World J. Surg. 15, 738-744, 1991
0
World Journal of Surgery 9 1991 by the Soci(~t6 lnternationale de Chirurgie
Diagnosis and Treatment of Patients with Parathyroid Carcinoma: An Update and Review Takao Obara, M.D. and Yoshihide Fujimoto, M.D. Department of Endocrine Surgery, Institute of Clinical Endocrinology, Tokyo Women's Medical College, Tokyo, Japan Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. However, to our best knowledge, at least 163 cases of functioning parathyroid carcinoma appeared in the English literature from 1981 to 1989. We summarize the available information obtained from the reports of those patients and compare it with previous descriptions of the disease. The etiology of parathyroid carcinoma is usually obscure, but the possibility of a radiation-induced malignant change in the parathyroid gland became evident in a few patients. Clinical manifestations, including age, sex, symptoms, and biochemical findings in this review were comparable to those in previous reviews. Noulnvasive localization studies such as ultrasonography may offer a diagnostic clue to parathyroid carcinoma. Measurement of DNA content is a useful adjunct for making the histologic diagnosis of parathyroid carcinoma and prediction of the clinical outcome. Since the initial operation offers the best chance for cure, preoperative suspicion and intra-operative recognition of the parathyroid cancer are essential. The initial operation should be en bloc resection of the tumor, avoiding rupture of the tumor capsule and spillage of tumor cells. As parathyroid carcinoma is a slow-growing but tenacious malignancy, repeated resection of local recurrent tumors or even distant metastases is effective for palliation of recurrent hypercalcemia and occasional cure. When hyperealcemia is refractory to surgical therapy or no recurrent tumor can be identified, other modalities of therapy must be considered. New drugs to control hypercaleemia by inhibiting bone resorption may hold promise in patients with recurrent parathyroid carcinoma.
Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (HPT). It is very important for every surgeon to be aware of the disease. The hypercalcemia it engenders may have catastrophic consequences, but this hypercalcemia can be cured only by an en bloc resection at the time of the initial operation. Proper management of the recurrent disease can result in control of the hypercalcemia, often in palliation, and occasionally in a cure [1, 2]. The natural course of parathyroid carcinoma is still not completely understood, since the experience of a single surgeon or institution with this carcinoma is limited. Pathologic criteria for definite diagnosis are not well established and therapeutic approaches vary. Holmes and coworkers [3] reviewed 42 cases of parathyroid carcinoma with unequivocal evidence of both malignancy and Reprint requests: Takao Obara, M.D., Department of Endocrine Surgery, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162, Japan.
HPT collected from the literature reported from 1933 to 1968, and Shane and Bilezikian [4] wrote a collective review of the 62 patients reported in the English literature from 1969 to 1981. To our best knowledge, at least 160 more cases of parathyroid carcinoma were reported in the English literature between the rest of 1981 and the end of 1989 [1, 2, 5-59]. In reviewing these reports, we would like to update what we know about parathyroid carcinoma and what should be done clinically for patients with the carcinoma. Methods
This review is exclusively directed to cases of parathyroid carcinoma in primary HPT. To be included in this review, the parathyroid carcinoma had at least one of the following features: (1) evidence of local invasion of adjacent organs (thyroid, trachea, esophagus, strap muscle, nerves); (2) evidence of metastasis in the cervical lymph node(s) or a distant site; and (3) characteristic histopathology as described by Schantz and Castleman [60]. We have experience with 22 patients with parathyroid carcinoma at our institution and have reported most of the cases elsewhere [1, 2, 21, 37, 61]. In addition, to our best knowledge, 141 patients with functioning parathyroid carcinoma have been reported in the English literature over the past 9 years. Therefore, since the first case description in 1933, almost 270 cases of parathyroid carcinoma have been reported in the English literature. We summarize the available information for the 163 newly reported patients and compare it with previous descriptions of the disease. Incidence
