Rahel Zipkin, Sophia Getzowa, Elisabeth Sanderson-Damberg: Three Women From Early-20th-Century Bern, Switzerland—Their Lives, Research, and Impact on Pathology of the Thyroid

The correct identification of solid cell nests (SCNs) is an important issue in thyroid pathology because of the spectrum of differential diagnoses of this type of lesion. Ten cases of 295 consecutive thyroidectomies showed the presence of SCNs at histological examination. The identification of the exact SCN type required the distinction of the cystic and solid pattern; SCNs were usually composed of a mixture of main cells (MCs) and C-cells (CCs). The immunohistochemical calcitonin stain identified CCs easily, both inside SCNs and dispersed in islets at the periphery. For the characterization of MCs, we added the utility of p40 to p63. The use of thyroid transcription factor-1 (TTF-1) helped in their identification, as MCs did not react with this marker; the combination of TTF-1 and p40 or p63 IHC stains was useful for the characterization of cystic SCNs of both types 3 and 4. The negativity of mouse monoclonal mesothelioma antibody (HMBE-1) and a very low proliferative index (MIB-1) supported the diagnosis. [Correction added on 23 November 2015, after online publication: MIB-1 was incorrectly defined, the expanded form was deleted.] We discourage the use of galectin-3 (Gal-3) and cytokeratin-19 (CK-19), as they have an important overlap with papillary thyroid carcinoma. The complete absence of any B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations is an additional fundamental finding. We reviewed the most relevant morphological and immunohistochemical features of SCNs and have provided a genetic analysis of the BRAF gene because of its expanding use in thyroid pathology.

Telomerase expression and proliferative activity suggest a stem cell role for thyroid solid cell nests

In order to study the histological features and the histogenesis of the solid cell nest (SCN) of the human thyroid gland, 388 glands obtained from autopsy cases were examined in detail. The SCN is located in the interfolllcular space, as one or several groups of cells which show a large, light cytoplasm and nucleus. It Is circumscribed by a basement membranelike structure and is separated from the surrounding follicles. The size of the SCN first increases as age increases and then it tends to decrease as age advances further. This is similar to that of the follicles. Although the shape of the SCN usually appears to be round under single histological section, reconstruction revealed that the SCN takes a very irregular form, and that apparently separated groups of SCNs seen in a single section are actually connected with each other and form one SCN. The SCN was found in 81 cases (21%): 74 cases had one SCN, 13 cases had two to four SCNs in one lobe, 4 cases had two to six SCNs in two lobes. It was found in both fetus and aged with equal incidence. The number of SCNs was found equally in two lobes, and never found in the isthmus. No amyloid deposition, keratinizations or intercellular bridges are found in the SCN. Four out of 388 cases examined had aberrant thymus tissues and two of them were located closely to the SCN.Various hypothesis about the histogenesis of the SCN have been reviewed. However, the present study warrants none of them.

p63 Expression in Solid Cell Nests of the Thyroid: Further Evidence for a Stem Cell Origin

Aims: To provide new insights into characterising solid cell nests and gain information that might help distinguish between solid cell nests and C cells. Methods: Thyroid tissue specimens from patients...

Immunohistochemical detection of p53 homolog p63 in solid cell nests, papillary thyroid carcinoma, and hashimoto’s thyroiditis: a stem cell hypothesis of papillary carcinoma oncogenesis

Solid cell nests (SCNs) are usually distinguished on conventional H&E-stained sections; however, the morphological heterogeneity in SCNs and hyperplasia of these ultimobranchial body remnants can mimic other diagnostic entities including but not limited to papillary microcarcinoma. In order to confirm the thyroid follicular epithelial origin and exclude the possibility of SCNs, most diagnosticians use immunohistochemical biomarkers of thyroid follicular epithelial cells and/or those of SCNs. While the expression profile of monoclonal PAX8 has not been reported previously in SCNs, the status of TTF-1 expression using the 8G7G3/1 clone has been inconsistent among several studies. Given the potential diagnostic pitfalls, this series investigated the expression profile of GATA3, monoclonal PAX8, and TTF-1 (SPT24), along with p63, p40, monoclonal calcitonin, monoclonal CEA, and HBME-1 in a tissue microarray (TMA) of 56 SCNs. SCNs were all diffusely and strongly positive for TTF-1 (SPT24), p63, and p40, and were negative for monoclonal PAX8 and calcitonin. Positivity for GATA3 and monoclonal CEA was identified in 41 (73.2%) and 36 (64.3%) of SCNs. In addition, 18 (32.1%) SCNs displayed HBME-1 reactivity. These findings expand the immunohistochemical correlates of SCNs by demonstrating positivity for GATA3 and TTF-1 (SPT24), and negativity for monoclonal PAX8. The identification of monoclonal CEA expression and HBME-1 in SCNs also underscores the limitations of these select biomarkers in the distinction of C cell proliferations and papillary microcarcinoma, respectively. The findings of this series also suggest that positivity for TTF-1 (SPT24) alone should not be used to confirm the thyroid follicular epithelial origin. Therefore, the combined use of TTF-1 (SPT24) and monoclonal PAX8 in association with p63 or p40 provides an accurate distinction of SCNs.

