Level III and IV soft tissues, superior mediastinal contents, overlying ... mediastinal dissection, and extended left paratracheal ... Anatomie Pathologique. 1933 ...
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Parathyroid Carcinoma: Evaluation and Interdisciplinary Management Gary L. Clayman, M.D., D.D.S.1 Hernan E. Gonzalez, M.D., Ph.D.2 Adel El-Naggar, M.D., Ph.D.3 Rena Vassilopoulou-Sellin, M.D.4 1
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
2
Section of Surgical Oncology–Head and Neck Surgery, Facultad de Medicina Pontificia Universidad Catolica de Chile, Santiago, Chile.
3
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
4
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
BACKGROUND. A review of recent reports found a distinct clinical behavior pattern in the rare clinical entity of parathyroid carcinoma, although to the authors’ knowledge information on oncogenetic changes, prognostic factors, and the potential benefits of adjuvant therapy remain fragmented and scarce. In this report, a composite review of the literature and The University of Texas M. D. Anderson Cancer Center (M. D. Anderson) experience are presented using the presentation of a patient to illustrate critical issues in the evaluation and interdisciplinary management of patients who are afflicted with this disease.
METHODS. The current study reflects a retrospective case review of patients who were diagnosed with parathyroid carcinoma, treated, and followed at M. D. Anderson from 1983 to 2002. To assure standardization of pathologic diagnosis as well as evaluations and interdisciplinary management, the investigators reviewed all cases using predetermined criteria within their specialties. RESULTS. It is interesting to note that M. D. Anderson data showed classic pathologic features that were not always present in all parathyroid carcinomas (at most, some features were noted in 37% of patients). Other results of interest indicated local recurrence rates that appeared lower if adjuvant radiation was applied after initial surgery, independent of the type of surgery or disease stage. In the authors’ experience, 70% of patient’s tumors exhibited local invasion, although their 5-year survival rate of 85% was consistent with that reported previously, and their 10-year survival rate was somewhat higher at 77%. CONCLUSIONS. Parathyroid carcinoma is a rare clinical entity that requires interdisciplinary evaluation and management. Comprehensive surgical excision of parathyroid carcinomas with verification of normalization of intraoperative parathyroid hormone levels should be sought. Cancer 2004;100:900 –5. © 2004 American Cancer Society.
KEYWORDS: adjuvant radiation therapy, head and neck, comprehensive surgical excision, parathyroid carcinoma.
P Address for reprints: Gary L. Clayman M.D., D.D.S., Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 441, Houston, TX; Fax: (713) 794-4662; E-mail: gclayman@ mdanderson.org Received December 2, 2003; revision received December 8, 2003; accepted December 9, 2003. © 2004 American Cancer Society DOI 10.1002/cncr.20089
arathyroid carcinoma is a rare neoplasm that reportedly accounts for ⬍ 1% of cases of primary hyperparathyroidism.1– 4 de Quevain5 described this entity first in 1904 in a patient who presented with a nonfunctioning lesion. Subsequently, in 1933, Sainton and Millot6 described the first functioning parathyroid carcinoma. Although parathyroid carcinoma is an uncommon disease, a growing number of clinical reports have established a rather distinct pattern of clinical behavior. However, our current knowledge regarding the oncogenetic changes, prognostic factors, and potential benefits of adjuvant therapy remain scarce. Thus, our ability to establish more rational therapeutic strategies is limited. The objectives of this report were to review the molecular, pathologic, and clinical features of parathyroid
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carcinoma and to discuss the role of adjuvant radiation therapy using a clinical case to illustrate our management strategies.
MATERIALS AND METHODS This study reflects a review of literature that includes our retrospective case review of patients who were diagnosed with parathyroid carcinoma, treated, and followed at The University of Texas M. D. Anderson Cancer Center (M. D. Anderson) from 1983 to 2002.7 To assure standardization of pathologic diagnoses as well as of their evaluations and interdisciplinary management, our investigators reviewed all cases using predetermined criteria within their specialties. In addition, the retrospective chart review and accompanying waivers of consent were reviewed and approved by the Institutional Review Board. We abided by all associated rules and regulations in the conduct of the current study.
