Diagnosis and Surgical Treatment of Mediastinal Parathyroid Tumors M. ROTHMUND, L. DIETHELM, H. BRUNNER, F. KUMMERLE
Experience and problems in the localization, diagnosis and surgical treatment of mediastinal parathyroid tumors are reported. Arteriography, pneumomediastinum and, especially, selective blood withdrawal with assay of parathyroid hormone, have proven valuable to the authors. Scintigram, intravital staining methods and venography are less productive. Retrosternal parathyroid tumors that can be removed from a Kocher incision should not, for practical reasons, be classified with the mediastinal tumors. The authors recommend the onephase operation. If, after an intensive search of the neck and behind the sternum, no tumor has been found, it is advisable to incise the sternum step by step and revise the anterior mediastinum in the same session.
From the Surgical University Clinic, and the Institute for Clinical Radiology, University of Mainz, Germany
purposes of immunosuppression, 23 (9Wo) had ectopic parathyroid glands in the anterior mediastinum. Eighteen parathyroids were found in the thymus gland or in immediate relation to it. Wang,39 on the basis of autopic studies, also cited a 20Wo incidence of intramediastinal parathyroids. The fact that a sizable number of normal parathyroid glands are likewise located in the anterior THE SEARCH for parathyroid tumors in primary hyper- mediastinum militates, in our estimation, against the view parathyroidism still presents problems despite held by many authors5'21'31 that because of their numerous advances in preoperative diagnostics3'7'17'23'24'38 greater weight the parathyroid tumors are displaced from and considerable standardization of procedures for their normal position into the anterior mediastinum by surgical exploration.21'2831'32 Difficulties arise especially force of gravity. if examination of the entire neck region is fruitless Generally, the incidence of intramediastinally localized and dystopic localization of the parathyroid tumor in the parathyroid tumors is reported to be 5 or 20%'o (Table 1). The reason for these strikingly divergent figures may lie mediastinum is to be expected. The intramediastinal location of parathyroid glands is in varying definitions and interpretations by different of ontogenetic origin. They develop during ontogeny authors of the localization. from the outgrowths from the dorsal epithelium of the If all tumors that are situated behind the superior third and fourth branchial pouches. On their way to sternal margin or lower are subsumed under the term the lower neck region, the parathyroids developing "mediastinal," they will be found to account for onefrom the third branchial pouch overtake those stemming fifth of the total number in nearly all groups. This from the fourth and may generally be found in the area statement is correct from a topographic-anatomical viewof the lower pole of the thyroid. In about one-fifth point but is not relevant to the surgical practice. We of the cases they are entrained into the anterior would suggest that the term intramediastinal be applied mediastinum by the thymus, which springs from the to only those tumors which require sternotomy or ventral epithelium of the two branchial pouches. They thoracotomy for extirpation. On the basis of this intermay be found inside the thymus gland, adhering to its pretation the percentage of intramediastinal parathyroid capsule or, without any relation to it, in the anterior or, tumors initially cited by Nathaniels et al.,21 for exrarely, posterior mediastinum. Kurtay and Crile18 found ample, would be reduced to 5%, for extirpation of the that among 120 patients who were operated on because tumor required sternotomy in only 19 of their 400 patients. of primary hyperparathyroidism or thymectomized for From 1965 to 1974 we treated 50 patients with primary hyperparathyroidism at the Surgical University Submitted for publication April 15, 1975 Clinic in Mainz. Fifty-six parathyroid tumors were found. 139
140
Ann. Surg. a February 1976
ROTHMUND AND OTHERS TABLE 1. Incidence of Intramediastinal Parathyroid Tumors Reported in the Literature
Arteriography
Author
No. of Cases
Intramediastinal
t
Cope, 1941 Norris, 1947 Hellstrom, Ivemark, 1962 Romanus et al., 1967 Nathaniels et al., 1970 Scholz et al., 1973 Kummerle et al., 1974
49 322 138 130 400 abt. 1000 50
9 17 8 5 84 14 7
18.4 5.3 5.8 3.8 21 1.4 14
Thirty-three tumors were typically localized near the superior or inferior pole of the thyroid. Ten were found, after subtotal thyroidectomy, to lie within the thyroid gland. Six tumors could be displaced and removed from their retrosternal position by means of Kocher's operation (Table 2). In 7 patients exploration of the anterior or posterior mediastinum was necessary for removal of the parathyroid tumor (Table 3). Compared with the literature, this rate is very high. The reasons are that we refuse deep retrosternal manipulations without visual control, and, on the other hand, that many patients are referred to us after unsuccessful neck operation. Of the 7 patients mentioned here, 3 had been operated on in another hospital before.
Localization Techniques Inasmuch as parathyroid tumors are seldom palpable, the techniques of localization are of great importance. Angiography, pneumomediastinum and, most recently, selective determination of parathyroid hormone after withdrawal of blood from the thyroid veins have proven to be useful methods. In our experience, selenomethionine scintiscanning and intravital staining with toluidine blue are less productive (Table 4). Scintiscan Studies
Good results have occasionally been obtained with angiography of parathyroid tumors by injection of contrast media into the thyrocervical trunk or into the inferior thyroid artery. Borm and Werner4 confirmed the localization of 13 adenomas in 17 patients operatively. They used the method that Seldinger33 described in 1954,
in which the contrast medium is injected via the ulnar artery into the subclavian artery. They always performed the puncture bilaterally in one session. Kuntz and Goldsmith,17 used the approach from the two cubital arteries and through superimposed projections of angiograms and parathyroid scans succeeded in localizing 12 of 15 solitary adenomas in 15 patients, and 4 of 6 multiple tumors in 3 cases. Silinkova-Malkova,3637 who initially employed the same technique, obtained better results after using the femoral artery approach and injecting the radiopaque medium via an Oedmann catheter into the subclavian artery ahead of the thyrocervical trunk. Selective visualizations of the thyrocervical trunk from the femoral artery according to the Hettler technique were performed in 16 of our patients. A parathyroid tumor was found, and its presence operatively confirmed, in 7 cases. This variant is considered technically difficult but promises better results than the Seldinger method. It is, however, associated with complications of the type that have been described with vertebralis angiography. Hellstrom and Ivemark14 reported cerebral complications in 2 out of 9 angiographed patients. Ackermann and Winer' as well as Wang40 also mentioned complications due to the method. Among our patients, three developed cerebral complications. Signs of an acute cerebral circulatory disturbance, subsequently reflected in focal EEG symptoms, occurred in a female patient during the examination. She died a few days after the examination without having been operated on. Another female patient developed a homonymous hemianopia, and another, a male patient, suffered for several weeks from CNS-related vomiting. For these reasons we tend to prefer the less hazardous examination via the ulnar artery.
