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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1615-1620
Copyright © 1997 by The Endocrine Society

Endocrinological Oncology

In Situ Evidence of Neoplastic Cell Phagocytosis by Macrophages in Papillary Thyroid Cancer1

Antonino Fiumara, Antonino Belfiore, Giovanna Russo, Edvige Salomone, Gabriella M. Santonocito, Orazio Ippolito, Riccardo Vigneri and Pietro Gangemi

Servizio di Anatomia ed Istologia Patologica, Presidio Ospedaliero Vittorio Emanuele II; and Istituto di Medicina Interna e di Malattie Endocrine e Metaboliche, Cattedra di Endocrinologia (A.B., G.M.S., R.V.), and Cattedra di Chirurgia (O.I., R.V.), University of Catania, Catania, Italy 95123

Address all correspondence and requests for reprints to: Antonino Belfiore, M.D., Istituto di Medicina Interna e di Malattie Endocrine e del Metabolismo, Cattedra di Endocrinologia, P.zza S. Maria di Gesù 1, 95123 Catania, Italy. E-mail: endo.uni.ct{at}mail.tau.it


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We evaluated the occurrence, tissue distribution, and prognostic value of tumor-associated macrophages in 121 papillary thyroid carcinomas using immunohistochemical staining with anti-CD68 antibody in archival paraffin-embedded sections. Lymphocytic infiltration and dendritic cell presence were also evaluated. Three groups were identified according to the presence and characteristics of macrophages: 1) tumors without evidence of infiltrating macrophages: (n = 35); 2) tumors with infiltrating macrophages but no evidence of neoplastic cells phagocytosis (n = 68); and 3) tumors with infiltrating macrophages and in situ evidence of active neoplastic cell phagocytosis (n = 18).

Neoplastic cell phagocytosis by macrophages was positively correlated with both lymphocytic infiltration and dendritic cells (P = 0.0000), whereas it was negatively correlated with vascular invasion (P = 0.0032). Distant metastases developed in none of the 18 tumors with neoplastic cell phagocytosis, but occurred in 15 of 103 of the remaining tumors (P = 0.0647) and were significantly and negatively associated with lymphocytic infiltration or dendritic cells.

The present study indicates, therefore, that immune reaction, involving neoplastic cell phagocytosis by macrophages and lymphocytic infiltration, plays a role in the development of distant metastases in patients with papillary thyroid cancer.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
MACROPHAGES and lymphocytic infiltrates may be found in the context of or surrounding a variety of malignancies and are commonly believed to represent the host’s immune response to the tumor (1). According to this view, a more favorable clinical evolution has been reported in various malignancies when associated with dense lymphocytic infiltrates (1). Less defined is the role of tumor-associated macrophages, which represent a major component of the lymphoreticular infiltrates of tumors (2). As it is difficult to identify macrophages in conventionally stained tissue sections, few studies have addressed the distribution and characteristics of tumor-associated macrophages. The role of tumor-associated macrophages has, therefore, been studied mainly in in vivo models (2).

Papillary cancer of the thyroid is a particularly suitable model to study tumor-associated macrophages, because it is frequently associated with signs of immune reaction, including lymphocytic infiltration (3) and the presence of dendritic cells (4). Furthermore, molecules involved in the immune reaction, such as intercellular adhesion molecule and/or HLA class II molecules may be aberrantly expressed in transformed thyrocytes both in vivo and in vitro (5, 6, 7).

Therefore, we studied the tissue distribution and prognostic significance of tumor-associated macrophages in a retrospective series of 121 papillary thyroid carcinomas. Macrophages were identified by immunohistochemistry, with the specific antibody anti-CD68, in paraffin-embedded tissue sections (8, 9). We found tumor-infiltrating macrophages in approximately 70% of the cases. Interestingly, phagocytosis of neoplastic cells by macrophages was observed in approximately 15% of tumors, and none of these tumors developed distant metastases. These data suggest that macrophages may affect papillary thyroid cancer progression and, therefore, may be important targets for future immunotherapy.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues and patients

The study was carried out in archival, paraffin-embedded tissues from 121 patients with thyroid papillary cancer. All patients had undergone total thyroidectomy plus pre- and paratracheal lymph node dissection. Postsurgery, distant metastases were diagnosed when, in addition to high serum thyroglobulin levels, the metastatic tissue was localized by total body scanning and, in most cases, by other imaging tests (standard x-rays, computed axial tomography scan, nuclear magnetic resonance imaging, and bone scan). Diagnosis of regional lymph node recurrence was made when ultrasound evidence of suspicious lymph nodes was confirmed by either radioiodine uptake or a cytological finding of neoplastic epithelial cells and/or high thyroglobulin levels in the aspirates.

