H U M A N PATHOLOGY
VOLUME 6 NUMBER 6 November 1975
Current Topics
THE TEAM APPROACH TO PRIMARY HYPERPARATHYROIDISM* SAXFORO I. ROTtt, M.D.,'i CHItJ-A,~ WANG, M.D.,+ and JoHN T. l'oa-rs, JR., M.D.w T h e diagnosis and treatment o f primary hyllerllarathyroidisnl have becolne m o r e and more dilticuh as newer facts are discovered about the disease and nttmerous conflicting reports o f asymptomatic, ~-3 normocalcemic, z-5 and hypocalcemic hyperparatlwroidisnl 6 and hyperparatlwroidism with grossly and histologically normal parathyroid glands 7 Imve appeared. Further primary Iwperparatlwroidism has been claimed to be present in as many as 2.5 patients per 1000 population, ns-a~ Tile protean manifestations of tile disease with its man)' and varied symlltoms, often initially subtle, make the correct diagnosis difficult to establish at times. Thougll patients with this disease Imve frequently shown little change in their condition for over 20 years, t~' tz progressive organ deterioration, particularly of tile kidneys and bones, lnay eventually be associated with significant morbidity and mortality. DIAGNOSIS Usually the first m e m b e r of the team with the o p p o r t u n i t y to make the diagnosis o f *Study SUl)ported in part b)' grant CA-10668 from the National Cancer Institute, USPtlS. tProfessor and Chairman, Deparnucnt of PathologT, University of Arkansas College of Medicine. Chief of l'athology, University of Arkansas tlospital, Little Rock, Arkansas. :[:Assistant Clinical Professor of Surgery, llarvard Medical School. Visiting Surgeon, Massachusetts General l lospital, Boston, Massachusetts. w of Medicine, Harvard Medic:d School. Chief of Endocrine Unit and Physician, Massachusetts General tlospital, Boston, Massachuscns.
plinmry Iwperparatlwroidisnl is the p r i m a r y physician. Renal stones most often provide the first clue to the diagnosis, tilougll many otller signs and symptonls may arouse the st,spicion o f tile patient's physician, leading to serum calcium and phospllorus determinations. ~a Most recently tile practice o f obtaining serum calcium determinations as part o f routine medical evaluations has led to the detection o f h y p e r p a r a t h y r o i d i s m in totally asymptomatic patients. Tile presence o f increased osteoelastic activity, osteitis fibrosis, or brown m i n o r s in bone biopsy specimens fiom patients with local lesions o r general osteopenia enables the pathologist to suggest the diagngsis o f primary hyperparathyroidisna. Once tile suspicion o f primary h y p e r p a r a thyroidism is raised, the most important laboratory determinations are the serum calcium and pllospllorus. Without an elevation o f the serum calcium and a depression o f the serum plloslfllorus level (in the absence o f renal dysfunction), it is diflicuh to confidently make the diagnosis of l)rimary IWllerllarathyroidism,H though o t h e r tests have been suggested as methods o f improving tile diagnosis o f prinmry hyperllarath)Toidism. 14-a~ llowever, in o u r experience if tile serum calcimn and phosllhorus levels are o f borderline significance, the other tests are often also borderline. When other causes o f hyllcrcalcemia have bccn excluded, the final decision must often be m a d e on the basis o f an experienced cmlocrinologistinternist's jtJdgmcnt. 14 Radioimnmnoassay o f serum for parathyroid h o r m o n e is often difficuh to interpret, requiring a cleat" u n d e r s t a n d i n g of the fundamental physiology o f the paratlwroids a n d o f the limitations o f the tcclmiqucs.3z-4~ It has bcen dcterinined recently that the biosynthesis, control o f secretion, and metabolism o f parathyroid h o r m o n e are quite complex. Multiple, chemically discrete precursors and subfragments o f paratlwroid hormone, products of hornlone biosynthesis and metabolism, are
645
H U M A N P A T H O L O G Y - - V O L U M E 6, NUMBER 6 found within the gland 4t or in circulating blood. 4z-s~ There is general agreement that the principal torm of immuuoreactive hormone detected in blood is a large fragment, biologically inert, that comprises the middle and carboxy terminal two-thirds of the peptide, tile biologically active amino terminal end having been removed from this prominent circulating fragmenc T h e r e is only a very low concentration of intact hormone. Assays based on antisera detecting the carboxy terminal fragment, even thougla not detecting biologically active forms of hormone, do correlate well with plffsiological and clinical indices of parathyroid secretory activity. It is essential, however, that a serum calcium level be determined with the same sanlple with which the parathyroid hormone level is determined. Rarely venous catheterization with the removal o f slnall vein samples for llarathyroid hormone assay by an experienced venographt~r-radiologist may assist in firmly establishing the diagnosis of primary hyperparathyroidisnl, st-ss Patients with a level of llorlnone in the vein draining one gland different fi'ont the level in the vein draining tile other glands would be highly suggestive of hyperlmrathyroidisnt due to a singlc atlenoma, s5 hi primary hyperplasia the levels from all the veins draining the parathyroid glands should be elevated in comparison with the levels in the general circulation, and the venous catheterization would n o t b e a useful test in establishing a diagnosis? 6 THERAPY
