LETTERS
Figure 2. Immunohistochemical staining of transthoracic needle biopsy specimen demonstrating the tumor to be (A) p40 nuclear stain positive, (B) CK5
cytoplasmic stain positive, and (C) T TF-1 stain negative, consistent with squamous cell carcinoma. All images 3200 magnification.
trigger for acute SIADH in our patient. Clinicians should keep in
mind this phenomenon when referring patients for diagnostic or
therapeutic interventions in NSCLC and monitor such patients
for any subsequent signs or symptoms associated with acute
hyponatremia.
Author disclosures are available with the text of this letter at
www.atsjournals.org.
Acknowledgment: The authors thank Dr. Nathan Dunsmore of the
Greater Baltimore Medical Center Pathology Department for providing the
biopsy specimen images.
Bruce F. Sabath, M.D.
John W. Logan, M.D.
Gurkeerat Singh, M.D.
Greater Baltimore Medical Center
Baltimore, Maryland
References
1 Sørensen JB, Andersen MK, Hansen HH. Syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) in malignant disease.
J Intern Med 1995;238:97–110.
2 Seki K, Segawa M, Kusajima Y, Saito K. Syndrome of inappropriate
secretion of antidiuretic hormone associated with resection of
pulmonary squamous cell carcinoma [in Japanese]. Kyobu Geka
2010;63:133–137.
3 Kotoulas C, Panagiotou I, Tsipas P, Koutoulakis E. Inappropriate
antidiuretic hormone secretion due to squamous cell lung cancer.
Asian Cardiovasc Thorac Ann 2015;23:579–581.
4 Azzopardi JG, Freeman E, Poole G. Endocrine and metabolic
disorders in bronchial carcinoma. BMJ 1970;4:528–530.
Prognostic Value of the Yale Grading System for
Superior Vena Cava Syndrome
To the Editor:
Superior vena cava (SVC) syndrome requires prompt diagnosis
and multidisciplinary treatment (1). Several definitive and
palliative treatment options exist for SVC syndrome, depending
on the cause, severity of symptoms, extent of disease, and
patient status (2, 3). To date, there have not been any
randomized studies comparing different treatment modalities,
partially because of the heterogeneity of the patient population.
1862
5 Higashihara K, Kimbara Y, Suzuki Y, Kawate E, Takahashi H. Severe
hyponatremia due to inappropriate secretion of antidiuretic
hormone following pleurodesis. Intern Med 2009;48:1069–1071.
6 Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal
sodium loss and hyponatremia probably resulting from
inappropriate secretion of antidiuretic hormone. Am J Med 1957;23:
529–542.
7 Tho LM, Ferry DR. Is the paraneoplastic syndrome of inappropriate
antidiuretic hormone secretion in lung cancer always attributable to
the small cell variety? Postgrad Med J 2005;81:e17–e18.
8 Monsieur I, Meysman M, Noppen M, de Greve J, Delhove O, Velckeniers
B, Jacobvitz D, Vincken W. Non-small-cell lung cancer with multiple
paraneoplastic syndromes. Eur Respir J 1995;8:1231–1234.
9 McDonald P, Lane C, Rojas GE, Masood A. Syndrome of inappropriate
anti-diuretic hormone in non-small cell lung carcinoma: a case
report. Ecancermedicalscience 2012;6:279.
10 Littlewood TJ, Smith AP. Syndrome of inappropriate antidiuretic
hormone secretion due to treatment of lung cancer with cisplatin.
Thorax 1984;39:636–637.
11 Kundaje GN, Shenoy P. A case of syndrome of inappropriate
antidiuretic hormone (SIADH) secretion due to a metastatic
squamous cell carcinoma. J Assoc Physicians India 1982;30:
253–254.
12 Fukabori T, Nakamura T, Kida T, Fujita Y, Goto T, Hiramori N, Fujii T,
Iwasaki Y, Nakagawa M. Syndrome of inappropriate antidiuretic
hormone secretion following cisplatinum and vindesine
administration in a patient with squamous cell carcinoma of the lung
[in Japanese]. Gan To Kagaku Ryoho 1991;18:1213–1216.
13 Vanhees SL, Paridaens R, Vansteenkiste JF. Syndrome of
inappropriate antidiuretic hormone associated with chemotherapy-
induced tumour lysis in small-cell lung cancer: case report and
literature review. Ann Oncol 2000;11:1061–1065.
Copyright © 2016 by the American Thoracic Society
This study was presented in abstract form at the American
Radium Society 95th Annual Meeting, April 27–May 1, 2013,
Scottsdale, Arizona.
Given the multiple options for management and the need for a
timely work-up, classification systems have been developed to help
stratify patients and to identify the most appropriate intervention.
Yu and colleagues devised the Yale grading system on the basis of
the consensus of experts in the field (4); however, it was not
validated with patient outcomes. Thus, we attempted to validate
the prognostic significance of the Yale grading system using the
outcomes from our cohort of patients with SVC syndrome. This
study was presented in abstract form at the American Radium
AnnalsATS Volume 13 Number 10 | October 2016
 LETTERS