Although good results in the visualization of parathyroid tumors with 75Se-methionine have been reported,213 statistically validated data are scanty."26'340 Pneumomediastinum Even after introduction of the photoscanner the perTomograms of the mediastinum following transtracheal centage of positive results did not increase. We had in insufflation of carbon dioxide gas were puncture selenomethionine scans made in 21 patients but were able to confirm the indicated localization operatively TABLE 2. Localization of 56 Parathyroid Tumors in 50 Patients in only 4 cases. The examination failed in the case of small, difficulty localizable tumors displaying little Localization Number hormonal activity. Nevertheless this method seems to us Eutopic 33 to be justified since, apart from the relatively high Ectopic radiation load, direct complications are rare. Conintrathyroid 10 retrosternal 6 ceivably, better results can be obtained after stimulaintramediastinal 7 tion of the parathyroid tumors with glucagon.2
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ROTHMUND AND OTHERS Ann. Surg. * Februairy 1976 only in the case of parathyroid tumors situated in the cervical region behind the superior thyroid poles. Pneumomediastinum is advisable also after exploration of the neck and the anterior mediastinum. Yet the tumor must be at least about 10 mm in diameter. Vital Staining With Toluidine Blue Since the selective staining of parathyroid glands, pancreas and corpus ventriculi mucosa after intravenous administration of toluidine blue in the dog had been described, it was logical that an attempt should be made to achieve vital staining of the parathyroids in man, either by direct preoperative intravenous infusion or by intraoperative injection into the inferior thyroid artery. 15 More recent studies in dogs confirmed that the dye is selectively concentrated in the parathyroids. By comparison with the neck musculature, the concentrations reached 30:1 and 42:1, respectively.20 The observations in humans are contradictory.15 We administered
I.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~1 FIG. la. (Case 2 of Table 3) Demonstration of a right posterior mediastinal tumor by pneumomediastinum in a case of persistent primary hyperparathyroidism after exploration of the neck (twice) and the anterior mediastinum.
prepared in 8 of our patients. In 3, we were able to demonstrate tumors in the mediastinum by this method. In 2 cases these were tumors in the posterior superior mediastinum; the third was a parathyroid adenoma, weighing 12 g, that was located directly behind the corpus sterni. One tumor in the posterior mediastinum was detected angiographically before surgery. However, the films obtained in the anteroposterior direction of the beam had led to the assumption that the adenoma was located retrosternally. The pneumomediastinum was not prepared until after the unsuccessful exploration of the retrosternal space. This permitted accurate localization of the tumor and its removal by right-sided thoracotomy.6 Pneumomediastinum is a method that is not very stressful, unlikely to cause complications, and at the same time effective. Silinkova-Malkova36'37 detected by this method 33 of 44 parathyroid tumors in 40 patients. All adenomas localized in the mediastinum were reliably demonstrated. Difficulties are to be anticipated
FIG. lb. See legend for Fig. Ia.
Vol. 183 . No. 2
MEDIASTINAL PARATHYROID TUMORS
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143
Selective Venous Blood Withdrawal and Radioimmunoassay for Parathyroid Hormone Good results in the preoperative localization of parathyroid tumors have been obtained with selective venous blood sampling from the cervical and thyroid veins and determination of the parathyroid hormone concentration in the samples by radioimmunoassay.3'9'23,24'27'29'30'34'38 To this end blood is taken from the venous plexus of the thyroid, the jugular vein, the brachiocephalic vein, and the superior vena cava through a catheter inserted into the femoral vein. This is done on both sides of the neck. The diagnostic value of this method, introduced by Reitz and associates,27 has been impressively demonstrated of late. O'Riordan et al.23 definitely localized the parathyroid tumors in 24 out of 29 patients who were examined by a large vein puncture. Other authors did not obtain good results with this method. Of late, blood sampling from small veins of the thyroid
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toluidine blue preoperatively by infusion to 6 patients at a concentration of 6 mg/kg body weight during one hour and failed to achieve a sure selective staining of the subsequently localized adenoma in all of these cases. Monitoring revealed no cariotoxic side effects. On the basis of our experience we are of the opinion that this method is devoid of clinical significance.
FIG. 3. (same case as Figs. 1 and 2): Selective angiography of the
right inferior thyroid artery shows the tumor again. Now demonstration of two different tissues-one surrounding the other-is achieved. Microscopic examination after surgery reveals a struma aberrata vera with a centrally placed parathyroid tumor.
