Atypical Parathyroid Adenoma Research Articles

Immunohistochemical Expression of E‐Cadherin in Atypical Parathyroid Adenoma

Atypical parathyroid adenoma (APA) is a rare entity, sharing clinical symptoms like solid palpable mass in the neck, laboratory changes with very high serum calcium and parathyroid hormone levels, and some histopathological features with parathyroid carcinomas (PC). However, clinical behavior of APA seems to comply with benign parathyroid tumors (PA). There is some evidence that loss of the membranous staining pattern of E-Cadherin (E-Cad) suggests a key role of epithelial mesenchymal transition in the tumorigenesis of PC. Thus, the aim of this study was to compare clinical and surgical characteristics and immunohistochemical expression of E-Cad in APA, PC, and PA. Data of patients who underwent surgery for primary hyperparathyroidism (pHPT) between 1985 and 2010 were retrospectively evaluated. All data were analyzed with special regard to distinctive criteria of APA, including trabecular growth, broad fibrous bands, nuclear atypia, mitosis, pseudocapsular invasion or strong adherence to the surrounding tissue, and potential invasive growth of a grossly altered and enlarged parathyroid gland. In addition, laboratory and clinical data were evaluated and additional immunohistochemical staining with E-Cad was performed in suspicious APA patients with available tissue. In 68 patients (39 female, 29 male), the parathyroid tumor was suspicious for APA. In 46 patients, a bilateral cervical exploration was performed. 15 patients underwent an en bloc resection including a hemithyroidectomy and lymphonodular dissection of the ipsilateral central compartment due to the malignant macroscopic aspect of the parathyroid. In seven patients, a focused parathyroid resection was done. The available parathyroid tissue of 38 APA patients was immunopositive for membranous E-Cad staining. During follow-up, only one patient with a successful initial surgery suffered from recurrent pHPT due to another solitary PA 10 years after initial surgery but without evidence of malignancy. In contrast to PC, parathyroid tumors suspicious for APA are characterized by a strong membranous E-Cad staining and, like PA, by a benign clinical course.

Evaluation of clinical and biochemical features of patients with atypical parathyroid adenoma: a retrospective study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract No. 400 - Parathyroid venous sampling: indications, techniques, and outcomes

-To define the indications for parathyroid venous sampling (PVS).-To provide a detailed pictoral review of the relevant parathyroid venous anatomy necessary for PVS.-To provide a step by step technical guideline for performing successful PVS, including use of pre-procedural imaging, wire/catheter choice, localization of sampling and address challenges which may arise during these steps.-Provide a case based review of the imaging findings based on our institution’s experience.-Address and review the current role of PVS in perioperative management of pHPT.-Briefly discuss outcomes and concordance with surgical pathology. Endocrine venous sampling continues to emerge as an important tool for assisting in the diagnosis of various endocrine disorders. Specifically, the role of selective venous sampling in hyperparathyroidism continues to gain popularity due to the ability to more accurately localize atypical parathyroid adenomas when compared to more conventional non-invasive imaging techniques, particularly in patients requiring re-operation. PVS may also be an extremely useful tool when all other imaging findings remain negative or discordant in the setting of primary hyperparathyroidism. Although PVS remains a relatively rare procedure, interventional radiologists should be aware of the indications, technical factors and challenges related to the procedure. Procedure details will include catheter tips and tricks used to select the parathyroid veins. Venous samples should be obtained from several different veins including superior and inferior thyroid, internal jugular, innominate and intercostal veins. PTH gradients assist in localization of parathyroid adenomas. A correlation between surgical pathology and parathyroid venous sampling is made. Parathyroid venous sampling is an effective tool in the evaluation of parathyroid adenoma, particularly in the setting of hyperparathyroidism and negative non-invasive imaging. Interventional radiologists should become familiar with this procedure as it may be a last resort imaging modality.

Atypical Parathyroid Adenoma Complicated with Protracted Hungry Bone Syndrome after Surgery: A Case Report and Literature Review.