Table 1. Classification of 50 patients with SVC syndrome using the Yale SVC syndrome grading system

Severity Class Yale Definition Yale Estimated No. Patients Percent of

Incidence (%) Total (%)

0 Asymptomatic: radiographic SVC obstruction 10 15 30

in the absence of symptoms
1 Mild: edema in the head or neck, 25 7 14
cyanosis, plethora
2 Moderate: edema in the head or neck with 50 11 22
functional impairment
3 Severe: mild to moderate cerebral edema, 10 10 20
laryngeal edema, or diminished cardiac reserve
4 Life-threatening: significant cerebral edema, 5 4 8
laryngeal edema, or hemodynamic compromise.
5 Fatal: causing death. ,1 3 6

Definition of abbreviations: SVC = superior vena cava.

Society 95th Annual Meeting, April 27–May 1, 2013, Scottsdale, significantly associated with the increasing likelihood of the patient
Arizona. being able to be discharged home after treatment (P = 0.001).

Methods Discussion
After receiving institutional review board approval, we conducted Most commonly caused by cancer, SVC syndrome was long
a retrospective chart review of the Oregon Health and Science considered one of the true oncologic emergencies (1).
University’s patient database from 2008 to 2011. Patient encounters
with International Classification of Diseases, Ninth Revision code, Table 2. Demographics, cause, and presenting symptoms for
459.2, compression of vein, were identified and the medical records 50 patients with SVC syndrome presenting to Oregon Health
were reviewed. Encounters that were associated with SVC and Science University between 2008 and 2011
compromise or that produced symptoms associated with SVC
syndrome were included, whereas all other encounters were Demographics, Cause, and Patients
excluded. Patient variables including demographics, hospitalization Presenting Symptoms
data, presenting symptoms, physical examination findings,
tumor characteristics, and therapeutic interventions were Age, median (IQR), yr 57 (38–67)
collected. All patients were assigned the respective Yale SVC Sex
syndrome grade (4) on the basis of their initial presentation (Table 1). Male 27 (54)
Data analysis was performed using JMP, Version 12.0.1 (SAS Female 23 (46)
Institute Inc., Cary, NC, 1989–2000). Wilcoxon or Kruskal-Wallis Underlying cause of SVC syndrome
Oncologic 30 (60)
tests were performed for continuous variables. The Cochran– SCLC 5 (10)
Armitage trend test was performed for between-group NSCLC 11 (22)
comparisons of categorical variables by Yale severity class (an Lymphoma 7 (14)
ordinal variable). P values ,0.05 were considered significant. Other malignancy 7 (14)
Nononcologic 20 (40)
Nontumor thrombus 14 (28)
Other 6 (12)
Results Asymptomatic at presentation, diagnosed 15 (30)
radiographically
Our chart review identified 50 patients with a diagnosis of SVC Presenting with vascular symptoms
Neck/chest vein distension 19 (38)
syndrome at OSHU during the 4-year period of this study. Extremity edema 16 (32)
Demographics, cause, and presenting symptoms are given in Table 2. Facial edema 24 (48)
Fifteen patients (30%) were classified as grade 0 according to Presenting with respiratory symptoms
the Yale SVC syndrome grading system, whereas 7 (14%), 11 (22%), Dyspnea 31 (62)
10 (20%), 4 (8%), and 3 (6%) were classified as grades 1 to 5, Cough 18 (36)
Presenting with CNS symptoms
respectively (4) (Table 2). Visual changes 1 (2)
Yale SVC syndrome grade was not significantly associated with Altered mental status 3 (6)
differences in hospital admission, length of hospital stay, need Obtundation 1 (2)
for urgent treatment (defined as intubation, stenting, or other
Definition of abbreviations: CNS = central nervous system; IQR =
intervention to preserve life or alleviate SVC obstruction within 48 h interquartile range; NSCLC = non-small cell lung cancer; SCLC = small cell
of admission), ICU admission, ventilator requirement, or treatment lung cancer; SVC = superior vena cava.
modality (Table 3). Decreasing Yale SVC syndrome grade was Results are presented as No. (%) unless otherwise noted.

