Thorax (1974), 29, 553.

Carcinoid tumour of the thymus with systemicmanifestations: a radiological and pathological study

R. M. LOWENTHAL', J. M. GUMPEL, L. KREEL,J. E. McLAUGHLIN2, and D. B. L. SKEGGS

Departments of Medicine and Radiology, Northwick Park Hospital, Watford Road,Harrow, Middlesex; and Departments of Pathology and Radiotherapy, Royal Free Hospital,

North-Western Branch, Lawn Road, London NW3

Lowenthal, R. M., Gumpel, J. M., Kreel, L., McLaughlin, J. E., and Skeggs. D. B. L.(1974). Thorax, 29, 553-558. Carcinoid tumour of the thymus with systemic manifesta-tions: a radiological and pathological study. Following recent reports of an unusualmediastinal tumour described as 'mediastinal endocrine neoplasm of probable thymicorigin, related to carcinoid tumour' (Rosai and Higa, 1972), a further case, in a 72-year-old man, has been studied.

Polyarthropathy was the presenting feature, and the patient also had clubbing ofthe fingers and clinical evidence of a probable proximal myopathy and a peripheralneuropathy. These non-metastatic systemic manifestations have not previously beendescribed with this type of tumour.By retrograde thymic venography the tumour was conclusively shown to be arising

in the thymus, as had been suspected but not proven in previously described cases.Histologically the typical picture, including areas of cells with true rosette formationand cells with argyrophil granules, was seen.

In contrast to the more usual thymic tumours, this type of neoplasm responds poorlyto radiotherapy, but surgical treatment may give good results. Therefore, in a situationwhere the possibility of carcinoid tumour of the thymus exists, it is imperativethat tissue be obtained for histological diagnosis before any therapeutic decision ismade.

Recent reports have drawn attention to anunusual type of primary mediastinal tumour,histologically resembling carcinoid tumours inother sites (Rosai and Higa, 1970; Rosai and Higa,1972). We report here the clinical and pathologicaldetails of a case in which a number of previouslyunreported non-metastatic systemic manifesta-tions were present, and in which the location ofthe tumour in the thymus was confirmed by radio-logical techniques.

CASE REPORTS

A man aged 72 presented with a nine-month historyof gradually worsening polyarthritis with pain andswelling affecting particularly the wrists, hands, hips,'Present address and address for correspondence: MRC LeukaemiaUnit, Royal Postgraduate Medical School, Du Cane Road, LondonW12 OHS'Present address: Institute of Pathology, The London Hospital,London El

and knees, and with paraesthesiae in the fingers. Fortwo months he had experienced difficulty in holdingcups and in raising himself from the sitting position.For a few weeks he had had malaise, anorexia withslight weight loss, and dyspnoea on climbing stairs. Hewas a pipe smoker consuming two ounces of tobaccoper week. Six months previously he had undergone aroutine herniorrhaphy; at that time no systemicdisease had been suspected.He was an ill-looking man with prominent finger

clubbing. Wrist extension was limited to 50° bilater-ally and the metatarsophalangeal joints were tender.There was clear evidence of free synovial fluid in bothknees. The heart rate was 72/min with-from timeto time-the characteristics of pulsus bigeminis. Theblood pressure was 170/110 mmHg. There was aharsh systolic ejection-type murmur heard maximallyin the second left intercostal space anteriorly. Theliver was firm and enlarged, the edge being 5 cm belowthe right costal margin. Neurological examinationsuggested a mild proximal myopathy with weakness

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of the deltoids, left triceps, and trunk and thighmuscles. There was also slight blunting of light touchsensation on the fingers.The haemoglobin was 13A4 g/ 100 ml, the white

blood count was normal, and the erythrocyte sedimen-tation rate 14 mm in one hour. Routine biochemicalestimations, including blood urea and serum electro-lytes, serum proteins, serum alkaline phosphatase,serum calcium and phosphate, and serum uric acid,were all normal. Cytological examination of thesputum on several occasions revealed no malignantcells. Antinuclear and thyroid microsomal antibodieswere present in low titre in the serum (1: 10); testsfor other tissue antibodies were negative. The electro-cardiogram (ECG) showed frequent atrial ectopicbeats; this dysrhythmia was intermittent. A phono-cardiogram showed a late systolic murmur spillingover the aortic second sound (Fig. 1), thus indicatingthat it was arising from the pulmonary region.

A2PA 2ASM

CAR-\a<

*ECG

FIG. 1. Phonocardiogram from pulmonary area (PA)showing an ejection-type late systolic murmur (SM)spilling over the aortic second sound. S,, first heartsound; A2, aortic, and P2, pulmonary component ofthe second sound; CAR, carotid trace; ECG,electrocardiogram.