The previously reported incidence of parathyroid carcinoma in patients with primary HPT varied from 5% [2--4]. Shane and Bilezikian [4] suggest that the true incidence is probably 14 mg/dl in 65% of the cases. These observations are in accord with results previously published (Table 2) [2-4]. With a markedly elevated serum calcium level, the plasma parathyroid hormone (PTH) level was significantly high. In 68% of 53 patients whose data were available, the circulating level of PTH was >5 times the upper limit of the normal range. As the previous reviews noted, patients with functioning
Author [reference] yr Period of review Number of cases Female :male ratio Average age in yr (range) Manifestations (%) Serum calcium (mg/dl) > 14 rng/dl Bone disease Palpable neck mass Renal involvement Pancreatitis Hypercalcemic crisis No symptoms Local recurrence following surgery Lymphatic metastasis Distant metastasis
Holmes et al. [3] 1969
Shane and Bilezikian [4] 1982
Obara and Fujimoto 1990
1933-1968 46 0.8:1 44 (12-72)
1968--1981 62 1.2 : 1 48 (18--73)
1981-1989 163 1.2:1 46.6 (13-78)
15.9 75 73 52 32 15
15.5 70 70 48 60 10
65
2 47
15.0 65 39 34 48 5.5 12 2 36
32 21
11 24
17 25
parathyroid carcinoma frequently have clinically severe HPT [2-4]. In the present study, the patients with parathyroid carcinoma showed a similar frequency of severe metabolic manifestations. A cervical mass was palpable in 34% of the patients, 48% of the patients had various renal disorders (renal stone, renal dysfunction, nephrocalcinosis, or pyelonephritis), and 39% of the patients had bone disease. Parathyroid crisis occurred in 12% of the patients and pancreatitis in 5%. Only 3 patients were asymptomatic; their elevated serum calcium concentrations were detected incidentally on biochemical screening [38, 47, 49]. Diagnosis
A definite pre-operative diagnosis of parathyroid carcinoma is usually not possible on the basis of clinical manifestations alone in patients with HPT. Levin and associates [45] state that the metabolic manifestations in patients with parathyroid carcinoma are comparable with those of patients with parathyroid adenoma having profound hypercalcemia. Notwithstanding, the present review confirms that carcinoma is sufficiently suspicious in patients with marked hypercalcemia (>14 mg/dl), a palpable neck mass, or severe HPT. Greater elevation of immunoreactive PTH levels also should raise the assumption of parathyroid carcinoma. Although Stock and colleagues [66] report that several patients with parathyroid carcinoma had elevated plasma levels of human chorionic gonadotropin (hCG), it remains to be clarified whether measurement of hCG is a useful clue to identify patients at risk pre-operatively. Noninvasive localization studies are useful adjuncts for making the pre-operative diagnosis of parathyroid carcinoma. Real time ultrasonography of the neck is most useful for an initial pre-operative localization study of primary HPT. Several investigators have described the sonographic features of parathyroid carcinoma. Malignancy should be considered when ultrasonography demonstrates signs of gross invasion and marked irregularity of the tumor margin [55, 67, 68]. Ultrasonography is also useful for detection of nonpalpable cervical lymph node metastasis. A positive 67gallium citrate scan is obtained in some
740
patients with parathyroid cancer [43, 56]. Some authors report that fine needle aspiration biopsy has successfully revealed parathyroid carcinoma [32, 39, 42, 59]. The risk of tumor cell spillage with aspiration biopsy still must be seriously considered. At the initial exploratory neck operations for primary HPT surgeons should always be aware of the possibility of parathyroid carcinoma and recognize the condition intra-operatively. In cases without severe metabolic manifestations of HPT or palpable neck mass, the diagnosis can be made only at the time of surgery [28]. Macroscopically, the diagnosis of parathyroid cancer may be suggested by a firm gland surrounded by dense fibrous tissue that is pale white and adheres to surrounding structures [27]. Direct invasion of the thyroid and other adjacent tissues is frequently seen. When a parathyroid tumor is likely to be carcinoma, an incisional biopsy of the mass must be avoided. Otherwise, local dissemination of the tumor cells inevitably occurs. Histopathology