ROTHMUND AND OTHERS
144
TABLE 4. Localization Techniques Used in Primary Hyperparathyroidism
Parathyroid scintiscans Arteriography Pneumomediastinum Toluidine blue method Selective determination of parathyroid hormone
Positive
Negative
Doubtful
Total
4 7 3
14 8* 4 5
3 1 1 1
21 16 8 6
17
2
1
21
Examination discontinued because of cerebral circulatory disturbances in one of these cases. *
plexus, chiefly the two inferior thyroid veins and their branches, where the hormone is not yet diluted by blood from the head and upper thorax region, has proved its superiority. Small vein sampling, although requiring more time and being technically more difficult, in view of its improved results should be preferred to large vein sampling, if possible.3'9'29'30'38 A simultaneous venogram of the thyroid and neck is indispensable because the strictly side-split drainage of the parathyroid blood, described by Doppmann and Hammond,8 is not always present.29'30'38 In patients with a solitary adenoma an unilateral concentration gradient of at least 2:1 is diagnostic. Bilaterally elevated values indicate the presence of several adenomas or hyperplasia. In the case of intramediastinal tumors, the values found in the brachiocephalic vein and the superior vena cava were elevated by comparison with the inferior thyroid vein. We for our part were able to confirm the presence of 17 out of 21 parathyroid adenomas by this method.
Operative Technique for One-Time Procedure A typical Kocher neck incision is performed. Following exposure of the capsule the two halves of the thyroid are displaced. The posterior surface of the thyroid capsule is carefully scanned. Importance should be attached particularly to careful, bloodless preparation since hematomas in the loose connective tissue may conceal differences of color. Scanning of the posterior side of the thyroid, its lower and upper poles and of the thyroid compartments in the broadest sense will localize the majority of the parathyroid glands. If not, the larger environment of the thyroid, the perivascular sheaths of carotid artery and jugular vein, the paralaryngeal region, and the esophagotracheal sulcus (via careful handling of the recurrent laryngeal nerve) are examined. Particular attention must be paid to the course of the inferior thyroid artery since the area it supplies encompasses a large number of likewise ectopic parathyroids. If the search proves negative, a careful digital examination is made of the retrostemal connective tissue, notably on the left paratracheally as far as the
Ann.
Surg. * February 1976
aortic arch, and as far as the subclavian artery on the right. Excessive blunt exploration without visual control should be avoided. Even though in our own patients digital exploration caused no injury to mediastinal organs, we may call attention to the report by Nathaniels et al.2' who described the development of a bilateral pneumothorax following uncontrolled exploration of the retrosternal space. If this further exploration remains unsuccessful, the two halves of the thyroid are subtotally resected. The tissue thus removed is immediately cut into slices and searched for suspicious areas. The entire material is turned over to the pathologist for histologic processing. If no parathyroid tumor has been found by this time, biopsy from a normally appearing parathyroid gland should be attempted in order to check on the possibility of hyperplasia. If there is no hyperplasia, we do not-in contrast to most authors5'21'26'31'32 terminate the procedure at this point. The immediately ensuing sternotomy and exploration of the anterior mediastinum do represent a substantial extension of the intervention but in our estimation they are more justifiable than a second operation later on. The likelihood that the parathyroid tumor will be located in the anterior mediastinum is great. In only about 1-2% of patients is it situated in the posterior mediastinum and requires removal by thoracotomy. However, this requires comprehensive preoperative preparation of each patient with primary hyperparathyroidism that should make it possible to follow through with an intrathoracic operation without any delay. Exploration extends primarily to the thymus and the surrounding mediastinal connective tissue. Even if a tumor is found in the anterior mediastinum outside the thymus gland, its removal is indicated because parathyroids are fairly often present in the glandular parenchyma. If no tumor is discovered, both the thymus and the surrounding adipose and connective tissue are extirpated and carefully prepared. Painstaking work-up of the material by the pathologist is in-
dispensable. By this procedure we succeeded in localizing 56 parathyroid tumors. Discussion When parathyroid tumors are multiple and ectopic, they are more difficult to find and to remove surgically. As methods of localization, we prefer arteriography, pneumomediastinum, and above all selective blood sampling and radioimmunologic determination of parathyroid hormone. However, we have been using this last technique for a short time only and have not yet
Vol. 183 * No. 2
MEDIASTINAL PARATHYROID TUMORS
applied it to a patient with a mediastinal tumor. We consider it inadvisable to perform a surgical exploration without use of a localization technique, though this has been recommended by some authors.1'21'26'31'40 In our opinion surgical exploration should include the anterior mediastinum in the same session if cervical examination has not uncovered a parathyroid tumor. We find that after careful exploration and conscientious hemostasis a second operation has become unnecessary provided rapid section examination of the numerous tissue specimens is assured. In view of improved anesthesiologic conditions and standardized operative techniques we believe that operation in two phases is superfluous. Our favorable experience with all those patients in whom we performed cervical and mediastinal exploration in a single session (Cases 3, 5 and 7 in Table 3) has made us turn away from the two-phase procedure. The sternum is incised step by step. If the location of the mediastinal adenoma permits, partial sternotomy may suffice. In case total exploration of the anterior mediastinum is necessary, opening of the entire sternum is indispensable. References 1. Ackerman, N. B. and Winer, N.: Evaluation of Methods for Localizing Parathyroid Tumors. Am. J. Surg., 122:699, 1971. 2. Askar, F. S., Naya, J. L. and Smith, E. M.: Parathyroid Scanning with 75Se-selenomethionine and Glucagon Stimulation. J. Nucl. Med., 12:751, 1971. 3. Bilezikian, J. P., J. L. Doppman, P. M. Shimkin, et al.: Preoperative Localization of Abnormal Parathyroid Tissue. Am. J. Med., 55:505, 1973. 4. Borm, D. and Werner, H.: Angiographic Localization of Parathyroid Adenomas. Zbl. Chir., 89:1537, 1964. 5. Cope, O.: The Occurrence of Parathyroids in the Anterior Mediastinum and the Division of the Operation into two Stages. Ann. Surg., 114:706, 1941. 6. Diethelm, L., Gerok, W., Kummerle, F., et al.: Primary Hyperparathyroidism Due to Multiple, Eutopic Parathyroid Tumors. Dtsch. Med. Wschr., 94:2593, 1969. 7. Doppmann, J. L.: Staining of Parathyroid Adenomas by Selective Arteriography. Radiology, 92:527, 1969. 8. Doppmann, J. L. and Hammond, W. G.: The Anatomic Basis of Parathyroid Venous Sampling. Radiology, 95:603, 1970. 9. Eisenberg, H., J. Palotta and L. M. Sherwood: Selective Arteriography, Venography and Venons Hormone Assay in Diagnosis and Localization of Parathyroid Lesions. Am. J. Med., 56:810, 1974. 10. Evans, W. E., Armstrong, R. G. and Dawson, R. G.: Hyperparathyroidism. Review of Twenty-four Cases. Am. J. Surg., 116: 456, 1968. 11. Goodman, M. L., Egdahl, R. H., Kemp, A. and Carey, L. C.: Hyperparathyroidism from Intrathyroid Parathyroid Adenomas. Arch. Pathol., 87:418, 1969. 12. Hainze, S., Kummerle, F. and Baissler, R.: Acute Hyperparathyroidism with Ectopic Parathyroids Localized in the Thymus. Dtsch. Med. Wschr., 95:671, 1970. 13. Haubold, U.: Scintiscanning in Hyperparathyroidism. Diagnostik,
4:258, 1971. 14. Hellstrom, J. and Iveymark, B. I.: Primary Hyperparathyroidism. Acta Chir. Scand. Suppl., 294, 1962.
