax requiring a chest tube

• The incidence of pneumothorax can be decreased if the thoracentesis is performed by experienced interventional radiologists with ultrasound guidance.


Indication for Chest Drain Insertion

BTS guidelines for the insertion of a chest drain. D Laws, E Neville, J Duffy, on behalf of the British Thoracic Society Pleural Disease

Group, a subgroup of the British Thoracic Society Standards of Care Committee, Thorax 2003;58(Suppl II):ii53–ii59

Course in the Wards (-) DOB, comfortable VS Stable Decreased Breath Sounds at L

CTT output: 500mL/day

Clopidogrel Resumed Decreased O2 at 2 lpm

Tramadol was given for pain

8th Hospital Day


CTT output: 350cc/day

Cell Cytology

11th Hospital Day

Cell Cytology of Pleural Fluid

Reddish Fluid and a volume approximately 600ml for cell cytologic Evaluation

Chronic Inflammatory Pattern with Reactive Mesothelial Hyperplasia

Repeat Pleural Fluid Cytology: Atypical Mesothelial Cells

Cytologic Examinations

• The nuclei of malignant cells may exceed 50 µm in diameter, in contrast with mesothelial cell nuclei, which rarely exceed 20 µm in diameter.

• Small lymphocytes, by comparison, have a diameter of approximately 10 µm.

• Mesotheliomas tend to have true papillary aggregation, multinucleation with atypia, and cell-to-cell apposition, whereas adenocarcinomas tend to have acinus-like structures and balloon-like vacuolation


Cytology

Malignant effusions can be diagnosed by pleural fluid cytology alone in only 60% of cases.

If the first pleural cytology specimen is negative, this should be repeated a second time. [B]

Both cell blocks and fluid smears should be prepared for examination and, if the fluid has clotted, it needs to be fixed and sectioned as a histological section. [B]




Immunohistochemical Staining CEA, CK 7, Calretenin, CK

20

12th Hospital Day



Bone Scan

Contemplated Pleurodesis if CTT output is < 100cc/day

13th Hospital Day

Bone Scintigraphy No Evidence of Bone Metastasis


CTT output: 0cc/day

CT Scan of Chest

Pleurodesis done Doxurubicin

15th Hospital DayNon-Contrast and Contrast CT

Bilateral Pleural Effusion, Larger Amount on the Left side

The Tip of the Thoracotomy Tube is in the Left Major Fissure

Small Amount of Fluid Collections in the Pericardial Sac

Ground Glass Opacity in the Left <Lower Lobe Secondary to Compressive Atelectasis or infiltrates

Prerequisites for Pleurodesis

• Significant symptoms that are relieved when pleural fluid is evacuated

• Evidence of complete re-expansion of the lung without evidence of bronchial obstruction or fibrotic-trapped lung

• Daily tube drainage is less than 150 mL/day• Reserved for those cases where there is no

other therapeutic alternative, or when this has already failed

• If the patient undergoing pleurodesis is receiving corticosteroid therapy



CT Scan

• Useful in distinguishing empyema with air fluid levels from lung abscess

• Identify pleural thickening, which suggests that the patient has an exudative effusion. • In one study, 36 of 59 exudative effusions

(61%) had associated pleural thickening, whereas only 1 of 27 transudates (4%) had associated pleural thickening (45).

• An added bonus with CT is the clear demonstration of bone pathology such as metastases or tuberculosis.

CT Scan

CT scans for pleural effusion should be performed with contrast enhancement. [C]

In cases of difficult drainage, CT scanning should be used to delineate the size and position of loculated effusions. [C]

CT scanning can usually differentiate between benign and malignant pleural thickening.



