Biologic basis for the treatment of microscopic, occult well-differentiated thyroid cancer.

BACKGROUND: Management of thyroid microcancer or occult well-differentiated thyroid cancer (OWDTC) is controversial. Our present study compared some clinical features of OWDTC and gross well-differentiated 10-mm thyroid carcinoma (GWDTC), which may offer a basis for treatment policy. METHODS: From 1964 to 2000, 1000 patients underwent thyroidectomy for thyroid cancer. We randomly selected 428 cases for study in which node sampling was carried out in 88% of GWDTC and 60% of OWDTC and who were demographically comparable. All data were obtained by chart review and analyzed by chi-square test. RESULTS: With the maximum limit of 10 mm for defining OWDTC, we found 113 such cases with a mean size of 6.1 mm and 315 GWDTC cases with a mean size of 27.6 mm. The incidence of metastatic nodal disease was 16.8% in OWDTC cases and 25.7% in GWDTC cases (P = .057). Distant metastases occurred in 1 of 113 (0.9%) cases of OWDTC and 11 of 315 (3.5%) cases of GWDTC (P = .149). After a mean follow-up time of 55.8 months, neck metastatic recurrent disease occurred in 3 of 113 (2.7%) cases of OWDTC and 7 of 315 (2.2%) cases of GWDTC (P = .770). OWDTC was found in 11.1% of the GWDTC group undergoing an operation. Multicentricity occurred in 31.9% of OWDTC cases and 35.9% of GWDTC cases (P = .447). No cause-specific death occurred. CONCLUSIONS: One cannot be dogmatic in treatment of microcancer, but one is justified in extending similar treatment principles for OWDTC as in GWDTC, which in our center usually indicates near-total thyroidectomy and consideration for radioactive iodine ablation.

Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer.

Papillary carcinoma (PC) represents the most common malignancy of the thyroid gland. Therefore, the assessment of fine needle aspiration biopsies of thyroid nodules rests heavily on the identification of nuclear features of PC. The ret/PTC oncogene, formed by several gene rearrangements, is specific for PC among thyroid tumors. In this study we examined thyroid aspirates for the presence of ret/PTC gene rearrangements by RT-PCR and Southern hybridization. We prospectively collected thyroid aspirates in Cytolyt solution and prepared slides for cytological examination using the ThinPrep method. All remaining material was then used for nucleic acid extraction with subsequent RT-PCR for the housekeeping gene PGK-1 to ensure ribonucleic acid integrity, for thyroglobulin to ensure the presence of follicular epithelial cells, and for the three most common ret/PTC gene rearrangements (ret/PTC-1, -2, and -3). The results of the first 73 cases with surgical follow-up were correlated with the cytological diagnosis and final histopathology. ret/PTC gene rearrangements were detected in 17 of 33 samples (52%) that were PC on histopathology; the presence of gene rearrangements was confirmed by molecular analysis of corresponding surgically resected frozen tissue. There were no false positives. The identification of ret/PTC gene rearrangements refined the diagnosis of PC in 9 of 15 specimens (60%) that would otherwise have been considered indeterminate and in 2 of 6 that were considered insufficient for cytological diagnosis. The results indicate that RT-PCR for ret/PTC is a specific marker that can be applied to fine needle aspiration biopsies and improves the diagnosis of malignancy when used as an adjunct to traditional cytology.

Correlation of p53 mutations in ThinPrep-processed fine needle breast aspirates with surgically resected breast cancers.