Hungry Bone Syndrome refers to the severe and prolonged hypocalcemia and hypophosphatemia, following parathyroidectomy in patients with hyperparathyroidism. We present the case of an eighteen-year-old woman with a four-year history of hyporexia, polydipsia, weight loss, growth retardation, and poor academic performance. The diagnostic work-up demonstrated primary hyperparathyroidism with hypercalcemia of 13.36 mg/dL, a PTH level of 2551 pg/mL, bone brown tumors, and microcalcifications within pancreas and kidneys. Neck ultrasonography revealed a parathyroid adenoma of 33 × 14 × 14 mm, also identified on 99Tc-sestamibi scan. Bone densitometry showed decreased Z-Score values (total lumbar Z-Score of −4.2). A right hemithyroidectomy and right lower parathyroidectomy were performed. Pathological examination showed an atypical parathyroid adenoma, of 3.8 g of weight and 2.8 cm in diameter. After surgery she developed hypocalcemia with tetany and QTc interval prolongation. The patient required 3 months of oral and intravenous calcium supplementation due to Hungry Bone Syndrome (HBS). After 42 months, she is still under oral calcium. Usually HBS lasts less than 12 months. Therefore we propose the term “Protracted HBS” in patients with particularly long recovery of 1 year. We present a literature review of the diagnosis, pathophysiology, and treatment of HBS.

Modern Experience with Aggressive Parathyroid Tumors in a High-Volume New England Referral Center

Parathyroid carcinoma (PTCA) is an exceptionally rare malignancy, often with a clinical presentation similar to that of benign atypical parathyroid adenoma. Its low incidence portends unclear guidelines for management. Accordingly, thorough examination of clinical and pathologic variables was undertaken to distinguish between PTCA and atypical adenomas. This was a retrospective analysis of a prospective database at a tertiary academic referral center. Between September 2001 and April 2014, 3,643 patients were referred for surgical treatment of PHPT. Of these, 52 harbored aggressive parathyroid tumors: parathyroid carcinomas (n=18) and atypical adenomas (n=34). We analyzed the surgical and clinicopathologic tumor characteristics, and did a statistical analysis. We measured preoperative and intraoperative variables, and postoperative and pathologic outcomes. Parathyroid carcinoma patients present with significantly increased tumor size (3.5 cm vs 2.4 cm, respectively; p=0.002), mean serum calcium (13.0 vs 11.8 mg/dL, respectively; p=0.003) and intact parathyroid hormone (iPTH) levels (489 vs 266 pg/mL, respectively; p=0.04), and a higher incidence of hypercalcemic crisis, compared with patients with atypical adenomas (50% vs 19%, respectively; p=0.072). Parathyroid carcinoma more frequently lacks a distinct capsule (47.1% vs 12.9%, respectively; p=0.03) and adheres to adjacent structures (77.8% vs 20.6%, respectively; p=0.017). Of note, there was no significant difference in loss of parafibromin expression between groups. Clinical distinction between PTCA and atypical adenomas is of critical importance in determining the appropriate extent of resection and follow-up. Loss of parafibromin has not been shown to distinguish between PTCA and atypical adenoma; clearer definition of clinicopathologic criteria for PTCA is warranted and may lead to improved postoperative management.

