Causes of Failed Initial Exploration for Hyperparathyroidism

HPT following a prior cervical or mediastinal exploration for hypercalcemia can be divided arbitrarily into persistent (defined as hypercalcemia recurring within 6 months after initial operation) or recurrent (hypercalcemia recurring after 6 months of normocalcemia following initial operation).2 3

The former denotes missed pathology and the latter refers to newly developed pathology. The distinction of these two categories has been loosely applied since it is possible that a physiologically insignificant amount of hyperfunctioning tissue that was present at the first operation could proliferate and produce a biochemical recurrence several years later.2

It has been estimated that 2% to 10% of surgical failures may be attributed to an incorrect diagnosis.4 However, this is much less of a problem today with the advent of a reliable radioimmunoassay for intact parathyroid hormone (PTH). In patients with renal disease, PTH clearance is compromised by impaired renal clearance and may lead to spurious elevations of PTH levels if the hormone is measured by assays that fail to detect intact PTH molecular structures. In such circumstances, the measurement of PTH using double-antibody methods will help resolve this issue. Another, albeit rare, diagnostic pitfall are patients with benign familial hypocalciuric hypercalcemia (BFHH). This disorder is associated with moderate hypercalcemia and normal or slightly elevated blood PTH levels. BFHH can be diagnosed by a positive family history of hypercalcemia at times associated with unsuccessful parathyroid surgery, a 24-hour urinary calcium excretion of less than 100 mg, and the calculated value of calcium-to-creatinine clearance ratio of less than 0.014 Other causes of hypercalcemia (intake of thiazide diuretics or lithium, vitamin D intoxication, sarcoidosis, multiple myeloma, malignancy, and paraneoplastic syndromes) rarely cause confusion today in the diagnosis of primary HPT. This is largely due to the accuracy and sensitivity of the currently available intact PTH assays.

In contrast to the incorrect diagnosis of primary HPT, inexperience on the part of the surgeon is a major cause of surgical failure because of the lack of knowledge regarding parathyroid embryology and knowing the usual "hiding places" of the parathyroid glands; the inability to recognize and excise an abnormal gland; failure to recognize and adequately treat multiple gland disease; failure to locate an ectopic gland; the presence of supernumerary glands; errors on frozen section examination; incomplete excision of invasive parathyroid carcinoma; or parathyromatosis (i.e., multiple nodules of hyperfunctioning parathyroid tissue scattered through the neck and mediastinum) due most often to spillage of diseased tissue during removal or rarely due to abnormal embryologic development. The anatomy and embryologic descent of the parathyroid glands are variable in 20% of patients.5 Inability to recognize an anomalous location of an abnormal gland or the inability to perform a bloodless, thorough dissection of the neck is a common cause for failed cervical exploration by the inexperienced endocrine surgeon.

Although multiple-gland disease accounts for 5% to 15% of patients undergoing initial exploration, up to 37% of patients who come to reoperation have multiple-gland disease rather than a single adenoma.2-3'6,7 This heterogeneous group of patients includes patients with familial HPT and multiple endocrine neoplasia (MEN) types 1 and 2. The logistic difficulty in diagnosing some of these rare conditions can be attributed to a negative family history and the disparity of size of the enlarged glands, although all are hypercellular (unequal or asymmetrical hyperplasia).

In general, the location and excision of an adenoma, visual identification of all parathyroid glands, and biopsy of a second suspicious gland constitute a safe and effective strategy for most patients with primary HPT undergoing initial operation. In multiple-gland hyperplasia, it is vitally important to adequately reduce the amount of functioning parathyroid tissue to prevent recurrence without being overly aggressive and creating an aparathyroid state with the need for chronic calcium and vitamin D supplementation— a regimen that is unpleasant for the patients and that has a poor rate of patient compliance. Subtotal parathyroidectomy (3.5-gland resection: leaving ±50 mg viable parathyroid tissue) or total parathyroidectomy with immediate forearm reimplantation is considered the treatment of choice for patients with familial HPT.8-9 The incidence of supernumerary ("fifth") glands in 1% to 6% of patients with MEN 1 adds further surgical difficulty. Routine transcervical thymectomy for the possible removal of a supernumerary fifth gland is indicated in all patients with MEN 1. Undoubtedly, failure to identify multiple-gland disease and to remove adequate functioning parathyroid tissue, the presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction invariably lead to persistent or recurrent hypercalcemia.9

Despite the success of this approach, there is a steady push toward a more limited, or focused, cervical exploration, often under local anesthesia and increasingly on an outpatient basis.1 Considerable interest has been focused on the adoption of minimally invasive approaches including endoscopic, video-assisted, and radio-guided parathyroidectomy for primary HPT.10-11 Application of these techniques depends on an accurate preoperative sestamibi scanning or the use of intraoperative gamma probe technology to locate the adenoma as well as the increasing availability of the intraoperative "quick" PTH assay to confirm surgical success. However, the fact that there are numerous types of minimally invasive parathyroidectomy, and that no firmly established method has been accepted as the standard technique, makes evaluation and comparison with the open approach difficult.10 These new approaches should be evaluated carefully and compared objectively with the excellent results obtained when surgical expertise alone is used.1 In addition, these techniques can be applied only to selected patients12-13 and have potential pitfalls that could result in surgical failure.14 Persistent or recurrent HPT occurs in a small but significant proportion of patients after the initial exploration and continues to pose a management dilemma and technical challenge to the surgeon. The newer techniques and technology need to be particularly carefully evaluated in this complex subset of patients with HPT.

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