Abnormal Nuclear Structures (Micronuclei,Nuclear Blebs,Strings, and Pockets) in a Case of Anaplastic Giant Cell Carcinoma of the Thyroid: An Immunohistochemical and Ultrastructural Study

The authors report a case of a 70-year-old woman with an anaplastic giant cell thyroid carcinoma, along with immunohistochemical and electron microscopic findings. Histologically, the tumor is characterized by mononucleated and multinucleated giant cells, lack of architectural cohesion, atypical mitoses, and extensive areas of coagulative necrosis. Tumor cells showed AE1/AE3 positivity as well as nuclear overexpression of p53 and ki-67. Semithin sections revealed multiple nuclei with heterogeneous size ranging from micronuclei to large-size (giant) nuclei. Micronuclei were confirmed by electron microscopy that disclosed also the presence of nuclear blebs, strings, and pockets. Morphological findings of these abnormal nuclear structures in conjunction with p53 and Ki-67 nuclear overexpression suggested a faulty mitotic checkpoint/mitotic catastrophe in the progression of anaplastic giant cell thyroid carcinoma.     

Abnormal nuclear structures (micronuclei, nucleoplasmic bridges, and nuclear buds) in a pleomorphic giant cell carcinoma of the stomach

A rare case of pleomorphic giant cell carcinoma of the stomach in a 70-year-old man is reported. Characteristic microscopic findings included a general lack of architectural cohesiveness, aggregates of mononucleated or multinucleated giant cells, extensive areas of coagulative necrosis, and numerous mitoses. Immunohistochemically, tumor cells displayed cytoplasmic immunoreactivity for cytokeratin AE1/AE3 as well as overexpression of p53 and Ki-67. Electron microscopy revealed paranuclear tonofilaments bundles in giant cells confirming their epithelial nature. Furthermore, giant cells contained two or more nuclei with heterogeneous size, nucleoplasmic bridges, nuclear buds, and micronuclei. Similar abnormal nuclear structures have been closely related to breakage-fusion-bridge type of mitotic disturbances in tumor cell lines, and have not been previously reported in a human tumor.     

Abnormal Nuclear Structures (Micronuclei,Nucleoplasmic Bridges,and Nuclear Buds) in a Pleomorphic Giant Cell Carcinoma of the Stomach

A rare case of pleomorphic giant cell carcinoma of the stomach in a 70-year-old man is reported. Characteristic microscopic findings included a general lack of architectural cohesiveness, aggregates of mononucleated or multinucleated giant cells, extensive areas of coagulative necrosis, and numerous mitoses. Immunohistochemically, tumor cells displayed cytoplasmic immunoreactivity for cytokeratin AE1/AE3 as well as overexpression of p53 and Ki-67. Electron microscopy revealed paranuclear tonofilaments bundles in giant cells confirming their epithelial nature. Furthermore, giant cells contained two or more nuclei with heterogeneous size, nucleoplasmic bridges, nuclear buds, and micronuclei. Similar abnormal nuclear structures have been closely related to breakage-fusion-bridge type of mitotic disturbances in tumor cell lines, and have not been previously reported in a human tumor.     

Coexistent anaplastic and differentiated thyroid carcinoma: an immunohistochemical study

The aim of the present study was to clarify the underlying molecules that might contribute to the highly aggressive behavior of anaplastic thyroid carcinoma. We selected 5 cases of anaplastic thyroid carcinoma that had a differentiated area to determine differences in the molecules of undifferentiated and differentiated cancer cells. We immunohistochemically examined the localization of nuclear antigen (Ki-67), proliferating cell nuclear antigen (PCNA), p53, apoptotic protease-activating factor-1 (Apaf-1), CD26, galectin-3, E-cadherin, and CD147. We found increased Ki-67, PCNA, and p53 labeling indices; decreased levels of Apaf-1, CD26, galectin-3, and E-cadherin; and overexpression of CD147 in the undifferentiated area compared with the differentiated area. These findings indicate high proliferative properties, suppression of apoptosis, disruption of cell-cell interaction, and induction of matrix metalloproteinases in the undifferentiated areas. Thus the molecules examined might be useful for evaluating the aggressive nature of this tumor and the prognosis.     