RESULTS AND DISCUSSION Pathology The pathologic diagnosis of parathyroid carcinoma, in some patients, begins intraoperatively with the finding of an indurated mass invading surrounding structures, which may include the strap musculature, the ipsilateral thyroid lobe, and the muscularis of the esophagus, trachea, and/or recurrent laryngeal nerve.8 Parathyroid carcinomas tend to be localized in the inferior parathyroid glands.7,9,10 Important in establishing surgical management approaches, metastatic lymphadenopathy was never observed in our 20-year experience at M. D. Anderson at the time of the initial presentation of untreated patients.7 Macroscopically, whereas parathyroid adenomas tend to be soft, oval, and brownish-red to tan in appearance, pathologic specimens of parathyroid carcinomas tend to be larger in size (often ⬎ 3 cm), firm in consistency, lobulated, and have a dense, fibrous capsule. Nevertheless, some parathyroid carcinomas are small and localized when resected, presenting a challenge to the pathologist. Histologic features for parathyroid carcinoma have been described by Shantz and Castelman2 and include 1) uniform sheets of cells arranged in a lobulated fashion with intervening fibrous trabeculae; 2) capsular and/or vascular invasion; and 3) the presence of mitotic figures, which should be differentiated clearly from those observed in endothelial cells. In our recent analysis of 27 patients with parathyroid carcinoma, fibrous bands, mitosis, and vascular invasion were observed individually in 37% of patients. Capsular invasion was observed in 26% of patients, and trabeculae and lymphatic invasion in were observed in only 11% of patients.7
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These findings, together with those from the other authors cited, highlight the fact that those “classic pathologic features” are not always present in parathyroid carcinoma.11 Furthermore, mitotic figures and trabecular architecture also may be observed in parathyroid adenomas.11
Molecular Oncogenesis Several oncogenes and tumor suppressor genes have been linked to parathyroid carcinoma. The loss of a region on chromosome 13 has been reported by several authors.12–14 This deletion contains the coding regions for the retinoblastoma (RB) and hereditary breast carcinoma susceptibility gene (BRCA2) tumor suppressor genes. Furthermore, immunohistochemical studies also have shown loss of RB immunostaining in parathyroid carcinoma.15,16 However, Shattuck et al.17 recently reported the absence of tumor-specific somatic mutations in RB and BRCA2 genes, suggesting that they are unlikely to act as classic tumor suppressor genes in the pathogenesis of parathyroid carcinomas. Therefore, although reduced expression of these genes may participate in parathyroid malignant transformation, 13q loss warrants further investigation. A more recently described tumor suppressor is the HRPT2 gene, which is associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome.18 Somatic mutations of this gene were found in four of four sporadic parathyroid carcinomas.19 HRPT2 is a ubiquitously expressed, evolutionarily conserved gene. Its inactivation is involved directly in predisposition to HPT-JT and in the development of some sporadic parathyroid tumors. It has been proposed that HRPT2 mutations constitute an early event that may lead to parathyroid malignancies, and intragenic mutations of HRPT2 may be a marker of malignant potential in both familial and sporadic parathyroid tumors.19 It has been shown that the cyclin D1 or parathyroid adenoma 1 (PRAD1) oncogene is over-expressed frequently in parathyroid carcinoma, and it also has been proposed that PRAD1 plays an important role in the malignant transformation of parathyroid carcinomas.20,21 Further understanding of the oncogenetic changes in parathyroid neoplasms will provide better tools for diagnosis and ultimately may allow for the development of more rational biologic-targeted therapy.
