carcinoma (12%), GI tumors (10.

7%), pulmonary tumors

(10.7%), urinary tumors (7%), and others (14%).1 These
patients included five (8.9%) with lung cancer, with patient
age ranging from 57 to 69 years. Moreover, data show only
one patient presenting with vesicle lesions, three with thoracic dermatomal involvement, and one without metastasis
(two with lymph nodes). The time from lung cancer diagnosis to zosteriform skin metastasis varied from being simultaneous to 1 year.1
Several theories reportedly explain the mechanisms of
zosteriform skin metastasis. Some reported on previous
herpes zoster infection over the same areas of skin metastasis
wherein the skin loses its immunologic ability (Koebnerlike phenomenon).2 In others, surgical implantation was
reported as the cause of skin metastasis. However, in the
present case, the patient did not have a history of herpes
zoster, trauma, or surgical procedures. Further, other reports
implied a pathogenesis related to the lymphatic system,
which was demonstrated by focal cancer embolism in
enlarged lymphatic vessels.3 The retrograde flow due to
mass obstruction may lead to skin metastasis.4
In the current case, the patient developed new-onset
zosteriform skin metastasis over the right-side upper chest
wall just after right-upper-limb and shoulder erythematous
swelling. The condition may be explained by cancer embolism in dilated lymphatic ducts shown by pathology study,
which included the obviously delayed lymphatic flow and
dermal backflow over the right upper limb (compatible with
the right-upper-limb swelling and band-like skin metastasis) documented by lymphoscintigraphy. Thus, it can be
assumed that backflow of the chest wall also developed,
bringing tumor emboli to the skin as zosteriform metastasis. On the other hand, radiation therapy is not considered
a major cause because the site of therapy was on the rightside back not on the exact areas of zosteriform metastasis.
One study of 579 patients with lung cancer showed that
large cell carcinoma has the greatest tendency for spread to
the skin (10.3%), whereas epidermoid carcinoma has the
least tendency to do so. Most patients with skin metastasis
have adenocarcinoma.5 Median survival interval after skin
involvement is about 4 months.5 The patient died 13 months
after diagnosis of zosteriform skin metastasis.

Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be discussed in this article.

References
1. Savoia P, Fava P, Deboli T, Quaglino P, Bernengo MG. Zosteriform cutaneous metastases: a literature meta-analysis and
a clinical report of three melanoma cases. Dermatol Surg.
2009;35(9):1355-1363.
2. Zalaudek I, Leinweber B, Richtig E, Smolle J, HofmannWellenhof R. Cutaneous zosteriform melanoma metastases
arising after herpes zoster infection: a case report and review
of the literature. Melanoma Res. 2003;13(6):635-639.
3. Kamisawa T, Takahashi M, Nakajima H, Egawa N. Gastrointestinal: zosteriform metastases to the skin. J Gastroenterol
Hepatol. 2006;21(3):620.
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4. Kondras K, Zalewska A, Janowski P, Kordek R. Cutaneous

multifocal melanoma metastases clinically resembling herpes
zoster. J Eur Acad Dermatol Venereol. 2006;20(4):470-472.
5. Hidaka T, Ishii Y, Kitamura S. Clinical features of skin metastasis from lung cancer. Intern Med. 1996;35(6):459-462.

Severe Pulmonary
Hypertension Associated
With Emphysema
A New Phenotype?
Yochai Adir, MD, FCCP; Robert Shachner, MD; Offer Amir, MD;
and Marc Humbert, MD, PhD

Mild to moderate precapillary pulmonary hypertension (PH) is a common complication of COPD and
has typically been related to severe airflow limitation
associated with chronic hypoxemia. Previous studies
focusing specifically on patients with emphysema
found that worsening PH was associated with progression of airflow obstruction. In the present report,
we describe a new phenotype of COPD with severe precapillary PH in patients presenting with progressive
dyspnea, normal spirometry, severely reduced diffusion
capacity of the lung for carbon monoxide, and highresolution CT scans of the chest showing diffuse centrilobular emphysema. CHEST 2012; 142(6):16541658
Abbreviations: Dlco 5 diffusion capacity of the lung for carbon
monoxide; HRCT 5 high-resolution CT; mPAP 5 mean pulmonary
artery pressure; PAP 5 pulmonary artery pressure; PH 5 pulmonary hypertension