Mutations of the p53 gene are one of the most common genetic changes found in cancer; their presence may be prognostic and even influence treatment for breast cancer. In this study, we investigated whether DNA could be extracted from the residual cells left in ThinPrep-processed breast fine-needle aspirates and whether p53 gene changes could be detected in the DNA. The results were then correlated with DNA extracted from the matched formalin-fixed, paraffin-embedded, surgically resected breast cancer when available. DNA was successfully extracted from 54 of 62 aspirates and all 31 surgical specimens. p53 gene mutations were detected in 10 of the 54 cytology specimens (18.5%) and consisted of base pair substitutions or deletions. Silent or intronic p53 changes were found in five additional aspirates. One of the aspirates had two gene alterations, resulting in a total of six gene changes. Five of these changes were located in introns 6 or 9 and the sixth was a silent (no amino acid change) change in exon 6. p53 Polymorphisms were detected in nine aspirates (16.3%) and were located in codon 47 (one aspirate), codon 72 (six aspirates), and codon 213 (two aspirates). All cases with surgical material available showed identical p53 mutations, alterations, and polymorphisms in the resected tumors compared with those detected in the corresponding aspirates. The results of this study show that DNA suitable for analysis of p53 gene sequence changes can be successfully extracted from ThinPrep-processed breast fine-needle aspirates, and that identical alterations are detected in both the cytology and surgical specimens.

Estrogen and progesterone receptor contents in ThinPrep-processed fine-needle aspirates of breast.

This study was undertaken to assess the potential value of ThinPrep-processed (Cytyc, Boxborough, MA) smears from malignant breast fine-needle aspirates (FNAs) for the determination of estrogen receptor (ER) and progesterone receptor (PR) status. The ER and PR content of 142 malignant FNAs were compared with the results of the surgically excised tumors in which the assay was done by enzyme immunoassay in 97 cases or by immunohistochemistry in 45 cases. Monoclonal antibodies directed against ER-1D5 (Dako, Carpinteria, CA) and PR-1A6 (Dako) were used with the antigen retrieval technique. By using enzyme immunoassay and immunohistochemistry as standards, the overall accuracy for ER was 97% and for PR was 89%. The results of this study show that the ThinPrep smear with microwave antigen retrieval pretreatment is a reliable method and a suitable alternative for hormone receptor analysis in breast carcinoma.

Breast fine-needle aspiration. A comparison of ThinPrep and conventional smears.

Fine-needle aspiration (FNA) of the breast has been used in our institution since 1969. In August 1993, ThinPrep (Cytyc Corp, Boxbotough, MA) processing of breast FNA biopsy specimens was introduced. Comparing conventionally prepared breast FNA specimens (21,193 cases) with ThinPrep processed material (7,903 cases) shows a decrease in the unsatisfactory rate with the ThinPrep processing (29.5% to 27.7%) with no significant change in sensitivity (84.4% vs 86.3%) or positive predictive value (96.5 vs 95.0%). However, there is a slight decrease in specificity (98.6% vs 96.5%) and negative predictive value (91.1% vs 88.0%) with the ThinPrep specimens. The results span 28 years, during which time the breast cancer population has changed, with a higher prevalence of malignancy in the last decade of our study. When the 4 most recent years of conventional cytology are compared with the 4 years of ThinPrep processing, there is no significant difference in diagnostic accuracy. The results of the present study show that the ThinPrep processing technique provides an effective method for preparing breast FNA. specimens.

Rhabdomyosarcoma with rhabdoid-like features.

We describe an unusual case of a rhabdomyosarcoma (RMS) in that it had rhabdoid-like cells histologically and occurred in a female who had undergone bone marrow transplantation for chronic myelogenous leukemia. The tumor was composed of loosely cohesive cells with abundant eosinophilic cytoplasm and exhibited PAS-negative paranuclear inclusions. The tumor cells had positive vimentin, muscle-specific actin, sarcomeric actin and desmin immunoreactivity. Ultrastructurally, the tumor cells contained aggregates of thin and thick filaments. In situ hybridization did not detect human papillomavirus or cytomegalovirus DNA, or EBV DNA or RNA. The tumor fulfilled the current criteria for a diagnosis of RMS; however, it could not be further classified. The tumor appears to have a good prognosis as there has been no evidence of recurrence five years after resection. As this is the first case report, to our knowledge, of this type of tumor following bone marrow transplant, the significance of this association is not yet clear.