646
After the diagnosis of hyperl)arathyroidisnl has been established, it must then be decided whether surgical therapy is warranted. The criteria that we have adopted ftlr operative intervention are similar to those of Purnell et al? If therapy is indicated, the patient should undergo elective exploration unless a parathyroid crisis threatens sT'ss or the serum calcit, m level is above 15 rag. per 100 ml., in which case exploration becomes an emergency. Medical therapy to lower the serum calcium level temporarily has recently beconle available to avert a parathyroid crisis, hs9 Sophisticated tests for the preoperative localization of pathologic glands are often intpractical and unnecessary in primary exploratory operations lor an experienced surgeon, ahhough the 70 nlin. esophagram may oiler a clue to the localization of a parathyroid tumor in 25 to 30 per cent of the patients. Stimulation and suppression studies wit}l immunoassay have not been successfid in differentiating the various types o f pathologic change. 6~ If there has been previous surgery, the
November 1975
situation is reviewed prior to exploration by the entire tealn. The previous operative notes, tile tissne slides, and the pathology report are reviewed. Carefnl re-evaluation of the patient's history, signs, symptoms, radiographic changes, serum and urine chemistries, and parathyroid hormone levels is undertaken to establish definitively that the patient does have primary hyperparathyroidism, that there is no nonparathyroid cause for the hypercalcemia, an21 that the patient's signs and symptoms truly warrant surgical re-exploration. Ultimately an experienced, skillfld parathyroidsurgeon with an intimate knowledge o f the physiology, anatomy, and pathology of the parathyroids 9has the best chance of successfully treating this disease. 1,1 doing the proper operation at the first exploration (ahvays easier than succeeding ones) it is necessary to understand that approximately 80 per cent of the patients with primary hyperparathyroidism have pathologic involvenlent of only one gland (adenoma)?' is, e,-GG "Fhe inci'dence of adenomas in two glands is less than 1 per cent, and approximately 15 per cent of the patients have hyperplasia of all four glands. Carcinoma occurs in less than "t per cent of tile patients With primary hyperparathyroidisnl. In our practice, the surgeon enters the neck on one side or the Other as determined by palpation of the neck, the esophagram, the prediction from venography or angiography, or a guess (Fig. 1). An attempt is made to identif)' two parathyroid glands grossly on the first side explored. If an enlarged abnormal gland and a normal gland are identified, the diagnosis of an adenonm is estahlished and the contralateral side o f the neck is not explored, since less than I per cent of the patients have douhle adenomas. If hoth parathyroids appear normal, if both appear enlarged, or if only one enlarged or normal gland is identified, tile exploration is extended to the opposite side. No parathyroid tissue is removed until tile pathologist is in the operating room and has with the surgeon grossly evaluated the parathyroid glands exposed. After the surgeon and pathologist are satisfied that all identifiable parathyroid glands sought have been seen, and if an adenoma and normal gland(s) have been identified, tile adenoma is removed and 0.1 to 0.2 cm. biopsy specimens of all the normal gland(s) that have been grossly identified are taken. It is rare in primary explorations for biopsies of fat, lynlph nodes, or thyroid to require frozen section for identification. Frozen sections of the parathyroid biopsy specintens may help in confirming parathyroid tissue and detecting hyperplastic changes.
CURRENT TOPICS Figure 1.
Flow sheet for operative intervention in primary h)perparathyroidisnt.
Procedure
I. Explore one side of neck
,
Result
Action
Final Diagnosis
A. Find one normal and- - - ~ one abnormal gland
Mark and perform biol,sy----* Adenoma (carcinoma) of'normal gland; remove abnormal gland in toto; dose
x \
"aB Find O111} ofte or t',~o on,, ,,he abnorma'
D" Find t~voabnormal glands , A. One abnormal gland and one to three norlnal glands identified (on both sides)
Ii. Explore secorid side after IB ~
*
B
IX'. Explore second side after IDa
V. Mediastinostom)" after !i B ~ B VI. Mediastinostom)"bafter IIIB or IVD
~ Deferred
Explore second side
~ Deferred
Explore second side-
~ llyperplasia
Mark and obtain biopsy of all normal glands identified; remove abnormal gland in toto; close
.Mark and obtain biopsy of----~ B. Onl) normal glands are all glands identified; close identified (on both sides) , A. One or two normal glands Mark and obtain biopsy of----~ are identified on the all normal glands identisecond side fied and remn~e the abnormal gland in toto; close Subtotally remove the para---* . One or t',voabnormal glands are identified on thyroid tissue identified, the second skfe lea~ing adequate portion of one gland to maintain euparathyroid condition; close A. One or two abnormal Subtotally remove all para-----* glands are identified on thyroid identified, leaGng the second side enough parathyroid tissue to maintain enparathyroid state; close ) A. Find an abnormal gland--* Remove abnormal gland;e----~ close
IlL Explore second s i d e . . after IC
"
Explore second side
.