Patients were classified for the extent of disease at presentation as previously described (10): class I, 41 patients with intrathyroid disease; class II, 24 patients with positive cervical lymph nodes; class III, 50 patients with extrathyroid tumor invasion; and class IV, 6 patients with distant metastases. The follow-up time of the 121 patients ranged from 25–118 months (median, 63).

Histopathological examination

The diagnosis of papillary carcinoma was made according to the WHO criteria (11, 12). For each case all histological slides were reviewed, including multiple sections of all excised neoplastic and nonneoplastic thyroid tissue and lymph nodes. The occurrence of peritumoral lymphocytic infiltrate and/or concomitant Hashimoto’s thyroiditis was recorded.

Immunohistochemical staining procedure

Monoclonal antibody anti-CD68, PGM1 clone, was used to identify macrophages (9). It was used at a 1:100 dilution after treatment with trypsin (0.5 mg/mL). An anti-S-100 protein polyclonal antibody (1:300 dilution) was used to stain dendritic cells (4). Anti-epithelial membrane antigen (EMA) monoclonal antibody, E29 clone, was used (1:100 dilution) as a marker of thyroid epithelial cells (13). Anti-CD20 and anti CD45-RO antibodies were used to identify B and T lymphocytes, respectively. All antibodies were obtained from Dako (Copenhagen, Denmark).

Paraffin-embedded sections were deparaffinized, incubated with approximately 100 µL of the primary antibody at room temperature for 30 min, and then processed for the biotin-streptavidin-peroxidase method using 3-amino-9-ethylcarbazole as substrate. Counterstaining was carried out with Mayer’s hematoxylin. Negative controls included omission of the primary antibody. In selective cases a double immunohistochemical staining was carried out using as first layer the anti-CD68 antibody followed by a biotinylated antibody and streptavidin-peroxidase plus 3-amino-9-ethylcarbazole as revealing system. The anti-EMA antibody was used as the second primary antibody, and the reaction was developed by the alkaline phosphatase method using as substrate 5-bromo-4-cloro-3-indoxil phosphate/nitro blue tetrazolium chloride.

Statistical analysis

The distribution of clinicopathological characteristics was compared in the different groups with the use of contingency tables and {chi}2 test. The relationship between metastasis-free interval and covariates as well as hazard ratios were calculated with the Cox proportional hazard regression model (14). A Cox multivariate analysis, including all relevant prognostic factors indicated by univariate analysis, was carried out using the occurrence of distant metastases as the end point. Kaplan-Meier plots were used to demonstrate the difference in the risk to develop distant metastases between groups, and the log rank test used to evaluate the differences between curves.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Characteristics of tumor-infiltrating macrophages in papillary thyroid tumors

According to results obtained by staining sections with anti-CD68 monoclonal antibody, the 121 papillary thyroid carcinomas were subdivided into 3 groups.

Tumors without evidence of infiltrating macrophages. Thirty-five of 121 (28.9%) cases were included in this group. Low degree lymphocytic infiltrate was present in 5 cases. Dendritic cells were present in 7 cases (20%). They were always located in the papillar axis in close contact with the basal membrane and were often interdigitating the neoplastic cells lining the papillary structures.

