Seiji Kuma

An Observation Trial Without Surgical Treatment in Patients with Papillary Microcarcinoma of the Thyroid

The recent prevalence of ultrasound-guided fine-needle aspiration biopsy has resulted in a marked increase in the number of patients with papillary microcarcinoma (maximum diameter, </= 10 mm) of the thyroid detected by this sophisticated tool. On the other hand, it is debatable whether patients with papillary microcarcinoma should always undergo surgery after diagnosis, because a high incidence of occult papillary carcinoma has been observed in autopsy studies. Thus, we proposed observation without surgical therapy as a treatment option in 732 patients diagnosed with papillary microcarcinoma by the above technique from 1993 to 2001. One hundred sixty-two patients chose observation and were classified as the observation group. During the follow-up period for patients in the observation group, more than 70% of tumors either did not change or decreased in size compared to their initial size at diagnosis. They enlarged by more than 10 mm in 10.2%, and lymph node metastasis in the lateral compartments appeared in only 1.2% of patients during follow-up. On the other hand, 570 patients chose surgical treatment at diagnosis and 56 patients in the observation group who underwent surgery after a period of follow-up were classified as the surgical treatment group. Of these 626 patients, lymph node dissection was performed in 594 patients, and metastasis was confirmed histologically in 50.5%. Multiple tumor formation was seen in 42.8% of patients. In this group, the rate of recurrence was 2.7% at 5 years and 5.0% at 8 years after surgery. Our preliminary data suggest that papillary microcarcinomas do not frequently become clinically apparent, and that patients can choose observation while their tumors are not progressing, although they are pathologically multifocal and involve lymph nodes in high incidence.

Cribriform‐morular variant of papillary thyroid carcinoma: a pathological and molecular genetic study with evidence of frequent somatic mutations in exon 3 of the β‐catenin gene

The cribriform‐morular variant (C‐MV), an unusual and peculiar subtype of papillary thyroid carcinoma (PTC), has been observed frequently in familial adenomatous polyposis (FAP)‐associated thyroid carcinoma and also in sporadic thyroid carcinoma. In this paper, five young women with the C‐MV of PTC, aged 22–34 years at cancer diagnosis, are reported; two of them had attenuated FAP. Grossly, one FAP‐associated tumour and one sporadic tumour were multicentric and the others were solitary. Histologically, the tumours were encapsulated and exhibited a combination of cribriform, follicular, trabecular, solid, and papillary patterns of growth, with morular areas. Immunohistochemically, the tumour cells showed cytoplasmic expression of thyroglobulin, neuron‐specific enolase, epithelial membrane antigen, high‐ and low‐molecular‐weight cytokeratins, vimentin, and bcl‐2 protein; nuclear expression of oestrogen and progesterone receptors, and retinoblastoma protein; and cytoplasmic and nuclear accumulation of β‐catenin. Germline mutations of the adenomatous polyposis coli (APC) gene were investigated using the protein truncation test in four subjects, including two FAP individuals. Germline APC mutation was identified in only one FAP patient with the multicentric C‐MV of PTC, who had a thymidine deletion at codon 512, resulting in a frameshift leading to a premature stop codon. No loss of heterozygosity of loci close to the APC gene was detected in tumour tissues from these four patients. Somatic mutation analysis of exon 3 of the β‐catenin gene (CTNNB1) revealed alterations in seven tumours from all five individuals: one at a serine residue (codon 29), three at amino acids adjacent to serine or threonine residues (codons 22, 39, and 44), and three at other amino acids (codons 49, 54, and 56). Moreover, each of two different tumours examined from two patients with the multicentric C‐MV of PTC, had different somatic mutations of the CTNNB1 gene. Taken together, these data suggest that accumulation of mutant β‐catenin contributes to the development of the C‐MV of PTC. Copyright

Cribriform-morular variant of Papillary Thyroid Carcinoma: Clue to Early Detection of Familial Adenomatous Polyposis-associated Colon Cancer