Letters 1863
 LETTERS

Table 3. Treatment course and outcomes for 50 patients with SVC syndrome

Treatment Course and All Patients Yale Severity Class P Value

Outcomes (N = 50)
Class 0 Class 1 Class 2 Class 3 Class 4 Class 5
(n = 15) (n = 17) (n = 11) (n = 10) (n = 4) (n = 3)

Treatment setting: hospital 41 (82) 12 (80) 6 (86) 10 (91) 7 (70) 3 (75) 3 (100)
admission, No. (column %)
Length of hospital stay, 3.5 (1–9) 2 (1–6) 6 (1–12) 5 (2–15) 2 (0–7) 13 (1–24) 9 (5–18) 0.414
median (IQR), d
Required urgent treatment,* 19 (38) 5 (33) 0 (0) 8 (73) 2 (20) 2 (50) 2 (67) 0.271
No. (%)
Required ICU admission, 19 (38) 4 (27) 3 (43) 5 (45) 2 (20) 2 (50) 2 (67) 0.378
No. (column %)
Length of ICU stay, median 3 (1.25–8.75) 0 (0–1) 0 (0–5) 0 (0–3) 0 (0–1) 5 (0–21) 1 (0–2) 0.602
(IQR), d
Required ventilator, 10 (20) 3 (20) 2 (29) 2 (18) 0 (0) 2 (50) 1 (33) 0.818
No. (column %)
Length of time on the ventilator, 5.5 (1.75–7.25) 0 (0–0) 0 (0–1) 0 (0–0) 0 (0–0) 3.5 (0–19) 0 (0–1) 0.322
median (IQR), d
Treatment,† No. (column %)
Surgical resection 5 (10) 2 (13) 1 (14) 1 (9) 1 (10) 0 (0) 0 (0) 0.953
Stent placement 8 (16) 0 (0) 0 (0) 3 (27) 4 (40) 1 (25) 0 (0) 0.056
Radiotherapy 16 (32) 4 (27) 1 (14) 4 (36) 2 (20) 3 (75) 2 (67) 0.106
Chemotherapy 10 (20) 3 (20) 0 (0) 1 (9) 1 (20) 2 (50) 2 (67) 0.066
Supportive care 11 (22) 3 (20) 1 (14) 3 (27) 3 (30) 1 (25) 1 (33) 0.464
Disposition, No. (column %) 0.001
Discharged home 38 (76) 13 (87) 7 (100) 8 (73) 9 (90) 1 (25) 0 (0)
Discharged to SNF 5 (10) 1 (6.5) 0 (0) 2 (18) 0 (0) 2 (50) 0 (0)
Discharged to hospice 2 (4) 0 (0) 0 (0) 1 (9) 1 (10) 0 (0) 0 (0)
Died during admission 5 (10) 1 (6.5) 0 (0) 0 (0) 0 (0) 1 (25) 3 (100)

Definition of abbreviations: ICU = intensive care unit; IQR = interquartile range; SNF = skilled nursing facility; SVC = superior vena cava.
*Urgent treatment defined as intubation, stenting, or other intervention to preserve life or alleviate SVC obstruction within the first 48 h of admission.
†
Some patients received more than one treatment modality during the episode of care; P values are calculated for between-group comparisons of having
received each treatment individually.