人甲状腺髓样癌内凋亡细胞检测和bcl-2、p53及Ki-67的免疫组化研究

目的：检测甲状腺髓样癌内凋亡细胞、ｂｃｌ－２、ｐ５３和Ｋｉ－６７，探讨其与患者的预后关系。方法：在２１例甲状腺髓样癌内，用ＤＮＡ末端标记方法检测凋亡细胞和用免疫组织化学技术检测ｂｃｌ－２、ｐ５３及Ｋｉ－６７的表达。结果：在２１例甲状腺髓样癌标本中，凋亡细胞ｂｃｌ－２、ｐ５３和Ｋｉ－６７的检出率分别为８１％，１００％，６２％和７１％。ｂｃｌ－２阳性物质位于肿瘤细胞的胞浆内，少数病例则位于膜上。ｐ５３蛋白阳性主要位于胞核内，少数病例也同时见于胞浆内。Ｋｉ－６７抗原主要位于肿瘤细胞核内。本研究结果表明，ｂｃｌ－２和肿瘤细胞凋亡之间有密切关系（Ｐ＜０．０１）。ｂｃｌ－２阳性细胞检出率较高的病例，凋亡细胞检出率则较低；反之，凋亡细胞检出率则较高。ｐ５３和Ｋｉ－６７阳性细胞检出率和细胞凋亡无相关性（Ｐ＞０．０５）。结论：ｂｃｌ－２具有抑制细胞凋亡的作用。上述各因素检测结果与患者存活率无统计学意义。ｂｃｌ－２肿瘤蛋白在甲状腺髓样癌中高表达，可作为该肿瘤的一个新的标记物，对预后的判断可能也有一定的意义     

Expression of the GLUT1 glucose transporter, p63 and p53 in thyroid carcinomas

Only few studies have evaluated the usefulness of the GLUT1 and p63 status of thyroid carcinomas in revealing tumorigenesis. We studied GLUT1, p53, and p63 immunoexpression in a total of 86 cases of various thyroid carcinoma types to determine the biological significance of GLUT1 and p63 expression in thyroid carcinomas. GLUT1 was detected in six cases of anaplastic carcinoma and in one case of poorly differentiated carcinoma with membranous staining. p63 was detected in five cases of anaplastic carcinoma, in one case of poorly differentiated carcinoma, and in five cases of papillary carcinoma with nuclear positivity. p53 was detected in six cases of anaplastic carcinoma, in one case of poorly differentiated carcinoma, and in one case of follicular carcinoma with nuclear positivity. Five of seven cases of anaplastic carcinoma expressed all three of these markers. The results suggest that GLUT1, p63, and p53 are not expressed in well-differentiated thyroid carcinomas, and that they are usually expressed late in the course of thyroid tumor progression. These data strongly suggest that in anaplastic carcinomas, impairment of p53-mediated repression results in increased GLUT1 and p63 expression, and that this probably reflects the differential regulation of hypoxia-responsive pathways and basal/stem cell regulatory pathways.     

Medullary carcinoma of the thyroid. Giant cell type.

This report presents a rare histological variation of medullary (C-cell) carcinoma of the thyroid, referred to as giant cell type, which is similar to that found in anaplastic carcinoma of the thyroid, or choriocarcinoma. The giant cells in this case possessed specific immunofluorescence for calcitonin and secretory granules in the cytoplasm. The giant cells were tumor cells of medullary carcinoma and could be distinguished from anaplastic carcinoma of the thyroid by various histological characteristics, such as nuclear invagination, an intermingled pattern of giant cells with typical small solid cells, infrequency of mitosis, and the existence of amyloid stroma.     

An ultrastructural study of nuclear and centriolar configurations in multinucleated giant cells.