The chest radiograph (Fig. 2) revealed a left-sidedanterior mediastinal mass, accentuated by the rightanterior oblique position, its lower margin forminga slight angle with the left heart border. The masswas closely applied to the main pulmonary arteryand, in appearance and its position, was highly sug-gestive of a left-sided thymoma. In view of thenegative sputum cytology it was considered importantto show whether the tumour was within the thymusor whether a normal thymus was being displaced bythe mass. Retrograde thymic venography confirmedthe presence of a thymic tumour with a very vascularproximal portion. An interesting feature was theoutlining of an anterior aortic venous plexus from theinjection of the thymic vein (Fig. 3).

After only a few days in hospital, comparison withan earlier radiograph showed an extremely rapidincrease in the size of the tumour. An urgent

transfer of the patient for radiotherapy was thereforearranged.

Cobalt teletherapy was given by a multiple fieldtechnique. After 11 days, when the tumour hadreceived an effective dose of 1150 rads, the patientdeveloped cardiac failure with a pericardial rub anda large left pleural effusion. He was given digitalis anddiuretics, and radiotherapy was suspended. Theeffusion was tapped twice. No malignant cells wereidentified in the straw-coloured fluid. After two weekshis condition had improved sufficiently to allow radio-therapy to be resumed, and a total modal dose of4,000 rads was reached 53 days after the start oftreatment. The tumour regressed only slightly(original treatment field 15 5 X 17 cm; final field15-5 X 13,5 cm). There was brief clinical improve-ment, but eight weeks after the end of therapy hewas readmitted to hospital almost moribund. Theliver was massively enlarged and a metastatic skinnodule was identified over the left loin. He died thefollowing day.

PATHOLOGICAL FINDINGS Necropsy revealed a tumourin the anterior mediastinum invading the parietalpericardium posteriorly but not involving visceralpericardium or myocardium, and the left lunglaterally, which on section presented a homogeneouswhite cut surface interspersed with small areas ofnecrosis. A 5 cm diameter haemorrhagic nodule waspresent on the posterolateral aspect of the left parietalpleura inferiorly. Other tumour deposits were foundin the right lobe of the liver (weight 3,000 g), the leftlobe of the thyroid, the left adrenal (weight 65 g),the right adrenal (weight 10 g), and in the sub-cutaneous tissue of the left loin. No abnormality wasseen on dissection of the bronchial tree, and thepituitary, pancreas, gastrointestinal tract, and testeswere all unremarkable. No parathyroids were identi-fied. The heart showed myocardial hypertrophy, butno valve lesion was seen and the endocardial surfacesappeared normal.The gross appearances suggested a diagnosis of

malignant thymoma with multiple metastases.Microscopy revealed a tumour composed of

relatively uniform round or polygonal cells ofmedium size with central vesicular nuclei and eosino-philic cytoplasm. Areas composed of tall cells show-ing rosette formations were prominent (Fig. 4). Theluminal border of these cells appeared as a distincteosinophilic membrane and a little weakly PAS-positive material was present in the lumen. Nomucin production could be demonstrated. Muchnecrosis and moderate numbers of mitoses were seen.Staining for argentaffin granules by the diazo andMasson Fontana technique was negative but argyro-phil granules could be demonstrated by the- Bodianmethod (Fig. 5). A Congo red stain for amyloidwas negative. Electron microscopic examination ofthe formalin-fixed postmortem material after post-fixation in osmic acid and staining with uranyl

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Carcinoid tumour of the thymus with systemic manifestations

FIG. 2. Postero-anterior chest radio-graph on admission demonstrating aleft-sided anterior mediastinal tumour.

FIG. 3. Retrograde flow of contrastmedium from thymic plexus demon-strates a peri-aortic venous plexus.

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556 R. M. Lowenthal, J. M. Gumpel, L. Kreel, J. E. McLaughlin, and D. B. L. Skeggs

FIG. 4. Tumour showing rosette formations (H and E X40).

FIG. 5. Tumour cells containing argyrophil granules (Bodian X400).

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Carcinoid tumour of the thymus with systemic manifestations

acetate showed no evidence of mucin secretion orcilia on the luminal border of the rosettes. Auto-lytic changes had destroyed most cytoplasmicstructures and although membrane-bound granuleswere present they could not be certainly identified.

DISCUSSION

In many important respects the case reportedhere corresponds to those described by Rosai andHiga (1972) as mediastinal endocrine neoplasm ofprobable thymic origin related to carcinoidtumour. Our case was male, as were 14 of the 16described by them, though ours was older thanany of theirs at diagnosis (present case, age 72;age range of previously reported cases, 21 to 66).Histologically the presence of true rosettes andof argyrophil cells is typical, as is the location inthe anterior mediastinum. In our case we havebeen able to confirm absolutely the situation ofthe tumour in the thymus by retrograde thymicvenography. No bronchial connection was dis-covered at necropsy, nor was there evidence ofa primary tumour in the lung, pancreas or else-where. On histological and anatomical grounds,therefore, the likelihood that the tumour aroseelsewhere than in the thymus would seem remote.