ild to moderate precapillary pulmonary hypertension (PH) is a common complication of COPD and
is associated with increased morbidity and mortality.1,2
Severe precapillary PH (mean pulmonary artery pressure
[mPAP] . 35-40 mm Hg and pulmonary artery wedge
pressure 15 mm Hg) is unusually reported in COPD
patients.3,4 These patients may exhibit a distinctive pattern
with less severe airflow limitation but more severe hypoxemia,
hypocapnia, decreased diffusion capacity of the lung for carbon monoxide (Dlco), and significantly impaired survival.5
Manuscript received November 4, 2011; revision accepted March 24,
2012.
Affiliations: From the Pulmonary Division (Dr Adir), the Radiology
Division (Dr Shachner), and the Cardiology Division (Dr Amir),
Carmel Medical Center, Faculty of Medicine, The Technion, Institute of Technology, Haifa, Israel; Universit Paris-Sud (Dr Humbert),
Facult de Mdecine, Le Kremlin-Bictre; Assistance Publique
Hpitaux de Paris (Dr Humbert), Service de Pneumologie, Hpital Bictre, Le Kremlin-Bictre; and Institut National de la Sant et
de la Recherche Mdicale (Inserm) U999 (Dr Humbert), Centre
Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.
Correspondence to: Yochai Adir, MD, FCCP, Pulmonary Division, Carmel Medical Center, 7 Michal St, Haifa, Israel; e-mail:
adir-sh@zahav.net.il
2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.11-2816
Selected Reports

Table 1Clinical Characteristics of the Three Patients

Patient No.
1
2
3

Age, y

BMI, kg/m2

Smoking, pack-y

Duration of Symptoms BD, mo

CAD

HTN

DM

HPL

CT Scan Score
Emphysema Ratio, %

74
87
82

24.8
23.5
23.2

90
100
40

18
24
12

1
1
1

2.6
9.4
3.2

BD 5 before diagnosis; CAD 5 coronary artery disease; DM 5 diabetes mellitus; HPL 5 hyperlipidemia; HTN 5 hypertension.

In the present report, we describe a new phenotype of

patients with severe precapillary PH, presenting with severe
dyspnea, normal spirometry, markedly reduced Dlco, and
high-resolution CT (HRCT) scans of the chest showing diffuse centrilobular emphysema.

of PH were excluded. Oxygen therapy failed to reduce pulmonary artery pressure (PAP). Right-sided heart catheterization was performed, revealing severe precapillary PH
(Table 3).

Discussion
Case Report
We report three elderly, male, heavy smokers, who presented with progressive dyspnea, marked hypoxemia, and
hypocapnia (Table 1). On evaluation by an experienced
radiologist, a helical angioscan of the chest excluded pulmonary thromboembolic disease but was notable for diffuse
emphysema with no evidence of interstitial lung disease
(Fig 1). Quantitative measures of emphysema for the whole
lung (CT scan emphysema score) were performed using
lung density software on a dedicated CT scan workstation
(Extended Brilliance workspace 4.5; Philips Healthcare)
(Fig 2). Of note, lung function tests revealed normal spirometry (Fig 3) with severely reduced Dlco and normal
lung volumes (measured by body plethysmograph) (Table 2).
Doppler echocardiography showed elevated estimated
systolic pulmonary artery pressure, with no evidence of
congenital heart disease or patent foramen ovale, normal
left ventricular function, and right ventricular enlargement with reduced function. There was no evidence on
echocardiography of diastolic dysfunction. Other causes

Mild to moderate PH has been reported in up to

one-third of patients with COPD and has typically been
related to severe airflow limitation associated with chronic
hypoxemia.1,4 Previous studies focusing specifically on
patients with emphysema found that worsening PH was
associated with progression of airflow obstruction.6,7 Classically, PH in emphysema has been attributed to several factors, including hypoxia leading to reactive vasoconstriction
and pulmonary vascular remodeling, the loss of a significant portion of the pulmonary vascular bed, and compression of alveolar vessels from hyperinflation. However,
moderate COPD is observed in a small subgroup of patients
with disproportionate pulmonary vascular disease. This
subgroup is characterized by moderate airway obstruction
contrasting with significant hypoxia, normo- or hypocapnia,
and significantly impaired survival.
Chaouat et al3 evaluated 998 patients with stable COPD
for the presence of PH by right-sided heart catheterization. Eleven patients (1.1%) had severe PH (defined as
mPAP . 40 mm Hg) with a similar phenotype combining

