Diffuse Airway Narrowing From Carcinoma Metastatic to the Bronchial Submucosa

ciation between the two disorders. Furthermore, th ere is no acceptable neuroanatomic or physiologic explanation for isolated dermatomal hyperhidrosis in eve ntual organic involvement of either the sympathetic trunk or a single intercostal nerve. Failure to recognize a cutaneous syndrome as possibly paraneoplastic may have significant consequences as it may be the first indication of a new or recurrent tumor, underscoring th e importance of reporting potential paraneoplastic syndrom es, such as localized hyperhidrosis . REFERENCES

FIGURE 2. CT scan of th e c hest showing a nodu lar lesion in th e posterior segment of the upper lobe oF the left lung.

era! paroxysmal hyperhidrosis involving the forehead, the face, the upper hemithonu, the shoulder, and the arm related to widespread involvement of the intercostal nmve and the sympathetic chain. Lambe1t and coworkers 4 described a case of unilateral hyperhidrosis in the same areas associated with a left paraspinal IgD lambda myelomatous tumor. Hyperhidrosis was reported to disappear in this case after irradiation 4 Some reports of bronchial carcinoma causing ipsilateral paroxysmal hyperhidrosis related to encroachment of the tumor on the sympathetic trunk or intercostal ne1ves also have been repmted. 5 · 7 Unilateral segmental hyperhidrosis over a solitary dermatome is even more unusual, and difficult to explain neuroanatomically and physiologically, as stimulation of a single anterior root usually results in sympathetic effects over the distribution of numerous sympathetic ganglia. Further, there is a d ermatomal overlap of sympathetic inne1vation. Poo)H reported a case of an osteoma of the tenth dorsal vertebra that produced unilateral hyperhidrosis on the left side, initially a long the TlO dermatome but rapidly evolving over a pe1 iod of 5 months to involve the complete left side of the trunk from the axilla to Tl2. Dworin and Sober0 described a 23-year-old woman with idiopathic unilateral hyperhidrosis involving the eighth thoracic right-sided dermatome. McCoy11 reported t he case of an apical pulmonary adenocarcinoma with contralateral localized hyperhidrosis; the mechanism of this ph enom enon is unknown. The patie nt reported h erein suffered from unilateral right-sided dennatomal hyperhidrosis contralateral to an upper lo be pulmonary ade nocarcinoma. It was not possible in this case to prove that the tumor antedated th e hyperhidrosis; however, it is well-known that occult cancers may exist without clinically evident symptoms many years before th eir detection . Previous reports of un explained locali zed hyperhidrosis contralateral to malignant tumors , 11 · 12 together with the findings in this patie nt and in view of the rarity of this dennatologic manifestation , suggest a possible causal relationship between unilateral localized or segmental hyperhidrosis and malignant tumors rath e r than a coincidental asso-

1 Kurzrock R, Cohe n PR. Cutaneous paraneoplastic synd romes in solid tumors. Am J M ed 1995; 99:662-671 2 Free man R, Waldorf HA, Dover JS. Autonomic ne urode nn atology: disorders of sweating and flush ing. Semi Neurol 1992; 12:394-407 3 Stanford F. Sympathetic ne1ve involve ment with mesothelioma of th e pleura. Br J Dis C hest 1976; 70:134-138 4 Lambert M, Kanyi nda JM, Richard F, et al. Unilateral hype rhidrosis associated with intrathoracic IgD la mbda myelomatou s tumor. Clin Oncol H Coli Hadiol 1993; 5:65-66 5 Middleton WG. Bronchial carcinoma with pleural spread causing unilateral thoracic hype rhidrosis. Br Med J1976; 2:63 6 Walsh JC, Low PA, Allsop JL. Localized sympathetic overactivity: an uncommon complication of lung cancer. J Ne urol Neurosurg Psychiatly 1976; 36:93-95 7 Poh SC. Bronchial carcinoma with he mi lateral hype rhidrosis. Singapore Med J 1978; 19:59-60 8 Pool JL. Uni lateral thoracic hyperhidrosis caused by osteoma of the tenth dm·sal vertebra. J Neurosurg 1956; 13:111-115 9 Dworin A, Sober AJ. Unilateral segmental hyperhidrosi s. Arch Dennatol 1978; 114:770-771 10 Sato KT, Ri chardson A, Timm DE , e t !a. One-step iodine starch method for direct visualisation of sweating. Am J M ed Sci 1988; 295:528-531 11 McCoy BP. Apical pulmomuy adenocarcinoma with contralateral hyperhidrosis. Arch Dermatol 1981; 117:659-661 12 Brown HC. Unilateral lumbar sympathectomy due to retroperiton eal tumor. Br Med J1978; 1:1101

