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