Intraoperative Assessment of Parathyroid Gland Pathology A Common View From the Surgeon and the Pathologist

Transcription

1 ANATOMIC PATHOLOGY Intraoperative Assessment of Parathyroid Gland Pathology A Common View From the Surgeon and the Pathologist V. A. LiVOLSI, MD, AND R. HAMILTON, MD It is estimated that 100,000 new cases of primary hyperparathyroidism are diagnosed each year in the United States. 1,2 Although some of these patients will be treated by medical means if the disease is determined to be mild and asymptomatic, most undergo surgical exploration of the neck in an attempt to remove hyperfunctioning parathyroid tissue. Therefore, most surgical specimens of parathyroid lesions are obtained from patients with hyperparathyroidism. Important factors in the surgical treatment of hyperparathyroidism include the embryologic development of the parathyroid glands and their anatomic and histologic features. DEVELOPMENT OF THE PARATHYROID GLANDS The parathyroid glands develop from the third and fourth branchial pouches. The third branchial pouch gives rise to the thymus and inferior parathyroid glands. The superior parathyroid glands, which migrate to lie adjacent to the upper poles of the thyroid, develop with the fourth branchial pouch (actually the fourth-fifth pharyngeal complex). 3 ANATOMY OF THE PARATHYROID GLANDS The position and number of the parathyroid glands vary. Variation in position of the glands can present problems in surgical exploration of the neck. In the search for abnormal parathyroid tissue in patients with hypercalcemia, there may be difficulty in locating the diseased gland(s); in addition, the surgeon may inadvertently traumatize or remove parathyroid glands because of the vagaries of their anatomic position. 3 " 8 There is greater variability in the location of the lower parathyroid glands. The upper glands may be found close to or actually within the thyroid capsule or located behind the pharynx or the esophagus, lateral to the larynx. 6,9 The lower glands, which usually lie near the lower pole of the thyroid gland, may be found in the paratracheal area or close to or within the From the Department of Pathology and Laboratory Medicine and Department of Surgery. University of Pennsylvania Medical Center, Philadelphia, Pennsylvania. Manuscript received August 20, 1993; accepted August 23, Address reprint requests to Dr. LiVolsi: Surgical Pathology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Founders 6.042, Philadelphia, PA thymus in the superior mediastinum. The glands tend to be bilaterally symmetrical. Eighty-four percent of healthy adults have four parathyroid glands. 4 One percent to 7% of adults have three glands, and 3% to 13% have five parathyroid glands. 3 " 8 As many as 12 parathyroid glands have been identified in autopsies in endocrinologically healthy adults. 3 The parathyroid glands measure 2-7 mm in length, 2-4 mm in width, and.5-2 mm in thickness; are reniform; and are soft and brown-to-rust. The color varies with fat content, the degree of vascular congestion, and the number of oxyphil cells present. 5,8 The weight of the parathyroid glands varies with sex, race, and nutritional status. 8 The combined weight of all parathyroid tissue in a healthy man is approximately 120 mg and in a healthy woman approximately 145 mg. 5,8 The weight of each gland is mg. 5 ' 8 Each parathyroid gland is enveloped by a thin fibrous capsule that extends into the parenchyma as fibrous septa dividing the gland into lobules. A capillary network is surrounded by nests and cords of parenchymal cells. Small clusters of cells are interspersed with foci of adipose tissue. The distribution of fat and parenchymal cells in the parathyroid gland is uneven, so that biopsy specimens from a normal parathyroid gland may be predominantly fat, predominantly parenchymal cells, or an equal mixture of the two. Historically, the 50:50 ration of cells to fat has been accepted as normal for adults. Several studies have indicated that parathyroid glands from healthy persons show significantly less than 50% stromal fat. 5,10 " 13 Dufour and Wilkerson 10 " and Decker and colleagues 12 have shown that approximately 17% fat is normal in an adult parathyroid gland. Normal parathyroid cells are chief cells; oxyphils and clear cells reflect different morphologic and functional expressions of the same parenchymal cell. Oxyphils are found initially in glands of patients at puberty, apparently increase with age, and may form small microscopic nodules. Intracellular fat is found in 80% of parenchymal cells in the euparathyroid state. 5,12,13 Little lipid is present in the actively secreting parathyroid cell. 14 DISEASES OF THE PARATHYROID GLANDS The initial approach to a case of hypercalcemia is a series of biochemical tests, usually followed by surgical exploration of the neck. 2 Many patients have elevation of parathyroid hormone in the serum, indicating that one or more parathyroid glands are hypersecreting parathyroid hormone. Hence they 365