Understanding the Genetic Basis of Parathyroid Carcinoma

Parathyroid carcinoma has always been difficult to diagnose pathologically. In fact, most parathyroid tumors which are classified as carcinoma do not recur after excision, and most parathyroid tumors which actually metastasize or recur repeatedly in the neck are not recognized as malignant at first presentation. In 2002, germline HRPT2 (also known as CDC73) mutation was reported as the cause of hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant hereditary tumor syndrome associated with a lifetime risk of parathyroid carcinoma approaching 15 %. Subsequently, bi-allelic inactivation or mutation of HRPT2 has been reported in the majority of parathyroid carcinomas that actually behave in a malignant manner but very rarely in sporadic benign parathyroid disease. Furthermore, germline testing for HRPT2 mutation in patients presenting with parathyroid carcinoma often identifies occult HPT-JT syndrome even in the absence of a family history or other syndromic manifestations. HRPT2 mutation testing is not readily available, and loss of expression of parafibromin (the protein encoded by HRPT2) as determined by immunohistochemistry has been used as a surrogate marker of HRPT2 mutation. Immunohistochemistry for parafibromin can be technically difficult and has been deployed by different investigators with variable enthusiasm and success. However, proponents have found immunohistochemistry for parafibromin useful to definitively confirm a pathological diagnosis of parathyroid carcinoma, predict a worse outcome in definite parathyroid carcinomas, triage formal genetic testing for HPT-JT syndrome, and predict the outcome of histologically atypical parathyroid adenomas.

An Interesting Case of Life-Threatening Hypercalcemia Secondary to Atypical Parathyroid Adenoma versus Parathyroid Carcinoma.

Context. Severe hypercalcemia is a life-threatening condition. Atypical parathyroid adenoma and parathyroid carcinomas are uncommon causes which can be difficult to differentiate. Objective. We report a case of a 36-year-old male with very high serum calcium due to a possible atypical parathyroid adenoma versus parathyroid carcinoma. Case Illustration. A serum calcium level of 23.2 mg/dl was noted on admission. He was initially treated with IV hydration, pamidronate, and salmon calcitonin to lower his calcium levels. He also underwent a surgical en bloc resection of parathyroid mass. Pathology showed a mixed picture consistent with possible atypical adenoma versus parathyroid carcinoma. However, due to the possible involvement of the recurrent laryngeal nerve, parathyroid carcinoma was more likely. Also after operation the patient developed hungry bones syndrome and his calcium was replaced vigorously. He continues to be on calcium, vitamin D, and calcitriol supplementation. Results. A review of the literature was conducted to identify previous studies pertaining to parathyroid adenomas and parathyroid cancer. Conclusion. We thereby conclude that hypercalcemia requires very careful monitoring especially after operation. Also it can be very difficult to distinguish between atypical parathyroid adenomas and parathyroid carcinomas as in our case and no clear cut guidelines yet exist to differentiate the two based on histology.

Concerrent follicular adenoma and multiple ectopic parathyroid glands with an atypical parathyroid adenoma

Ectopic intrathyroid parathyroid glands may be the cause of primary hyperparathyroidism, parathyroid adenoma or carcinoma. Intrathyroid parathyroid tumors are not common lesions and are difficult to diagnose, both clinically and histologically; especially when the patient has no hyperparathyroid symptoms. A 45-year-old Thai woman was treated as having non-toxic goiter for 20 years. She was diagnosed with papillary carcinoma of the thyroid gland with lung metastases. During investigations of her hemoptysis and right lung atelectasis, incidental bilateral lobe enlargement was detected of her substernal thyroid gland, with multiple hypodense nodules on both lobes. Total thyroidectomy was performed after cytological studies failed to give a definite diagnosis. She did not have hyperparathyroid symptoms and her serum calcium level prior to surgery was normal (8.4mg/dL, normal 8.4-10.2 mg/dL). The surgical specimen revealed concurrent follicular adenoma with degenerative changes (left lobe, 5.5 × 7.0 cm), multiple ectopic parathyroid (right lobe, 0.5 × 0.7 cm) and atypical parathyroid adenoma (right lobe, 2.5 × 3.5 cm). The occurrence of ectopic lesions is explainable on an embryologie basis. Non-functioning parathyroid adenoma is uncommon and coexisting thyroid tumors are rare.

Identification and Functional Characterization of Three NoLS (Nucleolar Localisation Signals) Mutations of the CDC73 Gene

Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.