Value of electron microscopy and immunohistochemistry in the diagnosis of soft tissue tumors.

Light microscopy alone is often insufficient to type a soft tissue tumor. In this study 142 consecutive soft tissue tumors (benign or malignant), for which both electron microscopy (EM) and immunohistochemistry (IHC) had been performed, were reviewed to assess the contribution of these two modalities to making the final diagnosis. A tentative diagnosis (58 cases) or differential diagnosis (84 cases) was made following light microscopical examination. Ultrastructural and immunohistochemical features were then reviewed. Overall, EM more often contributed to diagnosing the tumor type than IHC (80 vs. 65%), with a statistically significant difference (p = .001). This was most apparent in high-grade sarcomas (grade III); the contribution of the two modalities was similar in benign and low-grade malignant tumors. IHC more often than EM (33% vs 22%) did not provide information to aid in typing of the tumor. However in 47% of the cases in which one of the two modalities was noncontributory, the other technique was helpful in reaching a diagnosis. These findings suggest that both IHC and EM are necessary to properly evaluate soft tissue tumors.

Alveolar soft part sarcoma: review of nine cases including two cases with unusual histology.

AIM: Alveolar soft part sarcoma is a very rare tumour. Nine cases are reviewed in order to identify new aspects of this tumour. METHODS AND RESULTS: The clinical course, histological, immunohistochemical and ultrastructural features of nine cases of alveolar soft part sarcoma were reviewed. Proliferative activity and p53 protein accumulation were assessed immunohistochemically. The patients were aged between 18 and 70 years. In the cases with sufficient follow-up, survival was variable with two patients dying within 5 months and four alive at 4 years. Histologically all tumours had an alveolar component but one case also had a spindle component and another case had a pseudoglandular pattern. Six cases showed desmin immunoreactivity, one was muscle-specific actin positive, two were positive for S100 protein and three were positive for vimentin. MIB-1 immunostaining was seen in up to 35% of cells. Two cases showed p53 protein accumulation. CONCLUSIONS: There appeared to be no correlation between short term survival (4 years or less) and clinical presentation, adjuvant treatment, tumour size, histological grade, vascular invasion by tumour, proliferative index, or p53 protein accumulation. Although unusual, spindle cell or pseudoglandular components can be seen in alveolar soft part sarcoma.

Aneurysmal cyst of soft tissue: report of a case with serial magnetic resonance imaging and biopsy.

We report a case of an extraosseous aneurysmal cyst arising in the left retroclavicular soft tissue of a 29-year-old woman. A magnetic resonance imaging (MRI) scan showed a solid lesion within soft tissue, abutting the clavicle without bone involvement. An incisional biopsy was interpreted as showing osteoclast rich nodular fasciitis with prominent vascularity. A second MRI 5 months later showed intralesional cystic change with areas of increased signal on T2-weighted images, still without any bony defect. The lesion was excised. Histological examination revealed large vascular spaces lined focally by giant cells. The remainder of the lesion was composed of an admixture of spindle cells and osteoclast-like giant cells. The histological and ultrastructural appearance was that of an aneurysmal bone cyst; however, in view of the lack of any bony involvement, a diagnosis of aneurysmal cyst of soft tissue was made. Primary aneurysmal cysts of soft tissue are rare; this is the third well-documented case in the literature, and the first to describe both the MRI appearance and the histological evolution from a solid to multiloculated lesion.

Primary leiomyosarcoma of bone: report of seven cases and review of the literature.