145
15. Hurvitz, R. J., Hurvitz, I. S. and Morgenstern, L.: Invivo Staining of the Parathyroid Glands and Pancreas. Arch. Surg., 95: 274, 1967. 16. Kummerle, F., Rothmund, M., Diethelm, L. and Brunner, H.: Primary Hyperparathyroidism with Mediastinal Localization of Adenoma. Dtsch. Med. Wschr., 99:983, 1974. 17. Kuntz, C. H. and Goldsmith, R. E.: Selective Arteriography of Parathyroid Adenomas. Radiology, 102:21, 1972. 18. Kurtay, M. D. and Crile, G., Jr.: Aberrant Parathyroid Glands in Relationship to the Thymus. Am. J. Surg., 117:705, 1969. 19. Mayor, G.: Surgery of Parathyroid Glands. Langenbecks Arch. Klin. Chir., 319:209, 1967. 20. Mortenson, R. A. and McRae, J.: Toluidine Blue-0 and Its Analogs as Parathyroid and Pancreatic Scanning Agents. Arch. Surg., 100:710, 1970. 21. Nathaniels, E. K., Nathaniels, A. M. and Wang, C. A.: Mediastinal Parathyroid Tumors: A Clinical and Pathological Study of 84 Cases. Ann. Surg., 171:165, 1970. 22. Norris, E. H.: The Parathyroid Adenoma: A Study of 322 Cases. Int. Abstr. Surg., 84, 1947. 23. O'Riordan, J. L. H., Kendall, B. E. and Woodhead, J. S.: Preoperative Localisation of Parathyroid Tumors. Lancet, 11:1172, 1971. 24. Powell, D., Shimkin, P. M., Doppmann, J. L., et al.: Primary Hyperparathyroidism. Preoperative Tumor Localization and Differentiation Between Adenoma and Hyperplasia. N. EngI. J. Med., 286:1169, 1972. 25. Pyrah, L. N., Hodgkinson, A. and Anderson, C. K.: Primary Hyperparathyroidism, A Critical Review. Br. J. Surg., 53:245, 1966. 26. Rienhoff, W. F., Jr., Reinhoff, W. F. III, Brawley, R. K. and Shelley, W. M.: The Surgical Treatment of Hyperparathyroidism. Ann. Surg. 168:1061, 1968. 27. Reitz, R. E., Pollard, J. J., Wang, C. A., et al.: Localization of Parathyroid Adenomas by Selective Venous Catheterization and Radioimmunoassay. N. Engl. J. Med., 281:348, 1969. 28. Romanus, R., Heimann, P. and Nilsson, O.: Surgical Experience in 130 Cases of Hyperparathyroidism. Langenbecks Arch. Klin, Chir., 319:197, 1967. 29. Rothmund, M., R. Guenther, B. Heicke, et al.: Selektive Blutentnahme und Parathormonbestimmung beim primaren Hyperparathyreoidismus Dtsch. Med. Wschr., 99:2557, 1974. 30. Rothmund, M. H., Brunner, F. Kummerle, et al.: Lokalisationsdiagnostik von Epithelkorperchentumoren durch Parathormonbestimmung. Chirurg., 46:221, 1975. 31. Scholz, D. A., Purnell, D. C., Woolner, L. B. and Clagett, 0. T.: Mediastinal Hyperfunctioning Parathyroid Tumors. Ann. Surg., 178:173, 1973. 32. Schwaiger, M. and Rodeck, G.: Surgery of the Parathyroid Glands. Chirurg., 40:294, 1969. 33. Seldinger, S. I.: Localization of Parathyroid Adenomata by Arteriography. Acta Radiol., 42:353, 1954. 34. Shimkin, P. M., Powell, D., Doppmann, J. L., et al: Parathyroid Venous Sampling. Radiology, 104:571, 1972. 35. Shimkin, P. M., Doppmann, J. L., Powell, D., et al.: Demonstration of Parathyroid Adenomas by Retrograde Thyroid Venography. Radiology, 103:63, 1972. 36. Silinkova-Markova, E.: The Roentgenologic Localisation of Parathyroid Adenomata. Radiol. Diagn. (Berlin), 2:51, 1961. 37. Silinkova-Malkova, E. and Balcar, V.: Roentgenologic Preoperative Localization of Parathyroid Adenomas. Radiology, 11:103, 1971. 38. Tomlinson, S., Clements, V. R., Smith, M. J. G., et al.: Selective Catheterisation of the Thyroid Veins for Pre-operative Localisation of Parathyroid Tumors. Br. J. Surg., 61:633, 1974. 39. Wang, C. A.: Postmorten Studies of Parathyroid Distribution. Quoted from Nathaniels, et al.21 40. Wang, C. A., Reitz, R. E., Pollard, J. J., et al.: Localizing of Hyperfunctioning Parathyroids. The Surgeon's Riddle. Am. J. Surg., 119:462, 1970.
