Morbidity & Mortality

Jaspreet Singh Grewal, M.D.Internal Medicine PGY-3

1-16-08

Chief Complaint:

54-year-old Caucasian female

5 day history of :

Shortness of breath

Dyspnea on exertion

Chest tightness

Dizziness

Generalized weakness

Positive:

Palpitations

Chronic hematuria due to rectovaginal fistula

Decreased appetite

Weight loss

Negative:

Hx of recent travel

Calf pain

Orthopnea

Paroxysmal nocturnal dyspnea

Lower extremity edema

Fever

Cough

Recurrent stage 1C, grade 3 papillary serous adenocarcinoma

of the ovaries s/p chemotherapy

Recent CT & PET scans confirmed extensive metastasis

Rectovaginal fistula

Hx of recurrent Staph Haemolyticus & GNB bacteremia,

currently on doxycycline

S/P TAH & BSO, pelvic & aortic lymph node

dissection, & debulking in 1998

Cholecystectomy

Rectovaginal fistula repair × 2 w/ diversion ileostomy

Mediport placement

Oxycontin

Vicodin

Pepto-Bismol

Doxycycline

ALLERGIES: NKDA

Father: DM

Significant FH of colorectal cancer

20 pack-yr. smoking hx. Quit in 1989.

ETOH: Occasionally

No Illicit drug use

Code Status: DNR/DNI

Pulmonary Thromboembolism (PTE)

Congestive Heart Failure (CHF)

Chronic Obstructive Pulmonary Disease (COPD)

Myocardial Infarction (MI)

Atypical Pneumonia

Pulmonary Metastasis

Pleural Effusions

Vital Signs in ER:

T: 97.0°F

BP: 111/87 mmHg

HR: 119 bpm

RR: 20/min

O2 sat: 92% on room air

General Examination:

Frail, mild respiratory distress

Anicteric, acyanotic, no lymphadenopathy

HEENT: No JVD

Extremities: No edema

Skin: Candidal rash in the inguinal area

Heart: Accentuated pulmonic component of the S2

Lungs: CTAB

Abdomen:

Soft, mild tenderness

No hepatosplenomegaly

Ileostomy bag is present

Central Nervous System: No focal neuro deficits

Arterial blood gas (ABG): 7.52/23/60/23/92% at room air

Electrocardiogram (EKG): Sinus tachy w/ a rate of 110 bpm LAD Incomplete RBBB

Complete blood count (CBC): 12.2 9.8 272 35.6

Electrolytes : 134 98 18

4.1 23 1.1 94

D-dimer: 3485 ng/mL

Alkaline phosphatase (ALK): 234 IU/L

Liver enzymes & Serum Bilirubin: NL

Troponin I: Peaked at 0.08 ng/mL

International Normalized Ratio (INR): 1.09

Recent CA-125: >6000 U/mL

Fig. A. Chest roentgenogram (CXR) showed no evidence of parenchymal disease or signs of fluid overload or any mass lesion

Fig. B. Computed Tomography Angiogram

Fig. C. Computed Tomography Angiogram

Computed Tomography (CT) Angiogram (Fig. B & C):

No evidence of pulmonary embolus or pulmonary

parenchymal & pleural disease

Enlarged lymph nodes in left axilla & subpectoral

regions (unchanged from prior CT-chest)

No hilar or mediastinal lymphadenopathy

Pulmonary Embolism (PE)

COPD

Congestive Heart Failure (CHF)

Myocardial Infarction (MI)

Systemic Bacteremia

Anemia

Given ASA in the ER

Transferred to PCU bed

Oxygen by Nasal Canula & NMT’s

Low-dose β-blocker

Vancomycin & Cefepime

2D-Echocardiogram

Infectious Disease, Pulmonary & Gyn-Oncology consulted

2D-Echocardiogram on Hospital Day - 1:

Nl LV EF: 65%

Mod to severe TR

Severe PH (60 mmHg)

LVH

Pulmonary Consult Recommendations:

Findings not consistent w/ PH

R/o COPD, OSA & CHF

Complete PFT

Night-time pulse oximetry on RA

Ambulatory pulse oximetry

Chemical Stress Study

O2 sats stable at rest

O2 sats: 87% on ambulation

Blood cx: NGTD

Urine cx: 40,000 CFU of yeast

ASA was d/c’d secondary to gross hematuria

Considered Pulmonary Angiography to r/o PE

Infectious Disease Consult Recommendations:

R/o Mediport infection & endocarditis

Repeat blood cx’s

Continue vancomycin & discontinue cefepime

Consider TEE & discontinue Medi-port if repeat blood cxs

are positive

Gyn-Oncology Consult Recommendations:

R/o chemotherapy (Taxol) associated cardiomyopathy

Consider PET scan to r/o lymphatic spread of tumor in chest

Not a candidate for aggressive chemotherapy

Continued to have DOE, stable on O2 by NC at rest

Dobutamine Stress Echocardiogram: Day – 3

Cancelled after obtaining resting images

Resting images severe RT ventricular dilation &

mod to severe RT ventricular systolic dysfunction

Flattening of interventricular septum: Severe RT

sided pressure overload

Cardiology Consult Recommendations:

Pulmonary Hypertension of unclear etiology

Likely related to Pulmonary Emboli or Lymphangitic

spread

Hydration

Hold off anti-coagulation secondary to hematuria

Pulmonary Hypertension of unclear etiology

Subsegmental Pulmonary Embolism

Congestive Heart Failure

Persistent Bacteremia

COPD

Lymphangitic spread of tumor in the chest

2D-Echocardiogram: Day – 4

• Nl LV, LVEF = 68%

• Markedly enlarged RT heart chambers w/ mod-severe

RT ventricular dysfunction

• Mod TR

• Mod PH (56 mmHg)

Reported chest heaviness & SOB at rest

O2 sats: 92% (RA) 100% (4L NC)

EKG: New ST-T wave changes in the ant. leads

Troponin I peaked: 0.35 ng/mL

ABG:

7.45/20/113/14/99% on 4L NC

Final blood cx: NG

NTG SL & i/v morphine PRN

NMT’S failed to improve symptoms

Cardiology:

Not a candidate for cath secondary to risk of exsanguination

Continue conservative Mx

No heparin due to gross hematuria

BLE Doppler: Neg

Despite supportive treatment, patient deteriorated

Severe hypoxemia:

O2 sats: 77% (3L NC) 94-96% (100% NRB)

Patient died on Hospital Day #5

Post Mortem performed

PATHOLOGIST’S FINAL IMPRESSION:

Disseminated microemboli of adenocarcinoma involving

distal pulmonary arterioles w/ secondary

microthrombus: patient’s pulmonary symptoms due to

arterial changes of pulmonary hypertension

PATHOLOGIST’S FINAL IMPRESSION:

Extensive metastatic ovarian carcinoma: liver (20%

of the parenchyma), splenic capsule, retroperitoneal

nodes, & peritoneal surfaces

GROSS EXAMINATION:

Lungs:

Grossly normal

Few bilateral less than 1cm areas of sub-pleural

hemorrhage & blood clots in few small distal

arteries

GROSS EXAMINATION:

Heart:

Weighed 360 grams

Normal sized atrias & ventricles

The left ventricular myocardium was 15mm thick &

the right was 4mm thick

Low power hematoxylin & eosin staining showing diffuse obliteration of the pulmonary arterioles w/ organizing thromboemboli, intimal proliferation & rare

aggregates of carcinoma

Fig. D Fig. E

High power hematoxylin & eosin staining showing complete occlusion of the pulmonary arteriole by fibrin-platelet thrombus, small aggregates of metastatic

carcinoma & medial hypertrophy

Fig. F Fig. G

HISTOPATHOLOGICAL FINDINGS IN THE LUNG

Diffuse changes in pulmonary arterioles (Fig. D, E, F & G)