Multinucleated giant cells were examined with electron microscopy from (1) four peripheral giant cell granulomas of the jaws, (2) a central giant cell tumor of the maxilla, (3) five giant cell tumors of tendon sheath, (4) experimentally induced foreign body granulomas in rats, (5) a virus-induced sarcoma, and (6) osteoclasts from the mandibles of rats and (7) the femurs of hamsters. The purpose of the study was (1) to examine the location and arrangement of the nuclei and the centrioles of the multinuclueated cells and compare them with the osteoclast which has previously been thought to have a unique arrangement and (2) to observe whether the physical location of the centrioles and the nuclei were such that the nuclei could undergo mitosis within the cytoplasm. All of the multinucleated cells were found to have a similar arragnement of nuclear concentration areas and nucleus-free areas. A giant centrosphere containing multiple pairs of centrioles was found in the nucleus-free areas, unassociated with any particular nucleus. In the case of the foreign body giant cell and the osteoclast, this giant centrosphere was located very close to the foreign material or bone. When occasional single pairs of centrioles were found, they were located in the area of nuclear concentration, closely associated with a particular nucleus at the periphery. These findings have shown that a common centrosphere containing multiple centrioles is not an exclusive feature of the osteoclast as was previously thought. The findings suggest that a mononuclear cell containing a centriole pair fuses to the larger cell and maintains its centriole pair in close proximity to its nucleus for a short period of time, during which it may undergo mitotic activity. Eventually, the centrioles proceed to a common centrosphere whereas the nuclei aggregate in another area making further mitotic activity an unlikely possibility.     

Expression of p53 gene product and cell proliferation marker Ki-67 in Ewing's sarcoma: correlation with clinical outcome

Overexpression of tumor suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associated with poor prognosis in some tumors. We studied p53, Ki-67, and HER-2/neu immunohistochemical expression in archival biopsies of 37 patients with Ewing's sarcoma (ES). Patients with ES were treated at four Israeli hospitals between 1982 and 2000. Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry for p53, Ki-67, and HER-2/neu. More than 300 cells were counted on each slide, and the percentage of positively stained nuclei was computed. p53 overexpression was defined as nuclear staining of >2.3% of cells, Ki-67 overexpression as nuclear staining of >8.3% malignant cells. HER-2/neu staining was scored semiquantitatively on a scale of 0 to 4+. Twenty-two of 37 patients are alive and well, with mean follow-up time of 38 months. There was overexpression of p53 in 16 patients (43%) and of Ki-67 in 21 patients (57%). The correlation between p53 and Ki-67 overexpressions was 0.61. We found no overexpression of HER-2/neu. Median relapse-free survival (RFS) was statistically significantly shorter for patients with p53 overexpression (25 months) than for patients with negative staining (>92 months). The prognostic value of p53 overexpression was also significant after adjusting for tumor location and age. Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance. Our study suggests that p53 is a predictor of RFS in patients with ES. More patients must be studied to assess the validity of this observation.     

ANAPLASTIC CARCINOMA OF THE THYROID WITH OSTEOCLAST-LIKE GIANT CELLS

An unusual anaplastic thyroid carcinoma with osteoclast-like giant cells is reported in a 72-year-old woman. Monotonous proliferation of variously sized mononuclear tumor cells interspersed with numerous osteoclast-like multinucleated giant cells was dominant. A small area of papillary carcinoma merging with the anaplastic carcinoma was disclosed. Immunohistochemically, tumor cells forming papillary pattern were positive for both thyroglobulin and keratin. Cells and cell clusters positive for keratin were found in anaplastic carcinoma. Electron microscopically, the anaplastic carcinoma cells displayed prominent mitochondria, a rough endoplasmic reticulum, and intermediate cell junctions. The cell clusters formed irregular lumina into which numerous microvilli were extended and which contained colloid-like material. Occasionally incomplete basal laminae were present. Cell clusters showing transitional pictures from cell clusters to multinucleated giant cells and multinucleated giant cells engulfing mononuclear tumor cells were observed by both light and electron microscopy. Findings from this study support the conclusion that anaplastic tumor cells arise in preexisting differentiated thyroid cancer and that associated multinucleated giant cells are formed by the fusion of carcinoma cells.     

Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas

Papillary thyroid carcinomas in humans are associated with the ret/PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret/PTC1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53-/- mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret/PTC1-induced thyroid tumors. The majority of p53-/- mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret/PTC1 mice developed thyroid carcinomas, but tumors in p53-/- mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/- mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/- mice 相似文献   

Expression of p53 in human esophageal carcinoma: an immunohistochemical study with correlation to proliferating cell nuclear antigen expression.

Immunolocalization of the nuclear protein p53 tumor suppressor gene product is considered to be one of the best methods of detecting a mutated form of p53. We have studied p53 immunohistochemically by using monoclonal antibody pAb1801 in 15 cases of esophageal squamous cell carcinoma. Immunoreactive p53 was observed in the nuclei of tumor cells in 4% paraformaldehyde-fixed, frozen sections (12 of 15) and paraffin-embedded sections (11 of 15), but not in routinely processed (10% formalin-fixed) specimens. p53 expression was closely correlated with the malignant phenotype, including dysplasia. p53 was not observed in histologically normal mucosa, except in three cases in which scattered immunoreactivity was observed in parabasal and basal cells. Immunostaining of ki67 and proliferating cellular nuclear antigen on adjacent tissue sections revealed that p53 expression was strongly correlated with ki67 and proliferating cellular nuclear antigen in carcinoma and dysplastic cells, but not in normal mucosa, suggesting involvement of the mutated form of p53 in the cell cycle of malignant cells. Immunohistochemical patterns of p53 were not related significantly to clinicopathologic parameters in the cases examined. Therefore, p53 expression was strongly associated with the proliferation of carcinoma cells but not with that of normal cells in esophageal carcinoma.     

Immunohistochemical and molecular analysis of p53, MDM2, proliferating cell nuclear antigen and Ki67 in benign and malignant peripheral nerve sheath tumours

A series of 26 malignant peripheral nerve sheath tumours (MPNST) and 24 benign peripheral nerve sheath tumours (BPNST) were analysed immunocytochemically for p53 expression and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Ki67 (with MIB1). In 23/26 MPNST, 5%–65% of the tumour cell nuclei were immunoreactive for Ki67 with MIB1 while none of the 24 BPNST had nuclear staining exceeding 5%. Greater than 50% nuclear PCNA staining was detected in 25/26 MPNST compared with 8/24 BPNST; 17/26 MPNST showed 5–100% nuclear staining for p53 (13/26>20%), whereas none of the BPNST had nuclear staining exceeding 1%. The Ki67, PCNA and p53 immunostaining results correlated significantly with benign versus malignant (P<0.001, P<0.001 and P<0.005, respectively) as well as mitotic rate (P<0.001, P<0.05 and P<0.05). Ki67 immunostaining results correlated significantly with PCNA and p53, as did p53 with Ki67 and PCNA (P<0.001 in both). Stepwise (logistic regression forward) multivariate analysis of the variable, benign versus malignant, revealed the strongest correlations with PCNA (P=0.007) and Ki67 (P=0.021). Direct confirmation of the presence of p53 protein was obtained by western blot analysis of 3 MPNST and 5 BPNST. Two MPNST, showing 90% and 30% immunoreactivity, were positive for p53, while one MPNST with 5% immunoreactivity and all 5 BPNST were negative. Southern blot analysis performed on the two MPNST with high p53 protein levels revealed no amplification of the MDM2 gene, suggesting that high p53 levels in MPNST are likely to be due to mutation. The results also indicate that PCNA and Ki67 are potentially useful in distinguishing BPNST from MPNST, particularly in problematic cases of cellular schwannoma versus MPNST. The detection of p53 in a large percentage of cells of a plexiform neurofibroma giving rise to MPNST and Ki67 in 5% and 25% of cells of two similar cases suggests that malignant transformation may be detected in some cases by p53 and proliferation markers prior to overt histological evidence of malignancy.     

