Central nervous system lymphoma presenting as dysphagia

Central Nervous System Lymphoma Presenting as Dysphagia S T A N L E Y B. B E N J A M I N , MD, J O H N E I S O L D , MD, D O N A L D C. G E R H A R D T , MD, and D O N A L D O. C A S T E L L , MD

Two patients are presented having lymphomatous involvement of the central nervous system in whom dysphagia was the predominant symptom. All indicated studies failed to reveal evidence of direct esophageal involvement, and the dysphagia improved during treatment of the neural component. Esophageal manometric studies revealed abnormalities of the striated muscle portion of the esophagus. These two case histories suggest that invasion of the central nervous system with lymphoma may produce abnormalities of the neuromuscular control of esophageal function resulting in dysphagia.

Esophageal i n v o l v e m e n t in the patient with lymp h o m a is not a rare event. Dysphagia has been reported in 5.4% of patients with malignant lymphoma (1). Mass lesions in the distal esophagus have been found in 2.6% of patients, and an extrinsic mass in 3.3% of patients with l y m p h o m a (3). An achalasia-like s y n d r o m e has been reported in patients with and without direct l y m p h o m a t o u s involvement of the esophagus (4, 5). D y s p h a g i a as a presenting s y m p t o m of central nervous system involvement with l y m p h o m a , in the absence of evidence of direct esophageal involvement, has not been reported, based on our review of the English literature. We report two patients in w h o m dysphagia was the presenting s y m p t o m of central nervous system invasion with l y m p h o m a . Manuscript received January 15, 1981; revised manuscript received April 14, 1981; accepted April 27, 1981. From the Gastroenterology Division, National Naval Medical Center and the Uniformed Services University, School of Medicine, Bethesda, Maryland 20014. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or the Department of Defense. Supported by Department of the Navy, Clinical Investigation Program #0-06-1398. Address for reprint requests: Dr. Stanley B. Benjamin, Gastroenterology Division, National Naval Medical Center, Bethesda, Maryland 20014. Digestive Diseases and Sciences, Vol. 27, No. 2 (February 1982)

MATERIALS AND M E T H O D S Manometric studies were performed using an ovalshaped, six-lumen polyvinyl catheter, having four manometric orifices 5 cm apart at 90 ~ angles in cross-section (diameter: 4.5 x 6.6 mm; internal diameter of each lumen: 0.8 mm) and two blind central tubes as a core to maintain the oval shape. This type of catheter allows radial orientation in the upper esophageal sphincter (6). A pneumohydraulic capillary infusion system (Arndorfer Specialties, Inc.) was used for continuous infusion of each lumen at a rate of 0.5 ml/min, producing a system with a pressure rise rate of 400 mm Hg/sec. A standard esophageal manometric study was performed with the catheter passed nasally or orally. Lower esophageal sphincter (LES) pressures were obtained by a station pull-through technique. Values represent the mean of the pressures recorded from the four orifices. Esophageal peristalsis was measured with the distal catheter orifice placed 2 cm above the LES. Ten "wetswallows" (5 cc water boluses) were administered, each separated by a 30-sec interval. Amplitude represents the pressure difference between the esophageal baseline and the wave peak and is expressed as the mean value for the ten wet swallows. Upper esophageal sphincter (UES) resting tone was measured by a station pull-through technique. Pressures for each direction (anterior, posterior, lateral) represent the maximum value recorded for each orientation. Manometric tracings from the patients in this report were coded and read blindly by one of the authors (D.O.C.). Case 1. A 62-year-old white male (patient C.R.) presented in December 1977 with a two-month history of 155

BENJAMIN ET A L

Fig 1. Esophageal manometric tracing from patient C.R. prior to therapy. Incomplete relaxation of the upper esophageal sphincter (UES) and markedly decreased peristaltic amplitude in the proximal esophagus can be seen. Distances for each orifice refer to distance in centimeters from the anterior nares. WS identifies wet swallows.