Experience and problems in the localization, diagnosis and surgical treatment of mediastinal parathyroid tumors are reported. Arteriography, pneumomediastinum and, especially, selective blood withdrawal with assay of parathyroid hormone, have proven valuable to the authors. Scintigram, intravital staining methods and venography are less productive. Retrosternal parathyroid tumors that can be removed from a Kocher incision should not, for practical reasons, be classified with the mediastinal tumors. The authors recommend the onephase operation. If, after an intensive search of the neck and behind the sternum, no tumor has been found, it is advisable to incise the sternum step by step and revise the anterior mediastinum in the same session.
From the Surgical University Clinic, and the Institute for Clinical Radiology, University of Mainz, Germany
purposes of immunosuppression, 23 (9Wo) had ectopic parathyroid glands in the anterior mediastinum. Eighteen parathyroids were found in the thymus gland or in immediate relation to it. Wang,39 on the basis of autopic studies, also cited a 20Wo incidence of intramediastinal parathyroids. The fact that a sizable number of normal parathyroid glands are likewise located in the anterior THE SEARCH for parathyroid tumors in primary hyper- mediastinum militates, in our estimation, against the view parathyroidism still presents problems despite held by many authors5'21'31 that because of their numerous advances in preoperative diagnostics3'7'17'23'24'38 greater weight the parathyroid tumors are displaced from and considerable standardization of procedures for their normal position into the anterior mediastinum by surgical exploration.21'2831'32 Difficulties arise especially force of gravity. if examination of the entire neck region is fruitless Generally, the incidence of intramediastinally localized and dystopic localization of the parathyroid tumor in the parathyroid tumors is reported to be 5 or 20%'o (Table 1). The reason for these strikingly divergent figures may lie mediastinum is to be expected. The intramediastinal location of parathyroid glands is in varying definitions and interpretations by different of ontogenetic origin. They develop during ontogeny authors of the localization. from the outgrowths from the dorsal epithelium of the If all tumors that are situated behind the superior third and fourth branchial pouches. On their way to sternal margin or lower are subsumed under the term the lower neck region, the parathyroids developing "mediastinal," they will be found to account for onefrom the third branchial pouch overtake those stemming fifth of the total number in nearly all groups. This from the fourth and may generally be found in the area statement is correct from a topographic-anatomical viewof the lower pole of the thyroid. In about one-fifth point but is not relevant to the surgical practice. We of the cases they are entrained into the anterior would suggest that the term intramediastinal be applied mediastinum by the thymus, which springs from the to only those tumors which require sternotomy or ventral epithelium of the two branchial pouches. They thoracotomy for extirpation. On the basis of this intermay be found inside the thymus gland, adhering to its pretation the percentage of intramediastinal parathyroid capsule or, without any relation to it, in the anterior or, tumors initially cited by Nathaniels et al.,21 for exrarely, posterior mediastinum. Kurtay and Crile18 found ample, would be reduced to 5%, for extirpation of the that among 120 patients who were operated on because tumor required sternotomy in only 19 of their 400 patients. of primary hyperparathyroidism or thymectomized for From 1965 to 1974 we treated 50 patients with primary hyperparathyroidism at the Surgical University Submitted for publication April 15, 1975 Clinic in Mainz. Fifty-six parathyroid tumors were found. 139
140
Ann. Surg. a February 1976
ROTHMUND AND OTHERS TABLE 1. Incidence of Intramediastinal Parathyroid Tumors Reported in the Literature
Arteriography
Author
No. of Cases
Intramediastinal
t
Cope, 1941 Norris, 1947 Hellstrom, Ivemark, 1962 Romanus et al., 1967 Nathaniels et al., 1970 Scholz et al., 1973 Kummerle et al., 1974
49 322 138 130 400 abt. 1000 50
9 17 8 5 84 14 7
18.4 5.3 5.8 3.8 21 1.4 14
Thirty-three tumors were typically localized near the superior or inferior pole of the thyroid. Ten were found, after subtotal thyroidectomy, to lie within the thyroid gland. Six tumors could be displaced and removed from their retrosternal position by means of Kocher's operation (Table 2). In 7 patients exploration of the anterior or posterior mediastinum was necessary for removal of the parathyroid tumor (Table 3). Compared with the literature, this rate is very high. The reasons are that we refuse deep retrosternal manipulations without visual control, and, on the other hand, that many patients are referred to us after unsuccessful neck operation. Of the 7 patients mentioned here, 3 had been operated on in another hospital before.
Localization Techniques Inasmuch as parathyroid tumors are seldom palpable, the techniques of localization are of great importance. Angiography, pneumomediastinum and, most recently, selective determination of parathyroid hormone after withdrawal of blood from the thyroid veins have proven to be useful methods. In our experience, selenomethionine scintiscanning and intravital staining with toluidine blue are less productive (Table 4). Scintiscan Studies
Good results have occasionally been obtained with angiography of parathyroid tumors by injection of contrast media into the thyrocervical trunk or into the inferior thyroid artery. Borm and Werner4 confirmed the localization of 13 adenomas in 17 patients operatively. They used the method that Seldinger33 described in 1954,
in which the contrast medium is injected via the ulnar artery into the subclavian artery. They always performed the puncture bilaterally in one session. Kuntz and Goldsmith,17 used the approach from the two cubital arteries and through superimposed projections of angiograms and parathyroid scans succeeded in localizing 12 of 15 solitary adenomas in 15 patients, and 4 of 6 multiple tumors in 3 cases. Silinkova-Malkova,3637 who initially employed the same technique, obtained better results after using the femoral artery approach and injecting the radiopaque medium via an Oedmann catheter into the subclavian artery ahead of the thyrocervical trunk. Selective visualizations of the thyrocervical trunk from the femoral artery according to the Hettler technique were performed in 16 of our patients. A parathyroid tumor was found, and its presence operatively confirmed, in 7 cases. This variant is considered technically difficult but promises better results than the Seldinger method. It is, however, associated with complications of the type that have been described with vertebralis angiography. Hellstrom and Ivemark14 reported cerebral complications in 2 out of 9 angiographed patients. Ackermann and Winer' as well as Wang40 also mentioned complications due to the method. Among our patients, three developed cerebral complications. Signs of an acute cerebral circulatory disturbance, subsequently reflected in focal EEG symptoms, occurred in a female patient during the examination. She died a few days after the examination without having been operated on. Another female patient developed a homonymous hemianopia, and another, a male patient, suffered for several weeks from CNS-related vomiting. For these reasons we tend to prefer the less hazardous examination via the ulnar artery.