Negative Parafibromin Staining Predicts Malignant Behavior in Atypical Parathyroid Adenomas

The histopathological criteria for carcinoma proposed by the World Health Organization (WHO) are imperfect predictors of the malignant potential of parathyroid tumors. Negative parafibromin (PF) and positive protein gene product 9.5 (PGP9.5) staining are markers of CDC73 mutation and occur commonly in carcinoma but rarely in adenomas. We investigated whether PF and PGP9.5 staining could be used to predict the behavior of atypical parathyroid adenomas--tumors with atypical features that do not fulfill WHO criteria for malignancy. Long-term outcomes were compared across four groups: group A, WHO-positive criteria/PF-negative staining; group B, WHO(+)/PF(+), group C; WHO(-)/PF(-); and group D, WHO(-)/PF(+). Eighty-one patients were included in the period 1999-2012: group A (n = 13), group B (n = 14), group C (n = 21), and group D (n = 33). Mortality and recurrence rates, respectively, for group A were 15 and 38%, for group B 7 and 36%, for group C 0 and 10%, and for group D 0 and 0%. The PGP9.5(+) ratios for groups A to D were 85, 78, 71, and 12%, further informing prognosis. Five-year disease-free survival for groups A to D were 55, 80, 78, and 100%, respectively. Tumor recurrence was significantly associated with PF (p = 0.048) and PGP9.5 (p = 0.003) staining. Although WHO criteria are essential to differentiate parathyroid carcinoma from benign tumors, the presence of negative PF staining in an atypical adenoma predicts outcome better, whereas PF-positive atypical adenomas do not recur and can be considered benign. PF-negative atypical adenomas have a low but real recurrence risk and should be considered tumors of low malignant potential.

Atypical parathyroid adenoma presenting with severe hypercalcemia: a case report

Atypical parathyroid adenoma presenting with severe hypercalcemia: a case report

Differential Diagnosis of Atypical Parathyroid Adenoma and Parathyroid Carcinoma in a Case With Severe Hypercalcemia

Atypical parathyroid adenoma is among the tumors diagnosed difficultly and including some histological features of parathyroid carcinoma. In literature, no definite criteria have been considered to be present to distinguish atypical parathyroid adenoma preoperatively from parathyroid carcinoma. A 65-year-old woman was admitted to our clinic with complaints of arthralgia, myalgia, fatigue and loss of appetite. She had severe hypercalcemia (serum calcium 17.2 mg/dL) and hypophosphatemia (serum phosphate 1.9 mg/dL) along with an elevated intact parathyroid hormone level of 879 pg/mL. Renal functions were within normal limits. The patient was administered with intravenous hydration and diuretic treatments because of severe hypercalcemia. Six sessions of hemodialysis were performed. In neck ultrasonography, multinodular goitre was detected. Tc- 99m sestamibi scintigraphy revealed a focal involvement at the middle-inferior region of left thyroid lobe. Neck magnetic resonance imagination revealed a nodular lesion in size of 22 × 14 mm at the posterior region of left thyroid lobe. Parathyroidectomy guided by intraoperative gamma probe was performed. The lesion was histopathologically consistent with atypical parathyroid adenoma. In the postoperative period, serum calcium and intact parathyroid hormone levels were decreased as levels of 7 mg/dL and 42.6 pg/mL, respectively. We reported an atypical parathyroid adenoma accompanied by severe hypercalcemia and hyperparathyroidism. J Med Cases. 2013;4(6):357-361 doi: https://doi.org/10.4021/jmc1198w

Ectopic atypical parathyroid lipoadenoma: a rare cause of severe primary hyperparathyroidism

Parathyroid lipoadenomas are a rare and benign variant of parathyroid adenomas that are defined morphologically by an abundance of fat cells. They may be functional with secretion of parathyroid hormone or nonfunctional. We present a case of a parathyroid lipoadenoma in a patient presenting with clinical manifestations of severe primary hyperparathyroidism. Unusual features in this case included the ectopic location of the lipoadenoma in the mediastinum, the significant size of 6.6×3.4cm, and weight of 30.1g. In addition to the large size of this generally benign type of parathyroid neoplasm, histologic findings included focal band-forming fibrosis compatible with the diagnosis of an atypical parathyroid adenoma. In conclusion, this case illustrates a difficult case of an ectopic functioning parathyroid lipoadenoma with chronic sequelae due to severe hyperparathyroidism.