Diffuse Airway Narrowing From Carcinoma Metastatic to the Bronchial Submucosa* Identification by Chest CT Darren B . Taichman, MD, PhD; Cregan; Tina, MD, FCCP; judith Aronchick, MD; Caml Reynolds, MD; W. Roy Smythe, MD;f John R. Roberts, MD, FCCP; and Daniel Haller, MD

The differential diagnosis of dyspnea in p atients with prior malignancy and nondiagnostic c hest radiographs is broad. We report a case of breast carcinoma diffusely metastatic to the bronchial submu cosa presenting as obstructive airway disease. Chest radiographs failed to su ggest metastatic disease as the cause of dyspnea. CT, however, reveale d the CHEST I 11 4 I 4 I OCTOBER, 1998

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unusual finding of diffusely thickened and narrowed airways. Carcinoma confined to airway submucosa was identified using bronchial biopsy. We suggest that diffuse airway narrowing from submucosal metastasis can be demonstrated by CT and should be added to the differential diagnosis of dyspnea in cancet· patients with nondiagnostic chest radiographs and evidence of airflow obstruction. (CHEST 1998; 114:1217-1220) Key words: breas t neoplasms; bronchial m::oplasms; metastasis; tomography, radiograph-computed

Abb1·eviation: PFT = pulmomuy function testing

p

atients with malignancies metastatic to the thorax present with a variety of respiratory symptoms, including cough, hemoptysis, chest pain , and dyspnea. The diffe rential diagnosis is usually broad. Findings on chest radiographs such as pleural effusions, pneumothorax , lobar atelectasis, interstitial disease, or pare nchymal masses frequently reveal a potential cause for the symptoms. Initial chest radiography, however, often fails to suggest an etiology, therefore prompting additional diagnostic testing. We discuss a patient with breast cancer metastatic to the airways presenting with dyspnea and airflow obstruction and th e unusual radiographic finding of diffusely narrowed proximal bronchi demonstrated using chest CT. CASE REPORT A 65-year-old woman with a hist01y of metastatic breast cancer presented with progressive dyspnea on exertion. Adenocarcinoma of the right hreast m etastatic to a supraclavicular lymph node (T3, N3, MO, stage JIIB ) was diagnosed 12 years earlier; she received radiation and chemotherapy followed by modified right radical mastectomy. She had a complete clinical response, with no evidence of residual cUsease. Adjuvant tamoxifen chemotherapy was administered for the following 12 years. Four years after her initial diagnosis, stage I (T l , Nl, MO ) inhltrating lobular carcinoma was detected in th e left breast and the patient unde rwe nt modified left radical mastectomy. The patient was well until3 months prior to presentation when she developed slowly progressive dyspnea on exertion. Dyspnea eventually limited h er exertion to climbing a single flight of stairs or \valking l to 2 blocks. She also reported inte rmittent wheezing but no associated fever, cough, sp utum production, chest pain, or palpitations. Stab.le two-pillow mthopnea had been present for *From the Divisions of Pulmonary and Critical Care (Drs. Tino and Taichman) and On~ol og:y (Dr. Haller), Department of MedJ<.: tne; Departme nt of Rad10logy (Dr. Aronclm:k ); Department of Pathology and Laboratory Medicine (Dr. H.eynolds ); Division of Thoracic Surgery (Drs. Roberts and Smythe), Depaltment of Surgety; University of Pennsylvania Medical Center, Philadelphia, PA. fCurrently at MD Anderson Cancer Center, University of Texas , Houston , TX. Manusctipt received May 26, 1998; revision accepted June 16, 1998. Correspondence to: Gregory Tinv, MD, Pulmonary and Critical Care Division, Unh;ersity of Pennsylvania Medical Center, 3600 Spwce Street, 831 Gates Building , Philadelphia, PA 19104-4283; e-mail: [email protected]. ed tt 1218