Although good results in the visualization of parathyroid tumors with 75Se-methionine have been reported,213 statistically validated data are scanty."26'340 Pneumomediastinum Even after introduction of the photoscanner the perTomograms of the mediastinum following transtracheal centage of positive results did not increase. We had in insufflation of carbon dioxide gas were puncture selenomethionine scans made in 21 patients but were able to confirm the indicated localization operatively TABLE 2. Localization of 56 Parathyroid Tumors in 50 Patients in only 4 cases. The examination failed in the case of small, difficulty localizable tumors displaying little Localization Number hormonal activity. Nevertheless this method seems to us Eutopic 33 to be justified since, apart from the relatively high Ectopic radiation load, direct complications are rare. Conintrathyroid 10 retrosternal 6 ceivably, better results can be obtained after stimulaintramediastinal 7 tion of the parathyroid tumors with glucagon.2
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ROTHMUND AND OTHERS Ann. Surg. * Februairy 1976 only in the case of parathyroid tumors situated in the cervical region behind the superior thyroid poles. Pneumomediastinum is advisable also after exploration of the neck and the anterior mediastinum. Yet the tumor must be at least about 10 mm in diameter. Vital Staining With Toluidine Blue Since the selective staining of parathyroid glands, pancreas and corpus ventriculi mucosa after intravenous administration of toluidine blue in the dog had been described, it was logical that an attempt should be made to achieve vital staining of the parathyroids in man, either by direct preoperative intravenous infusion or by intraoperative injection into the inferior thyroid artery. 15 More recent studies in dogs confirmed that the dye is selectively concentrated in the parathyroids. By comparison with the neck musculature, the concentrations reached 30:1 and 42:1, respectively.20 The observations in humans are contradictory.15 We administered
I.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~1 FIG. la. (Case 2 of Table 3) Demonstration of a right posterior mediastinal tumor by pneumomediastinum in a case of persistent primary hyperparathyroidism after exploration of the neck (twice) and the anterior mediastinum.
prepared in 8 of our patients. In 3, we were able to demonstrate tumors in the mediastinum by this method. In 2 cases these were tumors in the posterior superior mediastinum; the third was a parathyroid adenoma, weighing 12 g, that was located directly behind the corpus sterni. One tumor in the posterior mediastinum was detected angiographically before surgery. However, the films obtained in the anteroposterior direction of the beam had led to the assumption that the adenoma was located retrosternally. The pneumomediastinum was not prepared until after the unsuccessful exploration of the retrosternal space. This permitted accurate localization of the tumor and its removal by right-sided thoracotomy.6 Pneumomediastinum is a method that is not very stressful, unlikely to cause complications, and at the same time effective. Silinkova-Malkova36'37 detected by this method 33 of 44 parathyroid tumors in 40 patients. All adenomas localized in the mediastinum were reliably demonstrated. Difficulties are to be anticipated
FIG. lb. See legend for Fig. Ia.
Vol. 183 . No. 2
MEDIASTINAL PARATHYROID TUMORS
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Selective Venous Blood Withdrawal and Radioimmunoassay for Parathyroid Hormone Good results in the preoperative localization of parathyroid tumors have been obtained with selective venous blood sampling from the cervical and thyroid veins and determination of the parathyroid hormone concentration in the samples by radioimmunoassay.3'9'23,24'27'29'30'34'38 To this end blood is taken from the venous plexus of the thyroid, the jugular vein, the brachiocephalic vein, and the superior vena cava through a catheter inserted into the femoral vein. This is done on both sides of the neck. The diagnostic value of this method, introduced by Reitz and associates,27 has been impressively demonstrated of late. O'Riordan et al.23 definitely localized the parathyroid tumors in 24 out of 29 patients who were examined by a large vein puncture. Other authors did not obtain good results with this method. Of late, blood sampling from small veins of the thyroid
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toluidine blue preoperatively by infusion to 6 patients at a concentration of 6 mg/kg body weight during one hour and failed to achieve a sure selective staining of the subsequently localized adenoma in all of these cases. Monitoring revealed no cariotoxic side effects. On the basis of our experience we are of the opinion that this method is devoid of clinical significance.
FIG. 3. (same case as Figs. 1 and 2): Selective angiography of the
right inferior thyroid artery shows the tumor again. Now demonstration of two different tissues-one surrounding the other-is achieved. Microscopic examination after surgery reveals a struma aberrata vera with a centrally placed parathyroid tumor.
ROTHMUND AND OTHERS
144
TABLE 4. Localization Techniques Used in Primary Hyperparathyroidism
Parathyroid scintiscans Arteriography Pneumomediastinum Toluidine blue method Selective determination of parathyroid hormone
Positive
Negative
Doubtful
Total
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21 16 8 6
17
2
1
21
Examination discontinued because of cerebral circulatory disturbances in one of these cases. *
plexus, chiefly the two inferior thyroid veins and their branches, where the hormone is not yet diluted by blood from the head and upper thorax region, has proved its superiority. Small vein sampling, although requiring more time and being technically more difficult, in view of its improved results should be preferred to large vein sampling, if possible.3'9'29'30'38 A simultaneous venogram of the thyroid and neck is indispensable because the strictly side-split drainage of the parathyroid blood, described by Doppmann and Hammond,8 is not always present.29'30'38 In patients with a solitary adenoma an unilateral concentration gradient of at least 2:1 is diagnostic. Bilaterally elevated values indicate the presence of several adenomas or hyperplasia. In the case of intramediastinal tumors, the values found in the brachiocephalic vein and the superior vena cava were elevated by comparison with the inferior thyroid vein. We for our part were able to confirm the presence of 17 out of 21 parathyroid adenomas by this method.