Adenoma (carcinoma)
Deferred Adenoma (carcinoma)
tt)perplasla
I lyperplasia
Adenoma
Find nothing Close ~ ? ~ A. Find an abnormal gland--* Remove abnoruml gland;"---. Ilyperlflasia close
*After clinical re-evaluation of the patient anti re-exploration of an)' region in which parathyroid tissue was not previously identified. nFor recurrent h)perparathyroidism. First re-explore that region of tl~e neck in wlfichno parath) roid gland was identified. eSubtotally remove the abnormal gland if not sure that adequate parafl0rold tissue remains in the neck. nAil patients with the multiple endocrine syndrome and fanfilial histories of primary hyl)erparatl~yroidismare assumed to Imve and are treated for primary chief cell hyperplasia. H o w e v e r , b e c a u s e o f the c o m p l e x i t y o f the c h a n g e s in p a r a t h y r o k l histology with age a n d n u t r i t i o n , a n d t h e i n t r a g [ a n d u l a r variation in the n o r m a l histologic patterns~ 6"64 u n l e s s t h e p a t h o l o g i s t is higlfly e x p e r i e n c e d in parat h y r o i d p a t h o l o g y , the d i a g n o s i s o f h y p e r p l a s i a by fi'ozen section o f 0. I to 0.2 cm. biopsy s p e c i m e n s m a y not be conclusive. A n i m p o r t a n t clue is t h e f i e q u e n t p r e s e n c e o f S u d a n - p o s i t i v e lipid d r o p l e t s in the c h i e f cells o f t h e s u p p r e s sed n o r m a l g l a n d a n d t h e i r s p a r s i t y in cases o f a d e n o m a a n d c h i e f cell h y p e r p l a s i a .67 I f t h e single t u m o r is s e e n to b e b o u n d d o w n to t h e s u r r o u n d i n g tissue, to lie fibrotic, o r to be e x t r e m e l y d e n s e a n d t o u g h , a c a r c i n o n m shottld be s u s p e c t e d a n d c a r e t a k e n to r e m o v e t h e g l a n d intact with t h e s u r r o u n d i n g tissue. T h i s may r e q u i r e critical e v a h t a t i o n o f r e c q r -
r e n t n e r v e i n v o l v e t n e n t , since it i s i m l l o r t a n t not It) sacrifice tile n e r v e unless absolutely necessary. I f f o u r a b n o r m a l g l a n d s (hyl)erplasia) a r e i d e n t i f i e d , t h r e e a r e r e m o v e d COml)letely a n d a b o u t 100 rag. o f t h e f o t t r t h g l a n d is left (in clear cell hyl)erplasia 400 rag. o f tissue is left). T h e choice o f t h e g l a n d to be left is d e t e r m i n e d o n t h e basis o f size, g r o s s a p p e a r a n c e , a n d t h e location o f t h e vascular supply. All g h n t d s o n b o t h s i d e s shotfld be i d e n t i fied in p a t i e n t s with a familial lfistory o f h y p e r p a r a t h y r o i d i s m o r with t h e m t t h i p l e e n d o c r i n e neoplasia s y n d r o m e , since a h n o s t all t h e s e p a t i e n t s h a v e clfief cell h y p e r p l a s i a . T h i s a p p r o a c h to t h e t r e a t m e n t o f h y p e r p a r a t h y r o i d i s m , h o w e v e r , can be f o l l o w e d o n l y if b o t h t h e s u r g e o n a n d t h e p a t h o l o g i s t h a v e a
647
HUMAN I'ATHOLOGY-VOLUME
648
6, NUMBER 6
cleat" ttnderstanding o f the gross and microscopic alterations o f the normal paratltyroid glaltds witlt age, the patient's physical condition, and other factors affecting the liist01ogic a p p e a r a n c e o f normal parathyroid glands. 54 It is also extremely i m p o r t a n t tllat the sttrgeon and the pathologist u n d e r s t a n d tile embryology o f the glands nttd clearly indicate the location o f all paratltyroid glands identified, snbjected. to biopsy, and removed. Discrepancies on this point between the snrgeon's operati've note and the pathologist's report are difficuh to explain. If there is substantial question in the ntind o f the surgeon or pathologist about tile diagnosis after exploration o f the first side, the decision as to whether to extend the exploration to the second side should be made o n the basis o f whether the sttrgeon feels front a clinical point of view that a second exploration poses a greater or lesser risk for the patient than the Inorbidity o f the exploration o f the second side at the first operzition. If only normal glands are fomld in the n e c k , the printary operation should be terininated with a biops)" of ;ill identified paratliyroid glands; metal clips o r long sutures sllould be used to nlark tile glands identified. Care should be taken to leave all four glands viable. One should never renlove as litany as