2 366 ANATOMIC PATHOLOGY have hyperparathyroidism. 2 The pathologic entities responsible for this condition are (in descending order of frequency): adenoma, hyperplasia of multiple glands, primary carcinoma of the parathyroid, or, rarely, other unusual lesions. Parathyroid Adenoma A parathyroid adenoma is responsible for 30% to 90% of cases of primary hyperparathyroidism. Most authors with large experience believe that 75% to 80% of primary hyperparathyroidism is caused by a solitary adenoma. 815,16 Parathyroid adenomas are located more commonly in the lower glands. Grossly, an adenoma appears as an oval redbrown nodule that is is circumscribed or encapsulated. The lesion often replaces one parathyroid gland, with areas of hemorrhage and cystic degeneration sometimes seen, especially in large lesions. Occasionally in small adenomas, a grossly visible rim of normal yellow-brown parathyroid tissue may be seen. Weights of adenomas vary from 250 mg to several grams. 8 Microscopically, adenomas are usually encapsulated lesions composed of nests of parathyroid chief cells arranged around a delicate capillary network. Some lesions appear multinodular. Stromal fat is usually absent. 17 Approximately 50% of adenomas disclose a normal rim or even atrophic parathyroid tissue outside the adenoma capsule. The cells in the rim tend to be smaller and more uniform with abundant cytoplasmic fat. However, the absence of a rim does not preclude the diagnosis of adenoma because large tumors may have overgrown the preexisting normal gland or the rim may have been lost during sectioning. The cells in adenoma range from small and bland to severely atypical. Bizarre multinucleated cells with dark, crinkled nuclei may be seen. In large tumors, zones of fibrosis, areas of hemorrhage, cholesterol clefts and occasional areas of calcification may be found. The nonadenomatous glands in a patient with a parathyroid adenoma may show normal to increased cytoplasmic fat content and normal weight. 18 " 24 In approximately 10% of cases, microscopic examination of biopsy specimens from "normal" glands shows areas of hypercellularity, so-called "microscopic hyperplasia." 23,24 Although this feature may represent a true increase in parenchymal cells, the difficulty in the definition of "normal" or, more likely, sampling errors probably account for this. This may also account for some of the wide variation in percentages of pathologic entities causing hyperparathyroidism. In the nonadenomatous glands, the cells may be enlarged, show clear vacuolated cytoplasm and the nests show peripheral nuclear palisading. 25 Adenomas composed solely or almost exclusively of oxyphilic or oncocytic cells can occur although they are unusual. 26 " 30 Double adenomas if they occur are extremely rare. Most patients who have so-called double adenomas will, over a period of time, return with recurrent hyperparathyroidism and in fact have four gland hyperplasia. The diagnosis of double adenoma can be made only if two glands are enlarged and histologically abnormal; the remaining glands are normal; there is no family history of parathyroid disease; and permanent cure of hypercalcemia follows excision of the enlarged glands alone. 31 " 39 Primary Parathyroid Hyperplasia Primary parathyroid hyperplasia is divided into two main groups: the common one, chief-cell hyperplasia, and the less common, water clear-cell hyperplasia. Chief-cell hyperplasia accounts for 15% of hyperparathyroidism in most series although some reports indicate that about half of primary hyperparathyroidism is produced by hyperplasia. 38,41 Approximately 30% of patients with chief-cell hyperplasia have familial hyperparathyroidism or one of the syndromes of multiple endocrine neoplasia. 41,42,46 " 49 On gross inspection, all four glands are enlarged equally or unequally. If unequal in size the lower glands are usually larger. 52,53 Occasionally one gland is much larger than the others and conveys the surgical impression of an adenoma. The weight of all four glands usually is 1-3 g. Microscopically, diffuse hyperplasia with solid masses of chief cells is seen and there is minimal to no intercellular fat. Nodular or pseudoadenomatous hyperplasia consists of circumscribed nodules of chief, transitional or oxyphil cells, each nodule devoid of fat, and with there being little fat in the intervening stroma. Usually in hyperplasia there is no rim of normal tissue, although different areas of a hyperplastic parathyroid gland may show different amounts of stromal fat and mimic a "rim" of normal parathyroid tissue. Clear-cell or water clear-cell hyperplasia is very rare. 8,54 " 56 The collective weight of the parathyroid glands in these cases always exceeds 1 g and often is 5-10 g. The glands are irregular and show pseudopods and cysts; a distinct mahogany color is seen grossly. Histologically, the glands are composed of diffuse sheets of clear cells without any mixture of other type. Parathyroid Carcinoma Carcinoma of the parathyroid accounts for 1% to 2% of primary hyperparathyroidism. Very rarely, parathyroid carcinoma can occur in the setting of familial endocrine disease 57,58 or as a sequela of secondary hyperparathyroidism. 