Tumors with infiltrating macrophages but no evidence of neoplastic cells phagocytosis. Sixty-eight of 121 (56.2%) cases were included in this group. Either mononucleated macrophages or giant multinucleated cells, foreign body type, were present. Accordingly, 2 subgroups were identified. The first group consisted of 44 of 121 (36.4%) tumors with mononucleated macrophages. CD68-positive cells could morphologically be distinguished into 2 subtypes: a) small monocyte-like cells with intensely positive cytoplasm and small round nucleus; these cells were located in the papillar axis or in the interfollicular stroma (Fig. 1AGo) and sometimes were seen in the process of migrating through the basal membrane; and b) medium/large mononucleated cells with a CD68-positive granule-rich cytoplasm and a round or kidney-shaped nucleus; these cells were scattered in the papillar axis (especially medium size cells) or were located in the interpapillar or in the follicular lumen (especially large cells). In some cases, they were associated with regressive changes (hemorrhage and calcifications). In other cases, in the absence of regressive changes, large mono- or binucleated cells were located in the interpapillar lumen in close contact with neoplastic thyrocytes (Fig. 1BGo). In this group of tumors lymphocytic infiltrate was present in 25 of 44 (56.8%) cases, and dendritic cells were present in 19 of 44 (43.2%) cases. The second group consisted of 24 of 121 (19.8%) tumors with giant multinucleated cells, foreign body type. In these cells immunostaining was mostly granular, sometimes diffuse, and less intense than that in mononucleated macrophages. Monolayer sheets of epithelial neoplastic cells with regressive changes partially covered by CD68-positive coarse granules were sometimes observed in the interpapillar lumen. Serial sections showed that granule exocytosis from macrophages probably caused this phenomenon. In this group, lymphocytic infiltrate was observed in 18 of 24 (75.0%) cases, and dendritic cells were present in 15 of 24 (62.5%) cases.



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  		Figure 1. Micrographs showing different phases of neoplastic cell phagocytosis by macrophages in papillary cancer of the thyroid. Immunohistochemical staining was carried out with anti-CD68 antibody in (A, B, D, E, and G), with anti-EMA antibody (H), and with the two antisera (CD68, red; EMA, black; E and F). Original magnification: A, x200; B–H, x400. A, Mononucleated macrophages scattered in the stroma; B, CD-68-positive mononucleated macrophages, in the process of fusing and sequestering neoplastic thyrocytes; C, D, F, H, multinucleated macrophages contacting neoplastic thyrocytes which shed into the interpapillary lumen; G and H, phagocytosis of neoplastic thyrocytes by one (G) or two multinucleated macrophages in the process of fusing (E).\.

 
Tumors with infiltrating macrophages and in situ evidence of active neoplastic cell phagocytosis. Eighteen of 121 (14.9%) tumors were included in this group. These tumors were characterized by the presence of multinucleated CD68-positive cells. Large multinucleated (5–10 nuclei) cells with large CD68-positive coarse cytoplasmic granules were present in the interpapillar or intrafollicular lumen of these tumors (Fig. 1Go, C–H). Some of them contacted the neoplastic cells with pseudopodia (Fig. 1DGo), some showing one or more phagosomes containing one or more neoplastic cells (Fig. 1Go, E–G). Neoplastic cells contacted by macrophages appeared of large size, polygonal, intensely EMA positive, and detached from adjacent cells (Fig. 1HGo). EMA positivity was gradually lost in thyroid neoplastic cells when they were included in a phagosome. Lymphocytes, either in contact with macrophages or within a phagosome, were frequently observed. Mononucleated macrophages and giant multinucleated cells, foreign body type, may also be present in these tumors. Lymphocytic infiltration was observed in 15 cases (83.3%), and dendritic cell infiltration was seen in 17 cases (94.4%).

Association with autoimmune thyroiditis

In 10 cases thyroid cancer was associated with histological evidence of diffuse lymphocytic thyroiditis. Nine of these cases also had circulating antithyroid antibodies. All patients were euthyroid, except one with subclinical hypothyroidism (TSH, 7.5 mol/L; normal, 0.3–4.5). Tumor-associated lymphocytes (typically represented by T cells, some of them migrating into the interpapillary or the intrafollicular lumina and in close contact with macrophages) were present in 8 cases, dendritic cells in 5, and nonphagocytosing macrophages in 8. At variance with tumor-associated lymphocytes, typical thyroiditis infiltrate was predominantly represented by B cells with scattered T cells and by germinal centers (a nucleous of B cells surrounded by T cells).

Tumor characteristics at presentation and tumor outcome in relation to tumor-associated macrophages

The presence of macrophages and neoplastic cell phagocytosis was positively associated with both lymphocytic infiltration and the presence of dendritic cells (P = 0.000) and was negatively associated with vascular invasion (P = 0.0032; Table 1Go). A more advanced disease (classes III and IV) was observed in tumors without macrophages compared to those with neoplastic cell phagocytosis (group 1 vs. group 3, P = 0.0425; Table 2Go).