CTT removed

17th Hospital Day

Course in the Wards (-) DOB, comfortable VS Stable Discharged

Home Medications: HR (Rimactactazid) 300mg/tab 1

tablet OD E 400mg/tab 1 tablet BID before

meals Ipratropium + Salbutamol beulization

every 8 hrs. Lactulose 15 ml OD HS Pantoprazole 40mg/tab 1 tab OD HS

21th Hospital Day

Course in the Wards Home Medications:

Cefixime 200mg/tab 1 tablet BID PO Digoxin 0.25 mg/tab 1 tablet OD PO Clopidogrel 75mg/tab 1 tablet OD

PO Losartan 50mg/tab 1 tablet OD PO Simvastatin 80 mg/ tab 1 tablet OD

PO Metformin 500mg/tab 1 tablet OD

PO Trimetazidine 1 tablet BID PO Essentiale Forte 1 capsule BID PO

21th Hospital Day

Immunochemical StainingCEA (-)

CK 7 (+)

CK20 (-)

Calretenin (+)

Immunochemical Staining

• Best markers for adenocarcinoma • Carcinoembryonic antigen (CEA) • MOC-31 (or B72.3, Ber-EP4, or BG8)

• Best markers for mesothelioma • Calretinin and cytokeratin


Final Diagnosis

• Malignant Pleural Effusion Secondary to Mesothelioma

• HCVD, Congestive Heart Failure NYHC I Secondary to CAD

• S/P AMI• S/P PTCA• DM Type 2, controlled

Clinical Manifestation of Pleural Effusion

• Pleuritic chest pain • Inflammation of the pleura, specifically,

the parietal pleura as the visceral pleura does not have pain fibers.

• Dull, aching chest pain rather than pleuritic chest pain• Pleural malignancy

• Either pleuritic chest pain or dull, aching chest pain • The parietal pleura is probably involved

and that the patient - exudative pleural effusion.



• A second symptom - dry, nonproductive cough• The mechanism is not clear, although it

may be related to pleural inflammation • Lung compression by the fluid may

bring opposing bronchial walls into contact, stimulating the cough reflex



• The third symptom is dyspnea. • PE acts as a space-occupying process

in the thoracic cavity and therefore reduces all subdivisions of lung volumes

• Larger PE obviously cause a significant reduction in lung volumes.


Clinical Manifestations of Pleural Effusion

• Tactile fremitus:• Absent or attenuated because the fluid

absorbs the vibrations emanating from the lung

• Much more reliable than percussion for identifying both the upper border of the pleural fluid and the proper site to attempt a thoracentesis.



• Percussion:• Dull or flat• Dullness is maximum at the lung bases

where the thickness of the fluid is the greatest

• If the dullness shifts as the position of the patient is changed, one can be almost certain that free pleural fluid is present



• Breath Sounds:• Auscultation over the pleural fluid

characteristically reveals decreased or absent breath sounds

• Pleural rub. • Coarse, creaking, leathery sounds

most commonly heard during the latter part of inspiration and the early part of expiration, producing a to-and-fro pattern of sound


Epidemiology – Malignant Mesotehlioma

• There is widespread variation in the incidence of malignant mesothelioma in England: two Strategic Health Authorities have 30 cases annually while two have 100 cases per year.

• Asbestos fibres are the cause of most cases of mesothelioma. Evidence from two British studies suggests that the proportion of men with mesothelioma directly attributable to occupational asbestos exposure may be about 85%, and this is consistent with evidence from studies in other countries.

BTS statement on malignant mesothelioma in the UK, 2007British Thoracic Society Standards of Care Committee

Epidemiology – Malignant Mesothelioma

• Malignant mesothelioma will increase in incidence over the next 5–10 years. It is inexorably progressive with a very poor 5-year survival and a median survival of 8– 14 months.

• Simian virus 40 (SV40), a DNA virus, has been implicated as a cofactor in the causation of malignant mesothelioma


Bruce W.S. Robinson, M.D., and Richard A. Lake, Ph.D. Advances in Malignant Mesothelioma. New England Journal Medicine

2005;353:1591-603.