59,60 Schantz and Castleman, 61 in their classic paper describing the pathologic features of parathyroid carcinoma, indicate that these tumors tend to be large (average weight 12 g) and characteristically show a trabecular arrangement of tumor cells divided by thick fibrous bands. Capsular and blood vessel invasion is seen, and mitotic figures are readily found. 61,62 The presence of capsular invasion alone is not equated with malignancy because large parathyroid adenomas may have hemorrhaged, with consequent fibrosis and trapping of tumor cells within the capsule. An important clue to the diagnosis of parathyroid carcinoma is the surgical finding of adherence to or invasion into local structures. However, adhesions to neighboring structures may be found in large adenomas, in which degenerative changes occur and fibrous adhesions develop. Vascular invasion is not meaningful except if seen outside the capsule of the neoplasm. Invasion into nerves, soft tissue and the esophagus may be noted. Metastases, which can be found in 30% of patients sometime in the course of the disease, are unusual at the time of presentation but may be identified in regional lymph nodes. 61 " 73 It is not rare to underdiagnose parathyroid carcinoma prospectively as an adenoma. Only retrospectively the diagnosis is reached when there is local recurrence of tumor in the neck. In these cases, the initial lesion may have had certain atypical A.J.C.P. September 1994

3 LiVOLSI AND HAMILTON 367 Assessment of Parathyroid Pathology TABLE 1. MAXIMS FOR THE SURGEON Avoid risking total parathyroidectomy; do not create hypoparathyroidism. Remove the entire adenoma; do not leave fragments behind. Anticipate another possible operation; do not create needless scar. Identify important remaining parathyroid gland fragments; document locations. Label with clips, sutures as indicated. Save tissue for frozen preservation before submission to the pathologist. Know and record the location of every specimen submitted to the pathologist. Dictate an accurate, comprehensive operative note, including operative findings and anatomical features as well as procedures performed. histologic features, but insufficient pathologic evidence to diagnose malignancy. 2,61,73 It was long believed that mitotic figures are virtually never found in a benign parathyroid adenoma; their presence in tumor cells should raise the suspicious of malignancy. However, recently this has been called into question and parathyroid tumors with mitotic activity may in fact be benign. 61,74,75 Ectopic Abnormal Parathyroid Glands Because of the embryologic migration patterns, parathyroid adenomas or other abnormal parathyroid tissue can occur in ectopic locations. Ectopic locations include the superior mediastinum, within the thymus, behind the esophagus or intrathyroidal. 9,76 " 80 Parathyromatosis Rare instances of hyperparathyroidism caused by primary hyperplasia can show nests of hyperplastic parathyroid cells in the neck outside of hyperplastic glands. 81 " 84 In some patients, these are discovered at thefirstneck exploration so that spillage during previous surgery could be excluded. It has been postulated that during embryologic development, nests of pharyngeal tissue containing parathyroid cells may be scattered throughout the adipose tissue of the neck and mediastinum. In the process of diffuse hyperplasia of the parathyroid glands, all functioning tissue may become hyperplastic and appear as separate fragments on histologic evaluation. More commonly, a similar lesion may occur after surgery as a result of spillage and implantation of hyperplastic parathyroid tissue in the neck 82,83 ; this type of lesion may occur in the setting of either primary or secondary hyperparathyroidism, but appears to be more common in multiglandular hyperplasia. THE INTRAOPERATIVE ASSESSMENT OF THE PARATHYROID GLANDS Keen powers of observation and interpretation are required of both the surgeon and the pathologist if the patient with parathyroid disease is to be properly treated. Accurate diagnosis and proper management of the patient's disease demand that the pathologist and the surgeon interact. Interaction as colleagues is facilitated if the pathologist and the surgeon meet personally, preferably in the operating room, where the pathologist can inspect the condition of the glands in situ, as well as in the laboratory, where both can examine the tissue microscopically. 