Clinicopathologic Characteristics of Atypical Parathyroid Adenoma in Comparison with Parathyroid Adenoma and Carcinoma

목적 : 일차성 부갑상샘항진증을 일으키는 질환인 부갑상샘종, 비정형 부갑상샘, 부갑상샘 암에 대하여 임상병리학적인 특징을 후향적으로 분석해보고 특히 비정형 부갑상샘의 특징에 대하여 알아보고자 하였다. 대상 및 방법 : 1993년 1월부터 2008년 12월까지 서울대학교병원에서 일차성 부갑상샘항진증으로 부갑상샘 절제술을 시행한 88명의 부갑상샘종 환자와 10명의 비정형 부갑상샘종 환자, 2명의 부갑상샘 암 환자의 의무기록을 후향적으로 분석하였다. 결과 : 비정형 부갑상샘종 군은 남녀 비율이 동일한데에 비하여 부갑상샘종은 여성에서, 부갑상샘 암은 남성에서 호발하였다. 비정형 부갑상샘종 군과 부갑상샘종 군의 평균연령은 비슷하였으나 부갑상샘 암 환자는 두 군에 비하여 낮았다(PA:50.18±15.07yrs, AA: 49.1±13.76yrs, PC: 44.0±18.39yrs, p=0.832). 술전 시행한 혈청 칼슘(PA: 11.90±1.46mg/dl, AA: 11.96±1.48mg/dl, PC: 14.25±2.76mg/dl, p=0.091), 이온화 칼슘(PA: 1.57±0.21mg/dl, AA: 1.54±0.34mg/dl, PC: 2.27mg/dl, p=0.008)에서는 비정형 부갑상샘종 군과 부갑상샘종 군이 비슷하고 부갑상샘 암 환자군은 더 높았다. 술전 부갑상샘호르몬은 부갑상샘 암 환자에서 가장 높았고 비정형 부갑상샘종, 부갑상샘종 환자 순으로 높게 측정되었다(335.30±465.40pg/ml, AA: 992.88±612.30pg/ml, PC: 1221.00±227.69pg/ml, p 결론 : 비정형 부갑상샘종은 임상병리학적 특성상 부갑상샘종과 부갑상샘 암의 중간단계에 위치한다고 할 수 있으며 이에 수술 후 면밀한 추적관찰이 필요하다고 할 수 있다.

Parafibromin and APC as Screening Markers for Malignant Potential in Atypical Parathyroid Adenomas

The identification of parathyroid carcinomas is based upon histopathological criteria in which an invasive growth pattern or distant metastasis is demonstrated. A dilemma arises when tumours present with atypical histopathological features but lack direct evidence of malignancy. Recently, reduced expression or loss of the tumour suppressor proteins parafibromin and adenomatous polyposis coli (APC) has been associated with parathyroid malignancy. We report results from APC and parafibromin expression analyses by immunohistochemistry and Western blot in five cases of atypical adenoma, a single case of carcinoma and 54 adenomas without atypical features. Complete loss of APC immunoreactivity and reduced expression of parafibromin was evident in two of the atypical adenomas and in the parathyroid carcinoma. By contrast, all adenomas displayed APC expression, including two cases with hyperparathyroidism 2 gene (HRPT2) mutations and loss of parafibromin expression. We conclude that loss of APC is a frequent molecular event in atypical adenomas and carcinomas, but not in adenomas. Following verification in an independent material, APC could become a valuable tool when assessing parathyroid tumours in the clinical setting. Furthermore, the molecular resemblance of atypical adenomas with carcinoma concerning parafibromin and APC expression indicates that atypical adenomas should be subjects to watchful follow-up.