Operative Technique for One-Time Procedure A typical Kocher neck incision is performed. Following exposure of the capsule the two halves of the thyroid are displaced. The posterior surface of the thyroid capsule is carefully scanned. Importance should be attached particularly to careful, bloodless preparation since hematomas in the loose connective tissue may conceal differences of color. Scanning of the posterior side of the thyroid, its lower and upper poles and of the thyroid compartments in the broadest sense will localize the majority of the parathyroid glands. If not, the larger environment of the thyroid, the perivascular sheaths of carotid artery and jugular vein, the paralaryngeal region, and the esophagotracheal sulcus (via careful handling of the recurrent laryngeal nerve) are examined. Particular attention must be paid to the course of the inferior thyroid artery since the area it supplies encompasses a large number of likewise ectopic parathyroids. If the search proves negative, a careful digital examination is made of the retrostemal connective tissue, notably on the left paratracheally as far as the
Ann.
Surg. * February 1976
aortic arch, and as far as the subclavian artery on the right. Excessive blunt exploration without visual control should be avoided. Even though in our own patients digital exploration caused no injury to mediastinal organs, we may call attention to the report by Nathaniels et al.2' who described the development of a bilateral pneumothorax following uncontrolled exploration of the retrosternal space. If this further exploration remains unsuccessful, the two halves of the thyroid are subtotally resected. The tissue thus removed is immediately cut into slices and searched for suspicious areas. The entire material is turned over to the pathologist for histologic processing. If no parathyroid tumor has been found by this time, biopsy from a normally appearing parathyroid gland should be attempted in order to check on the possibility of hyperplasia. If there is no hyperplasia, we do not-in contrast to most authors5'21'26'31'32 terminate the procedure at this point. The immediately ensuing sternotomy and exploration of the anterior mediastinum do represent a substantial extension of the intervention but in our estimation they are more justifiable than a second operation later on. The likelihood that the parathyroid tumor will be located in the anterior mediastinum is great. In only about 1-2% of patients is it situated in the posterior mediastinum and requires removal by thoracotomy. However, this requires comprehensive preoperative preparation of each patient with primary hyperparathyroidism that should make it possible to follow through with an intrathoracic operation without any delay. Exploration extends primarily to the thymus and the surrounding mediastinal connective tissue. Even if a tumor is found in the anterior mediastinum outside the thymus gland, its removal is indicated because parathyroids are fairly often present in the glandular parenchyma. If no tumor is discovered, both the thymus and the surrounding adipose and connective tissue are extirpated and carefully prepared. Painstaking work-up of the material by the pathologist is in-
dispensable. By this procedure we succeeded in localizing 56 parathyroid tumors. Discussion When parathyroid tumors are multiple and ectopic, they are more difficult to find and to remove surgically. As methods of localization, we prefer arteriography, pneumomediastinum, and above all selective blood sampling and radioimmunologic determination of parathyroid hormone. However, we have been using this last technique for a short time only and have not yet
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MEDIASTINAL PARATHYROID TUMORS
applied it to a patient with a mediastinal tumor. We consider it inadvisable to perform a surgical exploration without use of a localization technique, though this has been recommended by some authors.1'21'26'31'40 In our opinion surgical exploration should include the anterior mediastinum in the same session if cervical examination has not uncovered a parathyroid tumor. We find that after careful exploration and conscientious hemostasis a second operation has become unnecessary provided rapid section examination of the numerous tissue specimens is assured. In view of improved anesthesiologic conditions and standardized operative techniques we believe that operation in two phases is superfluous. Our favorable experience with all those patients in whom we performed cervical and mediastinal exploration in a single session (Cases 3, 5 and 7 in Table 3) has made us turn away from the two-phase procedure. The sternum is incised step by step. If the location of the mediastinal adenoma permits, partial sternotomy may suffice. In case total exploration of the anterior mediastinum is necessary, opening of the entire sternum is indispensable. References 1. Ackerman, N. B. and Winer, N.: Evaluation of Methods for Localizing Parathyroid Tumors. Am. J. Surg., 122:699, 1971. 2. Askar, F. S., Naya, J. L. and Smith, E. M.: Parathyroid Scanning with 75Se-selenomethionine and Glucagon Stimulation. J. Nucl. Med., 12:751, 1971. 3. Bilezikian, J. P., J. L. Doppman, P. M. Shimkin, et al.: Preoperative Localization of Abnormal Parathyroid Tissue. Am. J. Med., 55:505, 1973. 4. Borm, D. and Werner, H.: Angiographic Localization of Parathyroid Adenomas. Zbl. Chir., 89:1537, 1964. 5. Cope, O.: The Occurrence of Parathyroids in the Anterior Mediastinum and the Division of the Operation into two Stages. Ann. Surg., 114:706, 1941. 6. Diethelm, L., Gerok, W., Kummerle, F., et al.: Primary Hyperparathyroidism Due to Multiple, Eutopic Parathyroid Tumors. Dtsch. Med. Wschr., 94:2593, 1969. 7. Doppmann, J. L.: Staining of Parathyroid Adenomas by Selective Arteriography. Radiology, 92:527, 1969. 8. Doppmann, J. L. and Hammond, W. G.: The Anatomic Basis of Parathyroid Venous Sampling. Radiology, 95:603, 1970. 9. Eisenberg, H., J. Palotta and L. M. Sherwood: Selective Arteriography, Venography and Venons Hormone Assay in Diagnosis and Localization of Parathyroid Lesions. Am. J. Med., 56:810, 1974. 10. Evans, W. E., Armstrong, R. G. and Dawson, R. G.: Hyperparathyroidism. Review of Twenty-four Cases. Am. J. Surg., 116: 456, 1968. 11. Goodman, M. L., Egdahl, R. H., Kemp, A. and Carey, L. C.: Hyperparathyroidism from Intrathyroid Parathyroid Adenomas. Arch. Pathol., 87:418, 1969. 12. Hainze, S., Kummerle, F. and Baissler, R.: Acute Hyperparathyroidism with Ectopic Parathyroids Localized in the Thymus. Dtsch. Med. Wschr., 95:671, 1970. 13. Haubold, U.: Scintiscanning in Hyperparathyroidism. Diagnostik,
4:258, 1971. 14. Hellstrom, J. and Iveymark, B. I.: Primary Hyperparathyroidism. Acta Chir. Scand. Suppl., 294, 1962.