Thickening of the media

Narrowing of the lumina w/endothelial proliferation

Organizing & re-canalizing fibrin thrombi

Rare aggregates of metastatic carcinoma within the lumina

of the arterioles of both lungs

Bronchioles & alveolar spaces were largely unremarkable

FINAL DIAGNOSISFINAL DIAGNOSIS

Microscopic pulmonary tumor embolism (MPTE) is a clinical

syndrome of subacute cor pulmonale (SCP) due to multiple

tumor emboli to the pulmonary vasculature

Brill and Robertson first described “subacute cor pulmonale” in

patients w/ rapid development of right heart failure due to tumor

emboli in the lung*

*Brill IC, Robertson TD. Subacute cor pulmonale. Arch Intern Med 60:1043-1057, 1937

Rarely recognized antemortem, but is frequently encountered

during autopsy of cancer patients

Incidence based on autopsy studies is 0.9% - 26 % among

patients w/ solid tumors*

1 - 8% of the patients w/ pathological evidence of tumor emboli

have documented morbidity & mortality from MPTE†

*Schriner RW, Ryu JH, Edwards WD. Microscopic pulmonary tumor embolism causing subacute cor pulmonale: a difficult antemortem diagnosis. Mayo Clin Proc. 1991;66:143–148†Abelardo Montero, Antonio Vidaller, Francesca Mitjavila, David Chivite and Ramon Pujol. Microscopic Pulmonary Tumoral Embolism and Subacute Cor Pulmonale as the First Clinical Signs of Cancer. Acta Oncologica Vol. 38, No. 8, pp. 1116–1118, 1999

Breast, lung, gastric cancers are most commonly

associated w/ MPTE

MPTE can present at any time during the course of a

malignancy

Malignancy Number of Cases

Breast 29Stomach 12Lung 11Liver 9Prostate 8Pancreas 6Bone 4Undifferentiated carcinoma 4Ovary 3Bladder 3Cervix 3Colorectal 3Kidney 2Mesothelioma 2Wilms’ tumor 2Other* 8Total 109

* One each of the following: esophageal, parotid, melanoma, myxoma, thyroid, trophoblastic, vulvar carcinomas, & neurogenic sarcoma

Tumor metastasis to the lungs can be either Macroscopic or

Microscopic & can result in the following manifestations:

May remain asymptomatic (18-68% of tumor emboli

are discovered incidentally)

May present a clinical picture of thromboembolic

disease

May traverse capillary endothelium & form a

potential focus of metastasis

Arterial Tumor Embolism

Presence of isolated cells or clusters of tumor cells

w/in pulmonary arterial system

Not contiguous w/ metastatic foci

1) HYPOTHESIS for PH in MPTE:

Dysregulation of signaling pathways that normally

respond to the presence of an embolic cell or other

intravascular insult

Vascular Remodeling

2) HYPOTHESIS for PH in MPTE:

Tumor emboli

Pulmonary vascular resistance through mechanical occlusion

Vascular remodeling

Impaired pulmonary vasculature ability to adapt

In symptomatic patients, the mean percentage of the vessels

involved is 32% (Range: 12 - 40%)

Combination of the tumor emboli, clot & vascular changes

MAHA & DIC

Tumor-related Thrombotic Pulmonary Microangiopathy

(TTPM)

MPTE is characterized by:

Occlusion of the small pulmonary arteries, arterioles

& alveolar septal capillaries w/ tumor microemboli

With or without accompanying platelet-fibrin

thrombus

Minimal or no tumor invasion of arterial wall

Morphologic changes in the primary pulmonary resistance

vessels (small arteries and arterioles):

Medial & intimal hypertrophy w/ luminal narrowing or

occlusion

Intimal fibrosis

Fibrinoid necrosis of the internal elastic lamina

Smooth muscle colonization of the luminal neoplastic

lesions & associated microthrombi

Presents w/progressive cor pulmonale over wks-months:

Dyspnea (57-100% of the cases)

Pleuritic chest pain

Cough

Hemoptysis

Cyanosis

Abdominal pain

Symptoms > than the physical exam findings

Exam:

Tachycardia

Tachypnea

JVD

Elevated pulmonary pressures

• Augmented pulmonic component of the S2, & a S3

• Peripheral edema

• Ascitis

Classic signs of CHF seen in 15 - 20% of the patients

Pulmonary thromboembolism

Pleural effusions

Airway obstruction from a metastatic tumor mass

Pulmonary parenchymal metastasis

Adult respiratory distress syndrome (ARDS)

Infection (Opportunistic & non-opportunistic)

Severe Right-sided Heart Failure

Restrictive lung disease secondary to radiation and chemotherapy

Lymphangitic carcinomatosis (LC)

Microscopic pulmonary tumor embolism (MPTE)

Arterial Blood Gases (ABG):

• Hypoxemia, Hypocapnea & Respiratory Alkalosis

Liver function tests may be elevated from hepatic

congestion or metastasis

Chest Roentgenogram (CXR):

Normal in most cases

In less than 50% of the cases, prominent pulmonary

vasculature & cardiomegaly can be seen*

Electrocardiogram (EKG):

Non-specific, RAD w/ S1Q3 pattern

*Abelardo Montero, Antonio Vidaller, Francesca Mitjavila, David Chivite and Ramon Pujol. Microscopic Pulmonary Tumoral Embolism and Subacute Cor Pulmonale as the First Clinical Signs of Cancer. Acta Oncologica Vol. 38, No. 8, pp. 1116–1118, 1999

Echocardiogram:

Dilation of the RV w/ “D”-shaped LV

RV systolic pressure typically > 50 to 60 mmHg

Inc. Pulmonary Artery Pressures

Severe TR

CT Scan:

Usually non-diagnostic w/no evidence of pulmonary

parenchymal & lymphatic disease

Shepard et al described “dilated and beaded”

peripheral pulmonary arteries (especially

subsegmental) in a series of four cases*

*Shepard JA, Moore EH, Templeton PA, McLoud TC. Pulmonary intravascular tumor emboli: dilated and beaded peripheral pulmonary arteries at CT. Radiology. 1993;187:797–801

Ventilation-perfusion Scan:

Most effective imaging study

Reveals multiple small subsegmental perfusion defects w/ normal

ventilation

Segmental contour mapping & visualization of pleural fissures or

the “segmental contour” pattern, was first described by Sostman

and colleagues*

*Sostman HD, Brown M, Toole A, et al. Perfusion scan in pulmonary vascular/lymphangitic carcinomatosis: the segmental contour pattern. AJR Am J Roentgenol. 1981;137:1072–1074

PERFUSION SCAN IMAGES

Fig. H. Perfusion scan images in Microscopic Pulmonary Tumor Emboli (MPTE) showing segmental contour pattern

Pulmonary Angiography:

Poor sensitivity & specificity

Schriner et al: 13/15 patients no embolic disease by angiography*

When +ve, angiogram will demonstrate†

• Pruning or tortuosity of third to fifth order vessels

• Delayed filling of segmental arteries

• Subsegmental filling defects

*Schriner RW, Ryu JH, Edwards WD. Microscopic pulmonary tumor embolism causing subacute cor pulmonale: a difficult antemortem diagnosis. Mayo Clin Proc. 1991;66:143–148†Chakeres DW, Spiegel PK. Fatal pulmonary hypertension secondary to intravascular metastatic tumor emboli. AJR Am J Roentgenol. 1982;139:997–1000.

Schriner RW, Ryu JH, Edwards WD. Microscopic pulmonary tumor embolism causing subacute cor pulmonale: a difficult antemortem diagnosis. Mayo Clin Proc. 1991 Feb;66(2):143-8.