Figure 1. High-resolution CT scan of the chest. Representative images of the upper and lower lung
zones, showing diffuse emphysema. 1A, 1B, Patient 1. 2A, 2B, Patient 2. 3A, 3B, Patient 3.
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CHEST / 142 / 6 / DECEMBER 2012

1655

Figure 2. Three-dimensional image of the right lung (created by

the software for calculating the CT scan emphysema score) demonstrating diffuse emphysema (in red).

mild to moderate airway obstruction (median FEV1,

50% predicted), severe hypoxemia, hypocapnia, and a very
low Dlco. Thabut et al5 assessed pulmonary hemodynamic characteristics in 215 patients with COPD who
were candidates for lung volume reduction surgery or lung
transplant. Sixteen patients (3.7%) had severe PH (defined
as mPAP . 45 mm Hg) and similar clinical features.
These studies suggest that this small subgroup of patients
with severe PH may represent a subset of patients with
COPD in whom pulmonary vascular disease is predominant. Furthermore, although spirometry is mandatory for
the diagnosis of COPD and for determining its severity,
no correlation was found between the severity of airflow
obstruction and PAP in these patients.
Our reported cases had clinical characteristics similar
to those described by Chaouat et al3 and Thabut et al,5 with
the important exception of a normal spirometry. The coexistence of emphysema and normal spirometry was described

previously, especially in patients with mild emphysema.7

In patients with severe emphysema, the associated loss
of lung elastic recoil pressure usually leads to expiratory
airflow limitation. However, because maximal expiratory
flow depends on elastic recoil pressure, it is possible that
hyperinflation maintained recoil pressure at near-normal
values, explaining the normal spirometry results. These
patients had evidence of severe emphysema on HRCT scan
in concert with markedly reduced Dlco and normal
spirometry. According to GOLD (Global Initiative for
Chronic Obstructive Lung Disease) guidelines, based on
spirometry alone, they would not even be considered as
having COPD. Contrasting with FEV1 measures, there was
a clear association between the severity of emphysema on
HRCT and the reduction in Dlco.
A broadly similar phenotype was described in patients
with combined pulmonary fibrosis and emphysema syndrome.8 These patients had features similar to those of
the patients here, such as dyspnea, hypoxemia, normohypocapnia, severely reduced Dlco, and severe PH. However,
in these patients, the combination of hyperinflation and
high compliance of the emphysematous areas of the lungs
probably compensated for the volume loss due to fibrosis
of the lower lobes, explaining the normal spirometry values.
Severe hypoxemia with high alveolar-arterial gradient was
observed in these patients. When emphysema predominates, the main cause of hypoxemia is usually ventilationperfusion mismatch.9 However, the severe degree of
hypoxemia suggests that other factors may have been
involved, such as right to left shunting, although we were
unable to demonstrate intracardiac shunt. In addition,
low cardiac output might contribute to the observed hypoxemia, with increased oxygen tissue extraction in patients
with impaired hemodynamic status.
The reasons why patients with emphysema and no
airflow obstruction but with significant hypoxemia and
severely reduced Dlco may develop severe PH require
further discussion. One explanation may be an individual
sensitivity of the pulmonary vasculature to alveolar hypoxia. Indeed, it has been shown that some predisposed
individuals could respond to acute hypoxia with a marked
increase in pulmonary vascular resistance and PAP.10 Chronic

Figure 3. Spirometry results of the three patients demonstrating normal spirometry in each patient. A, Patient 1. B, Patient 2. C, Patient 3.
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Selected Reports

Table 2Laboratory and Lung Function Data of the Three Patients

Patient
No.
1
2
3

Pao2,
mm Hg

Paco2,
mm Hg

Dlco,
% Predicted

FEV1,
% Predicted

FVC,
% Predicted

FEV1/FVC, %

FEF50,
% Predicted

MMEF75-25,
% Predicted

TLC,
% Predicted

RV,
% Predicted

43
50
40

28
32
34

23
24
18

90
114
123

94
117
122

74
71
72

71
52
59

48
65
63

91
106
104

95
104
101

Dlco 5 diffusion capacity of the lung for carbon monoxide; FEF50 5 forced expiratory flow at 50% FVC; MMEF75-25 5 maximal midexpiratory flow
(the average expiratory flow over the middle half of the FVC curve); RV 5 residual volume; TLC 5 total lung capacity.