25,87,88 The surgeon should be familiar with normal and variant anatomic features of the neck and mediastinum. A refined ability to distinguish parathyroid glands from other structures by gross inspection is invaluable; otherwise, the pathologist must, laboriously, make the distinction. A surgeon who can identify, by anatomic location, the superior or inferior gland in question saves operating time and laboratory effort. In subsequent operations in which the number of parathyroid glands remaining after a past operation is uncertain, several samples from normal structures may be necessary to avoid inadvertent resection of normal parathyroid glands (Table 1). The pathologist must be equipped to examine multiple tissue specimens, some only a few milligrams, promptly upon receipt from the operating room. Samples of fat, lymph node, thymus, thyroid, and skeletal muscle must be distinguished from parathyroid tissue. The surgeon should record for the pathologist the dimensions and anatomic characteristics of the structures excised or sampled. For example, gross evidence of invasion of surrounding structures may confirm a suggested microscopic diagnosis of parathyroid carcinoma. All specimens should be labeled unequivocally, preferably by sequential letters or numbers, with a description of the probable source and location of the tissue. The pathologist and the surgeon should use identical labels to avoid confusion (Table 2). The surgeon usually submits the largest parathyroid gland found in toto. The pathologist weighs it, measures it, and examines it histologically. If the gland shows diffuse growth of chief cells, maybe a normal-appearing rim, a lack of fat, and bizarre nuclei, presumed adenoma may be diagnosed. However, a biopsy specimen of at least one other grossly normal-appearing gland should be obtained to document that only one gland was abnormal. If the histologic appearance of the largest gland is that of hypercellularity but other criteria for adenoma are not seen, biopsy of at least one more gland is needed. (In many centers, including ours, pathologists consider that excision of the largest abnormal gland and at least a biopsy of one more gland is essential for adequate diagnostic information with regard to the hyperparathyroidism 39 ). The weight ratio of parenchymal cells to fat and normal or abundant intracytoplasmic fat content in Familial Hypocalciuric Hypercalcemia Persons affected by this usually benign condition manifest the typical elevations of serum calcium and parathyroid hormone that characterize hyperparathyroidism, but excrete subnormal rather than excessive amounts of urinary calcium. They do not respond favorably to parathyroid resection. 85,86 Surgery is contraindicated. TABLE 2. MAXIMS FOR THE PATHOLOGIST Do not overinterpret clinical material; insist on biopsies of more than one gland. Report back to the surgeon whether each specimen is parathyroid or other tissue, hyperplastic or normal, small or large gland. Record the weight of specimens. Prepare a careful, labeled record of findings for every specimen. Vol No. 3

4 368 ANATOMIC PATHOLOGY TABLE 3. MAXIMS FOR BOTH SURGEON AND PATHOLOGIST Inadvertent or Incidental Parathyroidectomy Communicate with one another Consider the gross as well as the microscopicfindingswhen making a diagnosis. Small glands, even hyperplastic small glands, rarely cause recurrent hyperparathyroidism. Do not resect. Large glands, even those called normal microscopically, may cause recurrent hyperparathyroidism. Consider resection. the second gland strongly support that the first one is an adenoma. As discussed above, in normal parathyroid glands 80% of the cells are in the nonsecretory phase and contain intracytoplasmic fat. 89,90 Because all hyperfunctioning glands should be fatdepleted, can the assessment of fat content assist in the intraoperative differentiation between adenoma and hyperplasia? Advocates have promoted the use of fat stains (Sudan IV or oil red O) on parathyroid tissue removed at surgery. 21,91 " 95 A sample of an enlarged parathyroid gland is sent for frozen section and by Hematoxylin and eosin stain it is hypercellular with little or no stromal fat. Thus it is abnormal but either represents an adenoma or a hyperplastic gland. A biopsy specimen of a second parathyroid gland is frozen and is normocellular or minimally hypercellular. Fat stain shows abundant cytoplasmic fat in the latter specimen; hence, this is a normal gland. The enlarged gland, which shows minimal to no fat, represents an adenoma. Many authors have cautioned, however, that the fat stain cannot be the sole procedure on which to base a diagnosis. Although the fat stain is helpful, it gives accurate results in only approximately 80% of cases. The fat stain must be considered as an adjunctive technique in addition to gross findings, gland weight and size; it cannot be relied upon by itself. 