It is still difficult to distinguish, histologically, benign from malignant parathyroid tumors. One view is that the only characteristic microscopic finding of malignancy is invasion of surrounding structures or metastasis to lymph nodes or to other organs and that ultimate diagnosis of parathyroid carcinoma can be made with confidence only after recurrence or metastatic spread occurs [11]. However, if the diagnostic criteria are that strict, it is possible that some parathyroid carcinomas found at the early stage and successfully cured by the initial operation are missed [4]. In making the diagnosis of parathyroid carcinoma, many authors [2, 27] in principle adopt the same histologic criteria as those of Shantz and Castleman [60]: (1) fibrous capsule or fibrous trabeculae, or both, (2) a trabecular or rosette-like cellular architecture, (3) the presence of mitotic figures, and (4) capsular or vascular invasion, although they emphasize the importance of considering the overall picture rather than a single criterion. Other investigators express reservation regarding the significance of vascular and capsular invasion, and feel that mitotic activity alone is an unreliable indicator of malignancy [24]. Levin and coworkers [45] subdivide adenomas into 2 groups, typical and atypical. The atypical adenomas possess 1 or more of the histologic features usually considered requisite for a diagnosis of parathyroid carcinoma or are grossly adherent to an adjacent structure at the time of the operation. The authors state that cases of atypical parathyroid adenoma might represent cases of low-grade parathyroid carcinoma and patients with atypical adenoma should be monitored more carefully than patients with the typical benign form. The ultrastructural features of parathyroid carcinoma have been described [69-71]. In establishing the diagnosis of malignancy, however, electron microscopic investigation did not add significantly to light microscopy [69-71]. In almost all cases of parathyroid carcinoma described the microscopic features were those of the chief cell type. We experienced 2 cases of parathyroid carcinoma composed principally of oxyphilic cells [37]. In those cases, electron microscopic study revealed the typical oxyphilic cells packed with numerous mitochondria.
World J. Surg. Vol. 15, No. 6, Nov./Dec. 1991 DNA Content Analysis
DNA aneuploidy determined by cytometric analysis is a valuable marker of malignancy in some solid neoplasms and is associated with poor prognosis of the diseases. In other endocrine glands such as the thyroid and adrenal glands, analysis of the DNA content has successfully differentiated rapidly growing malignancies with poor prognosis from less aggressive lesions with similar histologic features. Recently, a few systematic studies on the occurrence of DNA aneuploidy in parathyroid carcinoma have appeared in the literature [72-75]. Levin and associates [73] found, by static cytometry, that 4 of 9 parathyroid carcinomas had an aneuploid pattern, whereas none of 32 adenomas showed an abnormal DNA pattern. We performed a flow cytometric study using paraffin-embedded specimens of parathyroid lesions from 49 patients, which included 14 primary and 11 locally recurrent or metastatic lesions from 16 carcinoma patients [74]. In our study, there was no difference in ploidy patterns between the primary and recurrent lesions of the carcinomas and in 5 (31%) cases the carcinomas expressed aneuploidy. These 2 studies show that unequivocal aneuploidy is significantly associated with malignancy of the parathyroid tumors. A recent flow cytometric analysis of parathyroid tumors using fresh material confirms that parathyroid carcinomas are more apt to be aneuploid than are adenomas, and determination of the DNA ploidy pattern is a valuable adjunct to the histologic diagnosis of parathyroid carcinoma [76]. Our previous study also suggests that the aneuploid parathyroid carcinomas tend to have a greater potential of distant metastasis and poorer prognosis [74]. In contrast to these observations, some authors state that DNA aneuploidy occurs commonly in parathyroid adenomas and has no role in histopathologic diagnosis [72, 77]. Further studies will clarify the significance of the DNA content of parathyroid tumors. Natural History