OBJECTIVE: To report seven cases of intraosseous leiomyosarcoma and compare them with the cases in the literature. DESIGN: Retrospective review of histologic, immunohistochemical, and ultrastructural features. Tumors were examined immunohistochemically for proliferative activity and p53 protein accumulation. SETTING: Mount Sinai Hospital, University of Toronto, Ontario, Canada. RESULTS: The histologic grade of the tumors ranged from I to III. All tumors showed vimentin and muscle-specific actin immunoreactivity and smooth muscle differentiation ultrastructurally. Proliferative activity was demonstrated immunohistochemically in five of the seven cases. Only one tumor showed p53 protein accumulation. CONCLUSION: Primary leiomyosarcoma of bone is an aggressive tumor with light microscopic, ultrastructural, and immunohistochemical features similar to leiomyosarcoma of soft tissue. The proliferative activity of these tumors does not appear to correlate with the histologic grade. p53 protein accumulation as detected by immunostaining is not common in these tumors.

Immunocytochemical staining on ThinPrep processed smears.

This study reports our first-year experience in the immunocytochemical staining of specimens prepared by the ThinPrep processor. The avidin-biotin-complex technique was applied to smears of 70 cytological specimens, including fine-needle aspiration samples from various sites (56 specimens), body fluids (13 specimens) and urine (one specimen). The specimens were collected in CytoLyt solution to lyse red blood cells and then resuspended in the processing solution. The smears were made by the processor and fixed in 95% alcohol. The panel of antibodies used included alpha-fetoprotein, carcinoembryonic antigen, cytokeratin, chromogranin A, HMB-45, beta-human chorionic gonadotropin (beta-HCG), Kappa, Lambda, Ki-1, leucocyte common antigen, L26, neuron-specific enolase, 013, prostatic acid phosphatase, prostatic-specific antigen, S100, thyroglobulin, UCHL-1, and vimentin. The various antigens could be easily demonstrated in the ThinPrep smears, except for some lymphoma markers. Nonspecific background staining caused by blood and proteinaceous debris was virtually absent. In general, the monolayer preparation made the interpretation easier than conventional preparations. The only problem with this technique was in the classification of lymphomas where immunotyping was inconclusive. Our preliminary results indicate that ThinPrep smears are suitable for immunocytochemical studies, except for the classification of lymphomas.

Secondary malignancy of the thyroid gland and its management.

BACKGROUND: Secondary cancer of the thyroid gland is widely acknowledged as infrequent but is a persistent problem requiring ongoing awareness, particularly with respect to clinical recognition and treatment. METHODS: From 1978 to 1993, a 15-year period, patients demonstrating secondary involvement of the thyroid gland as a surgical problem were collected and analyzed with regard to pathology, demography, behavior of primary and secondary disease, treatment, and patient outcome. RESULTS: In the 15-year span, 11 patients with secondary involvement of the thyroid gland were recognized, consisting of 3 men and 8 women with primary lesions occurring in oral cavity, esophagus, stomach, colon, pancreas, breast, skin, unknown, kidney, and lung. Needle biopsy produced a 90% malignancy rate but in only half of such cases was the diagnosis specific for secondary malignancy. Eight of 11 underwent palliative surgery, usually total thyroidectomy. No patient survived > 2 years. There was no undue surgical morbidity. One patient died of pulmonary embolus postoperatively. CONCLUSIONS: Secondary cancer of the thyroid is rare and can be detected by fine-needle aspiration biopsy in the face of clinical findings. Where indicated, palliative thyroidectomy can be effective, because other methods of treatment appear ineffective.

Intraosseous malignant peripheral nerve sheath tumor. Report of a case and review of the literature.

We report a case of a malignant peripheral nerve sheath tumor arising in the distal femur of a 28-year-old man who had no stigmata of von Recklinghausen's disease. Roentgenograms and computed tomographic scans of the distal femur showed a single lytic intraosseous lesion with minimal soft tissue extension. Light microscopy demonstrated a tumor composed of spindle cells with myxoid areas. There was some nuclear pleomorphism and mitotic activity. The tumor cells were immunoreactive for S100 protein and neuron-specific enolase. Ultrastructurally, there were cells with long processes, which were focally invested by basal lamina. Some cells had numerous micropinocytotic vesicles. The tumor recurred in the femur 15 months following the initial curettage. Computed tomographic scan of the lungs at that time showed a nodule, which has since enlarged. Primary osseous malignant peripheral nerve sheath tumors are uncommon. A literature review revealed only 18 previous cases, the majority of which occurred in the mandible or maxilla. This is a rare case of intraosseous malignant peripheral nerve sheath tumor of a long bone, with both immunohistochemical and ultrastructural confirmation of nerve sheath differentiation.