three and onehalf normal glands. T h o u g l i it is extremely rare for a paratllyroid gland to be completely inside a thyroid lobe, subtotal thyroidectonty is occasionally p e r f o r m e d in an attempt to locate a niissing parathyroid in the thyroid capsule, or enveloped amidst nnfltil~le thyroid nodulesY s Thoi,glt a p r o m p t fall in an elevated sert, m calciu,n level for a sustained period into tile norntal range usually signifies adequate surgical correction o f tire hyperparathyroidisnl, a significant but false positive t.ill in the serum calcimn levt~l (A[Ca] o f 2 to 3 nig. per 100 ntl.) lasting several weeks may follow a neck exploration or any otller operation in sonte patients with hyl~erl)arathyroidism. ,Xlediastinal , localization o f paratllyroid glands is corn,non,~9 particularly in the u p p e r a,tterior or posterior mediastinunt, but mediastinotomy is seldoni required3 ~'~9 Only 25 patients o f over 600 have reqtfired mediastinal exploration in o u r series. Mediastinotonty should not be d o n e d u r i n g the initial exploration. A thorouglt re-exploration o f those areas o f the neck where no p a r a t h y r o i d glands were identified shoukl precede the exploration o f the mediastinnm. Re-exploration presents the most dilticuh probleni and in our opinion should be undertaken onl)" b)" an experienced team in a large center accustomed to dealing with patients with hyl)erl)aratltyroidism. It is essential that tile patltologist who will be involved in tire o p e r a t i n g room review the p;tthology and It|story o f the patient. If on
November 1975
pathology review only normal parathyroid has been removed, the diagnosis is most likely an adenoma; if one or more abnormal but benign enlarged glands were removed, the diagnosis is almost surely primary hyperplasia; and if a malignant parathyroid m i n o r was previously removed, the diagnosis o f a metastatsis or recurrence must be considered. Only if both the surgical operative note and the pathology r e p o r t from the previous operation agree as to the glands r e m o v e d can some assurance be fell that the glands were removed as described. It is always assumed that parathyroid glands not histologically proved by biopsy have not been identified. Because o f the scarred natt, re o f the neck in cases of re-exploration, differential venous catheterization o f the small veins o f the neck with radioimmunoassay for elevated parathyroid h o r m o n e levels and angiograpl W o f the small arteries ntay help to localize the residual parathyroid tissue. Tire decisions about the amount o f tissue and which o f the rentaining glands will be removed should bc made prior to the re-exploration operation. T h e patient should always (except in rare cases o f malignant disease) bc left witlt at least 100 rag. o f identifiable residual parathyroid tissue, since it is not safe to assume that the unidentified parathyroids will maintain the patient in a euparatlayroid state. ht re-exploration operations, the pathologist may be called ill)on to d e t e r m i n e whetlier the tissue encased in scar is parathyroid tissue. In summary, the p r o p e r diagnosis and treatment o f primary hyperparathyroidism requires an experienced team interested in the disease, consisting o f an endocrinologist-internist, a radiologist, a surgeon, and a patliologist. T h e t r e a m i e n t o f this disease should not be u n d e r t a k e n liglitly, since tile patients wllo have difticulty are invariably tliose who have been i m p r o p e r l y o r inadequately treated initially. REFERENCES* I. I'urnell, I). C., Smith, I, I1., Scholz, I). A., Elveback, L. R., and Arnaud, C. D.: Primary hyperlmrath}roldism: a prospective study. Amer. J. Med., 50:671)-677, 1971. 3. l'urnell, D. C., Scliolz, D. A., Smith, L. ll., Sizemore, G. W., Black, B. M., Goldsmith, R. S., and Arnaud, D. C.: Treatment of I~rlmary hypcrl~arath)roidisn~. Amer. J. Med., 56:800-809, 1974. I-1. Raisz, I. G.: ('urrent concepts. The diagnosis of hyperparatllyroidism (or what to do until the immunoassay comes). New Eng. J. Med., 285:1006-1010, 1971. 32. Berson. S. A., Yalow, R. S., Aurback, (;. D., and l'otts, J. T., Jr.: hnmunoassay of bovine and human parathyroid hormone. Proc. Nat. Acad. Sci., 49:613-617, 1963. 6t. Roth, S. l.: Recent advances in parathyroid gland pathology. Amer. J. Med.. 50:612-622, 197 I.
*A complete list of ieferences can be obtained from Dr. R,,th.
