SYMPOSIUM ON INTRATHORACIC NEOPLASMS-Part II

Clinical Manifestations of Lung Cancer

ASHOKAKUMAR M. PATEL, M.D., STEVE G. PETERS, M.D.,

Division of Thoracic Diseases and Internal Medicine

The initial clinical manifestations of lung cancer are diverse and may occur with or without symptoms.
Manifestations of pulmonary malignant lesions are produced by local growth or invasion, metastatic
disease, or paraneoplastic processes. Patterns of local invasion such as Pancoast's syndrome or the
superior vena cava syndrome are relatively uncommon but well recognized. Metastatic lung cancer
can involve almost any anatomic area by hematogenous, lymphatic, or, occasionally, interalveolar
dissemination. Complications related to malnutrition, infection, electrolyte disturbances, and coexist-
ing diseases influence the initial manifestations. Although individual tumor cell types are associated
with characteristic features, no constellation of findings is pathognomonic for a specific histologic
variant. Because successful treatment of pulmonary carcinoma depends on early detection, awareness
of the typical clinical manifestations is important.

The clinical manifestations and diverse initial symptoms of
pulmonary malignant lesions remain a challenge in clinical
practice. Although the presymptomatic detection of lung
cancers has been emphasized, screening methods remain
controversial, and many patients have advanced disease at
the time of initial assessment.':" The estimated doubling
time or rate of growth of various lung tumors differs and
influences the possibility of early detection.' Because early
and successful treatment of lung cancer depends on early
detection, recognizing the clinical manifestations of lung
cancer becomes even more imperative. An awareness of the
potential complications that may result from the local
growth, as well as the metastatic and paraneoplastic effects,
of pulmonary malignant lesions is important. The patterns of
Individual reprints of this article are not available. The entire
Symposium on Intrathoracic Neoplasms will be available for pur-
chase as a bound booklet from the Proceedings Circulation Office
at a later date.
Mavo Clin Proc 1993; 68:273-277
initial clinical manifestations of lung cancer are outlined in
Table I.
The symptomatic manifestations of lung cancer may re-
sult from one of three major processes: (1) local growth of
the tumor, (2) intrathoracic or extrathoracic metastasis, or (3)
a paraneoplastic syndrome. The spectrum of initial pulmo-
nary complaints in patients with lung cancer is broad, rang-
ing from no symptoms to cough, dyspnea, hemoptysis,
hoarseness, anddysphagia,"? The relative frequencies of
symptoms and signs commonly associated with lung cancer
are summarized in Table 2.
LOCAL TUMOR GROWTH
Symptoms from local growth of a malignant pulmonary
lesion depend on the initial site and size of the tumor, as well
as involvement of surrounding structures. Typically, the site
of the tumor is classified as either central (endobronchial or
mediastinal) or peripheral (distal to major bronchi, pleural,
or chest wall). Local growth of mediastinal or centrally
273 © 1993 Mayo Foundation for Medical Education and Research
274 CLINICAL MANIFESTATIONS OF LUNG CANCER
Table I.-Patterns of Initial Clinical Manifestations
of Lung Cancer
Asymptomatic
Symptomatic
Local growth
Central
Endobronchial
Compression or invasion of adjacent structures
Esophagus
Trachea
Nerve involvement-phrenic, recurrent laryngeal,
brachial plexus, sympathetic chain, vagus
Major vessels-for example, superior vena cava
Thoracic duct
Pericardium, heart
Peripheral
Parenchymal
Pleural
Chest wall
Metastatic disease
Hematogenous-for example, central nervous system, bone,
bone marrow, liver, adrenal glands
Lymphatic
Interalveolar
Paraneoplastic (nonmetastatic) syndromes
occurring lesions can produce symptoms such as cough,
hemoptysis, or wheezing; obstruction and postobstructive
pneumonitis; dysphagia or recurrent aspiration (esophageal
extension); hoarseness (involvement of the recurrent laryn-
geal nerve); superior vena cava syndrome (vascular obstruc-
tion); chylothorax (thoracic duct); or palpitations and syn-
cope (pericardial irritation and cardiac involvementj.P'"
Cavitation of the tumor or postobstructive pneumonitis can
cause fever, chills, and a productive cough, a picture that
mimics an infectious process or abscess. 12 Peripheral lesions
may be associated with pleural or chest wall extension (or
both), resulting in chest pain, dyspnea, or cough. Pleural
involvement occurs in approximately 8 to 15% of patients
with lung cancer and is asymptomatic in approximately 25%
of these cases. When it is symptomatic, the major com-
plaints are dyspnea, cough, and chest pain." Other initial
manifestations of malignant pleural involvement include
pleural effusions, pleural plaques, and pneumothorax.l':"
Chest wall seeding through a needle tract, although rarely
symptomatic, may manifest as a palpable nodule over a prior
thoracentesis or needle biopsy site.":" In addition, neuro-
logic impingement of the brachial plexus (Pancoast's syn-
drome or apical tumors), the cervical sympathetic chain
(Homer's syndrome), or the phrenic nerve (paralysis of the
hemidiaphragm) may result from local extension of a pulmo-
nary malignant lesion.