18 out of 21 2 out of 1320 out of 24

Clear Lungs Perfusion defects Emboli

Right Heart Catheterization & Pulmonary Microvascular

Cytology (PMVC):

Can confirm the presence of malignant cells

A sample of pulmonary capillary blood

The aspirated blood is then filtered & stained w/

Papanicolaou method

PMVC Disadvantages:

Pulmonary megakaryocytes & endothelial cells may

mimic malignancy

Rarely, in patients w/ massive hepatic involvement, if the

sample is not wedged, malignant cells from hepatic veins

may contaminate the sample

Pulmonary wedge sampling is more sensitive in

Lymphangitic Carcinomatosis (LC) than MPTE

Videothoracoscopic or Transbronchial Lung Biopsy (TLB):

Sensitivity: TLB< open lung biopsy

Easier to perform & safer in patients w/severe

pulmonary compromise

Open Lung Biopsy:

Procedure of choice for definitive diagnosis

Significant risk to patients w/ low pulmonary reserve &

hypoxemia

Approach to the patient with known malignancy, dyspnea, & unremarkable CXR**Bassiri AG, Haghighi B, Doyle RL, Berry GJ, Rizk NW. Pulmonary tumor embolism. Am J Respir Crit Care Med. 1997 Jun;155(6):2089-95.

Overall survival is usually four to 12 weeks in the

patients, who have diagnosis made antemortem*

No randomized-controlled trials exist in the literature,

validating any modality of treatment

*Chatkin JM, Fritscher LG, Fiterman J, Fritscher CC, da Silva VD. Microscopic pulmonary neoplastic emboli: report of a case with respiratory failure but normal imaging. Prim Care Respir J. 2007 Apr;16(2):115-7.

Few reports of limited success w/ chemotherapy†‡

Vasodilators such as nitric oxide or Iloprost are

ineffective in alleviating the symptoms of pulmonary

hypertension in MPTE

†He XW, Tang YH, Luo ZQ, Gong LD, Cheng TO. Subacute cor pulmonale due to tumor embolization to the lungs. Angiology. 1989 Jan;40(1):11-7.‡Masson RG, Krikorian J, Lukl P, Evans GL, McGrath J. Pulmonary microvascular cytology in the diagnosis of lymphangitic carcinomatosis. N Engl J Med. 1989 Jul 13;321(2):71-6.

1 case of success w/ anti-hormone therapy in MPTE *

Anticoagulation w/ heparin or thrombolytic therapy is

not beneficial, but recommended †‡

If the diagnosis confirmed, treatment can be focused at

palliative therapy rather than aggressive chemotherapy

*Konduri S, Khan Q, Stites S. Pulmonary hypertension caused by metastatic breast cancer and its response to antihormone therapy and chemotherapy. Breast J. 2007 Sep-Oct;13(5):506-8.†Stucki A, Kruse A, Iff S, Stanga Z, Cottagnoud P, Gerber P. A rare cause of fatal right heart failure. Eur J Intern Med. 2006 Jan;17(1):68-70. ‡Steiner S, Plehn G, Reinecke P, Cohnen M, Schwartzkopff B, Hennersdorf MG, Strauer BE. Disseminated microvascular pulmonary tumor cell embolism: a rare cause of fulminant pulmonary hypertension. Onkologie. 2004 Dec;27(6):566-8.

Defined as the presence of tumor emboli in the

bronchovascular, interlobular, septal & subpleural

lymphatics

Microvascular tumor emboli are ultimately the source of

lymphangitic carcinomatosis

MPTE LC

Incidence Lower Higher

Clinical Course Subacute Gradual

Dyspnea More common (58%) Less common (46%)

Cough More common Less common

Cyanosis More common Less common

CXR & High Resolution Chest-CT Normal Abnormal

Right Ventricular Enlargement More common Less common

Association w/ Cor Pulmonale More common Less common

Histological Signs of Pulmonary Hypertension

More common Less common

Massive MPTE may be difficult to distinguish clinically

from acute Pulmonary Thromoembolism

MPTE should be in the differential for primary PH,

especially w/ a hx of cancer & resistance to treatment w/

anti-coagulation

AUTOPSY SHOULD BE PERFORMED:

In cases w/ known malignant tumors & respiratory

symptoms

Rapidly progressive respiratory failure & pulmonary

hypertension of unknown cause

Respiratory failure & findings of segmental contour pattern

on V/Q scan

William Patton, M.D.

Mohammad Salameh, M.D.

Ann Alpern, M.D.

Rebecca Daniel, M.D.

Rajeev Swarup, M.D.

Soumya Madala, M.D.

Eileen Robinson