Medical Management The morbidity and mortality associated with parathyroid carcinoma generally are due to parathyroid hormone (PTH) secretion and hypercalcemia rather than the tumor burden itself. Treatment modalities for hy-
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percalcemia, especially in patients with unresectable disease or without measurable disease, become of utmost importance. Conventional treatment with intravenous fluids, diuretics, and antiresorptive agents (such as bisphosphonates, gallium, or mithramycin) help to control or ameliorate the hypercalcemia. However, therapies like calcimimetic agents that focus on decreasing PTH secretion may be better at preventing complications and improving survival in patients with no curable disease.22
Surgical Management Patients with a preoperative suspicion of parathyroid carcinoma based on clinical and/or radiographic evidence of soft tissue extension should undergo a comprehensive soft tissue resection. This should include a thyroid lobectomy and excision of the strap musculature, the paratracheal fibrolymphatic compartment, and adjacent soft tissues, as required, without sacrifice of a normally functioning, recurrent laryngeal nerve unless it is involved circumferentially by malignancy. Portions of the sternocleidomastoid muscle also may be resected with the neoplasm.23,24 Comprehensive lymphadenectomy is not indicated except in the local area to achieve three-dimensional excision of the primary malignancy. Therefore, dissections of cervical lymphatic Levels I, II, or V rarely are indicated in these patients. Large neoplasms may include contents of cervical Levels III or IV based on the location of the primary tumor. The carotid artery should be identified and spared. Intraoperative analysis of intact PTH is recommended, especially in surgically naı¨ve patients, because significant reduction of PTH should be sought and observed. In patients with extensive soft tissue extension, normal values of intact PTH may not be observed intraoperatively, and the decrease may not be as rapid as expected compared with benign parathyroid disorders (15–30 minutes).
Adjuvant Radiotherapy In selected patients, adjuvant radiation therapy appears to decrease the local recurrence rate effectively. Radiation therapy reportedly improves the disease free interval, especially in high-risk patients.24 In the M. D. Anderson experience, the local recurrence rate appears to be lower if adjuvant radiation is applied after initial surgery, independent of the type of surgery and disease stage. For example, although it may be expected that patients with carcinoma confined to the gland (localized) would be less likely to develop recurrent disease, five of eight patients who did not receive postoperative radiation therapy did develop recurrences, including the one patient who underwent
comprehensive resection. However, it also must be realized that, in circumstances in which a parathyroid carcinoma is excised as though it were an adenoma (removal of the gland only, sparing all surrounding vascular and soft tissue structures), oncologic removal with margin is not achieved, and the risk of local recurrence will be increased. In the same light, although it may be expected that patients with locally invasive carcinomas would be more likely to develop recurrent disease, only 6 of 18 patients developed recurrences in our series: 3 patients after undergoing complete resection and 3 patients after undergoing comprehensive resection. It should be noted that only one of six patients who received adjuvant radiation therapy in this group had a recurrence that was independent of the extent of surgery. Although the small numbers of patients precluded quantitative analyses, it is intriguing to suggest that adjuvant radiation therapy may play an important role in local disease control for patients with parathyroid carcinomas.
Staging To our knowledge, there are no accepted staging criteria for parathyroid carcinoma. The usual tumorlymph node-metastasis (TNM) staging system cannot be applied to this disease for two reasons. First, parathyroid carcinoma is not a disease that frequently metastasizes to lymph nodes; and, second, tumor size does not appear to play a role in prognosis.22,25 In our patients and studies, we choose to use staging criteria based on clinical and histopathologic invasiveness of the tumor. In our experience, 70% of tumors exhibited local invasion, similar to the Princess Margaret Hospital experience.24 Whether this represents a referral bias to tertiary cancer referral centers or a true representation of the disease is unclear. We did not demonstrate a relation between initial extent of disease, regional invasiveness, and likelihood of recurrence. This may have been because of the small number of patients with this disease or, indeed, may reflect the unusual biology of this disease.
Survival Parathyroid carcinoma is a disease with an often indolent but progressive course. Our experience suggests that younger males (age ⬍ 45 years) who present with higher calcium levels (⬎ 13 mg/dL) tend to have more aggressive disease processes. Our 5-year survival rate of 85% was consistent with the rates from previous reports, but the 10-year survival rate was somewhat higher at 77%.3,26 Because the data were derived only from patients who were diagnosed in the past 20 years, the difference in long-term survival may relate
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FIGURE 1. Axial computed tomography scan of the neck with intravenous contrast showing an ill-defined mass involving the left thyroid lobe, lateral displacement of the carotid artery and internal jugular vein, and probable soft tissue extension into the paraesophageal muscularis.
to improvements in supportive medical care in general and, more specifically, in the control of hypercalcemia.