VOLUME 6 NUMBER 6 November 1975
Current Topics
THE TEAM APPROACH TO PRIMARY HYPERPARATHYROIDISM* SAXFORO I. ROTtt, M.D.,'i CHItJ-A,~ WANG, M.D.,+ and JoHN T. l'oa-rs, JR., M.D.w T h e diagnosis and treatment o f primary hyllerllarathyroidisnl have becolne m o r e and more dilticuh as newer facts are discovered about the disease and nttmerous conflicting reports o f asymptomatic, ~-3 normocalcemic, z-5 and hypocalcemic hyperparatlwroidisnl 6 and hyperparatlwroidism with grossly and histologically normal parathyroid glands 7 Imve appeared. Further primary Iwperparatlwroidism has been claimed to be present in as many as 2.5 patients per 1000 population, ns-a~ Tile protean manifestations of tile disease with its man)' and varied symlltoms, often initially subtle, make the correct diagnosis difficult to establish at times. Thougll patients with this disease Imve frequently shown little change in their condition for over 20 years, t~' tz progressive organ deterioration, particularly of tile kidneys and bones, lnay eventually be associated with significant morbidity and mortality. DIAGNOSIS Usually the first m e m b e r of the team with the o p p o r t u n i t y to make the diagnosis o f *Study SUl)ported in part b)' grant CA-10668 from the National Cancer Institute, USPtlS. tProfessor and Chairman, Deparnucnt of PathologT, University of Arkansas College of Medicine. Chief of l'athology, University of Arkansas tlospital, Little Rock, Arkansas. :[:Assistant Clinical Professor of Surgery, llarvard Medical School. Visiting Surgeon, Massachusetts General l lospital, Boston, Massachusetts. w of Medicine, Harvard Medic:d School. Chief of Endocrine Unit and Physician, Massachusetts General tlospital, Boston, Massachuscns.
plinmry Iwperparatlwroidisnl is the p r i m a r y physician. Renal stones most often provide the first clue to the diagnosis, tilougll many otller signs and symptonls may arouse the st,spicion o f tile patient's physician, leading to serum calcium and phospllorus determinations. ~a Most recently tile practice o f obtaining serum calcium determinations as part o f routine medical evaluations has led to the detection o f h y p e r p a r a t h y r o i d i s m in totally asymptomatic patients. Tile presence o f increased osteoelastic activity, osteitis fibrosis, or brown m i n o r s in bone biopsy specimens fiom patients with local lesions o r general osteopenia enables the pathologist to suggest the diagngsis o f primary hyperparathyroidisna. Once tile suspicion o f primary h y p e r p a r a thyroidism is raised, the most important laboratory determinations are the serum calcium and pllospllorus. Without an elevation o f the serum calcium and a depression o f the serum plloslfllorus level (in the absence o f renal dysfunction), it is diflicuh to confidently make the diagnosis of l)rimary IWllerllarathyroidism,H though o t h e r tests have been suggested as methods o f improving tile diagnosis o f prinmry hyperllarath)Toidism. 14-a~ llowever, in o u r experience if tile serum calcimn and phosllhorus levels are o f borderline significance, the other tests are often also borderline. When other causes o f hyllcrcalcemia have bccn excluded, the final decision must often be m a d e on the basis o f an experienced cmlocrinologistinternist's jtJdgmcnt. 14 Radioimnmnoassay o f serum for parathyroid h o r m o n e is often difficuh to interpret, requiring a cleat" u n d e r s t a n d i n g of the fundamental physiology o f the paratlwroids a n d o f the limitations o f the tcclmiqucs.3z-4~ It has bcen dcterinined recently that the biosynthesis, control o f secretion, and metabolism o f parathyroid h o r m o n e are quite complex. Multiple, chemically discrete precursors and subfragments o f paratlwroid hormone, products of hornlone biosynthesis and metabolism, are
645
H U M A N P A T H O L O G Y - - V O L U M E 6, NUMBER 6 found within the gland 4t or in circulating blood. 4z-s~ There is general agreement that the principal torm of immuuoreactive hormone detected in blood is a large fragment, biologically inert, that comprises the middle and carboxy terminal two-thirds of the peptide, tile biologically active amino terminal end having been removed from this prominent circulating fragmenc T h e r e is only a very low concentration of intact hormone. Assays based on antisera detecting the carboxy terminal fragment, even thougla not detecting biologically active forms of hormone, do correlate well with plffsiological and clinical indices of parathyroid secretory activity. It is essential, however, that a serum calcium level be determined with the same sanlple with which the parathyroid hormone level is determined. Rarely venous catheterization with the removal o f slnall vein samples for llarathyroid hormone assay by an experienced venographt~r-radiologist may assist in firmly establishing the diagnosis of primary hyperparathyroidisnl, st-ss Patients with a level of llorlnone in the vein draining one gland different fi'ont the level in the vein draining tile other glands would be highly suggestive of hyperlmrathyroidisnt due to a singlc atlenoma, s5 hi primary hyperplasia the levels from all the veins draining the parathyroid glands should be elevated in comparison with the levels in the general circulation, and the venous catheterization would n o t b e a useful test in establishing a diagnosis? 6 THERAPY