Hyperparathyroidism–jaw tumor syndrome: a report of three large kindred

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal disease caused by inactivating germ-line mutations of HRPT2 gene, with subsequent loss of Parafibromin expression. It is characterized by familial HPT, ossifying jaw tumors, and other associated neoplasms. Clinical, histopathological, and genetic features of three large Italian unrelated HPT-JT kindred were assessed. Three different germ-line HRPT2 inactivating mutations were identified. Seventeen affected members and six healthy mutation carriers were found. HPT was diagnosed in virtually all affected patients, at a median age of 36.3 years (range 11-71). In all cases, a single parathyroid involvement was found at surgery, although a metachronous multiglandular involvement causing recurrence after selective parathyroidectomy occurred in 17.6% of cases, after a mean disease-free interval of 13.7 years (range 5-27). Parathyroid carcinoma, atypical parathyroid adenoma, and jaw tumor occurred in one case; uterine involvement in 61.5% of women; other associated neoplasms were thyroid carcinoma (two cases) and renal and colon carcinoma (one case). Immunohistochemistry confirmed the loss of Parafibromin as the distinctive feature of the disease both in parathyroid and uterine tumors. HPT-JT has a frequent single-gland parathyroid involvement and a relatively increased risk of parathyroid carcinoma. The penetrance of the disease is high but incomplete. Regardless of the denomination of the syndrome, jaw tumors occur rarely, while uterine involvement is frequently present. Selective parathyroidectomy may be an effective strategy, but a prolonged follow-up is required because of the risk of recurrences and malignancies. A systematic investigation is also required because of associated malignancies.

Letter 2: Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma (Br J Surg 2007; 94: 566–570)

Letter 2: Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma (<i>Br J Surg</i> 2007; 94: 566–570)

Authors' reply: Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma (Br J Surg 2007; 94: 566–570)

Authors' reply: Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma (<i>Br J Surg</i> 2007; 94: 566–570)

Letter 1: Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma (Br J Surg 2007; 94: 566–570)

Letter 1: Intraoperative diagnosis and treatment of parathyroid cancer and atypical parathyroid adenoma (<i>Br J Surg</i> 2007; 94: 566–570)

Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis?

Parathyroid carcinoma, atypical parathyroid adenoma, and parathyromatosis can be differentiated relatively easily from typical parathyroid adenomas, but distinguishing them from each other is more difficult. A retrospective study of 28 consecutive patients with parathyroid carcinoma, 7 patients with atypical parathyroid adenoma, and 13 patients with parathyromatosis who were treated at the University of California at San Francisco Medical Center between 1966 and 2005 was performed. Patient demographics and clinical characteristics, indication for surgery, intraoperative findings, histopathologic characteristics, disease recurrence or persistence, site of invasion/metastases, and survival were compared in the 3 groups. Parathyroid carcinoma (19 of 28 patients) and atypical adenoma (4 of 7 patients) were significantly more common in men, whereas parathyromatosis was more common in women (10 of 13 patients) (P = .02). A palpable neck mass and hoarseness were almost exclusively present in patients with parathyroid carcinoma. Prior to the first parathyroid surgery, patients with parathyroid carcinoma were found to have higher blood calcium levels (>/=14 mg/dL in 16 of 26 patients [62%]), whereas only 1 of 6 patients with atypical adenoma (17%) and no patients with parathyromatosis were found to have profound hypercalcemia (P < .01). Intraoperatively, patients with parathyroid carcinoma and atypical adenoma presented with single lesions, whereas patients with parathyromatosis had multiple small lesions. Histopathologic findings were well defined in parathyroid carcinoma, but some findings overlapped in the 3 tumors studied. Patients with parathyroid carcinoma often differ from those with atypical parathyroid adenoma or parathyromatosis at the time of presentation because patients with parathyroid carcinoma have more profound hypercalcemia as well as invasive tumors. However, at times it is difficult to distinguish between these conditions both clinically and by final histologic examination.