Epidemiology – Malignant Mesothelioma

• Mesothelioma • Fifth to seventh decades• 70–80% of cases occur in men• Between the ages of 20 to 40 years

usually have a history of childhood exposure

• Typical presenting features are those of chest pain, dyspnea or both

• Physical examination is usually unremarkable except for signs of pleural effusion and pleural thickening due to tumour infiltration

Moore, J., Parker, R, Wiggins J. Review, Malignant MesotheliomaOrphanet Journal of Rare Diseases 2008, 3:34 doi:10.1186/1750-

1172-3-34


2005;353:1591-603.

Pathophysiology

• Four principal processes by which asbestos affects the pleura.• First, asbestos fibers may irritate the

pleura.• Shape of asbestos fibers• Fibers penetrating the lung induce

disease manifested • Scarring (plaques) • Frank malignant process

(malignant mesothelioma).


2005;353:1591-603.

Pathophysiology• Second, asbestos fibers may sever or

pierce the mitotic spindle of cells and thereby disrupt mitosis

• Third, asbestos induces the generation of ironrelated reactive oxygen species that cause DNA damage

• Fourth, asbestos induces phosphorylation of the mitogen-activated protein (MAP) kinases and of extracellular signal–regulated kinases (ERK) 1 and 2


2005;353:1591-603.

Key Biologic Features of Malignant Mesothelioma


2005;353:1591-603.

Suspected malignantmesothelioma:

diagnostic algorithm


Diagnostics Imaging for Malignant Mesothelioma

• Contrast-enhanced CT • Primary imaging modality used for the

evaluation of suspected malignant pleural disease.

• Malignant or inflammatory pleural disease enhances strongly, and the contrast allows differentiation between thickened pleura, effusion and underlying aerated or collapsed lung.



• CT features used to distinguish malignant from benign pleural disease were• (1) circumferential pleural thickening, • (2) nodular pleural thickening, • (3) parietal pleural thickening 1 cm,• (4) mediastinal pleural involvement.• Specificities:100%, 94%, 94% and 88%

respectively.• Sensitivities: 41%, 51%, 36% and 56%

respectively.



• Magnetic resonance imaging (MRI)• Limited role in the evaluation of malignant

mesothelioma• MRI, with its ability to scan in any plane,

has been used to accurately assess resectability prior to radical surgery

• 18F-fluorodeoxyglucose positron emission tomography (FDG PET)• May be useful in differentiating benign from

malignant pleural disease and might guide choice of biopsy site.


Histopathological analysis

• Malignant mesothelioma • EMA• Calretinin• WT1• Cytokeratin 5/6• HBME-1 (an anti–mesothelial cell

antibody) or• Mesothelin (more than 85 percent of

epithelioid


2005;353:1591-603.

Immunochemical Staining

• Electrochemiluminescence and micro-particle enzyme immunoassays of PF can detect tumor markers none of the available tumor markers has sufficient diagnostic yield to be used in routine clinical practice.

• Groups of immunohistochemical markers could lead to a diagnosis in approximately 80% of patients with malignant mesothelioma.

Heffner, J and Klein, J. Recent Advances in the Diagnosis and Management of Malignant Pleural Effusion, Mayo Clin Proctocol,

2008;83(2):235-250

Histopathological analysis


2005;353:1591-603.

Management of Malignant Mesothelioma

• Treatment Strategy:• Management of the pleural effusion.• Indications for prophylactic radiotherapy to

intervention sites.• Indications for chemotherapy.• Immediate supportive care requirements.• Compensation issues.• Suitability for radical surgery.• Suitability for clinical trial entry.• Referral to the specialist multidisciplinary

team.



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Treatment Strategy: Surgery

• Extrapleural pneumonectomy (EPP) (or pleuropneumonectomy)• Eradicate all macroscopic disease,

ideally with good clearance margins.• Operative mortality: 4–9%• Significant complications: Over 60% of

patients• A median survival of 19 months

following this radical operation with adjuvant chemotherapy and radiotherapy


Treatment Strategy: Surgery

• Debulking operation (cytoreductive surgery)• Less radical approach• Can be performed by VATS or thoracotomy• Has been reported to be effective in

preventing fluid recurrence • May also be associated with increased

survival although, like EPP, it has not yet been tested in a randomized trial


Treatment Strategy: Pleurodesis

• Early pleurodesis is a key aim for symptom control and prevention of the development of a trapped lung.