The histogenesis and clinical significance of solid cell nests (SCN) of the thyroid are not fully understood. From August 1987 to December 1989 a total of 2544 patients with thyroid and parathyroid diseases underwent surgery at Ito Hospital, and SCN were revealed within the thyroid parenchyma in 21 (0.8%). Distribution of SCN was not limited to the upper one-third of the lateral lobe, and SCN were found even in the isthmus lobe. In 5 cases microcysts were also noted within SCN, and their content was thought to be acidic proteoglycan. Immunohistochemical study revealed that SCN were negative for thyroglobulin and calcitonin but positive for carcinoembryonic antigen. Thirteen of 21 cases showed positive immunostaining with cytokeratin. Scattered calcitonin-positive cells were noted around the SCN. It is suggested from these findings that SCN of the thyroid are closely related to certain cells of ultimobranchial body vestiges which may be not of neuroectodermal origin but of endodermal origin.

Solid cell nests are generally believed to represent remnants of the ultimobranchial body, which can be found in the normal thyroid gland, occasionally associated with other branchial pouch remnants such as salivary gland, cartilage, and adipose tissue. We describe the case of a 44-year-old man incidentally found to have a large tumor in the left lobe of the thyroid. The tumor was a circumscribed growth consisting of distinctly lobulated proliferation of solid to cystic epidermoid cell nests and thyroid follicles in a fibromatous stroma, which merged into abundant adipose tissue and focally myxoid matrix. The solid epidermoid cell nests resembled solid cell nests and exhibited a p63+, GATA3+, galectin-3+, TTF1-, PAX8-, thyroglobulin- phenotypes, while the follicles were p63-, GATA3-, galectin-3-, TTF1+, PAX8+, and thyroglobulin+. RAS mutations were not found. This thyroid tumor may represent a hitherto undescribed "ultimobranchial body adenoma" in human.

A histologic and immunohistochemical study was performed to identify the histogenesis of solid cell nests (SCN), which were found incidentally in 11 thyroid glands obtained by surgery. Histologically, SCN consisted of small nests showing solid and cystic structures. Cystic features of SCN were found in 3 of the 11 cases (27%), with mucinous materials in their lumens. Some goblet cells were also present in three cases (27%). In one case, SCN were associated with lymphocyte aggregation. Immunohistochemical analysis using serial sections of the SCN showed that the cells comprising SCN were positive for calcitonin in 5 cases (45%), for carcinoembryonic antigen (CEA) detected using polyclonal antibody in 11 (100%), for CEA detected using monoclonal antibody in 3 (27%), for calcitonin gene related peptide in 2 (18%), for chromogranin A in 5 (45%), and for keratin in 11 (100%). These antigens were expressed concomitantly in the same SCN, but the number and distribution of the positive cells for the antigens were different for each antigen in the same SCN in each case. These findings strongly support the view that SCN are derived from the ultimobranchial body. In addition, the biologic function to produce the antigens may vary greatly in individual cells comprising SCN.