A careful search for these manifestations of lung cancer
may help direct further testing for determining the tissue
Mayo Clin Proc, March 1993, Vol 68
type and for appropriately staging the extent of disease. For
example, episodes of recurrent aspiration may be due to
neurologic impairment or to esophageal involvement by ex-
trinsic compression or by formation of a tracheoesophageal
fistula." A high index of suspicion is also prudent during the
subsequent interpretation of the available data. For instance,
a history of productive cough may lead to performance of
sputum cytology, but a negative result does not exclude the
diagnosis of a malignant process, especially if the lesion is
peripheral or submucosal. In addition, patients who have
hemoptysis at the time of initial assessment may have nor-
mal findings on plain chest roentgenographic studies.
Therefore, clinicians should consider the possibility of
bronchogenic carcinoma when examining such patients, es-
pecially those with a history of smoking or other major risk
factors for lung cancer.
Pancoast's Syndrome.-Current techniques are note-
worthy for the diagnosis of apical lung tumors (Pancoast's
syndrome) or pulmonary sulcus tumors. Initially described
more than 60 years ago, Pancoast's syndrome typically
manifests as (1) pain in the shoulder and medial aspect of the
scapula; (2) radicular pain with or without muscle wasting
along the distribution of the ulnar nerve; and (3) Homer's
syndrome, including ptosis, miosis, and hemifacial
anhidrosis.v-? Although most pulmonary sulcus tumors are
squamous cell carcinomas, small-cell carcinoma has been
described in 1 to 2% of cases." Thin-section magnetic
resonance imaging may delineate the extent of locally ad-
vanced disease more accurately than conventional computed
tomography, although the clinical practice in this area is
evolving." Transthoracic needle aspiration is frequently
being used for tissue diagnosis, but bronchoscopy may still
be necessary to assess the extent of endobronchial disease."
Superior Vena Cava Syndrome.-Since the initial de-
scription of the superior vena cava syndrome by Hunter" in
1757, major changes in the prevalence of etiologic factors
Table 2.-Approximate Frequencies of Initial Symptoms
and Signs of Lung Cancer
Approximate
Symptom or sign frequency (%)
Cough 75
Dyspnea 60
Chest pain 45
Hemoptysis 35
Other pain (bone, shoulder) 25
Clubbing, HPO* 21,5
Hoarseness 5-18
Dysphagia 2
Wheezing 2
*HPO = hypertrophic pulmonary osteoarthropathy.
Data from Andersen and Prakash" and Grippi.'
Mayo Clin Proc, March 1993, Vol 68
and in therapeutic approaches have been reported." Most
commonly, this syndrome results from extrinsic compres-
sion of the superior vena cava and secondary intraluminal
thrombosis. Major complaints consist of facial fullness or
flushing, headache, dyspnea, cough, and, occasionally,
edema of the upper extremities.P'" Less commonly, pain,
dysphagia, and syncope may occur. Accompanying physical
findings include prominent venous patterns on the face and
upper part of the trunk, papilledema, facial cyanosis, and,
occasionally, pleural effusion. Although bronchogenic car-
cinoma is now the most common cause of the superior vena
cava syndrome, previous common causes, such as tuberculo-
sis and chronic mediastinitis, should be considered."