Anaplastic carcinoma of the thyroid gland. An ultrastructural study on four cases.

Four cases of anaplastic carcinoma of the thyroid, composed of one small cell carcinoma and three giant cell carcinomas, were studied with electron microscope. In the case of small cell carcinoma, fine cytoplasmic interdigitations and junctional complex between apposing cytoplasmic membranes of neighbouring tumor cells and a few microlumina within tumor cell clusters surrounded by well-defined basal lamina were seen. In the cases of giant cell carcinoma, occasional cytoplasmic interdigitations as well as desmosomal structures were detected even in tumor cells markedly pleomorphic and anaplastic. Abundant cytoplasmic organelles including profiles of Golgi apparatus, rough endoplasmic reticulum and a few mitochondria were seen in the cytoplasm of tumor cell of all four cases. Of interest to note was that all giant cell carcinomas demonstrated evidences of fairly well differentiated tumor within anaplastic carcinoma, indicating probable pre-existing either benign or malignant epithelial neoplasm more differentiated, with its subsequent anaplastic transformation. Findings in the present study support an assumption that these anaplastic tumors are derived from the follicular epithelium of the thyroid gland. In addition, it can be said that tumor cells of the small cell carcinoma provide evidences suggesting functional differentiation of carcinoma cells to a certain extent, yet unable to produce thyroglobulin.     

ANAPLASTIC CARCINOMA OF THE THYROID GLAND An Ultrastructural Study on Four Cases

Four cases of anaplastic carcinoma of the thyroid, composed of one small cell carcinoma and three giant cell carcinomas, were studied with electron microscope. In the case of small cell carcinoma, fine cytoplasmic interdigitations and junctional complex between apposing cytoplasmic membranes of neighbouring tumor cells and a few microlumina within tumor cell clusters surrounded by well-defined basal lamina were seen. In the cases of giant cell carcinoma, occasional cytoplasmic interdigitations as well as desmosomal structures were detected even in tumor cells markedly pleomorphic and anaplastic. Abundant cytoplasmic organelles including profiles of Golgi apparatus, rough endoplasmic reticulum and a few mitochondria were seen in the cytoplasm of tumor cell of all four cases. Of interest to note was that all giant cell carcinomas demonstrated evidences of fairly well differentiated tumor within anaplastic carcinoma, indicating probable pre-existing either benign or malignant epithelial neoplasm more differentiated, with its subsequent anaplastic trasformation. Findings in the present study support an assumption that these anaplastic tumors are derived from the follicular epithelium of the thyroid gland. In addition, it can be said that tumor cells of the small cell carcinoma provide evidences suggesting functional differentiation of carcinoma cells to a certain extent, yet unable to produce thyroglobulin.     

Fine needle aspiration cytology of insular carcinoma of thyroid

Poorly differentiated (insular) thyroid carcinoma is defined as a thyroglobulin-producing non-follicular non-papillary thyroid carcinoma, having an intermediate behavior between well-differentiated and anaplastic carcinomas. FNAC is widely used as aid for workup of thyroid gland lesion. However, scant information is available in the literature about cytologic findings of this rare entity. Ten cases of surgically resected insular carcinoma with a corresponding cytology were selected. The cytologic smears and histological sections were reviewed for presence of cytomorphologic features including cellularity, predominant cytoarchitectural pattern, additional cytologic co-patters pattern, cell size, cell shape, nuclear pleomorphism, nuclear/cytoplasmic (N/C) ratio, chromatin pattern, amount of cytoplasm, mitotic figures, colloid, background debris, nuclear grooves, and intranuclear pseudoinclusions. In all the cases, the cells were arranged predominantly in solid clusters. Focal microfollicular pattern was identified in five cases of which three cases showed presence of inspissated colloid within the follicles. Singly scattered malignant cells and bare nuclei were seen in all cases. Cells were monomorphic, round with high N/C ratio, finely granular chromatin and inconspicuous nucleoli. Background showed presence of cellular debris in two cases. Mitotic figures were obvious and atypical mitosis was also identified. Cellular smears composed of monomorphic population of small cells arranged in large clusters and sheets with high N/C ratio and high mitosis suggest the possibility of insular carcinoma. Background cellular debris/necrosis also supports the diagnosis. Cell block preparation in these cases may be of additional help in accurate diagnosis.     

