Multinucleated Giant Cells’ Incidence, Immune Markers, and Significance: A Study of 172 Cases of Papillary Thyroid Carcinoma

Abstract

Multinucleated giant cells (MGCs) are often detected in cases of papillary thyroid carcinoma (PTC). Their origin and significance, however, has not been established. One possibility is that they form in response to injury induced by fine needle aspiration biopsy (FNAB). Other hypotheses are that the chemically-altered colloid produced by PTC induces MGCs to act as colloidophages, or else MGCs are a non-specific immune response ingesting neoplastic follicle cells. We assigned 172 cases of PTC a semi-quantitative score for MGCs. Cases with “many” MGCs were immunohistochemically stained for AEI/AEIII, CD68, and CD163 to assess for epithelial vs histiocytic differentiation, and for thyroglobulin and TTF-1 to assess for MGC ingestion of colloid or thyroid follicle cells respectively. Overall, we identified MGCs in 100/172 (58.1%) PTC specimens; in 45 (26.2%), “many” MGCs were found, while in 55 (31.9%) MGCs were “few.” The mean sizes of PTC in cases with many as opposed to rare/no MGCs was 2.50 cm vs 1.8 [P = 0.003]. The cases of PTC with many MGCs had higher multifocality (26/45 vs 51/127 [P = 0.06]), extrathyroidal extension (21/45 vs 36/127 [P = 0.03]), and recurrence (8/45 vs 9/127 [P = 0.08]), than did cases with rare or no MGCs. The majority of patients both with and without numerous MGCs had previous histories of FNA or hemilobectomy: 40/45 and 99/127 respectively (P = 0.062). The majority of MGCs were positive for CD68 (45/45), CD163 (44/45), thyroglobulin (34/45) and negative for AEI/AEIII (44/45) and TTF-1 (44/45). These results indicate that MGCs in PTC are of histiocytic origin. Cases of PTC with many MGCs have a significantly greater likelihood of extrathyroidal extension and greater tumor size than cases with few/no MGCs. MGCs appear to be functioning largely as colloidophages.

The presence of multinucleated giant cells: Noninvasive follicular thyroid neoplasm with papillary‐like nuclear features vs the follicular variant of papillary thyroid carcinoma

“…Characteristic features of the MGCs include dense cytoplasm, well‐demarcated irregularly shaped cellular boarders and multiple randomly assorted nuclei, and are of the type seen in PTC . This is to be differentiated from MGCs with foamy cytoplasm, smooth cellular boarders and fewer nuclei.…”

“…According to their results, the MGCs contained keratin, supporting an epithelial origin. However, subsequent studies have supported a histiocytic origin, as the MGCs were positive for histiocytic markers including CD 68, CD 163, thyroglobulin, lysozyme and alpha‐1‐antichymotrypsin and negative for epithelial markers including AE1/AE3, TTF‐1, and EMA …”

“…Brooks and colleagues proposed that the chemically altered colloid produced in PTC plays a role in generating the MGC reaction, as noted by the presence of MGCs either within follicles or cystically dilated spaces, regions of colloid deposition. With the advances in immunohistochemical techniques, there is little support for the nonspecific immune response theory …”

CD68/macrosialin: not just a histochemical marker

“…55 CD68 was also used to identify cells of macrophage lineage such as tissue histiocytes, multinucleated giant cells, Kupffer cells, and osteoclasts. 56 CD68 may be used in combination with transcription factor markers, pSTAT1, RBP-J, and CMAF to discriminate M1 and M2 macrophage polarization in vivo. 57 Ultrastructural studies of human atherosclerotic lesions demonstrated that CD68 is mostly located in lysosomes (Figure 3).…”

Histological perspective on the effects of tumor-associated macrophages in the tumor microenvironment surrounding papillary thyroid carcinoma

“…In 1863, Virchow proposed a theory about relationship between the immune response and cancer for the first time [8]. Beginning in the 1980s, studies about the tumor microenvironment and immune response to tumors have revealed that not only the features of the primary tumor but also tumor-related events may affect the prognosis [7,9,10,11,12,13]. On the other hand, immunotherapy models against thyroid carcinoma have been attempted since as early as 1975 [8].…”