approximately 2 years. She had never smoked and had no prior history of cardiopulmonary disease. Her only medication was tamoxifen. An empiric trial of diuretic the rapy had been ineffective at relieving her dyspnea. Physical examination was remarkable for mild tachypnea with audible wheezing. The re were mild, scattered, bilateral expiratmy wheezes, which increased with forced exhalation; no stridor was present. There was no evidence of congestive heart failure or other localizing findings. A radiograph of th e chest revealed a new 1-cm nodular density in the mid left lung fi e ld (Fig 1). A contrast-en hanced CT of th e chest confirmed th e prese nce of three nodules of < l em in diam e ter in th e left lung but failed to reveal evidence of lymphangitic carcinomatosis or lymphadenopathy. A follow-up, high-resolution CT of the chest was performed to furth er evaluate th e lung parenchyma. Thin section imaging did not demonstrate lymphangitic spread of tumor. Skeletal radiography, performed for her complaints of inter mittent hip pain, demonstrated multiple lytic and blastic lesions at the vertebrae, ribs , pelvis, and femurs. Left ventricular function was normal on echocardiogram. Pulmona1y function testing (PFT) demonstrated airflow obstruction (FVC 83% predicted, FEV 1 59% predicted, FEV/FVC ratio 57%) with a significant bronchodilator response, hyperinflation (RV 1.59% predicted ), and a normal diffusing capacity of th e lung for carbon monoxide (92% predicted). The flow volume loop was consistent with an obstructive ventilatory defect without evidence of uppe r airvvay obstruction. The patient was treated with inhaled albuterol and a course of prednisone. One month late r she reported significant improveme nt in her dyspnea and exercise tolerance. Pulmonmy function tests were unchanged. She continued her use of inhaled bronchodilators and corticosteroids but experienced recurrent, progressive dyspnea on exertion over the following 5 months, prompting furthe r evaluation. A subsequent chest radiograph did not show a significant change from th e earli er study. Chest CT, however, was also repeated and now demonstrated diflusely thickened and narrowed proximal airways (Fig 2). In particular, the lobar bronchi were diffusely thickened and markedly narrowed, and the process exte nded into the segmental airways. Both mainstem bronchi were also narrowed, although not as severely as the lobar bronchi. No extiinsic masses could be identifi ed adjacent to th ese ainvays. Segmental atelectasis involving the left upper lobe, lingula, right upper lobe, and right middle lobe was present. Progressive and debilitating dyspnea prompted hospital admission; flexible flberoptic bronchoscopy was performed to further evaluate the airways. The mucosa of both mainstern bronchi, both upper lo be bronchi , and the bronchus intermedius appeared smooth but diffusely edematous and mildly erythematous. Circumferential narro\\~ng was present in th ese airways with evidence of dynamic collapse during the respiratory cycle. No endobronchial tumor or distinct mucosal lesions were seen. Bronchial bnJshings were nondiagnostic; biopsies could not be performed because of respirat01y distress and associated m.yhemoglobin desaturation. The patient subsequently underwent rigid brunchoscopic examination that confirmed diffuse circumferential narrowing of the mainstem and segmental bronchi located most prominently at th e right upper lobe bronchus, which was reduced to a slit-like opening. There were no localized endobronchial lesions. Endobronchial biopsy revealed normal bronchial mucosa and tumor cells arranged in nests and single cells within the submucosa. Prominent angiolymphatic invasion was identified (Fig 3). The tumor cells stained positively for estrogen receptor and were histologically similar to the patient's ptior adenocarcinoma of the breast 12 years earli er. Selected Reports

FIG URE 1. Left , A: baseline c hes t r adiograph shows clear lungs. Right, B: at time of presentation , postanterior chest radiograph shows an isolated , new left lung nodul e, presumably representing a pulmonmy metastasi s.

She was treated with paclitaxel (Taxol; Bristol-Meyers Oncology; New York, NY) in addition to bronchodilator and systemic corticoste roid therapy, but her dyspnea continued to worsen. She developed cardiopulmonary arrest at hom e and subsequently di ed. DISCUSSION

Metastatic disease to the chest is a common consideration in patients with known malignancy presenting with respiratmy symptoms. While the diagnosis is often straightfmward, clinical, radiographic, or bronchoscopic evidence of metastatic disease may be subtle or even absent in many instances. In our patient, dyspnea and obstructive lung disease developed in the setting of known metastatic breast carcinoma. It was difficult to account for her clinical presentation by th e presence of a small parenchymal pulmonary nodule on the initial chest radiograph. Fmther radiographic evaluation did not demonstrate lymphangitic carcinomatosis or obstructing lesions of ai1ways. Airflow obstruction alone was present by PFT; the patient was treated for reactive airway disease, with some initial but nonsustain ed success. Additionally, the diffusing capacity of the lung for carbon monoxide was normal, arguing strongly against significant parenchymal or pulmonmy vascular processes contributing to her s ymptoms. The presence of diffuse metastasis to the bronchial submucosa as the cause of her airflow obstruction was not appreciated initially; it was suggested only on chest CT by th e presence of diffuse narrowing of ai1ways. Submucosal tumor metastasis was confirm ed histologically by performing a bronchoscopic biopsy. To our knowledge, this case represents the first repmted de monstration by CT of widespread submucosal involvement of th e airways by an epith elial tumor. Numerous studies comparing chest CT with endoscopy have de monstrated the high sensitivity of CT for detecting bronchoscopically evident airway lesions. While extremely