The cribriform-morular variant (CMV) of papillary thyroid carcinoma (PTC) is a rare histologic subtype of PTC that shows a combination of growth patterns including cribriform and spindle cell areas. The thyroid cancer with this unique histology was originally reported in patients with familial adenomatous polyposis (FAP), although it was later found in patients without polyposis as well. Because of its rarity, its clinical features are not clear. We reviewed seven patients with CMV-PTC who were found among 4194 patients with PTC in our pathology files between June 1991 and March 2003. The prevalence of CMV was 0.16% among all PTCs. We invited these patients to our hospital so we could obtain a detailed family history and recommend colonoscopic examination and germline APC gene analysis. Two patients without subjective symptoms had polyposis of the colon and colon cancers. Germline APC gene mutations were found in both patients. The father of a patient who refused the invitation was revealed to have undergone surgery for colon polyposis. In the remaining four patients, neither polyposis nor APC gene mutation was found. Common clinical features included a young age (mean 25 years), predominance of females, circumscribed tumors, negative node metastasis, and no recurrence of the thyroid cancer after surgery. Two of the three patients with colon polyposis had bilateral multiple thyroid tumors, whereas the remaining four (without polyposis) had a solitary tumor. The histopathology of CMV in patients with PTC should arouse a suspicion of FAP, especially if there are multiple tumors. This finding can lead to early detection of colon cancer.

Morules in cribriform‐morular variant of papillary thyroid carcinoma: Immunohistochemical characteristics and distinction from squamous metaplasia

Morules are a diagnostic clue to the cribriform‐morular variant (C‐MV) of papillary thyroid carcinoma, and are superficially similar to squamous metaplasia. In order to clarify the histogenesis of morules and differentiate them from squamous metaplasia, we immunohistochemically compared the morules in five cases of C‐MV with squamous metaplasia in six cases of diffuse sclerosing variant (DSV) of papillary thyroid carcinoma. The squamous metaplastic cells were immunopositive for low‐ and high‐molecular‐weight cytokeratin, whereas the morular cells were negative or focally positive. Vimentin‐positive cells were observed focally in the morules and squamous metaplasia, except for one case of CMV that showed intense positivity. The morular cells showed weak cytoplasmic positivity for beta‐catenin, and the cell membrane was not highlighted. Some nuclei of the morular cells were also positive for this antibody. Beta‐catenin was intensively positive along the cell membrane of the metaplastic cells, and did not react against the nuclei or cytoplasm. Bcl‐2 was positive in the morular cells, but negative in the metaplastic cells. S‐100 protein‐positive dendritic cells were observed in the metaplastic nests, but not in the morules. We argue that morules appear in connection with nuclear and cytoplasmic aberrant localization of beta‐catenin, and are not an early form of squamous metaplasia.

Cribriform‐morular variant of papillary thyroid carcinoma—Cytological and immunocytochemical findings of 18 cases

The purpose of this article was to describe cytologic findings of cribriform‐morular variant of papillary thyroid carcinoma (CMV‐PTC) in detail, to review previously reported cases, and to emphasize the diagnostic significance of this subtype. We examined 19 ultrasound‐guided fine needle aspiration (FNA) specimens from 18 CMV‐PTC patients. Cytologic features of CMV‐PTC were as follows, (1) hypercellularity, (2) papillary arrangement composed of tall columnar cells, (3) cribriform pattern, (4) morules, (5) spindle cells, (6) obscure ground‐glass nuclei, (7) peculiar nuclear clearing (PNC), (8) foamy or hemosiderin‐laden histiocytes, (9) hyaline materials, (10) absence of colloid in the background. The nuclear and cytoplasmic immunoreactivity of beta‐catenin and biotin‐positive PNC can indicate CMV‐PTC. We believe that cytologic diagnosis of CMV‐PTC is possible and it may lead to the early detection of polyposis coli. Diagn. Cytopathol. 2010;38:890–896.

Cytologic Features of Hyalinizing Trabecular Adenoma of the Thyroid

OBJECTIVE To clarify the cytologic findings of hyalinizing trabecular adenoma (HTA) in order to reduce erroneous diagnoses of papillary carcinoma. STUDY DESIGN Review of aspiration cytologic smears of 16 HTA cases and comparison with those of 20 papillary carcinoma cases. RESULTS The smears from HTA were slightly cellular, and 5 of 16 cases were insufficient for evaluation. Vague, curved nuclear palisading, radiating arrangement surrounding hyaline materials and yellow bodies were observed in 9 (81.8%) of 11 cases that had sufficient material. The tumor cells were mainly spindled; elongated, polygonal and stellate cells were also seen. In 9 of 11 cases, tumor cells with cytoplasmic processes were occasionally observed. The cytoplasm was faintly stained and somewhat filamentous. The cell border was indistinct. Neither papillary nor follicular structures were seen. Intranuclear cytoplasmic inclusions were identified in 100% of HTA and 75% of papillary carcinomas. The incidences of nuclear grooves in HTA and papillary carcinoma were 81.8% and 100%, respectively. CONCLUSION Cytologic findings indicating HTA are vague, curved nuclear palsiading; radiating arrangement surrounding hyaline material; elongated cells; cell processes; ill-defined cell border; faintly stained and filamentous cytoplasm; yellow bodies; and hyaline material in the background. All are useful cytologic characteristics in distinguishing HTA from papillary carcinoma. A lack of papillary architecture and sheetlike arrangement may also suggest HTA rather than papillary carcinoma.