91 " 95 Some pathologists, especially those with substantial experience in cytopathology, recommend intraoperative touch imprint smears stained for fat both as an identification method for parathyroid tissue and assessment of fat rich versus fat poor examples. 96 In the future the clinical pathologic laboratory may be able to help differentiate single gland from multiple gland disease with the aid of a rapid two site immunochemiluminometric assay for intact 97 parathyroid hormone performed during the course of parathyroid surgery. Bergenfelz and coworkers 97 report a mean decline in systemic venous hormone level of 86% within 15 minutes of excision of parathyroid adenomas in 13 patients. In seven patients with hyperplasia resection of a single gland led to a mean decline of only 27%. Grimelius and colleagues 88 described the use of antiparathyroid antibodies to assess the cause of increased parathyroid hormone release from pathologic glands. Should this technique prove reliable and cost effective in the future, the problems faced by both the pathologist and the surgeon during neck exploration for hyperparathyroidism may be alleviated (Table 3). The pathologist and the surgeon interact infiveclinical situations involving the parathyroid glands: (1) the incidental or inadvertent parathyroidectomy occurring in the course of thyroid or other neck operations, (2) the initial neck exploration for primary hyperparathyroidism due either to parathyroid adenoma or parathyroid hyperplasia, (3) the initial neck exploration for probable parathyroid hyperplasia as in multiple endocrine neoplastic syndromes or chronic renal insufficiency, (4) the subsequent operation for persistent or recurrent hyperparathyroidism, and (5) the operation for parathyroid carcinoma. During some operations on the neck, particularly thyroidectomy and laryngectomy, a normal parathyroid gland may be removed deliberately because en bloc resection of a malignant tumor is required or because the circulation to the gland is compromised. Inadvertent removal may occur during thyroidectomy if the parathyroid gland is within or intimately adjacent to the thyroid capsule. 3 " 8 If the surgeon is familiar with the appearance of normal parathyroid glands, she or he can recognize this event before submitting the specimen to the pathologist. The parathyroid gland in question should be set aside and a small sample submitted for immediate microscopic examination. Once confirmed as parathyroid tissue, the remnant of the gland should be diced into 1-mm cubes, each of which is then reimplanted in the sternothyroid or sternomastoid muscle. It is unwise to discard a normal parathyroid gland because subsequent surgery in the neck may damage the remaining parathyroid glands. First Operation for Primary Hyperparathyroidism In the usual first operation for hyperparathyroidism a single large parathyroid adenoma with three small, suppressed, normal parathyroid glands exists. In only one case infiveare there two or more large parathyroid glands. Adenomas and hyperplasia can be managed similarly. The surgeon is most likely to make the correct diagnosis and effect a cure by first identifying all four glands before any excision or biopsy is performed. If fewer than four parathyroid glands have been identified, the surgeon can proceed to obtain samples by the method to be described. While awaiting results, the surgeon should continue the exploration until satisfied that no large gland remains undetected. In patients who have undergone previous neck surgery, a lateral approach reflecting the thyroid lobe and strap muscles as a unit is helpful. 98 Samples of tissue to be analyzed by the pathologist are obtained as follows. The largest parathyroid gland in question is carefully dissected and removed completely, bearing in mind that fragments of tissue from an incompletely removed adenoma can be responsible for recurrent hyperparathyroidism. Dissection of each small gland is limited to exposure of the free margin opposite the vascular pedicle. A small biopsy specimen, usually 10% to 20% of each small gland is taken and set aside in a moist, saline environment. If two or more glands are enlarged, the diagnosis probably is multiple gland disease (hyperplasia). However, resection of the largest gland and biopsies of the remaining glands is an appropriate method to make the diagnosis. Transient postoperative hypocalcemia less than 8 mg/dl occurs in 40% of cases when biopsy specimens are taken from every normal gland. 99 A rapid technique useful for intraoperative assessment of parathyroid disease is density gradient measurements. 4,100 There is an almost linear relationship between density and parenchymal content of parathyroid tissue. In other words, the extracellular and intracellular fat present in normal parathyroid glands, but relatively sparse in hyperplastic glands and adenomas, results in a lesser density. The simple specific gravity test described by Wang and Reider 100 can be performed by the surgeon before specimens are given to the pathologist for microscopic study. Any periglandular fat should be stripped away. The possible adenoma is placed in 25% mannitol solution. Physiologic saline solution is added, with agitation, until A.J.C.P. September 1994