Local invasion of adjacent structures by parathyroid carcinoma was present at the initial operation in 38 patients in the current review of 163 cases. The thyroid gland was most commonly involved (24 cases), followed by the recurrent nerve (6 cases), the strap muscle, the esophagus, and the trachea. Cervical lymph nodes dissected at the initial operation were positive for metastasis in 7 patients, including 2 in our series [8, 9, 12, 31, 38]. Distant metastasis was present at the time of the initial surgery in 3 patients [11, 56, 76]. Following the initial operation, persistent HPT occurred in 7 patients and 60 patients experienced recurrence of parathyroid carcinoma. The mean interval between the initial operation and the first recurrence was 2.6 years, but the interval was >7 years in 4 patients. Usually patients with recurrent parathyroid carcinomas manifest hypercalcemia from the release of PTH from the recurrent tumor. It is worth noting, however, that in 2 patients metastatic parathyroid carcinomas were clinically nonfunctioning [41, 46]. The 2 patients had HPT clinically and biochemically at the initial operation. Of the 163 patients in this review, lymph node metastasis occurred in 28 (17%) patients, the most common site being the neck (23 cases), followed by the mediastinum (10 cases). Distant metastasis appeared in 41 (25%) patients, in the lung (25
T. Obara and Y. Fujimoto: Parathyroid Carcinoma
5 ~tl ~ 4
741
9 Lymphaticmetastasis I-I Distantmetastasis
I
n
3 ~
2
0 0
1
2
3
4
5
6
7
8
9
1 0 11
12 13 14 15 16 17 18 19 20
Number of Years
Fig. 1. Interval between the initial operation and the first clinical manifestation of metastasis in patients with parathyroid carcinoma.
cases), bone (9 cases); liver (6 cases), and pancreas (3 cases). There was a wide diversity in the interval between the initial operation and manifestation of metastasis (Fig. 1). Three patients in our series had evidence of metastasis at the initial operation. In contrast, another patient, who had an oxyphilic cell carcinoma [37], developed local recurrence and subsequent pulmonary metastasis, 6 years and 19 years after the initial operation, respectively. Follow-up information after the initial operation was available from the reports on 107 patients. Thirty-seven (34.6%) patients died; 2 of parathyroid disease that was not treated by surgery, 30 of recurrent or persistent hypercalcemia, and 5 from unrelated disease. For the patients who died of persistent or recurrent HPT, the average duration after the initial operation was 6.6 years (range, 1 month to 17 years). Seventy-one patients were alive; 45 showed no evidence of recurrent disease during the mean foll0w-up period of 4.6 years (range, 1 month to 19 years) and 26 had recurrence but have survived for an average approximately 7 years. One of the patients who underwent aggressive surgery to remove multiple recurrent lesions was alive 25 years after the initial operation [26]. Treatment
The most effective treatment of parathyroid carcinoma remains surgical. Unquestionably, failure to eradicate the carcinoma at the first operation often leads to repeated local recurrence or distant metastasis, and ultimate death of the patients with recurrent carcinoma is inevitable. The initial e n b l o c resection, avoiding rupture of the tumor capsule and spillage of tumor cells, represents the best chance for cure. Of 37 patients who were alive more than 1 year after surgery without recurrence of the disease, 26 (70%) patients had undergone e n b l o c resection of the tumor at the time of the initial operation. In Wang's series of 28 patients with parathyroid carcinoma, 50% were cured by e n b l o c resection [38]. In a neck operation, a large collar incision and a transverse section of the strap muscles provide a wide operative field. After the thyrOid and parathyroid glands are exposed, the anteromedial wall of the ipsilateral common carotid artery is freed from surrounding tissue along its entire length. The recurrent laryngeal nerve is then exposed at its most proximal end in the lower neck. An attempt should be made to do an e n
b l o c resection, which usually requires thyroid lobectomy and excision of paratracheal alveolar tissue, lymph nodes, and the thymic tongue. If the recurrent laryngeal nerve is involved, sacrifice of the nerve is necessary. There has been some controversy regarding the necessity of radical neck dissection. Holmes and colleagues [3] advocate prophylactic radical neck dissection at the initial operation. Currently, however, most surgeons reserve radical neck dissection for patients with grossly enlarged lymph nodes, patients with extensive local invasion, and patients with local recurrence [8; 11, 31, 38]. Although the reported incidence of cervical lymph node metastasis is