Thyroid nodular lesion: Analysis of cancer risk based on Kuma Hospital experience

It is a difficult question, whether it is malignant or not, when you follow up patients with thyroid nodular lesions. Cytological examination helps to solve this issue more accurately but a cancer risk still exists in patients with a negative cytology, non‐diagnostic or suspicious follicular neoplasms. Analysis of cancer risk in patients with benign thyroid nodular lesions was carried out among 1044 cases who underwent thyroid surgery at Kuma Hospital, Kobe, Japan, in 2000. The purpose of this study was to provide evidence of cancer risk in those patients in Japan. Among the 356 cases with benign nodular lesions, 99 cases of papillary carcinoma were found in the thyroid parenchyma. Seventy‐nine of the 99 cases were clinical cancer and were found preoperatively by cytology, while 20 out of 277 (7.22%) cases were found postoperatively as incidental carcinoma. The incidence of follicular carcinoma of a minimally invasive type in the index nodule was 22 out of 279 (7.89%) cases in patients who were surgically treated.

Parotid lipoadenoma with sclerotic and polycystic changes

Salivary gland lipoadenoma is a very rare benign tumor composed of adipose tissue and ductal component [4, 9, 10]. The ducts are lined by columnar cells, which are supported by a basal cell layer. Since the basaloid cells immunohistochemically lack evidence of myoepithelial differentiation but are positive for high molecular-weight (HMW) cytokeratin, they indicated striated duct origin. Acinar component is not present within this tumor. We have recently encountered a case of parotid lipoadenoma with stromal sclerosis and polycystic changes of the ducts. As salivary gland lipoadenoma with such findings has not been described, we report our case with immunohistochemical findings and differential diagnoses. The patient was a 68-year-old man with a mass of the right parotid gland for about 10 years. As the mass was gradually increased in size, he visited our hospital. A computed tomography (CT) scan and magnetic resonance imaging (MRI) study disclosed the solid tumor in the superficial lobe of the parotid gland. The resected tumor was an encapsulated, whitish solid mass, measuring 2.5×2.0×3.0 cm, with scattered minute holes. Microscopically, the tumor was composed of an intimate admixture of the glands, adipose tissue and sclerotic connective tissue (Fig. 1). Most of the glands were cystically dilated and contained proteinaceous fluid. The glands were lined by cuboidal to flat epithelial cells with bland oval to flat nuclei in their inner portion (Fig. 2). In the outer portion of the glands, basaloid cells that had smaller nuclei and flatter cytoplasm were present. The stroma was composed of fibrous connective tissue and mature adipose tissue. In

Cytological characteristics of papillary thyroid carcinoma on LBC specimens, compared with conventional specimens

The cytological findings in conventional specimens (C‐S) and liquid‐based cytology specimens (LBC‐S) are not quite same. The aim of this article is to clarify the cytological findings of papillary thyroid carcinoma (PTC) characteristic of LBC‐S.

Intrathyroidal epithelial thymoma/carcinoma showing thymus-like differentiation; comparison with thymic lymphoepithelioma-like carcinoma and a possibility of development from a multipotential stem cell.

The purpose of our article is to describe the immunohistochemical findings of intrathyroidal epithelial thymoma/carcinoma showing thymus‐like differentiation (ITET/CASTLE) of the thyroid in detail, to clarify the difference between ITET/CASTLE and thymic lymphoepithelioma‐like carcinoma (LELC), and to discuss the pathogenesis of ITET/CASTLE. We immunohistochemically examined five ITET/CASTLE and eight LELC cases. All of ITET/CASTLE cases were strongly positive for CD5, P63, high‐molecular‐weight cytokeratin and B‐cell CLL/lymphoma‐2. Carcinoembryonic antigen‐positive carcinoma cells were found in four ITET/CASTLE cases. Neuroendocrine marker‐positive carcinoma cells were scattered in all cases. Immunohistochemical findings in thymic LELC were essentially similar to those in ITET/CASTLE, but the sensitivity was different. There is a possibility that ITET/CASTLE and thymic LELC are not the quite same disease entity. We think that ITET/CASTLE is derived from ectopic thymus, but not related to solid cell nests.