• Thoracoscopy is an extremely useful diagnostic and therapeutic tool.

• Calibrated talc is the pleurodesis agent of choice.

• Indwelling pleural catheters are useful for symptom control in cases of trapped lung or where chemical pleurodesis has failed.


Treatment Strategy: Pleurodesis• Talc is the most effective sclerosant available for

pleurodesis. [B]• A small number of patients (<1%)may develop

acute respiratory failure following talc administration. [B]

• Tetracycline ismodestly effective, has few severe side effects, and is the preferred sclerosant to minimise adverse event rates. [B]

• Bleomycin is an alternative sclerosant with a modest efficacy rate but is expensive. [B]

• Pleuritic chest pain and fever are the most common side effects of sclerosant administration. [B]



• Sterile talc• Currently the most effective freely available

pleurodesis • Dose of the talc should not exceed 4 g,

• Should be calibrated to avoid the rare risk of the development of ARDS

• The intercostal tube should be clamped for 1 h after sclerosant administration and, in the absence of excessive fluid drainage (.250 ml/day), removed 24–48 h later.



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• Success rates (complete and partial response) for talc slurry range from 88% to 100% with a mean of 90%.

• In a recent randomised trial between talc slurry (5 g) and bleomycin (60 units), 90% of the talc group achieved a complete response at 2 weeks compared with 79% of the bleomycin group, which was statistically insignificant.


Treatment Strategy: Radiotherapy

• Palliative radiotherapy provides pain relief in about half of all patients.

• Palpable masses respond to radiotherapy in about half of all patients.

• Breathlessness and superior vena caval obstruction rarely respond to radiotherapy.

• Prophylactic radiotherapy may reduce chest wall implantation following invasive procedures, but may be most applicable for patients with a better prognosis and after more invasive procedures.


Treatment Strategy: Radiotherapy

• The current recommendation • Patients of good performance status

(and therefore longer survival) who have chest wall wounds should be referred for radiotherapy promptly and treated with a three-fraction schedule.


Treatment Strategy: Chemotherapy

• In general, palliative chemotherapy should be considered for all patients with performance status 0–2.

• The objective response rate that should be expected is of the order of 20–40%, and two randomised controlled trials have shown significant differences in survival between regimens, implying that chemotherapy may extend the life expectancy of some patients with mesothelioma.



• Until recently, all reviews of chemotherapy for malignant mesothelioma reported poor response rates (typically less than 15 to 20 percent) and, because of these low rates, did not recommend a standard of care.

• In a multicenter phase 3 study involving 448 patients, those treated with pemetrexed plus cisplatin had a longer overall median survival (12.1 months) than those treated with cisplatin alone (9.3 months) and had an objective response rate (shrinkage of the tumor by at least 50 percent) of 41 percent.


2005;353:1591-603.

New Approaches to Treatment for Mesothelioma


2005;353:1591-603.

Key Points:

• The most common cause of increased pleural fluid formation is increased interstitial fluid in the lung.

• Light's criteria identified 98% of the exudates correctly, but they were less accurate in identifying transudates, misclassifying 19 of 112 (17%).

• Pleural lymphocytosis is common in malignancy and tuberculosis.

• Ultrasound is more accurate than plain chest radiography for estimating pleural fluid volume and aids thoracentesis.

Key Points:

• Thoracentesis is probably the third leading cause of iatrogenic pneumothorax.

• CT features used to distinguish malignant from benign pleural disease.

• Groups of immunohistochemical markers could lead to a diagnosis in approximately 80% of patients with malignant mesothelioma.

• Calibrated talc is the pleurodesis agent of choice for Malignant Mesothelioma.

• Patients should be offered Surgery, Radiotherapy and Chemotherapy depending on the treatment strategy.

case presentation - malignant pleural effusion edited

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