Previously, the superior vena cava syndrome was consid-
ered a radiotherapeutic emergency. Although this percep-
tion no longer prevails, rapid histologic diagnosis to exclude
infection, lymphoma, and small-cell carcinoma is impor-
tant." Caution is advised when procedures such as veni-
puncture or lymph node biopsy are performed in patients
with this syndrome because the high venous pressures in the
upper extremities or neck may result in profuse bleeding.
Radiation therapy or chemotherapy (or both) may effectively
ameliorate the signs and symptoms of obstruction of the
superior vena cava, especially if small-cell carcinoma or
lymphoma is discovered."
METASTATIC DISEASE
The clinical manifestations of metastatic lung cancer may
result from hematogenous, lymphatic, or interalveolar dis-
semination.s-" Hematogenous spread to virtually all sites
has been reported but most commonly involves the central
nervous system, bones (especially the vertebrae, pelvis, and
femur), liver, and adrenal glands (Table 3). Metastatic le-
sions occur earlier and more frequently in small-cell carci-
noma than in other histologic types. Involvement of the liver
and adrenal glands is often asymptomatic, and laboratory
evaluation is usually needed to exclude spread to these struc-
tures. Tumor embolism from primary lung cancers and
pulmonary emboli from tumors in distant sites have been
reported recently by several authors.v" Microvascular sam-
pling of blood through a pulmonary artery catheter may help
establish a nonsurgical diagnosis of this serious condi-
tion. 34 .35 Approximately 10% of patients with bronchogenic
carcinoma, however, have pulmonary venous thrombo-
embolism or infarction-perhaps related to a hypercoagu-
lable state.
The detection of lymphatic spread is important for the
appropriate staging of lung cancer (this topic will be ad-
dressed in a subsequent contribution in this symposium).
Lymphangitic carcinomatosis involving the lung paren-
chyma has characteristic features on high-resolution com-
puted tomographyv-v-e-uneven nodular thickening of inter-
CLINICAL MANIFESTATrONS OF LUNG CANCER 275
Table 3.-Approximate Frequencies of
Metastatic Involvement of Organ Systems by Lung Cancer
Site or type Approximate
of involvement frequency (%)
Central nervous system 20-50
Cervicallymph nodes 15-60
Bone 25
Heart (includingpericardium) 20
Pulmonaryembolism, infarction 10
Pleural effusion 8-15
Pancoast's syndrome 4-8
Superior vena cava syndrome 4
Liver 1-35
Data from Andersen and Prakash" and Grippi."
lobular septa and bronchovascular bundles in a patierit with a
suspected or previously 'known malignant lesion are almost
pathognomonic of lymphatic spread and may obviate a de-
finitive invasive diagnosis. The associated symptoms of
cough, dyspnea, and fever depend on the extent ofparenchy-
mal involvement, the presence of a pleural effusion or
atelectasis, and the type of tumor.
Interalveolar spread of lung cancer may occur predomi-
nantly with bronchoalveolar carcinoma and result in
multicentric involvement." Bronchorrhea, the expectora-
tion of voluminous amounts of thin mucoid secretions, is
rarely the initial feature of bronchoalveolar carcinoma and
usually indicates extensive pulmonary involvement. Appar-
ently, the nodular variant of bronchoalveolar carcinoma is
less prone to such interalveolar dissemination" and, hence,
is more amenable to surgical resection.
Thus, metastatic disease associated with primary
bronchogenic carcinoma may involve lymphatic, hematog-
enous, or interalveolar dissemination. In addition, as men-
tioned previously, chest wall seeding through the needle
tract after thoracentesis or needle biopsy may occur.!':'?