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  		Table 1. Association between tumor-infiltrating macrophages and neoplastic cell phagocytosis with clinical and pathological papillary thyroid cancer characteristics in patients at the time of primary surgery

 

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  		Table 2. Tumor stages in patients with papillary tumors subdivided on the basis of the characteristics of infiltrating macrophages

 
To evaluate tumor outcome, we used as end point the occurrence of distant metastases, an event strongly associated with tumor-related deaths (15). The cumulative frequency of distant metastases was 6 of 35 (17.1%) in group 1, 9 of 68 (13.2%) in group 2, and 0 of 18 in group 3 (P = 0.0647, group 1 vs. group 3, by log rank test; Fig. 2AGo).



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  		Figure 2. Cumulative risk (Kaplan-Meyer plots) of distant metastases in patients with papillary carcinomas according to macrophages (A), lymphocytic infiltration (B), and dendritic cells (C).

 
Distant metastases occurred more frequently in tumors without lymphocytic infiltration than in those with lymphocytic infiltration (14 of 58 = 24.1% vs. 1 of 63 = 1.6%; P = 0.0012, by log rank test; Fig. 2BGo). Also, distant metastases occurred in 13 of 63 (20.6%) tumors without dendritic cells and in 2 of 58 (3.4%) with dendritic cells (P = 0.0102, by log rank test; Fig. 2CGo). Other established risk factors (age, sex, tumor size, and extrathyroid tumor extension) were also significant predictors of distant metastases at univariate analysis (Table 3Go). No distant metastases occurred in the group with lymphocytic thyroiditis. The exclusion of this group from the statistical analysis did not appreciably change the results.


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  		Table 3. Univariate analysis (Cox regression model) of patients with papillary thyroid carcinoma according to clinicopathological variables, using distant metastases as an end point

 
At Cox multivariate analysis only three variables were significantly related to the risk of developing distant metastases: lymphocytic infiltration (inversely related; P = 0.0054) and extrathyroid extension and age (directly related; P = 0.0255 and P = 0.0128, respectively; Table 4Go).


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  		Table 4. Multivariate analysis (Cox regression model) of patients with papillary thyroid carcinoma according to clinical and pathological variables, using distant metastases as an end point

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study we demonstrate in situ phagocytosis of neoplastic cells by tumor-infiltrating macrophages in a substantial proportion (15%) of papillary thyroid carcinomas. In addition, another 56% of papillary cancers had infiltrating macrophages but no evidence of neoplastic cell phagocytosis. No infiltrating macrophages were detected in the remaining tumors studied. Neoplastic cell phagocytosis was observed only in the interpapillary or the intrafollicular lumen, and only multinucleated macrophages were involved in the phagocytosis process. Neoplastic cell phagocytosis was strongly associated with the presence of dendritic cells and lymphocytic infiltration, suggesting, therefore, that it is part of the complex immunological host reaction to the cancer. Tumor necrosis, in contrast, was never associated with lymphocytic infiltration, dendritic cells, or phagocytosing multinucleated large macrophages.

Immune recognition and control of papillary cancer have been suggested (3, 16), and these are supported by both the fairly frequent finding of this tumor at the in situ stage when autopsy screening is carried out (17) and the frequent association of this slowly progressing tumor with the presence of autoimmune thyroiditis (18). Papillary cancers have also been shown to have a better cell-mediated immune response compared to controls and to follicular cancers. In particular, they have the highest proportion of activated monocytes and the highest activity in the leukocyte adherence inhibition assay (19).

In the last decade, tumor-associated macrophages have been studied in a variety of human malignancies using different immunohistochemical markers (20, 21). To the best of our knowledge, however, evidence of in situ neoplastic cells phagocytosis by macrophages has been reported only as an occasional finding (22, 23, 24). One possible explanation is that sensitive techniques were not used. Another possible explanation is that neoplastic cell phagocytosis occurs with a discrete frequency in only some tumors. As pathological examination reflects the tissue in a steady state at the moment of surgical resection, and phagocytosis is a dynamic and short lasting process, it is possible that this phenomenon is overlooked unless it is present at a high rate. When neoplastic cell phagocytosis is minimal, only mononucleated or giant/foreign body type cells may be observed.

The present observations suggest that the activation of the macrophage response may affect tumor behavior in papillary thyroid cancer. In our series, the presence of neoplastic cell phagocytosis by macrophages was associated with a less advanced tumor stage at presentation and with a trend for a reduced risk of distant metastases at follow-up (P = 0.0647). Furthermore, lymphocytic and dendritic cell infiltration were both strongly associated with neoplastic cell phagocytosis by macrophages, and both were associated with a favorable outcome, as previously reported (4, 25).