weight loss, night sweats, and oropharyngeal dysphagia for solids and liquids. During his initial evaluation, diffuse lymphadenopathy and hepatomegaly were noted. Chest radiograph revealed a left pleural effusion, but no evidence of mediastinal involvement. A right submaxillary lymph node biopsy demonstrated nodular, poorly differentiated lymphocytic lymphoma. Pleural cytologies were positive for malignant cells. Early in his hospitalization dysphagia became rapidly progressive, dysarthria was noted, he became unable to eat, had difficulty swallowing secretions, and had frequent coughing during swallowing. Odynophagia was absent, and no oral thrush was present. The pupils were equal, round, and reactive to light and accomodation; extraocular movements were normal. Motor and sensory examinations failed to reveal localizing findings. Tendon reflexes were symmetrically present. CPK values were normal. Barium swallow was reported as showing poor peristalsis, no evidence of intra- or extraluminal involvement with lymphoma, and no mucosal abnormalities. A lumbar puncture was performed and sheets of atypical lymphocytes were found in the cerebrospinal fluid. Manometrics were performed in December 1977. This study (Figure 1) revealed decreased resting tone of the

156

UES (posterior = 60 mm Hg, lateral = 30 mm Hg) with essentially absent relaxation [normal values in our laboratory with a radially oriented catheter are: posterior = 90110 mm Hg, lateral = 40-55 mm Hg, consistent with values obtained using a similar system (6)]. A marked decrease in peristaltic activity was noted in the proximal esophagus with multiple nonconducted swallows [mean = 10 mm Hg; normal value = 60-70 mm Hg (7)]. Distal esophageal peristaltic amplitude was also decreased (mean = 30 mm Hg; normal value = 50-110 mm Hg). The LES resting tone was normal (13 mm Hg; normal 10-30 mm Hg), and complete relaxation was present. A combination of systemic chemotherapy, CNS irradiation, and intrathecal methotrexate was initiated. No local therapy was given to the esophagus. His ability to swallow improved, and he was able to tolerate a soft diet within 10 days. Dysarthria was no longer noted. Complete remission was subsequently obtained. A repeat manometric study was performed in May 1978 (Figure 2). At this time UES resting tone was still decreased (posterior = 50 mm Hg, lateral = 30 mm Hg), but relaxation in response to a wet swallow was demonstrated. Peristaltic responses to swallowing were noted in the proximal esophagus with no nonconducted swallows. Digestive Diseases and Sciences, Vol. 27, No. 2 (Februaty 1982)

CNS L Y M P H O M A A N D D Y S P H A G I A

Fig 2. A pull-through across the upper esophageal sphincter (UES) from patient C.R. following therapy is shown. Complete relaxation of the upper esophageal sphincter is demonstrated in the proximal tracing. An increase in proximal esophageal peristaltic amplitude can also be seen.

Mean amplitude (mean = 36 mm Hg) was increased compared to the initial study but was still decreased compared to normal values. Distal esophageal peristaltic amplitude was normal (mean = 68 mm Hg). Lower esophageal sphincter pressure and relaxation were normal, The patient has had no further problems with dysphagia. Case 2. An 18-year-old white male (patient T.T.) presented in July 1978 with a small-bowel obstruction. At laparotomy the diagnosis of diffuse poorly differentiated lymphocytic lymphoma was made. Two courses of systemic chemotherapy were given. Up to the time of his transfer to the National Naval Medical Center on August 22, 1978, oropharyngeal dysphagia was not noted. On August 27, he noted the abrupt onset of dysphagia for solids and liquids, was unable to eat, and had difficulty swallowing secretions. No other localizing neurologic findings were present. Tendon reflexes and muscle strength were normal. There was no odynophagia, and no oral thrush present. He was afebrile. CPK values were normal. Chest x-ray was normal, without mediastinal masses, and barium swallow revealed no evidence of intra- or extraluminal involvement of the esophagus with Digestive Diseases and Sciences, Vol. 27, No. 2 (February 1982)