sensitive for detecting th e presence of ailway pathology, CT is imprecise in predicting whether disease will be primarily endobronchial, submucosal, or extrinsic to the ai1way.1 Indeed, in one retrospective study demonstrating a 90% overall sensitivity of CT for bronchoscopically defin ed pathology of the airway, cases involving predominantly submucosal metastatic disease were frequently not detected radiographically.2 Thus , the sensitivity of CT for submucosal tumor is not known. Airway narrowing is present radiographically in numerous conditions , such as inflammatory processes (sarcoidosis , Wegener's granulomatosis ), infection, amyloidosis , tracheobronchopathia osteochondroplastica, and, as in th e case presented h ere, infiltration by neoplasm. Golub and Castellino 3 recently reported a case of non-Hodgkin's lymphoma with diffusely thicke ned bronchial walls and bronchial narrowing seen on chest CT. Like our patient with metastatic breast cance r, this patient with lymphoma presented with dyspnea, wheezin g, obstructive-pattern PFTs , and a nondiagnostic plain chest radiograph. A similar presentation of dyspnea with marked wheezing was reported in a patient who died of diffuse peribronchial involve me nt by lymphoma; no abnormality of the airways was seen by plain chest radiograph, but no CT was obtained .4 As with our patient, bronchoscopic e xamination in th ese patients with lymphoma revealed inflamed and narrowed airways, with the notable absence of specific mucos al lesion (s) or endobronchial tumor. In anoth er series, the bron choscopic appearance of airways containing submucosal, but not epith elial, involveme nt by lung cancer is also similars Histopathologic correlation is provided, but the radiographic manifestations of these lesions are not presented . Th e in cidence of submucosal metastatic involve ment of the airways b y breast can cer or of other epithelial CHEST I 114 I 4 I OCTOBER, 1998

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tumors has not been defined . Further, th e freque ncy with which it presents as th e p redominant symptomatic process or with the unusual radiographic pattern described here is unknown . Th e demonstration of diffuse ly narrowed airways on chest CT of a patient with dyspn ea and/or airflow obstruction should, however, raise th e possibility of submucosal metastati c disease as an etiology. This entity should be added to th e differ-

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3. Endobronchial biopsy showi ng normal bronch ial mucosa and extensive tumor confined to angiolymphatic spaces (arrow). (Hematoxylin and eosin , original magnifi cation X 200. ) FICUHE

entia] diagnosis of dysp nea in a cancer patient with a nondiagnostic chest radiograph. REFERENCES 1 Naidech DP, Zerh oun i EA, Siegelman SS. Computed tomography and magn etic resonance of the thorax, 2nd eel. New York: Raven Press, 1991; 149 - 196 2 Naidich DP, Lee J, Garay SM , et al. Comparison of CT and fiberoptic bronchoscopy in th e evaluation of bronchi al disease. AJR Am J Roentgenol 1987; 148:1-7 3 Gollu b M J, Castell ino RA. Diffuse endobron chi al nonhodgkin 's lymphom a: CT demonstration. AJR Am J H.oentgenol 1995; 164:1093-1094 4 Scully RE, Mark EJ, McNeely BU. Case records of the Massachusetts Gene ral Hospital : case 25-1984. N Eng! JMed 1984; 310:1653-1661 5 Gemma A, Takenaka K, Andou M, et la. Bronchoscopic Hndings of ext ramural lung cancer invading the subepith eli um or submucosa. Lung Cancer 1995; 12:35-44

Tubulointerstitial Nephritis Induced by the Leukotriene Receptor Antagonist Pranlukast* Scott f. Schurman, MD; Ja nice M. Alderman, PharmD; Ma·rc Massanari, PhannD, FCCP; Atilano G. Lacsrm, MD; and Shamn A. Perlman, MD

2. Top , A: ches t CT at a el vel below the carin a, at th e level of main and ri ght pulmomuy mieri es. This shows marked narrowing o f th e left upper lobe and le ft lower lobe bronch i (s traight arrows ) as well as the narrowing of th e bronchus inte rm edius and right mi ddle lobe bronchus (c urved arrows) . Segmental atele ctasis in th e right middle ol be and lingula is also prese nt (arrowheads ). Bottom, B: taken from above the previous section, this one, at the level of the carin a, shows a marked narrowing of the right upper lobe b ronchus (arrow). F ICUHE

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A 7-year-old boy with asthma was recCivmg the leukotriene receptor antagonist pranlukast (Ultair; Smith Kline Beecham; Pittsburgh) as part of an openlabe l clinical trial. The patient's asthma improved, and he remained asymptomatic; but routine study evaluations 9 to 12 months into therapy showed microhematuria, proteinuria, glucosuria, anemia, and renal insufficiency. Renal biopsy demonstrated Selected Reports