0
World Journal of Surgery 9 1991 by the Soci(~t6 lnternationale de Chirurgie
Diagnosis and Treatment of Patients with Parathyroid Carcinoma: An Update and Review Takao Obara, M.D. and Yoshihide Fujimoto, M.D. Department of Endocrine Surgery, Institute of Clinical Endocrinology, Tokyo Women's Medical College, Tokyo, Japan Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. However, to our best knowledge, at least 163 cases of functioning parathyroid carcinoma appeared in the English literature from 1981 to 1989. We summarize the available information obtained from the reports of those patients and compare it with previous descriptions of the disease. The etiology of parathyroid carcinoma is usually obscure, but the possibility of a radiation-induced malignant change in the parathyroid gland became evident in a few patients. Clinical manifestations, including age, sex, symptoms, and biochemical findings in this review were comparable to those in previous reviews. Noulnvasive localization studies such as ultrasonography may offer a diagnostic clue to parathyroid carcinoma. Measurement of DNA content is a useful adjunct for making the histologic diagnosis of parathyroid carcinoma and prediction of the clinical outcome. Since the initial operation offers the best chance for cure, preoperative suspicion and intra-operative recognition of the parathyroid cancer are essential. The initial operation should be en bloc resection of the tumor, avoiding rupture of the tumor capsule and spillage of tumor cells. As parathyroid carcinoma is a slow-growing but tenacious malignancy, repeated resection of local recurrent tumors or even distant metastases is effective for palliation of recurrent hypercalcemia and occasional cure. When hyperealcemia is refractory to surgical therapy or no recurrent tumor can be identified, other modalities of therapy must be considered. New drugs to control hypercaleemia by inhibiting bone resorption may hold promise in patients with recurrent parathyroid carcinoma.
Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (HPT). It is very important for every surgeon to be aware of the disease. The hypercalcemia it engenders may have catastrophic consequences, but this hypercalcemia can be cured only by an en bloc resection at the time of the initial operation. Proper management of the recurrent disease can result in control of the hypercalcemia, often in palliation, and occasionally in a cure [1, 2]. The natural course of parathyroid carcinoma is still not completely understood, since the experience of a single surgeon or institution with this carcinoma is limited. Pathologic criteria for definite diagnosis are not well established and therapeutic approaches vary. Holmes and coworkers [3] reviewed 42 cases of parathyroid carcinoma with unequivocal evidence of both malignancy and Reprint requests: Takao Obara, M.D., Department of Endocrine Surgery, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162, Japan.
HPT collected from the literature reported from 1933 to 1968, and Shane and Bilezikian [4] wrote a collective review of the 62 patients reported in the English literature from 1969 to 1981. To our best knowledge, at least 160 more cases of parathyroid carcinoma were reported in the English literature between the rest of 1981 and the end of 1989 [1, 2, 5-59]. In reviewing these reports, we would like to update what we know about parathyroid carcinoma and what should be done clinically for patients with the carcinoma. Methods
This review is exclusively directed to cases of parathyroid carcinoma in primary HPT. To be included in this review, the parathyroid carcinoma had at least one of the following features: (1) evidence of local invasion of adjacent organs (thyroid, trachea, esophagus, strap muscle, nerves); (2) evidence of metastasis in the cervical lymph node(s) or a distant site; and (3) characteristic histopathology as described by Schantz and Castleman [60]. We have experience with 22 patients with parathyroid carcinoma at our institution and have reported most of the cases elsewhere [1, 2, 21, 37, 61]. In addition, to our best knowledge, 141 patients with functioning parathyroid carcinoma have been reported in the English literature over the past 9 years. Therefore, since the first case description in 1933, almost 270 cases of parathyroid carcinoma have been reported in the English literature. We summarize the available information for the 163 newly reported patients and compare it with previous descriptions of the disease. Incidence