lymphoma and no mucosal irregularities. Poor motility with pooling of barium in the hypopharynx was reported. On August 27, a manometric study (Figure 3) revealed abnormalities similar to case 1. Upper esophageal sphincter resting tone was reduced (posterior = 50 mm Hg, lateral = 30 mm Hg). No abnormalities of UES relaxation were noted. Proximal esophageal peristaltic amplitude was markedly decreased (mean = 18 mm Hg) with most swallows being nonconducted. Distal esophageal peristalsis, LES resting tone, and relaxation were normal. On the basis of our previous experience with patient C.R., the possibility of CNS lymphoma was suggested. A lumbar puncture revealed sheets of poorly differentiated lymphocytes. Combination therapy with systemic drugs, CNS irradiation, and intrathecal methotrexate was begun. Again no specific therapy was directed to the esophagus. By September 10, the patient was eating without difficulty. Manometry was repeated at this time (Figure 4). UES resting tone was still decreased (posterior = 35 mm Hg, lateral = 25 mm Hg) with normal relaxation. In the proximal esophagus, peristaltic waves in response to swallowing were now present and mean amplitude (36

157

BENJAMIN ET A L

Fig 3, Esophageal manometric tracing from patient T.T. prior to therapy. Decreased resting tone of the upper esophageal sphincter (UES) and decreased proximal esophageal peristaltic amplitude are apparent.

mm Hg) had increased. Distal esophageal peristalsis, resting LES tone, and relaxation were normal. A summary of the manometric data from both patients is listed in Table 1. DISCUSSION Dysphagia in a patient with lymphoma may have a variety of causes. The largest series is that of Rosenberg et al, in which a review of 1209 cases of malignant lymphoma revealed dysphagia as a presenting complaint in 5.4% of their patients (1). Initial radiographic evaluation failed to reveal evidence of esophageal involvement in any of these patients. The etiology of dysphagia in this large group of living patients was not elucidated. Direct esophageal involvement or extrinsic compression by a tumor mass are the anticipated etiologies of dysphagia in patients with malignant lymphoma (2, 3). Ehrlich et al reported on the pathologic findings of 323 patients with lymphoma (2). In their study, 7.4% (24/323) of these patients had evidence of lymphomatous involvement of the esophagus at autopsy. Dysphagia was reported to ] 58

have occurred in only one patient having a large tumor mass in the esophagus. Givler reviewed autopsy material from 149 patients with lymphoma and found pathologic evidence of esophageal invasion in 20.1% (30/149) of patients (3). Four patients had a bulky tumor mass, and all had dysphagia. An extrinsic mass compressing the esophagus was reported in 3.3% (5/149) of these patients, but no record of symptoms is available. A rare cause of dysphagia in patients with lymphoma is an achalasia-like syndrome with and without direct tumor involvement of the esophagus (4, 5). These patients have radiographic and manometric tracings identical to achalasia. In the two patients reported by Kelly, myotomy and bag dilitation were required (4). Involvement of the esophagus with Candida is not uncommon in lymphoma (2). Clinically this is usually manifested by dysphagia and odynophagia and should be suspected as a likely etiology in the lymphoma patient presenting with dysphagia (9). Neither of our patients had oral thrush, odynophagia, or mucosal irregularity on barium swallow. Digestive Diseases and Sciences, Vot. 27, No. 2 (February t982)

CNS LYMPHOMA AND DYSPHAGIA

Fig 4. Esophageal manometry from patient T.T. following therapy. Upper esophageal sphincter (UES) resting tone is still decreased. An increase in proximal esophageal peristaltic amplitude is now apparent.

Dysphagia secondary to CNS involvement with lymphoma has not been previously reported. Although 14.7% of the patients reported by Rosenberg had neurologic involvement, "palsies" of cranial nerves IX, X, or XII were reported in only three patients (one each), and no statement of esophageal

symptoms is available. In a recent retrospective review of central nervous system lymphoma by Young et al (8), CNS involvement was noted in 8.5% of their 445 patients during an eight-year period. O f the 38 patients with CNS lymphoma, cranial nerve dysfunction was noted in 42%. It is

TABLE 1. SUMMARYOF MANOMETRICDATA

Locution

Lower esophagea! sphincter pressure Distal esophagus? (peristaltic amplitude in mm Hg) Proximal esophagust (peristaltic amplitude in mm Hg) Upper esophageal sphincter pressr4re:~ Lateral Posterior Relaxation

Patient C.R.