Metastatic dissemination to the following organs or tissues
has been noted: umbilicus, kidney, subcutaneous nodules,
parotid gland, lingual gland, colon, eyelid, and thyroid
gland. Moreover, metastatic lung cancer has been associated
with subdural hematoma, acute psychiatric illness, unilateral
hyperhidrosis, and unilateral hyperlucent lung. 4o. s1
CHARACTERISTIC INITIAL PATTERNS
OF LUNG CANCER BY CELL TYPE
Although the initial symptoms of lung cancer are diverse,
certain characteristic clinical features are associated with
specific cell types. Squamous cell carcinoma, which arises
on the epithelial surface of the respiratory tract, usually
manifests as a large, central mass and is associated with
hemoptysis, obstruction, cavitation, or pleural effusion due
to nodal or thoracic duct involvement. Associated para-
276 CLINICAL MANIFESTATrONS OF LUNG CANCER
neoplastic states, such as hypercalcemia and clubbing, may
also occur. Adenocarcinoma of the lung is less likely to be
associated with smoking than are other histologic subtypes
and often originates as a solitary, peripheral lesion, although
lymphangitic metastatic lesions occasionally occur. The
bronchoalveolar subtype of adenocarcinoma may manifest
as bronchorrhea but often produces a multicentric "alveolar"
pattern on a chest roentgenogram that does not resolve with
antibiotic or corticosteroid therapy. A nodular variant of
bronchoalveolar carcinoma that appears more localized is
associated with a better surgical prognosis than is the
multicentric variant. Small-cell carcinoma differs from the
other cell types of primary lung cancer in initial manifesta-
tions and response to chemotherapy. Patients with small-cell
carcinoma of the lung usually have early submucosal and
metastatic involvement, as well as more paraneoplastic phe-
nomena. Finally, in addition to the constellation of clinical
findings associated with these individual cell types, some
patients have multiple lung cancers that are either synchro-
nous or metachronous lesions.
CONCLUSION
The clinical manifestations of lung cancer are diverse. The
goal of effective early detection must be the identification of
asymptomatic patients. Unfortunately, most patients with
carcinoma of the lung are symptomatic at the time of diagno-
sis. The initial symptoms may result from local tumor
extension, metastatic disease, or paraneoplastic phenomena
and depend partly on the specific cell type involved. The site
of the tumor, rapidity of tumor growth, mode of dissemina-
tion, and symptoms or signs elicited influence the initial
clinical manifestations, as do complications related to mal-
nutrition, infection, electrolyte disturbances, and coexisting
diseases. Finally, a high index of suspicion is needed to
improve the early detection of clinical manifestations associ-
ated with this common malignant disease.