The previously reported incidence of parathyroid carcinoma in patients with primary HPT varied from 5% [2--4]. Shane and Bilezikian [4] suggest that the true incidence is probably 14 mg/dl in 65% of the cases. These observations are in accord with results previously published (Table 2) [2-4]. With a markedly elevated serum calcium level, the plasma parathyroid hormone (PTH) level was significantly high. In 68% of 53 patients whose data were available, the circulating level of PTH was >5 times the upper limit of the normal range. As the previous reviews noted, patients with functioning
Author [reference] yr Period of review Number of cases Female :male ratio Average age in yr (range) Manifestations (%) Serum calcium (mg/dl) > 14 rng/dl Bone disease Palpable neck mass Renal involvement Pancreatitis Hypercalcemic crisis No symptoms Local recurrence following surgery Lymphatic metastasis Distant metastasis
Holmes et al. [3] 1969
Shane and Bilezikian [4] 1982
Obara and Fujimoto 1990
1933-1968 46 0.8:1 44 (12-72)
1968--1981 62 1.2 : 1 48 (18--73)
1981-1989 163 1.2:1 46.6 (13-78)
15.9 75 73 52 32 15
15.5 70 70 48 60 10
65
2 47
15.0 65 39 34 48 5.5 12 2 36
32 21
11 24
17 25
parathyroid carcinoma frequently have clinically severe HPT [2-4]. In the present study, the patients with parathyroid carcinoma showed a similar frequency of severe metabolic manifestations. A cervical mass was palpable in 34% of the patients, 48% of the patients had various renal disorders (renal stone, renal dysfunction, nephrocalcinosis, or pyelonephritis), and 39% of the patients had bone disease. Parathyroid crisis occurred in 12% of the patients and pancreatitis in 5%. Only 3 patients were asymptomatic; their elevated serum calcium concentrations were detected incidentally on biochemical screening [38, 47, 49]. Diagnosis
A definite pre-operative diagnosis of parathyroid carcinoma is usually not possible on the basis of clinical manifestations alone in patients with HPT. Levin and associates [45] state that the metabolic manifestations in patients with parathyroid carcinoma are comparable with those of patients with parathyroid adenoma having profound hypercalcemia. Notwithstanding, the present review confirms that carcinoma is sufficiently suspicious in patients with marked hypercalcemia (>14 mg/dl), a palpable neck mass, or severe HPT. Greater elevation of immunoreactive PTH levels also should raise the assumption of parathyroid carcinoma. Although Stock and colleagues [66] report that several patients with parathyroid carcinoma had elevated plasma levels of human chorionic gonadotropin (hCG), it remains to be clarified whether measurement of hCG is a useful clue to identify patients at risk pre-operatively. Noninvasive localization studies are useful adjuncts for making the pre-operative diagnosis of parathyroid carcinoma. Real time ultrasonography of the neck is most useful for an initial pre-operative localization study of primary HPT. Several investigators have described the sonographic features of parathyroid carcinoma. Malignancy should be considered when ultrasonography demonstrates signs of gross invasion and marked irregularity of the tumor margin [55, 67, 68]. Ultrasonography is also useful for detection of nonpalpable cervical lymph node metastasis. A positive 67gallium citrate scan is obtained in some
740
patients with parathyroid cancer [43, 56]. Some authors report that fine needle aspiration biopsy has successfully revealed parathyroid carcinoma [32, 39, 42, 59]. The risk of tumor cell spillage with aspiration biopsy still must be seriously considered. At the initial exploratory neck operations for primary HPT surgeons should always be aware of the possibility of parathyroid carcinoma and recognize the condition intra-operatively. In cases without severe metabolic manifestations of HPT or palpable neck mass, the diagnosis can be made only at the time of surgery [28]. Macroscopically, the diagnosis of parathyroid cancer may be suggested by a firm gland surrounded by dense fibrous tissue that is pale white and adheres to surrounding structures [27]. Direct invasion of the thyroid and other adjacent tissues is frequently seen. When a parathyroid tumor is likely to be carcinoma, an incisional biopsy of the mass must be avoided. Otherwise, local dissemination of the tumor cells inevitably occurs. Histopathology