Table 3Echocardiographic and Hemodynamic Data of the Three Patients

Patient
No.
1
2
3

LA size, cm

IVS size, cm

sPAP,
mm Hg

TAPSE, cm

RAP,
mm Hg

mPAP,
mm Hg

PWP,
mm Hg

Cardiac
Index, L/min/m2

PVR, mm Hg/L/min/m2

4.0
3.3
3.5

1.1
1.0
1.0

78
118
77

1.6
1.1
1.5

9
10
3

40
39
35

12
9
9

2.0
2.7
2.1

7.3
6.7
8.4

IVS 5 intraventricular septum; LA 5 left atrium; mPAP 5 mean pulmonary artery pressure; PVR 5 pulmonary vascular resistance; PWP 5 pulmonary wedge pressure; RAP 5 right atrial pressure; sPAP 5 systolic pulmonary artery pressure; TAPSE 5 tricuspid annular plane systolic excursion.

hypoxia in these patients might lead to pulmonary vascular remodeling, thus resulting in persistent increases in
PAP. Genetic predisposition could be responsible for the
different individual responses to alveolar hypoxia. A previous study suggested that the serotonin (5-HT) transporter
gene polymorphism could determine the severity of PH
in hypoxic patients with COPD.11 An insertion/deletion
polymorphism in the promoter region of the 5-HTT gene
results in long (L) and short (S) forms. Of note the L allele
drives a two- to three-fold higher rate of 5-HTT gene transcription than the S allele. In that study, Eddahibi et al11
showed that patients carrying the 5-HT transporter gene
LL genotype had higher mPAP compared with their SS
and LS counterparts. However, these patients had less pronounced hypoxemia than did the patients here or the
patients described by Thabut et al5 and Chaouat et al.3
Another hypothesis that may explain severe PH in these
patients is the coexistence of emphysema and pulmonary
vascular disease, which could be somewhat similar to idiopathic pulmonary arterial hypertension. However, more
epidemiologic and morphologic studies are needed to support this hypothesis.
Detection of PH in patients with COPD can be challenging because symptoms such as dyspnea and fatigue
are common and are usually the results of airflow limitation and hyperinflation in COPD. Indeed, in these patients,
there was a prolonged duration of symptoms until the diagnosis of severe PH was made. Therefore, when a patient
presents with severe dyspnea somewhat disproportionate
to the severity (or even absence in our present cases) of
airflow limitation, the presence of PH might be suspected.
It is important to identify this subgroup of patients because
they have a poor prognosis and may be candidates for specific management.12 Long-term oxygen therapy is recommended in patients with COPD and hypoxemia. However,
although in patients with mild to moderate PH long-term
oxygen therapy improves or at least stabilizes PAP, in
patients with severe PH, oxygen therapy appears insufficient to reverse or even stabilize PAP.13 In the absence of
lung pathologic assessment in these patients, we can only
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speculate that the severe PH might be due to a significant

and irreversible pulmonary vascular remodeling component, similar to that observed in pulmonary arterial hypertension. This hypothesis might argue in favor of the use
of drugs approved for pulmonary arterial hypertension in
this group of patients, but, based on the present evidence,
it is strongly recommended not to treat patients with
COPD with drugs dedicated to pulmonary arterial hypertension outside randomized controlled trials. Obviously,
eligible patients should be considered for lung transplant
when they present with this severe phenotype, but this
was not possible in this elderly population. Interestingly,
these patients were older and had comorbidities, including
systemic hypertension. As in the systemic circulation, the
pulmonary vasculature may be affected by age-associated
arterial remodeling,14 leading to pulmonary vascular stiffness and increases in systolic PAP. A recent populationbased study15 demonstrated that PAP increases with age.
In conclusion, we describe three patients with diffuse
emphysema and severe PH, with a similar phenotype comprising severe dyspnea, normal spirometry, and severely
reduced Dlco. Further studies are needed to better
describe this subgroup of patients and their management.

Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Humbert has
relationships with drug companies including Actelion Pharmaceuticals Ltd; AstraZeneca; Bayer; Chiesi Ltd; GlaxoSmithKline; Eli Lilly
and Company; Merck & Co, Inc; Novartis AG; Takeda Pharmaceuticals International GmbH; Pfizer, Inc; Stallergenes; Teva
Pharmaceuticals; and United Therapeutics Corp. In addition to
being an investigator in trials involving these companies, relationships include consultancy services and membership on scientific
advisory boards. Drs Adir, Shachner, and Amir have reported that
no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

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Selected Reports