REFERENCES
1. Woolner LB, Fontana RS, Sanderson DR, Miller WE, Muhm
JR, Taylor WF, et al. Mayo Lung Project: evaluation of lung
cancer screening through December 1979. Mayo Clin Proc
1981; 56:544-555
2. Fontana RS, Sanderson DR, Taylor WF, Woolner LB, Miller
WE, Muhm JR, et al. Early lung cancer detection: results of
the initial (prevalence) radiologic and cytologic screening in
the Mayo Clinic study. Am Rev Respir Dis 1984; 130:561-
565
3. Early Lung Cancer Cooperative Study Members. Early lung
cancer detection: summary and conclusions. Am Rev Respir
Dis 1984; 130:565-570
4. Flehinger BJ, Melamed MR, Zaman MB, Heelan RT,
Perchick WB, Martini N. Early lung cancer detection: results
of the initial (prevalence) radiologic and cytologic screening
Mayo Clin Proc, March 1993, Vol 68
in the Memorial Sloan-Kettering study. Am Rev Respir Dis
1984; 130:555-560
5. Geddes DM. The natural history of lung cancer: a review
based on rates of tumour growth. Br J Dis Chest 1979; 73:1-
17
6. Andersen HA, Prakash UBS. Diagnosis of symptomatic lung
cancer. Semin Respir Med 1982; 3:165-175
7. Grippi MA. Clinical aspects of lung cancer. Semin
Roentgenol 1990; 25:12-24
8. Hyde L, Hyde CI. Clinical manifestations of lung cancer.
Chest 1974; 65:299-306
9. Cohen MH. Signs and symptoms of bronchogenic carci-
noma. In: Straus MJ, editor. Lung Cancer: Clinical Diagno-
sis and Treatment. 2nd ed. New York: Grone & Stratton,
1983: 97-111
10. Strauss BL, Matthews MJ, Cohen MH, Simon R, Tejada
F. Cardiac metastases in lung cancer. Chest 1977; 71:607-
611
11. Adenle AD, Edwards JE. Clinical and pathologic features of
metastatic neoplasms of the pericardium. Chest 1982;
81:166-169
12. Wallace RJ Jr, Cohen A, Awe RJ, Greenberg D, Hadlock F,
Park SK. Carcinomatous lung abscess: diagnosis by
bronchoscopy and cytopathology. JAMA 1979; 242:521-
522
13. Chernow B, Sahn SA. Carcinomatous involvement of the
pleura: an analysis of 96 patients. Am J Med 1977; 63:695-
702
14. Dines DE, Cortese DA, Brennan MD, Hahn RG, Payne WS.
Malignant pulmonary neoplasms predisposing to spontane-
ous pneumothorax. Mayo Clin Proc 1973; 48:541-544
15. Prakash UBS. Malignant pleural effusions. Postgrad Med
1986 Oct; 80:201-206; 208-209
16. Sahn SA. Malignant pleural effusions. Clin Chest Med 1985
Mar; 6:113-125
17. Seyfer AE, Walsh DS, Graeber GM, Nuno IN, Eliasson AH.
Chest wall implantation of lung cancer after thin-needle aspi-
ration biopsy. Ann Thorac Surg 1989; 48:284-286
18. MUller NL, Bergin CJ, Miller RR, Ostrow DN. Seeding of
malignant cells into the needle track after lung and pleural
biopsy. J Can Assoc Radiol 1986; 37:192-194
19. Ryd W, Hagmar B, Eriksson O. Local tumour cell seeding by
fine-needle aspiration biopsy: a semiquantitative study. Acta
Pathol Microbiol Immunol Scand [AJ 1983; 91:17-21
20. Martini N, Goodner JT, D' Angio GJ, Beattie EJ Jr.
Tracheoesophageal fistula due to cancer. J Thorac
Cardiovasc Surg 1970; 59:319-324
21. Pancoast HK. Importance of careful roentgen-ray inves-
tigations of apical chest tumors. JAMA 1924; 83:1407-
1411
22. Pancoast HK. Superior pulmonary sulcus tumor: tumor
characterized by pain, Horner's syndrome, destruction of
bone and atrophy of hand muscles. JAMA 1932; 99: 1391-
1396
23. Johnson DH, Hainsworth JD, Greco FA. Pancoast's syn-
drome and small cell lung cancer. Chest 1982; 82:602-606
24. Heelan RT, Demas BE, Caravelli JF, Martini N, Bains MS,
McCormack PM, et al. Superior sulcus tumors: CT and MR
imaging. Radiology 1989; 170:637-641
25. O'Connell RS, McLoud TC, Wilkins EW. Superior sulcus
tumor: radiographic diagnosis and workup. AJR Am J
Roentgenol 1983; 140:25-30
Mayo Clin Proc, March 1993, Vol 68
26. Hunter W. The history of an aneurysm of the aorta, with
some remarks on aneurysms in general. Med Observ lnq
(Lond) 1757; 1:323-357
27. Parish JM, Marschke RF Jr, Dines DE, Lee RE. Etiologic
considerations in superior vena cava syndrome. Mayo Clin
Proc 1981; 56:407-413
28. Rodrigues N, Straus MJ. Superior vena caval syndrome. In:
Straus MJ, editor. Lung Cancer: Clinical Diagnosis and
Treatment. 2nd ed. New York: Grune & Stratton, 1983: 323-
333
29. Schraufnagel DE, Hill R, Leech JA, Pare JAP. Superior vena
caval obstruction: is it a medical emergency? Am J Med
1981; 70:1169-1174
30. Sculier JP, Evans WK, Feld R, DeBoer G, Payne DG, Shep-
herd FA, et al. Superior vena caval obstruction syndrome in
small cell lung cancer. Cancer 1986; 57:847-851
31. Hansen HH. Diagnosis in metastatic sites. In: Straus MJ,
editor. Lung Cancer: Clinical Diagnosis and Treatment. 2nd
ed. New York: Grune & Stratton, 1983: 185-200
32. Schriner RW, Ryu JH, Edwards WD. Microscopic pulmo-
nary tumor embolism causing subacute cor pulmonale: a
difficult antemortem diagnosis. Mayo Clin Proc 1991;