It is still difficult to distinguish, histologically, benign from malignant parathyroid tumors. One view is that the only characteristic microscopic finding of malignancy is invasion of surrounding structures or metastasis to lymph nodes or to other organs and that ultimate diagnosis of parathyroid carcinoma can be made with confidence only after recurrence or metastatic spread occurs [11]. However, if the diagnostic criteria are that strict, it is possible that some parathyroid carcinomas found at the early stage and successfully cured by the initial operation are missed [4]. In making the diagnosis of parathyroid carcinoma, many authors [2, 27] in principle adopt the same histologic criteria as those of Shantz and Castleman [60]: (1) fibrous capsule or fibrous trabeculae, or both, (2) a trabecular or rosette-like cellular architecture, (3) the presence of mitotic figures, and (4) capsular or vascular invasion, although they emphasize the importance of considering the overall picture rather than a single criterion. Other investigators express reservation regarding the significance of vascular and capsular invasion, and feel that mitotic activity alone is an unreliable indicator of malignancy [24]. Levin and coworkers [45] subdivide adenomas into 2 groups, typical and atypical. The atypical adenomas possess 1 or more of the histologic features usually considered requisite for a diagnosis of parathyroid carcinoma or are grossly adherent to an adjacent structure at the time of the operation. The authors state that cases of atypical parathyroid adenoma might represent cases of low-grade parathyroid carcinoma and patients with atypical adenoma should be monitored more carefully than patients with the typical benign form. The ultrastructural features of parathyroid carcinoma have been described [69-71]. In establishing the diagnosis of malignancy, however, electron microscopic investigation did not add significantly to light microscopy [69-71]. In almost all cases of parathyroid carcinoma described the microscopic features were those of the chief cell type. We experienced 2 cases of parathyroid carcinoma composed principally of oxyphilic cells [37]. In those cases, electron microscopic study revealed the typical oxyphilic cells packed with numerous mitochondria.
World J. Surg. Vol. 15, No. 6, Nov./Dec. 1991 DNA Content Analysis
DNA aneuploidy determined by cytometric analysis is a valuable marker of malignancy in some solid neoplasms and is associated with poor prognosis of the diseases. In other endocrine glands such as the thyroid and adrenal glands, analysis of the DNA content has successfully differentiated rapidly growing malignancies with poor prognosis from less aggressive lesions with similar histologic features. Recently, a few systematic studies on the occurrence of DNA aneuploidy in parathyroid carcinoma have appeared in the literature [72-75]. Levin and associates [73] found, by static cytometry, that 4 of 9 parathyroid carcinomas had an aneuploid pattern, whereas none of 32 adenomas showed an abnormal DNA pattern. We performed a flow cytometric study using paraffin-embedded specimens of parathyroid lesions from 49 patients, which included 14 primary and 11 locally recurrent or metastatic lesions from 16 carcinoma patients [74]. In our study, there was no difference in ploidy patterns between the primary and recurrent lesions of the carcinomas and in 5 (31%) cases the carcinomas expressed aneuploidy. These 2 studies show that unequivocal aneuploidy is significantly associated with malignancy of the parathyroid tumors. A recent flow cytometric analysis of parathyroid tumors using fresh material confirms that parathyroid carcinomas are more apt to be aneuploid than are adenomas, and determination of the DNA ploidy pattern is a valuable adjunct to the histologic diagnosis of parathyroid carcinoma [76]. Our previous study also suggests that the aneuploid parathyroid carcinomas tend to have a greater potential of distant metastasis and poorer prognosis [74]. In contrast to these observations, some authors state that DNA aneuploidy occurs commonly in parathyroid adenomas and has no role in histopathologic diagnosis [72, 77]. Further studies will clarify the significance of the DNA content of parathyroid tumors. Natural History