Ultrasonography and ultrasound-guided fine-needle aspiration biopsy of head and neck lesions: a surgical perspective.

A head and neck ultrasound-guided fine-needle aspiration clinic was set up to determine the role of ultrasound and ultrasound-guided fine-needle aspiration in the evaluation of patients with lesions in this region. One hundred ninety-five lesions were biopsied by ultrasound-guided fine-needle aspiration in 203 patients. Ultrasound detected 2 or more lesions in 14 (48%) of 29 patients with a clinically solitary thyroid nodule. Three (8.8%) of 34 lesions thought to be within the parotid gland were determined to be external. A pronounced learning curve was evident in the technique of ultrasound-guided fine-needle aspiration, particularly for nonpalpable disease. Adequacy of sampling for each 3-month period was 71%, 89%, and 94%, respectively. Seventy-four percent of central aspirations were satisfactory compared to 54% of peripheral aspirations. Ultrasound-guided fine-needle aspiration did not alter the clinical staging of metastatic neck disease in 8 patients having 10 neck dissections but proved useful in detecting nodal recurrence in 3 irradiated necks that did not proceed to surgery. The smallest node to harbor malignancy had 4-mm maximal axial diameter. We conclude that ultrasound and ultrasound-guided fine-needle aspiration are valuable adjuncts to the clinical examination.

Metastatic adamantinoma diagnosed by fine-needle aspiration biopsy of the lung.

We report two cases of metastatic adamantinoma to the lung diagnosed by FNAB. The cytologic appearance of the smears of each case was homogenous, containing small round and spindle cells with indistinct cytoplasm. The nuclei had delicate nuclear membranes, with finely dispersed chromatin and occasional micronucleoli. No pleomorphism was noted. Immunocytochemistry exhibited positive staining for keratin and vimentin. EM examination revealed numerous tonofilaments and well formed desmosomes. The cytologic diagnosis of metastatic adamantinoma can be made with the knowledge of a previous history of adamantinoma of bone, the comparison of the metastatic tumor with the original bone tumor, and the awareness of the long latency of the metastases. Immunocytochemistry and EM are needed to substantiate the diagnosis.

Ultrasound-guided fine-needle aspiration biopsy in the management of thyroid disease.

During a 23-month period, 59 patients were referred for ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) of the thyroid gland because of inadequate orthodox (office) FNAB, a clinically small lesion, or an occult lesion. Seventy percent of the group (41 patients) was referred for surgery, which revealed cancer in 37% of patients, adenoma in 19%, and benign disease in 44%. US-guided FNAB yielded false-positive reports in 0% of patients, false-negative reports in 5% to 12%, and inadequate aspirates in 32%. The US-guided FNAB technique had a sensitivity of 60% to 90%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 80%, and an accuracy of 85%. US-guided FNAB provides cytologic information in 60% of patients in whom a diagnosis cannot be established by orthodox (office) means, thus enhancing the diagnostic ability of clinicians who can recommend a treatment program with confidence.

Influence of fine-needle aspiration biopsy and frozen section examination on the management of thyroid cancer.