646
After the diagnosis of hyperl)arathyroidisnl has been established, it must then be decided whether surgical therapy is warranted. The criteria that we have adopted ftlr operative intervention are similar to those of Purnell et al? If therapy is indicated, the patient should undergo elective exploration unless a parathyroid crisis threatens sT'ss or the serum calcit, m level is above 15 rag. per 100 ml., in which case exploration becomes an emergency. Medical therapy to lower the serum calcium level temporarily has recently beconle available to avert a parathyroid crisis, hs9 Sophisticated tests for the preoperative localization of pathologic glands are often intpractical and unnecessary in primary exploratory operations lor an experienced surgeon, ahhough the 70 nlin. esophagram may oiler a clue to the localization of a parathyroid tumor in 25 to 30 per cent of the patients. Stimulation and suppression studies wit}l immunoassay have not been successfid in differentiating the various types o f pathologic change. 6~ If there has been previous surgery, the
November 1975
situation is reviewed prior to exploration by the entire tealn. The previous operative notes, tile tissne slides, and the pathology report are reviewed. Carefnl re-evaluation of the patient's history, signs, symptoms, radiographic changes, serum and urine chemistries, and parathyroid hormone levels is undertaken to establish definitively that the patient does have primary hyperparathyroidism, that there is no nonparathyroid cause for the hypercalcemia, an21 that the patient's signs and symptoms truly warrant surgical re-exploration. Ultimately an experienced, skillfld parathyroidsurgeon with an intimate knowledge o f the physiology, anatomy, and pathology of the parathyroids 9has the best chance of successfully treating this disease. 1,1 doing the proper operation at the first exploration (ahvays easier than succeeding ones) it is necessary to understand that approximately 80 per cent of the patients with primary hyperparathyroidism have pathologic involvenlent of only one gland (adenoma)?' is, e,-GG "Fhe inci'dence of adenomas in two glands is less than 1 per cent, and approximately 15 per cent of the patients have hyperplasia of all four glands. Carcinoma occurs in less than "t per cent of tile patients With primary hyperparathyroidisnl. In our practice, the surgeon enters the neck on one side or the Other as determined by palpation of the neck, the esophagram, the prediction from venography or angiography, or a guess (Fig. 1). An attempt is made to identif)' two parathyroid glands grossly on the first side explored. If an enlarged abnormal gland and a normal gland are identified, the diagnosis of an adenonm is estahlished and the contralateral side o f the neck is not explored, since less than I per cent of the patients have douhle adenomas. If hoth parathyroids appear normal, if both appear enlarged, or if only one enlarged or normal gland is identified, tile exploration is extended to the opposite side. No parathyroid tissue is removed until tile pathologist is in the operating room and has with the surgeon grossly evaluated the parathyroid glands exposed. After the surgeon and pathologist are satisfied that all identifiable parathyroid glands sought have been seen, and if an adenoma and normal gland(s) have been identified, tile adenoma is removed and 0.1 to 0.2 cm. biopsy specimens of all the normal gland(s) that have been grossly identified are taken. It is rare in primary explorations for biopsies of fat, lynlph nodes, or thyroid to require frozen section for identification. Frozen sections of the parathyroid biopsy specintens may help in confirming parathyroid tissue and detecting hyperplastic changes.
CURRENT TOPICS Figure 1.
Flow sheet for operative intervention in primary h)perparathyroidisnt.
Procedure
I. Explore one side of neck
,
Result
Action
Final Diagnosis
A. Find one normal and- - - ~ one abnormal gland
Mark and perform biol,sy----* Adenoma (carcinoma) of'normal gland; remove abnormal gland in toto; dose
x \
"aB Find O111} ofte or t',~o on,, ,,he abnorma'
D" Find t~voabnormal glands , A. One abnormal gland and one to three norlnal glands identified (on both sides)
Ii. Explore secorid side after IB ~
*
B
IX'. Explore second side after IDa
V. Mediastinostom)" after !i B ~ B VI. Mediastinostom)"bafter IIIB or IVD
~ Deferred
Explore second side
~ Deferred
Explore second side-
~ llyperplasia
Mark and obtain biopsy of all normal glands identified; remove abnormal gland in toto; close
.Mark and obtain biopsy of----~ B. Onl) normal glands are all glands identified; close identified (on both sides) , A. One or two normal glands Mark and obtain biopsy of----~ are identified on the all normal glands identisecond side fied and remn~e the abnormal gland in toto; close Subtotally remove the para---* . One or t',voabnormal glands are identified on thyroid tissue identified, the second skfe lea~ing adequate portion of one gland to maintain euparathyroid condition; close A. One or two abnormal Subtotally remove all para-----* glands are identified on thyroid identified, leaGng the second side enough parathyroid tissue to maintain enparathyroid state; close ) A. Find an abnormal gland--* Remove abnormal gland;e----~ close
IlL Explore second s i d e . . after IC
"
Explore second side
.