5 LiVOLSI AND HAMILTON 369 Assessment of Pa 'tyroid Pathology the tissue sinks. The gland believed to be normal is placed in an equivalent mixture and should float. The contrary result, both glands sinking under identical dilutions, suggests a diagnosis of parathyroid hyperplasia. At this point the four specimens, properly labeled, are submitted to the pathologist. Each specimen is labeled by number or letter, identified as a certain per cent of "probable parathyroid tissue or gland" from a specified location. In the laboratory microscopic preparations of all specimens are examined. Large glands may prove to be small glands with significant periglandular fat. Elements of hyperplasia may be seen in small glands that behave as normal glands. The microscopic findings and the gross anatomic findings should be discussed by the pathologist and the surgeon to arrive at a diagnosis. Many surgeons have advocated removal of three and one half or four of the parathyroid glands with autotransplantation, and others have said that because 75% to 80% of hyperparathyroidism is caused by a solitary functioning adenoma, that therapy is overly aggressive. The "conservative" school argues that if one gland is removed and another biopsied to prove that the other glands are normal, about 80% to 94% of patients with primary hyperparathyroidism can be cured, and there is virtually no risk of hypoparathyroidism. 101 " 103 The "liberal" school proposes that 30% to 50% of patients with primary hyperparathyroidism have recurrence of hypercalcemia and advocates removal of all but 75 mg of parathyroid tissue. 38 ' They consider that in experienced hands the risk of hypoparathyroidism is low. Some surgeons advocate unilateral cervical exploration for single adenomas localized preoperatively by ultrasonography 106,107 or isotope scan 108 because of its technical ease and low morbidity. However, an interesting mathematical and statistical analysis by Duh and associates 109 indicated that 8% of patients have multigland disease that may be missed if the initial surgical approach is unilateral neck exploration. In our experience, parathyroid adenoma is treated adequately by resection of the adenoma and biopsy of one or more grossly normal parathyroid glands. Parathyroid hyperplasia can be managed by subtotal resection of three or three and a half glands, preserving mg of well vascularized parathyroid tissue. The site of preserved gland fragment should be marked by a metal clip and a nonabsorbable suture, and carefully recorded in the operative note. Alternately, total parathyroidectomy with autotransplantation of 20 or so mm cubes of parathyroid tissue into the nondominant forearm musculature can be chosen. Where facilities for frozen tissue preservation are available, additional parathyroid fragments should be set aside for safety. The Initial Operation for Probable Parathyroid Hyperplasia Primary parathyroid hyperplasia may be suggested by family history or personal history of multiple endocrine neoplasia syndromes, types I and Ha. In chronic renal disease secondary and tertiary parathyroid hyperplasia may require surgical treatment. Here the surgeon's concern is to locate all glands, identify the specific parathyroid tissue to be left in the patient, and resect the remainder. Most surgeons choose to perform a subtotal parathyroidectomy, leaving one fragment of a well-vascularized gland in situ, approximately mg of tissue. Others prefer to perform a total parathyroidectomy with reimplantation of gland fragments into a convenient muscle, usually the brachioradialis of the nondominant forearm. Where facilities are available frozen preservation of parathyroid fragments add additional security against postoperative hypoparathyroidism. It is important to recognize that patients with hyperparathyroidism may recur (15%) so that second operations are not unusual. If gland fragments are left in the neck, they should be identified by suture and metal clip to facilitate identification at a second operation. If gland fragments are placed in forearm muscle, they should be placed in two groups so that at a second operation one of the groups can be resected and the other preserved. Recurrent hyperparathyroidism is so common in patients with renal failure who are not candidates for transplants that some groups advocate total parathyroidectomy without autotransplantation. However, all other patients require some parathyroid tissue to maintain calcium homeostasis. Permanent hypoparathyroidism is difficult to manage. The role of the surgical pathologist in the evaluation of secondary hyperparathyroidism is to identify parathyroid tissue at the time of frozen section to enable the surgeon to remove portions of this tissue for autotransplantation. Secondary hyperparathyroidism is not different histopathologically from primary hyperparathyroidism. 