Clinically, however, the present case showed anumber of features not previously associated withthis type of tumour. Except for three cases Rosaiand Higa reported separately (Rosai, Higa, andDavie, 1972) associated with multiple endocrineadenomatosis (MEA), their cases were eitherasymptomatic, the tumour being discovered onroutine chest radiographs, or were accompaniedby local symptoms only. In contrast, there was inour case a variety of systemic features of thenon-metastatic type. He had polyarthritis as theinitial manifestation, and clubbing of the fingers.He also had clinical evidence suggesting thepresence of a mild proximal myopathy, namely,difficulty in raising himself from the sitting posi-tion and weakness of the deltoids, left triceps, andtrunk and thigh muscles. A probable mild peri-pheral neuropathy was evidenced by symptoms ofparaesthesiae of the fingers and of difficulty inholding cups, and by the finding of blunting oflight touch sensation of the fingertips. Thesefeatures are well known in association with othertypes of tumour, for example, oat-cell carcinomaof the lung. However, it has been suggested thatthis also is derived from a secretory cell possiblyof neuro-ectodermal origin (Pearse, 1969;Weichert, 1970). There was no suggestionclinically or at necropsy of MEA or of hormoneproduction. The latter is often associated with

an epithelial type of thymoma, which may some-times be of similar endocrine origin (Macadamand Vetters, 1969), although this is not alwaysestablished (Lemon, Fine, Grasso, and Kinsell,1966).Our patient also had an intermittent dys-

rhythmia and a systolic ejection-type murmuroriginating from the pulmonary region. Atnecropsy the pulmonary valve was normal, and nodefinite cause for the murmur was identified, butit may have been caused by extrinsic pressure onthe pulmonary outflow tract by the large tumourmass in the anterior mediastinum.The aggressive behaviour of the tumour in our

case, with only a four-month survival fromdiagnosis and the presence at death of multiplemetastases, resembles that in the previouslyreported cases of carcinoid tumour of the thymuswith MEA (Rosai et al., 1972). These authorswere unable to find any histological distinctionbetween these cases and cases unassociated withMEA (Rosai and Higa, 1972), although the latterran a much more benign course.The poor response of the tumour to radio-

therapy (Rosai and Higa, 1972) is again confirmedin this case and contrasts with the typicallydramatic response of other thymic tumours tothis form of treatment (Skeggs, 1968). As surgicalexcision appears to be the only form of effectivetreatment (Rosai and Higa, 1972), it would seemimportant to obtain tissue for histological diag-nosis in any similar case by thoracotomy or bymediastinoscopy and biopsy (Skeggs, 1973). Onlythe most serious risk factors should contraindicatesuch a course of action.

REFERENCESLemon, F. C., Fine, M. B., Grasso, S. G., and Kinsell,

L. W. (1966). ACTH-like activity in a thymomaassociated with gonadal dysgenesis. Journal ofClinical Endocrinology, 26, 1.

Macadam, R. F. and Vetters, J. M. (1969). Finestructural evidence for hormone secretion by ahuman thymic tumour. Journal of ClinicalPathology, 22, 407.

Pearse, A. G. E. (1969). The cytochemistry andultrastructure of polypeptide hormone-producingcells of the APUD series, and the embryologic,physiologic, and pathologic implication of theconcept. Journal of Histochemistry and Cyto-chemistry, 17, 303.

Rosai, J. and Higa, E. (1970). Primary mediastinalcarcinoid tumour: clinicopathological study of7 cases. Laboratory Investigation, 22, 508.and (1972). Mediastinal endocrine neo-

plasm, of probable thymic origin, related tocarcinoid tumour. Clinicopathologic study of 8cases. Cancer, 29, 1061.

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R. M. Lowenthal, J. M. Gumpel, L. Kreel, J. E. McLaughlin, and D. B. L. Skeggs

-~I', -, and Davie, J. (1972). Mediastinal endocrineneoplasm in patients with multiple endocrineadenomatosis. A previously unrecognizedassociation. Cancer, 29, 1075.

Skeggs, D. B. L. (1968). Radiotherapy of thymictumours in myasthenia gravis. Proceedings ofthe Royal Society of Medicine, 61, 760.(1973). Complications associated with the radio-therapy of thymic tumours. Proceedings of theRoyal Society of Medicine, 66, 155.

Weichert, R. F. (1970). The neural ectodermal originof the peptide-secreting endocrine glands.American Journal of Medicine, 49, 232.

Requests for reprints to: Dr. R. M. Lowenthal,MRC Leukaemia Unit, Royal Postgraduate MedicalSchool, Du Cane Road, London W12 OHS.

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