Pleomorphic giant cell carcinoma of the prostate

We report the clinical and pathologic features of 2 cases of pleomorphic giant cell carcinoma of the prostate. One case was found at autopsy in a 77-year-old man and was composed of high-grade prostatic adenocarcinoma with prominent anaplastic giant cells. The patient presented with metastases to multiple retroperitoneal lymph nodes, liver, and lumbar vertebrae. The second case occurred in a 45-year-old man who underwent transurethral resection of the prostate and was found to have high-grade prostatic adenocarcinoma with an extensive anaplastic giant cell component. The patient presented with distant metastases and died within 9 months. Both regular adenocarcinoma and anaplastic giant tumor cells displayed cytoplasmic immunoreactivity for prostate-specific antigen, prostatic acid phosphatase, and keratin AE1/AE3; in one case, scattered cells were also positive for chromogranin and epithelial membrane antigen. Pleomorphic giant cell carcinoma is a rare variant of prostatic adenocarcinoma with a poor prognosis that should be considered in the differential diagnosis of prostatic pleomorphic tumors.     

Pleomorphic carcinoma with osteoclastic giant cells of the breast: Immunohistochemical differentiation between coexisting neoplastic and reactive giant cells

Herein is described a unique case of breast carcinoma with two different types of giant cells noted in both cytological and histological specimens. A 51-year-old Japanese woman noticed a hard mass in the upper outer quadrant of her left breast. Aspiration cytology exhibited numerous anaplastic giant cells; the cytological diagnosis was high-grade ductal carcinoma, although a few osteoclastic giant cells were also observed. A left simple mastectomy and sentinel lymph node biopsy were performed. Histologically, approximately 90% of the tumor was composed of giant cells; conventional invasive ductal carcinoma and ductal carcinoma in situ were found focally at the periphery of the tumor. The main part of the tumor contained both anaplastic, neoplastic giant cells and non-neoplastic, osteoclastic giant cells that were distinguishable from nuclear atypism. The presence of the two types of giant cells was also confirmed on immunohistochemistry using a histiocytic marker (CD68) and two epithelial markers (AE1/AE3 and CAM5.2). Based on the latest World Health Organization classification, the diagnosis was pleomorphic carcinoma with osteoclastic giant cells. To the authors' knowledge there has been no previous report on this subject except for a single case mentioned in Rosen's Breast Pathology .     

Involvement of centrosomes in nuclear irregularity of thyroid carcinoma cells

Nuclear irregularities including nuclear pseudoinclusions and nuclear grooves are characteristic of papillary thyroid carcinoma cells and are regarded as important diagnostic clues in histopathology. We observed nuclear features of thyroid carcinoma cell lines (KTC-1 and TPC-1) in various culture conditions and performed immunocytochemical examinations for cytoskeleton molecules to clarify the morphogenesis of thyroid carcinoma nuclei. We found that nuclear irregularities presenting as bean-like nuclei (BLNs) and donut-like nuclei (DLNs) appeared in cells from confluent cultures, but not in cells from sparse cultures. On immunocytofluorescence analyses, clusters of γ-tubulin, representing a centrosome, frequently localized at the indentation of BLNs or in the hole of DLNs of thyroid carcinoma cells. In conclusion, we suggest that cell-to-cell contact may affect nuclear changes such as BLNs and DLNs in cancer cell lines and that centrosomes may be involved in the morphogenetic process of these nuclear changes.