Adenoma (carcinoma)
Deferred Adenoma (carcinoma)
tt)perplasla
I lyperplasia
Adenoma
Find nothing Close ~ ? ~ A. Find an abnormal gland--* Remove abnoruml gland;"---. Ilyperlflasia close
*After clinical re-evaluation of the patient anti re-exploration of an)' region in which parathyroid tissue was not previously identified. nFor recurrent h)perparathyroidism. First re-explore that region of tl~e neck in wlfichno parath) roid gland was identified. eSubtotally remove the abnormal gland if not sure that adequate parafl0rold tissue remains in the neck. nAil patients with the multiple endocrine syndrome and fanfilial histories of primary hyl)erparatl~yroidismare assumed to Imve and are treated for primary chief cell hyperplasia. H o w e v e r , b e c a u s e o f the c o m p l e x i t y o f the c h a n g e s in p a r a t h y r o k l histology with age a n d n u t r i t i o n , a n d t h e i n t r a g [ a n d u l a r variation in the n o r m a l histologic patterns~ 6"64 u n l e s s t h e p a t h o l o g i s t is higlfly e x p e r i e n c e d in parat h y r o i d p a t h o l o g y , the d i a g n o s i s o f h y p e r p l a s i a by fi'ozen section o f 0. I to 0.2 cm. biopsy s p e c i m e n s m a y not be conclusive. A n i m p o r t a n t clue is t h e f i e q u e n t p r e s e n c e o f S u d a n - p o s i t i v e lipid d r o p l e t s in the c h i e f cells o f t h e s u p p r e s sed n o r m a l g l a n d a n d t h e i r s p a r s i t y in cases o f a d e n o m a a n d c h i e f cell h y p e r p l a s i a .67 I f t h e single t u m o r is s e e n to b e b o u n d d o w n to t h e s u r r o u n d i n g tissue, to lie fibrotic, o r to be e x t r e m e l y d e n s e a n d t o u g h , a c a r c i n o n m shottld be s u s p e c t e d a n d c a r e t a k e n to r e m o v e t h e g l a n d intact with t h e s u r r o u n d i n g tissue. T h i s may r e q u i r e critical e v a h t a t i o n o f r e c q r -
r e n t n e r v e i n v o l v e t n e n t , since it i s i m l l o r t a n t not It) sacrifice tile n e r v e unless absolutely necessary. I f f o u r a b n o r m a l g l a n d s (hyl)erplasia) a r e i d e n t i f i e d , t h r e e a r e r e m o v e d COml)letely a n d a b o u t 100 rag. o f t h e f o t t r t h g l a n d is left (in clear cell hyl)erplasia 400 rag. o f tissue is left). T h e choice o f t h e g l a n d to be left is d e t e r m i n e d o n t h e basis o f size, g r o s s a p p e a r a n c e , a n d t h e location o f t h e vascular supply. All g h n t d s o n b o t h s i d e s shotfld be i d e n t i fied in p a t i e n t s with a familial lfistory o f h y p e r p a r a t h y r o i d i s m o r with t h e m t t h i p l e e n d o c r i n e neoplasia s y n d r o m e , since a h n o s t all t h e s e p a t i e n t s h a v e clfief cell h y p e r p l a s i a . T h i s a p p r o a c h to t h e t r e a t m e n t o f h y p e r p a r a t h y r o i d i s m , h o w e v e r , can be f o l l o w e d o n l y if b o t h t h e s u r g e o n a n d t h e p a t h o l o g i s t h a v e a
647
HUMAN I'ATHOLOGY-VOLUME
648
6, NUMBER 6
cleat" ttnderstanding o f the gross and microscopic alterations o f the normal paratltyroid glaltds witlt age, the patient's physical condition, and other factors affecting the liist01ogic a p p e a r a n c e o f normal parathyroid glands. 54 It is also extremely i m p o r t a n t tllat the sttrgeon and the pathologist u n d e r s t a n d tile embryology o f the glands nttd clearly indicate the location o f all paratltyroid glands identified, snbjected. to biopsy, and removed. Discrepancies on this point between the snrgeon's operati've note and the pathologist's report are difficuh to explain. If there is substantial question in the ntind o f the surgeon or pathologist about tile diagnosis after exploration o f the first side, the decision as to whether to extend the exploration to the second side should be made o n the basis o f whether the sttrgeon feels front a clinical point of view that a second exploration poses a greater or lesser risk for the patient than the Inorbidity o f the exploration o f the second side at the first operzition. If only normal glands are fomld in the n e c k , the printary operation should be terininated with a biops)" of ;ill identified paratliyroid glands; metal clips o r long sutures sllould be used to nlark tile glands identified. Care should be taken to leave all four glands viable. One should never renlove as litany as