110 "" 3 Usually all four glands are enlarged; one or two glands may be of very great size." 4 Transplanted parathyroid tissue usually shows a take in the majority of cases, and occasionally part of this tissue may be removed if hyperfunction again becomes a problem. These lesions show small nests and islands of vascularized parathyroid tissue growing in muscle or fat. The success rate of cryopreserving hyperplastic parathyroid tissue is excellent 21 "; this tissue can be used to titrate patients and stabilize serum calcium in the appropriate range. 116 Subsequent Operation for Hyperparathyroidism Recurrent hyperparathyroidism developing a year or more after initial postoperative success, should be differentiated from persistent disease. 24 " 7 "" 9 The latter is more common with hypercalcemia developing shortly after surgery or within a year. Causes of persistent hypercalcemia include misinterpretation of the original pathologic specimen as an adenoma when it represented hyperplasia; multiple endocrine neoplasia syndrome; hyperfunctioning parathyroid tissue present in an ectopic location; or absence of the usual primary hyperparathyroidism but presence of an uncommon cause such as familial hypocalciuric hypercalcemia. Recurrent hypercalcemia, defined as a normocalcemic period at least 1 year after removal of all grossly abnormal glands, may result from recurrent tumor, probably a carcinoma misinterpreted on initial pathologic examination; seeding of abnormal parathyroid tissue at initial surgery; or development of a second adenoma or more likely metasynchronous development of multigland disease." 7 "" 9 Corrective approaches usually entail secondary surgery. Several techniques may be used to localize abnormal parathyroid tissue preoperatively, including differential isotope and magnetic resonance scans, ultrasonography, selective venous catheterization, and arteriography. Success rates for these modalities depend on the experience of those performing them. Most authors caution that the use of localizing studies is not necessary before the initial surgery Deftos and colleagues state, "To date, no preoperative imaging modality exists that is superior to operative localization by an experienced surgeon." 2 Successful nonoperative ablation of selected me- Vol. I No. 3

6 370 ANATOMIC PATHOLOGY diastinal parathyroid tumors localized by various noninvasive and invasive procedures has been reported. 122 Before surgery, the clinical course of the patient before and after past surgery should be known, and the medical records should be reviewed. Pertinent clinical history, including details of any operations in the neck, measures of chemical and hormonal imbalance, and results of any localizing studies, should be available. The pathologist should have the opportunity to examine tissue sections and reports from any past operations, biopsies, or needle aspirations. As accurately as possible, a count of glands removed and sampled should be available before subsequent operation. Localizing studies such as differential isotope scanning, ultrasonography, computerized tomography, and magnetic resonance imaging are usually but not uniformly helpful. 123 " 126 In the absence of localizing evidence for a mediastinal location, the subsequent operation is carried out in the neck. Sternotomy is rarely necessary; most mediastinal parathyroid glands are resectable from a neck incision, sometimes with the performance of a cervical thymectomy. The subsequent operation is best carried out by a surgeon with broad experience in identification of parathyroid glands. 2 Knowing where to explore, and recognizing what is found are essential qualities. 122,127 " 129 Preoperative localization by various noninvasive and invasive modalities is not uniformly possible. Localization by two means is preferred. Parathyroid glands have been found in bizarre, ectopic locations extending from the suprahyoid neck to the inferior mediastinum. Common locations for missing superior parathyroid glands include the tracheoesophageal groove behind the thyroid lobe, the junction of the recurrent laryngeal nerve and the larynx, and the tracheoesophageal groove extending posteriorly and inferiorly from the inferior thyroid artery into the posterior-superior mediastinum. The missing inferior parathyroid gland may lie in the thymus, beneath the thyroid capsule, or even in the carotid sheath. When all else fails, blind thymectomy or blind thyroid lobectomy may succeed. 