Local invasion of adjacent structures by parathyroid carcinoma was present at the initial operation in 38 patients in the current review of 163 cases. The thyroid gland was most commonly involved (24 cases), followed by the recurrent nerve (6 cases), the strap muscle, the esophagus, and the trachea. Cervical lymph nodes dissected at the initial operation were positive for metastasis in 7 patients, including 2 in our series [8, 9, 12, 31, 38]. Distant metastasis was present at the time of the initial surgery in 3 patients [11, 56, 76]. Following the initial operation, persistent HPT occurred in 7 patients and 60 patients experienced recurrence of parathyroid carcinoma. The mean interval between the initial operation and the first recurrence was 2.6 years, but the interval was >7 years in 4 patients. Usually patients with recurrent parathyroid carcinomas manifest hypercalcemia from the release of PTH from the recurrent tumor. It is worth noting, however, that in 2 patients metastatic parathyroid carcinomas were clinically nonfunctioning [41, 46]. The 2 patients had HPT clinically and biochemically at the initial operation. Of the 163 patients in this review, lymph node metastasis occurred in 28 (17%) patients, the most common site being the neck (23 cases), followed by the mediastinum (10 cases). Distant metastasis appeared in 41 (25%) patients, in the lung (25
T. Obara and Y. Fujimoto: Parathyroid Carcinoma
5 ~tl ~ 4
741
9 Lymphaticmetastasis I-I Distantmetastasis
I
n
3 ~
2
0 0
1
2
3
4
5
6
7
8
9
1 0 11
12 13 14 15 16 17 18 19 20
Number of Years
Fig. 1. Interval between the initial operation and the first clinical manifestation of metastasis in patients with parathyroid carcinoma.
cases), bone (9 cases); liver (6 cases), and pancreas (3 cases). There was a wide diversity in the interval between the initial operation and manifestation of metastasis (Fig. 1). Three patients in our series had evidence of metastasis at the initial operation. In contrast, another patient, who had an oxyphilic cell carcinoma [37], developed local recurrence and subsequent pulmonary metastasis, 6 years and 19 years after the initial operation, respectively. Follow-up information after the initial operation was available from the reports on 107 patients. Thirty-seven (34.6%) patients died; 2 of parathyroid disease that was not treated by surgery, 30 of recurrent or persistent hypercalcemia, and 5 from unrelated disease. For the patients who died of persistent or recurrent HPT, the average duration after the initial operation was 6.6 years (range, 1 month to 17 years). Seventy-one patients were alive; 45 showed no evidence of recurrent disease during the mean foll0w-up period of 4.6 years (range, 1 month to 19 years) and 26 had recurrence but have survived for an average approximately 7 years. One of the patients who underwent aggressive surgery to remove multiple recurrent lesions was alive 25 years after the initial operation [26]. Treatment
The most effective treatment of parathyroid carcinoma remains surgical. Unquestionably, failure to eradicate the carcinoma at the first operation often leads to repeated local recurrence or distant metastasis, and ultimate death of the patients with recurrent carcinoma is inevitable. The initial e n b l o c resection, avoiding rupture of the tumor capsule and spillage of tumor cells, represents the best chance for cure. Of 37 patients who were alive more than 1 year after surgery without recurrence of the disease, 26 (70%) patients had undergone e n b l o c resection of the tumor at the time of the initial operation. In Wang's series of 28 patients with parathyroid carcinoma, 50% were cured by e n b l o c resection [38]. In a neck operation, a large collar incision and a transverse section of the strap muscles provide a wide operative field. After the thyrOid and parathyroid glands are exposed, the anteromedial wall of the ipsilateral common carotid artery is freed from surrounding tissue along its entire length. The recurrent laryngeal nerve is then exposed at its most proximal end in the lower neck. An attempt should be made to do an e n
b l o c resection, which usually requires thyroid lobectomy and excision of paratracheal alveolar tissue, lymph nodes, and the thymic tongue. If the recurrent laryngeal nerve is involved, sacrifice of the nerve is necessary. There has been some controversy regarding the necessity of radical neck dissection. Holmes and colleagues [3] advocate prophylactic radical neck dissection at the initial operation. Currently, however, most surgeons reserve radical neck dissection for patients with grossly enlarged lymph nodes, patients with extensive local invasion, and patients with local recurrence [8; 11, 31, 38]. Although the reported incidence of cervical lymph node metastasis is