three and onehalf normal glands. T h o u g l i it is extremely rare for a paratllyroid gland to be completely inside a thyroid lobe, subtotal thyroidectonty is occasionally p e r f o r m e d in an attempt to locate a niissing parathyroid in the thyroid capsule, or enveloped amidst nnfltil~le thyroid nodulesY s Thoi,glt a p r o m p t fall in an elevated sert, m calciu,n level for a sustained period into tile norntal range usually signifies adequate surgical correction o f tire hyperparathyroidisnl, a significant but false positive t.ill in the serum calcimn levt~l (A[Ca] o f 2 to 3 nig. per 100 ntl.) lasting several weeks may follow a neck exploration or any otller operation in sonte patients with hyl~erl)arathyroidism. ,Xlediastinal , localization o f paratllyroid glands is corn,non,~9 particularly in the u p p e r a,tterior or posterior mediastinunt, but mediastinotomy is seldoni required3 ~'~9 Only 25 patients o f over 600 have reqtfired mediastinal exploration in o u r series. Mediastinotonty should not be d o n e d u r i n g the initial exploration. A thorouglt re-exploration o f those areas o f the neck where no p a r a t h y r o i d glands were identified shoukl precede the exploration o f the mediastinnm. Re-exploration presents the most dilticuh probleni and in our opinion should be undertaken onl)" b)" an experienced team in a large center accustomed to dealing with patients with hyl)erl)aratltyroidism. It is essential that tile patltologist who will be involved in tire o p e r a t i n g room review the p;tthology and It|story o f the patient. If on
November 1975
pathology review only normal parathyroid has been removed, the diagnosis is most likely an adenoma; if one or more abnormal but benign enlarged glands were removed, the diagnosis is almost surely primary hyperplasia; and if a malignant parathyroid m i n o r was previously removed, the diagnosis o f a metastatsis or recurrence must be considered. Only if both the surgical operative note and the pathology r e p o r t from the previous operation agree as to the glands r e m o v e d can some assurance be fell that the glands were removed as described. It is always assumed that parathyroid glands not histologically proved by biopsy have not been identified. Because o f the scarred natt, re o f the neck in cases of re-exploration, differential venous catheterization o f the small veins o f the neck with radioimmunoassay for elevated parathyroid h o r m o n e levels and angiograpl W o f the small arteries ntay help to localize the residual parathyroid tissue. Tire decisions about the amount o f tissue and which o f the rentaining glands will be removed should bc made prior to the re-exploration operation. T h e patient should always (except in rare cases o f malignant disease) bc left witlt at least 100 rag. o f identifiable residual parathyroid tissue, since it is not safe to assume that the unidentified parathyroids will maintain the patient in a euparatlayroid state. ht re-exploration operations, the pathologist may be called ill)on to d e t e r m i n e whetlier the tissue encased in scar is parathyroid tissue. In summary, the p r o p e r diagnosis and treatment o f primary hyperparathyroidism requires an experienced team interested in the disease, consisting o f an endocrinologist-internist, a radiologist, a surgeon, and a patliologist. T h e t r e a m i e n t o f this disease should not be u n d e r t a k e n liglitly, since tile patients wllo have difticulty are invariably tliose who have been i m p r o p e r l y o r inadequately treated initially. REFERENCES* I. I'urnell, I). C., Smith, I, I1., Scholz, I). A., Elveback, L. R., and Arnaud, C. D.: Primary hyperlmrath}roldism: a prospective study. Amer. J. Med., 50:671)-677, 1971. 3. l'urnell, D. C., Scliolz, D. A., Smith, L. ll., Sizemore, G. W., Black, B. M., Goldsmith, R. S., and Arnaud, D. C.: Treatment of I~rlmary hypcrl~arath)roidisn~. Amer. J. Med., 56:800-809, 1974. I-1. Raisz, I. G.: ('urrent concepts. The diagnosis of hyperparatllyroidism (or what to do until the immunoassay comes). New Eng. J. Med., 285:1006-1010, 1971. 32. Berson. S. A., Yalow, R. S., Aurback, (;. D., and l'otts, J. T., Jr.: hnmunoassay of bovine and human parathyroid hormone. Proc. Nat. Acad. Sci., 49:613-617, 1963. 6t. Roth, S. l.: Recent advances in parathyroid gland pathology. Amer. J. Med.. 50:612-622, 197 I.
*A complete list of ieferences can be obtained from Dr. R,,th.