However, emerging evidence suggests that SVC syndrome
is not a “one size fits all” diagnosis (5). In the absence
of life-threatening laryngeal or cerebral edema, many
investigators recommend a more measured, multidisciplinary
approach to the management of SVC syndrome, which
can allow for tissue to be obtained before treatment is
initiated (6, 7).
For many years, there was no standardized grading system
for the evaluation of SVC syndrome, which left clinicians without
clear guidelines when faced with a patient with SVC syndrome.
Randomized controlled trials evaluating the optimal treatment for
SVC syndrome are lacking, and the cause, extent, and severity of the
syndrome vary wildly among published studies, which makes
comparing treatment outcomes among modalities and institutions
challenging (8–12).
In 2008, Yu and colleagues proposed a purely clinical grading
scale on the basis of the severity of symptoms. The Yale SVC
syndrome grading system was created from expert opinion with no
correlation to patient outcomes (4). This system was derived
empirically and has not since been validated. In our analysis of
patients treated for SVC syndrome at an academic medical center,
we were not able to find many significant differences in outcomes
by the previously proposed Yale SVC syndrome grade. However,
decreasing Yale SVC syndrome grade was associated with
increasing likelihood of being able to be discharged home after
treatment.
This study is not without its limitations, particularly those
inherent to any single-institution retrospective review. There was
likely a selection bias in which patients were chosen to receive
certain therapeutic interventions on the basis of the extent of
disease, comorbid conditions, patient preference, and other factors
not captured in this study. The size of our study cohort was not
sufficient to exclude smaller differences in outcomes according to
Yale severity grade; however, we observed no apparent trends
toward differences in outcomes, with the possible exception of
hospital length of stay.
We also note that SVC syndrome was generally only one
component of the primary disease process afflicting the patients
included in this study. Patients with malignant and benign causes of
SVC syndrome often have other symptoms or functional deficits,
which greatly influence treatment course and ultimate patient
outcomes. This may be one of the main reasons for the lack of
statistically significant differences seen when patients were grouped
by Yale severity class.
Conclusions
This study provides information on demographics, SVC cause,
presenting symptoms, treatment, and outcomes for 50 patients with
SVC syndrome treated at a large academic medical center. We
attempted to validate the previously published Yale SVC syndrome
grading system but were not able to find many significant
differences in outcomes on the basis of the Yale grade. This may