9 In a series of 145 patients undergoing subsequent operation at the National Institutes of Health and described by Fraker and colleagues, patients were found to have a parathyroid adenoma as a cause for their persistent or recurrent hyperparathyroidism. Undescended parathyroid adenomas located at or superior to the carotid bifurcation were found in nine (9%). Only seven were localized preoperatively. With or without successful preoperative localization, the surgical procedure is usually challenging and not always successful. Scar tissue from previous operations may be difficult to penetrate and bleeding is likely to stain the operativefield.the surgeon may be forced to identify parathyroid glands in a bloody environment. By approaching the posterior aspect of the thyroid lobes laterally and lifting the thyroid gland and strap muscles as a unit away from the carotid sheath and prevertebral fascia, the surgeon may conducted the exploration a minimum of dissection through scar. Nothing defeats comfortable interaction between the pathologist and the surgeon more than the indiscriminate delivery to the laboratory of multiple random biopsy specimens containing scar, fat, lymph node, thymus, and thyroid but not parathyroid tissue. The surgeon should have the ability to recognize parathyroid tissue when encountered and confirm it by biopsy. However, in heavily scarred necks, several biopsy specimens yielding negative results over a prolonged period may prove necessary. The surgeon must be able to explore the neck without being destructive, particularly in subsequent operations. When the number of glands remaining after a past operation is uncertain, the surgeon must be careful not to accidentally create permanent hypoparathyroidism in the patient by inadvertently removing all remaining parathyroid tissue. To this end portions of parathyroid tissue identified at operation can be set aside at the operating table for later frozen preservation. Frozen preserved gland fragments can be held for months in readiness for autotransplantation if needed. If it appears very likely that all of the patient's parathyroid tissue exists in the surgical specimen, then a portion of the specimen can be salvaged before being sent to the pathologist by dicing a parathyroid gland into mm cubes and implanting them individually, preferably in two groups, in a convenient skeletal muscle such as the brachioradialis or sternomastoid. The Operation for Parathyroid Carcinoma Because of its rarity and the lack of specific histologic criteria, parathyroid carcinoma may go undiagnosed at the time of a first operation (19% of the 95 patients in one series 131 ) and should always be considered as a possibility at second operations. The possibility of carcinoma is magnified when hyperparathyroidism recurs quickly, is severe, and is associated with histologically atypical features. 132 Although parathyroid tumors that adhere to adjacent structures suggest malignancy, this gross surgical finding is not diagnostic. Should adherence to a relatively unimportant structure such as a thyroid lobe be noted the excision can be extended to include part of that structure. However, important adjacent structures such as the recurrent laryngeal nerve should be spared when the diagnosis of parathyroid carcinoma is not certain. Biopsy of adjacent lymph nodes in the central compartment of the neck or internal jugular chain may be helpful. Lymphatic and other metastases from parathyroid carcinoma may function, producing unpleasant syndromes and associated disease states of fulminant hypercalcemia. 133 An en bloc resection including parathyroid tumor, a portion or all of the adjacent thyroid lobe, the recurrent laryngeal nerve if involved, and a modified neck dissection is desirable. An attempt should be made by the surgeon to resect all accessible metastatic tumor as palliative treatment even if cure is not thought possible. Until new technologies facilitated surgical localization of abnormal parathyroid and allow the pathologist to distinguish one-gland from multigland disease unequivocally, debate will continue about whether unilateral neck exploration or bilateral exploration should be the initial surgical approach and about the number of glands that should be resected or sampled by biopsy. 39 ' We favor bilateral explorations and resection of single large glands. This approach, as discussed, represents a successful experience in the care of our patients with hyperparathyroidism. The surgeon and the pathologist should agree on a provisional diagnosis at the time of surgery. However, it is the postoperative clinical course that measures the accuracy of the diagnosis and the effectiveness of the surgical procedure. A subsequent clinicopathologic evaluation of the result of the patient's surgical care should be made, preferably at a combined conference involving the endocrinologist, the imaging physician, the surgeon, and the pathologist. A.J.C.P. 1994

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