Patient T.T.

Normal values (mm Hg)

Before

After

Before

After

10-30 50-100 60-70

13 13" 10"

17 68 36

10 62 18"

17 7O 36

40-55 90-110 Complete

30 60 Partial

30 50 Complete

30 56 Complete

25 35 Complete

*Majority of swallows were nonconducted. ?Values represent the mean of 10 wet swallows. SValues represent the maximum value observed during 0.5-cm pull-throughs of the UES. Digestive Diseases and Sciences, Vol. 27, No. 2 (February 1982)

159

B E N J A M I N ET A L

noteworthy that alterations of the swallowing mechanism as manifest by dysphagia were not noted in any of their patients. Our cases demonstrate alterations in proximal esophageal peristalsis in conjunction with, and presumably secondary to, CNS involvement with lymphoma. Although we can only speculate, the clinical data suggest a pseudobulbar palsy due to lymphoma involving the central nervous system, the cranial nerves, or both. Definite proof that these patients did not have esophageal invasion is not available. This would potentially have been provided by endoscopy with mucosal biopsy since lymphomatous involvement is most often seen in the lamina propria (3). However, the poor clinical condition of these patients, plus the fact that they were already proven to have widely disseminated (stage IV) disease led the patient's primary physicians to conclude that the risks of endoscopy outweighed the potential benefits. The rapid response of the patients to the intensive therapy of their CNS disease, the temporal association of the dysphagia with documentation of CNS invasion, and the proximal esophageal peristaltic abnormalities suggesting striated muscle dysfunction strongly suggest that CNS invasion with lymphoma was the etiology of their problem (10). In general dysphagia in the setting of lymphoma should suggest direct involvement with tumor. On the basis of our recent experience, however, one must consider the possibility of CNS involvement. As an aid to early diagnosis, esophageal manome-

160

try, with careful evaluation of the proximal esophagus and UES should be performed in these patients. Failure to define gross esophageal involvement in the patients with lymphoma and dysphagia would be an indication to carefully reevaluate the CNS, particularly with examination of the cerebrospinal fluid. REFERENCES 1. Rosenberg SA, Diamond HD, Jaslowitz B, Craver LF: Lymphosarcoma: A review of 1269 cases. Medicine 40:3184, 1961 2. Ehrlich A, Stalder G, Geller W, Sherlock P: Gastrointestinal manifestations of malignant lymphoma. Gastroenterology 54:1115-1121, 1968 3. Givler RL: Esophageal lesions in leukemia and lymphoma. Am J Dig Dis 15:31-36, 1970 4. Kelly M: Intraluminal manometry in the evaluation of malignant disease of the esophagus. Cancer 21:1011-1018, 1968 5. Davis JA, Kantrowitz PA, Chandler HL, Scharzki SC: Reversible achalasia due to reticulUm-cell sarcoma. N Engl J Med 293:130-132, 1975 6. Gerhardt DC, Shuck TJ, Bordeaux RA, Winship DH: Human upper esophageal sphincter. Gastroenterology 75:268-274, 1978 esophageal sphincter. Gastroenterology 75:268-274, 1978 7. Humphries TJ, Castell DO: Pressure profile of esophageal peristalsis in normal humans as measured by direct intraesophageal transducers. Am J Dig Dis 22:641-645, 1977 8. Young RC, Houser DM, Anderson T, Fischer RJ, Jaffe E, DeVita VT: Central nervous complications of non-Hodgkins lymphoma. Am J Med 66:435 443, 1979 9. Buckle R, Nichol WD: Painful dysphagia due to m~nilial esophagitis. Br Med J 1:821-822, 1964 10. Fischer RA, Ellison GW, Thoyer WR, Spiro HM, Glaser GH: Esophageal motility in neuromuscular disease. Ann Intern Med 63:229-248, 1965

Digestive Diseases and Sciences, Vol. 27, No. 2 (Februal~y 1982)