In order to delineate the influence of fine-needle aspiration biopsy (FNAB) and frozen section examination (FS) on the management of patients with thyroid cancer, a review of 310 patients with thyroid cancer, seen in follow-up during a 3-year period, was completed. Combined FNAB and FS examination were assessed in 225 patients, 172 (76%) with papillary carcinoma, 36 (16%) with follicular carcinoma, 13 (6%) with Hürthle cell carcinoma, and 4 (2%) with medullary carcinoma. The diagnosis according to FNAB was malignant in 78 patients (35%), cellular in 135 (60%), and benign in 12 (5%). All 78 patients with a malignant FNAB diagnosis had papillary cancer. The results of FS examination correlated with the FNAB findings in 74 patients (95%), whereas 4 patients (5%) had a false-negative FS diagnosis of "adenoma." Of the 135 patients with a cellular FNAB diagnosis, FS examination showed cancer in 75 (56%): 58 with papillary carcinoma, 7 with follicular carcinoma, and 10 with Hürthle cell carcinoma. Sixty patients (44%), 30 with papillary carcinoma, 27 with follicular carcinoma, and 3 with Hürthle cell carcinoma, had a cellular FNAB diagnosis and a FS diagnosis of a follicular neoplasm. Twelve patients (5%), 6 with papillary carcinoma, 4 with medullary carcinoma, and 2 with follicular carcinoma, had both false-negative FNAB and FS. From these results, we conclude that FS examination is indicated for intraoperative decision-making in patients with a cellular FNAB diagnosis but is unnecessary when the FNAB diagnosis is either benign or malignant. In order to avoid possible reoperation, near-total thyroidectomy should be presented as an alternative for the treatment of a hypofunctioning thyroid nodule when both FNAB and FS results are consistent with "follicular neoplasm."

Correlation of cytologic and histologic features in variants of papillary carcinoma of the thyroid.

Different morphologic variants have been described for papillary carcinoma of the thyroid, but little emphasis has been placed on their cytologic patterns. We studied fine needle aspiration (FNA) smears and histologic sections from 48 cases of papillary carcinoma, including 24 of the usual type, 13 of the follicular variant, 7 of the encapsulated variant and 4 of the tall cell variant, in an attempt to correlate the cytologic features and the different histologic variants. Single cells, monolayers and papillary fragments were present in all the variants. The presence of follicles was not restricted to the follicular variant. Nuclear grooves and cytoplasmic pseudoinclusions were present in most of the cases, with nuclear grooves the most common finding in all the variants (92.3-100%). Psammoma bodies were an infrequent finding (0-25%) and were absent from the follicular variant. Colloid was present in all the variants and was a frequent finding in the follicular variant (84.6%). The findings suggest that the exact histologic variant of papillary carcinoma cannot be predicted from the appearance of the fine needle aspirate.

Simple miniblock technique for cytology.

Seventy cytology specimens, including fine-needle aspirates from various sites, body effusions, and bronchoalveolar lavages were prepared with a cell block system. This technique, which uses a gelling reagent and a setting reagent to increase the recovery of material, is described in detail. Fifty-four cases had adequate material. To assess the efficacy of the technique, miniblock sections were compared with smears. In 23 cases (43%), the sections provided additional information for a definite diagnosis. The technique allows the recovery of minute cellular material and is valuable for histochemical and immunohistochemical studies.

Value of fine-needle aspiration in the diagnosis of Hürthle cell neoplasms.

The cytologic and histologic slides on all patients with a diagnosis of Hürthle cell tumor at Mount Sinai Hospital during the last 12 years were reviewed. There were 67 Hürthle cell tumors of which 15 (22%) were malignant. Four carcinomas (27%) occurred in a background of thyroiditis. Forty-three patients with Hürthle cell tumors had undergone preoperative fine-needle aspiration, of which 31 had satisfactory aspirates. For Hürthle cell neoplasia, fine-needle aspiration cytology had a sensitivity of 83.8% (26 of 31) and positive predictive value of 93% (26 of 28), provided that the aspirate was of adequate cellularity. All 3 cases predicted as Hürthle cell carcinoma on the basis of cellular and nuclear atypia were correctly predicted, but 3 carcinomas composed of bland cells were incorrectly predicted as adenomas. We conclude that aspiration cytology can differentiate nonneoplastic from neoplastic Hürthle cell lesions with high accuracy, but that the differentiation between benign and malignant lesions is less reliable.