66:143-148
33. Kvale PA. The cancer patient with dyspnea: unusual cause?
[editorial]. Mayo Clin Proc 1991; 66:215-218
34. Masson RG, Ruggieri J. Pulmonary microvascular cytology:
a new diagnostic application of the pulmonary artery catheter.
Chest 1985; 88:908-914
35. Masson RG, Krikorian J, Lukl P, Evans GL, McGrath J.
Pulmonary microvascular cytology in the diagnosis of
Iymphangitic carcinomatosis. N Engl J Med 1989; 321:71-
76
36. Munk PL, Muller NL, Miller RR, Ostrow DN. Pulmonary
Iymphangitic carcinomatosis: CT and pathologic findings.
Radiology 1988; 166:705-709
37. Muller NL, Miller RR. Computed tomography of chronic
diffuse infiltrative lung disease. Am Rev Respir Dis 1990;
142:1206-1215
38. Daly RC, Trastek VF, Pairolero PC, Murtaugh PA, Huang M-
S, Allen MS, et al. Bronchoalveolar carcinoma: factors
affecting survival. Ann Thorac Surg 1991; 51:368-376
CLINICAL MANIFESTATIONS OF LUNG CANCER 277
39. Tao LC, Delarue NC, Sanders D, Weisbrod G. Bronchiolo-
alveolar carcinoma: a correlative clinical and cytologic
study. Cancer 1978; 42:2759-2767
40. Saito H, Shimokata K, Yamada Y, Nomura F, Yamori S.
Umbilical metastasis from small cell carcinoma of the lung.
Chest 1992; 101:288-289
41. Olsson CA, Moyer JD, Laferte RO. Pulmonary cancer meta-
static to the kidney-a common renal neoplasm. J Urol
1971; 105:492-496
42. Oleksowicz L, Morris rc, Phelps RG, Bruckner HW. Pulmo-
nary carcinoid presenting as multiple subcutaneous nodules.
Tumori 1990; 76:44-47
43. Cantera JMG, Hernandez AV. Bilateral parotid gland
metastasis as the initial presentation of a small cell lung
carcinoma. J Oral Maxillofac Surg 1989; 47: 1199-1201
44. Monforte R, Ferrer A, Montserrat JM, Picado C, Palacfn A.
Bronchial adenocarcinoma presenting as a lingual tonsillar
metastasis. Chest 1987; 92:1122-1123
45. Wegener M, Borsch G, Reitemeyer E, Schafer K. Metastasis
to the colon from primary bronchogenic carcinoma present-
ing as occult gastrointestinal bleeding-report of a case. Z
Gastroenterol 1988; 26:358-362
46. Morgan LW, Linberg JV, Anderson RL. Metastatic disease
first presenting as eyelid tumors: a report of two cases
and review of the literature. Ann Ophthalmol 1987; 19:13-
18
47. Zirkin HJ, Tovi F. Tracheal carcinoma presenting as a thy-
roid tumor. J Surg Oncol 1984; 26:268-271
48. McKenzie CR, Rengachary S5, McGregor DH, Dixon AY,
Suskind DL. Subdural hematoma associated with metastatic
neoplasms. Neurosurgery 1990; 27:619-624
49. Ralston SH, Fogelman I, Lowe GDO. Oat cell carcinoma of
bronchus presenting as an acute psychiatric illness in young
women. Postgrad Med J 1982; 58:562-563
50. McEvoy M, Ryan E, Neale G, Prichard J. Unilateral
hyperhidrosis-an unusual presentation of bronchial carci-
noma. IrJ Med Sci 1982; 151:51-52
51. Allen ED, McCoy KS. Presentation of bronchial
mucoepidermoid carcinoma as unilateral hyperlucent lung.
Pediatr Pulmonol 1990; 8:294-297