Solid cell nests (SCN) associated with Hashimoto's thyroiditis may show some atypical nuclear features including prominent nuclear grooves, enlarged overlapping nuclei and nuclear clearing. These features are sometimes mistaken for papillary thyroid microcarcinomas especially when the SCN are numerous. We reviewed SCN associated with Hashimoto's thyroiditis in 12 patients selected from 1,420 archival routinely processed formalin-fixed, paraffin-embedded thyroid specimens of Hashimoto's thyroiditis in which there was more than ten SCN per slide. In addition to the atypical nuclear features, there was a distinct eosinophilic basement membrane surrounding the SCN. Immunohistochemical analysis showed that the SCN were strongly positive for p63, stained weakly for TTF-1 and were negative for thyroglobulin, HBME-1, and calcitonin. This was compared to papillary thyroid microcarcinomas which were strongly positive for thyroglobulin, TTF-1, HBME-1, and variably positive for p63, while calcitonin and chromogranin were negative. These histological and immunophenotypic features can be used to distinguish SCN from papillary thyroid microcarcinomas associated with Hashimoto's thyroiditis.

BRAF mutation in solid cell nest hyperplasia associated with papillary thyroid carcinoma. A precursor lesion?

Thyroid tubercle of Zuckerkandl (TZ) is a nodule arising from the posterolateral thyroid, considered to be a remnant of the ultimobranchial body (UB). Considering that C cells and solid cell nests also arise from the UB, we hypothesized that these would be present in the TZ. We examined the presence of C cells and solid cell nests in the TZ using the histological analyses of 21 patients with grade 2 or 3 TZs following Pelizzo’s grading system. Out of 21 TZs, 19 (90.5%) were located in the right lobe of the thyroid. Microscopically, solid cell nests were found within the TZ in 1 case (4.8%), and within the main thyroid tissues in 3 cases (14.3%). Calcitonin-positive C cells were scattered within the TZ in 1 case (4.8%), and within the main thyroid tissue in 15 cases (71.4%). The distribution of C cells within the main thyroid tissue was denser than that within the TZ. The above-mentioned results indicated the lack of C cells and solid cell nests in the TZ. Although the TZ may have an embryological origin different from that of ordinary thyroid tissue, it is unlikely that the remnants of the UB are involved in the formation of the TZ.

Carcinoma showing thymus-like differentiation (CASTLE) is a rare intrathyroidal neoplasm, a member of a tumor family probably arising from ectopic thymus or branchial pouch remnants. Thyroid solid cell nests (SCNs) may also be derived from branchial pouch remnants. SCNs express p63, carcinoembryonic antigen (CEA), and high molecular weight keratin (HMWK). To determine whether CASTLE and SCNs derive from similar embryologic origins/lines of differentiation, and to better differentiate CASTLE from other thyroid neoplasms, we compared p63, CD5, HMWK, and CEA staining of CASTLE and SCNs with other thyroid and thymic lesions. Seven CASTLE, 11 SCNs, 10 thymic carcinoma, 11 invasive thymoma, 12 thymoma, 28 papillary thyroid carcinoma, 4 thyroid squamous cell carcinoma, 2 childhood sclerosing carcinoma, 4 follicular adenoma, 6 follicular carcinoma, 4 poorly differentiated carcinoma, and 20 lymphocytic thyroiditis cases were analyzed. In normal thyroid, only SCNs stained for p63, HMWK, and CEA. The only CD5-positive cells in normal thyroid were T cells. Thymomas and normal thymus stained similarly to SCNs. All CASTLE and thymic carcinomas exhibited diffuse p63 and HMWK staining and all CASTLE cases and the majority of thymic carcinomas were positive for CEA and CD5. In contrast, none of the other thyroid neoplasms examined exhibited consistent staining for all 4 markers studied. These findings provide further evidence that CASTLE is distinct from other thyroid neoplasms, is probably of thymic origin, and may arise from branchial pouch remnants, the thyroid SCNs. Moreover CD5, HMWK, CEA and p63 can be used to help distinguish CASTLE from other thyroid neoplasms.

A systematic anatomical study of 100 adult human thyroids from autopsies was undertaken for the presence of solid cell nests (SCN). SCN were mainly located in the middle third, with a slight tendency to the upper third, of the lateral thyroid lobes, and placed along a central to paracentral and slightly dorsal longitudinal axis. Immunohistochemical studies for thyroglobulin revealed positive staining in follicular cells connected to SCN and, occasionally, in isolated cells lying within solid clusters from SCN. The anatomical position SCN showed in the present survey is comparable to that shown by the ultimobranchial body (UB) vestiges of human fetuses. The presence of thyroglobulin-positive cells within solid clusters, together with the existence of follicular cells connected to SCN, suggest that SCN may also be a probable source of follicular epithelium as occurs with the UB of some mammals.