145
15. Hurvitz, R. J., Hurvitz, I. S. and Morgenstern, L.: Invivo Staining of the Parathyroid Glands and Pancreas. Arch. Surg., 95: 274, 1967. 16. Kummerle, F., Rothmund, M., Diethelm, L. and Brunner, H.: Primary Hyperparathyroidism with Mediastinal Localization of Adenoma. Dtsch. Med. Wschr., 99:983, 1974. 17. Kuntz, C. H. and Goldsmith, R. E.: Selective Arteriography of Parathyroid Adenomas. Radiology, 102:21, 1972. 18. Kurtay, M. D. and Crile, G., Jr.: Aberrant Parathyroid Glands in Relationship to the Thymus. Am. J. Surg., 117:705, 1969. 19. Mayor, G.: Surgery of Parathyroid Glands. Langenbecks Arch. Klin. Chir., 319:209, 1967. 20. Mortenson, R. A. and McRae, J.: Toluidine Blue-0 and Its Analogs as Parathyroid and Pancreatic Scanning Agents. Arch. Surg., 100:710, 1970. 21. Nathaniels, E. K., Nathaniels, A. M. and Wang, C. A.: Mediastinal Parathyroid Tumors: A Clinical and Pathological Study of 84 Cases. Ann. Surg., 171:165, 1970. 22. Norris, E. H.: The Parathyroid Adenoma: A Study of 322 Cases. Int. Abstr. Surg., 84, 1947. 23. O'Riordan, J. L. H., Kendall, B. E. and Woodhead, J. S.: Preoperative Localisation of Parathyroid Tumors. Lancet, 11:1172, 1971. 24. Powell, D., Shimkin, P. M., Doppmann, J. L., et al.: Primary Hyperparathyroidism. Preoperative Tumor Localization and Differentiation Between Adenoma and Hyperplasia. N. EngI. J. Med., 286:1169, 1972. 25. Pyrah, L. N., Hodgkinson, A. and Anderson, C. K.: Primary Hyperparathyroidism, A Critical Review. Br. J. Surg., 53:245, 1966. 26. Rienhoff, W. F., Jr., Reinhoff, W. F. III, Brawley, R. K. and Shelley, W. M.: The Surgical Treatment of Hyperparathyroidism. Ann. Surg. 168:1061, 1968. 27. Reitz, R. E., Pollard, J. J., Wang, C. A., et al.: Localization of Parathyroid Adenomas by Selective Venous Catheterization and Radioimmunoassay. N. Engl. J. Med., 281:348, 1969. 28. Romanus, R., Heimann, P. and Nilsson, O.: Surgical Experience in 130 Cases of Hyperparathyroidism. Langenbecks Arch. Klin, Chir., 319:197, 1967. 29. Rothmund, M., R. Guenther, B. Heicke, et al.: Selektive Blutentnahme und Parathormonbestimmung beim primaren Hyperparathyreoidismus Dtsch. Med. Wschr., 99:2557, 1974. 30. Rothmund, M. H., Brunner, F. Kummerle, et al.: Lokalisationsdiagnostik von Epithelkorperchentumoren durch Parathormonbestimmung. Chirurg., 46:221, 1975. 31. Scholz, D. A., Purnell, D. C., Woolner, L. B. and Clagett, 0. T.: Mediastinal Hyperfunctioning Parathyroid Tumors. Ann. Surg., 178:173, 1973. 32. Schwaiger, M. and Rodeck, G.: Surgery of the Parathyroid Glands. Chirurg., 40:294, 1969. 33. Seldinger, S. I.: Localization of Parathyroid Adenomata by Arteriography. Acta Radiol., 42:353, 1954. 34. Shimkin, P. M., Powell, D., Doppmann, J. L., et al: Parathyroid Venous Sampling. Radiology, 104:571, 1972. 35. Shimkin, P. M., Doppmann, J. L., Powell, D., et al.: Demonstration of Parathyroid Adenomas by Retrograde Thyroid Venography. Radiology, 103:63, 1972. 36. Silinkova-Markova, E.: The Roentgenologic Localisation of Parathyroid Adenomata. Radiol. Diagn. (Berlin), 2:51, 1961. 37. Silinkova-Malkova, E. and Balcar, V.: Roentgenologic Preoperative Localization of Parathyroid Adenomas. Radiology, 11:103, 1971. 38. Tomlinson, S., Clements, V. R., Smith, M. J. G., et al.: Selective Catheterisation of the Thyroid Veins for Pre-operative Localisation of Parathyroid Tumors. Br. J. Surg., 61:633, 1974. 39. Wang, C. A.: Postmorten Studies of Parathyroid Distribution. Quoted from Nathaniels, et al.21 40. Wang, C. A., Reitz, R. E., Pollard, J. J., et al.: Localizing of Hyperfunctioning Parathyroids. The Surgeon's Riddle. Am. J. Surg., 119:462, 1970.