Representative Case Presentation Although parathyroid carcinoma may have distinct clinical features, it is not uncommon to arrive at the diagnosis intraoperatively or postoperatively. A high likelihood of suspicion should exist when evaluating patients who have PTH levels ⬎ 500 pg/mL and radiographic or ultrasonographic evidence of soft tissue extension. The following representative case illustrates these issues and demonstrates the interdisciplinary evaluation and management of these patients.
Patient I An African-American female, age 44 years, from the southeastern U.S. was referred with a preliminary diagnosis of medullary thyroid carcinoma. Her history dated back several months with a chief complaint of a nonpainful left lower neck mass, without complaints of changes in quality of voice or swallowing. Her ultrasound revealed a solid left thyroid mass and a benign-appearing cyst of the right thyroid lobe. Fineneedle aspiration cytology revealed a pleomorphicappearing lesion, which was chromagranin positive and cytokeratin negative. Her family history was negative for thyroid malignancies and endocrine disorders. She lacked symptoms of flushing or diarrhea. Physical examination revealed a left thyroid bed mass
FIGURE 2. (A) Intraoperative photograph of the comprehensive resection performed in the patient. The sternohyoid and sternothyroid strap muscles and the fascia surrounding the carotid artery and jugular vein been have removed in continuity with the paratracheal mass with thyroid invasion. Paraesophageal muscularis and pharyngeal constrictors also are resected. The recurrent laryngeal nerve, carotid artery, and internal jugular vein (IJV) are identified. (B) Parathyroid carcinoma comprehensive resection specimen prior to inking of margins. Level III and IV soft tissues, superior mediastinal contents, overlying strap musculature, and total thyroidectomy are demonstrated.
that measured 4 cm in cephalocaudad dimension and that was tethered to the tracheoesophageal apparatus. A computed axial tomography (CT) scan of the head and neck is shown in Figure 1. No CT or ultrasonographic evidence of cervical adenopathy was noted. Other systemic imaging was reviewed without evidence of neoplasia. Serologies showed a serum calcium level of 13.4 gm/dL, a calcitonin level of 18 pg/mL, a chromagranin A level 74 ng/mL, and a nondetectable level of carcinoembryonic antigen. It was noted that the patient was well hydrated and was managed promptly with biphosphonate. Laboratory
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FIGURE 3. (A) Carcinoma cells with intracytoplasmic immunostaining strongly positive for parathyroid hormone. (B) Cellular anaplasia and sarcomatoid transformation in hematoxylin and eosin staining. (C) Pathologic demonstration of vascular invasion of parathyroid carcinoma. studies for repeat serum calcium, PTH, and PTH-related peptide (PTHRP) were requested. Further analysis of her fine-needle aspiration biopsy was performed despite the scant nature of the specimen, including PTH and calcitonin immunohistochemical staining, both of which were negative, producing a presumptive fine-needle aspiration cytologic diagnosis of neuroendocrine neoplasm of thyroid favoring medullary thyroid carcinoma. The absence of PTHRP detection suggested that the hypercalcemia was not a result of hypercalcemia of malignancy. The preoperative intact PTH level was 659 pg/mL. The differential diagnosis included a neuroendocrine tumor of the thyroid as well as a parathyroid carcinoma. In light of these findings, surgery clearly was indicated independent of the two potential diagnoses. Figure 2A demonstrates the surgical defect of the total thyroidectomy and the left Level IV and V dissection, superior mediastinal dissection, and extended left paratracheal dissection. The resultant macroscopic pathologic specimen is shown in Figure 2B. Intraoperative PTH assays revealed a preincision PTH level of 529 pg/mL, a 15-minute postexcision level of 29 pg/mL, and a 30-minute postexcision level of 15 pg/mL. Final pathologic diagnosis suggested neuron-specific enolase and PTH positive carcinoma, consistent with
parathyroid carcinoma (Fig. 3A–C). The 12 surrounding cervical lymph nodes all were negative for metastases. Soft tissue extension into the paraesophageal muscularis, pharyngeal muscularis, and strap muscles was seen.
Summary We completed both a comprehensive literature review and a retrospective analysis of our 20-year history of patients with parathyroidism at M. D. Anderson. Through this report, we are able to provide added pattern-specific information on the interdisciplinary evaluation and management of this disease. In the future, a more thorough molecular understanding of these malignancies may provide the potential for more directed therapeutic strategies.
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