1864 AnnalsATS Volume 13 Number 10 | October 2016

 LETTERS
have been because of the heterogeneity of other presenting
symptoms and disease-related factors for patients with SVC
syndrome. Our results suggest that a more comprehensive
grading system might be advantageous in helping triage and treat
patients with SVC syndrome. Such a grading system should be
validated in a larger cohort of patients.
Author disclosures are available with the text of this letter at
www.atsjournals.org.
Emma B. Holliday, M.D.
The University of Texas MD Anderson Cancer Center
Houston, Texas
David A. Hampton, M.D., M.Eng.
University of Maryland Medical Center
Baltimore, Maryland
Charles R. Thomas Jr., M.D.
Shushan Rana, M.D.
Oregon Health & Science University
Portland, Oregon
References
1 Manthey D, Ellis L. Superior vena cava syndrome. In: Todd K,
Thomas CJ, editors. Oncologic emergency medicine: principles and
practice. Switzerland: Springer; 2016. pp. 211–220.
2 Mittal BB. Treatment of SVC syndrome. N Engl J Med 1980;302:61.
3 Rice TW, Rodriguez RM, Light RW. The superior vena cava syndrome:
clinical characteristics and evolving etiology. Medicine (Baltimore)
2006;85:37–42.
Bilateral Pleural Effusion: A Proposed Diagnostic
Decision Algorithm
To the Editor:
Bilateral pleural effusion (BPE) is not an uncommon finding in
clinical practice. There are currently no firm recommendations
on whether it is sufficient to perform a puncture on a single
side or whether it is necessary to routinely perform bilateral diagnostic
thoracentesis. A study by our group has shown that the cause of
the BPE is the same on both sides in almost 95% of patients; thus,
in the majority of cases, only a unilateral diagnostic thoracentesis
is required (1). However, the factors that may suggest the need
to perform bilateral thoracenteses have not been established.
Case Report
This case concerns a 47-year-old woman, with no relevant medical
history, and a clinical picture of 5 days onset of pleuritic chest pain
on the right side, fever, and dyspnea. In the hours before arriving at
the emergency department, she began to have pleuritic chest pain
on the left side. The vital signs were: temperature 38.58 C, blood
pressure 190/100 mm Hg, pulse 104 beats per minute, and
Author Contributions: L.F. was author/writer and performed conception and
design and approved the final version. E.S.J. was coauthor and performed
acquisition of data, revised the article critically, and approved the final
version. J.S.A. was coauthor and performed acquisition of data, revised the
article critically, and approved the final version. L.V. was author/writer and
performed conception and design and approved the final version.
Letters
4 Yu JB, Wilson LD, Detterbeck FC. Superior vena cava syndrome–a
proposed classification system and algorithm for management.
J Thorac Oncol 2008;3:811–814.
5 Parish JM, Marschke RF Jr, Dines DE, Lee RE. Etiologic
considerations in superior vena cava syndrome. Mayo Clin Proc
1981;56:407–413.
6 Schraufnagel DE, Hill R, Leech JA, Pare JA. Superior vena caval
obstruction: is it a medical emergency? Am J Med 1981;70:1169–1174.
7 Yellin A, Rosen A, Reichert N, Lieberman Y. Superior vena cava syndrome:
the myth–the facts. Am Rev Respir Dis 1990;141:1114–1118.
8 Leung ST, Sung TH, Wan AY, Leung KW, Kan WK. Endovascular
stenting in the management of malignant superior vena cava
obstruction: comparing safety, effectiveness, and outcomes
between primary stenting and salvage stenting. Hong Kong Med J
2015:21:426–434.
9 Bierdrager E, Lampmann LEH, Lohle PN, Schoemaker CM, Schijen JH,
Palmen FM, van der Heul C. Endovascular stenting in neoplastic
superior vena cava syndrome prior to chemotherapy or radiotherapy.
Neth J Med 2005;63:20–23.
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Banelli E, Enrici RM. Radiation therapy for oncological emergencies.
Anticancer Res 2001;21:2219–2224.
11 Wang Z-B, Ning F-L, Wang X-L, Cheng YF, Dong XJ, Liu CM, Chen
SS. Radiation dose is associated with prognosis of small cell lung
cancer with superior vena cava syndrome. Int J Clin Exp Med 2015;
8:4263–4268.
12 Lanciego C, Pangua C, Chacón JI, Velasco J, Boy RC, Viana A, Cerezo S,
Garcı́a LG. Endovascular stenting as the first step in the overall
management of malignant superior vena cava syndrome. AJR Am J
Roentgenol 2009;193:549–558.
Copyright © 2016 by the American Thoracic Society
respiratory rate 30/min. In the auscultation, a decrease in breath
sounds in both lung bases was observed, particularly on the
right. The blood test results highlighted white cells 14.3 3 103/µ
(85% segmented), an erythrocyte sedimentation rate of 87 mm/h,
arterial oxygen tension/pressure 77.4 mm Hg, arterial carbon
dioxide tension/pressure 31 mm Hg, and pH 7.38. The radiological
studies of the chest (X-ray and computed tomography) showed
a slight increase in density in the right middle pulmonary field,
accompanied by a BPE. The right PE was larger and loculated
(by ultrasound). A right thoracentesis was performed, and
on seeing the biochemistry results, the left side was also punctured.
The biochemical characteristics of the pleural fluid (PF) from
both sides are shown in Table 1. The sputum, PF, and blood cultures
were all negative, as well as the urinary antigen tests for Streptococcus
pneumoniae and Legionella. The diagnosis was parapneumonic BPE,
complicated on the right side and simple on the left.
Progress was favorable after initial treatment with antibiotics,
right chest drainage, and intrapleural urokinase. In view of the
lack of firm recommendations on what action to take with BPE,
we propose a diagnostic algorithm that responds to the needs of
clinicians. This algorithm, mainly based on the findings of the PF
analysis and the clinical-radiological characteristics presented by
these patients, takes into account the most common causes of BPE
and expert recommendations to avoid unnecessary actions and
without losing important clinical information.
Discussion
This case demonstrates that if unilateral thoracentesis had been
performed on the left side only, this would have resulted in a
1865