The mechanisms underlying the negative association between neoplastic cell phagocytosis by macrophages and distant metastases remains speculative. The negative correlation between phagocytosing macrophages and tumor vascular invasion, on the one hand, and the possible activity of phagocytosing macrophages in destroying micrometastases, on the other hand, are both potential mechanisms (26).

In conclusion, our study confirms that the immune system plays a major role in the clinical evolution of papillary thyroid cancer (3, 4, 25, 27), and together with other biological markers (28), the evaluation of the immune response may be relevant to the management of this tumor. It also indicates that phagocytosing macrophages are an important component of this immune response. Furthermore, our study suggests possible therapeutic strategies for metastatic papillary thyroid cancer by enhancing the tumoricidal activity of macrophages (26).


   Footnotes
 
1 This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro. Back

Received October 18, 1996.

Revised January 17, 1996.

Accepted January 31, 1996.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Underwood JCE. 1974 Lymphoreticular infiltration in human tumours: prognostic and biological implications: a review. Br J Cancer. 30:538–548.[Medline]
  2. Mantovani A, Bottazzi B, Colotta F, Sozzani S, Ruco L. 1992 The origin and function of tumor-associated macrophages. Immunol Today. 13:265–270.[CrossRef][Medline]
  3. Baker J. 1995 The immune response to papillary thyroid cancer. J Clin Endocrinol Metab. 80:3419–3420.[CrossRef][Medline]
  4. Schroeder S, Schwarz W, Rehpenning W, Loning T, Bocker W. 1988 Dendritic/Langherans cells and prognosis in patients with papillary thyroid carcinomas. Immunocytochemical study of 106 thyroid neoplasms correlated to follow-up data. Am J Clin Pathol. 89:295–300.[Medline]
  5. Belfiore A. Mauerhoff T. Pujol-Borrell R, et al. 1991 De novo HLA class II and enhanced HLA class I molecule expression in SV-40 transfected human thyroid epithelial cells. J Autoimmun. 4:397–414.[CrossRef][Medline]
  6. Lucas-Martin A, Foz-Sala M, Todd I, Bottazzo GF, Pujol-Borrell R. 1988 Occurrence of thyrocyte HLA class II expression in a wide variety of thyroid disease: relationship with lymphocytic infiltration and thyroid autoantibodies. J Clin Endocrinol Metab. 66:367–75.[Abstract]
  7. Tolosa E, Roura C, Marti E, Belfiore A, Pujol-Borrell R. 1992 Induction of ICAM-1 but not LFA-3 in thyroid follicular cells. J Autoimmun. 5:1019–1025.
  8. Kaluza J. 1992 The monoclonal antibody (MAB) CD 68 allows the immunocytochemical identification of macrophages in primary and metastatic brain tumors in paraffin embedded tissues. Folia Histochem Cytobiol. 30:125–128.[Medline]
  9. Falini B, Flenghi L, Pileri S, et al. 1993 PG-M1: a new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule. Am J Pathol. 142:1359–1372.[Abstract]
  10. De Groot LJ, Kaplan EL, McCormick M, Strauss FH. 1990 Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab. 71:414–424.[Abstract]
  11. Heidinger C, Williams ED, Sobin LH. 1988 World Health Organization histological typing of thyroid tumors, 2nd ed. Berlin: Springer-Verlag; 9–11.
  12. Rosai J. 1993 Papillary carcinoma. Monogr Pathol. 35:138–165.
  13. Pinkus GS, Kurtin PJ. 1985 Epithelial membrane antigen–a diagnostic discriminant in surgical pathology. Hum Pathol. 74:620–624.
  14. Cox DR. 1972 Regression models and life-tables. J R Stat Soc B. 34:187–202.
  15. Mazzaferri EL. 1993 Thyroid carcinoma: papillary and follicular. In: Mazzaferri L, Samaan NA, eds. Endocrine tumors. Cambridge: Blackwell; 278–333.
  16. Boyd CK, Baker JR. 1996 The immunology of thyroid cancer. Endocrinol Metab Clin North Am. 25:159–179.[CrossRef][Medline]
  17. Bisi H, Fernandes VS, deCamargo RYA, Koch L, Abdo AH, deBrito T. 1989 The prevalence of unsuspected thyroid pathology in 300 sequential autopsies with special references to the incidental carcinoma. Cancer. 64:1888–1893.[CrossRef][Medline]
  18. Haapala AM, Soppi E, Morsky P, Salmi J, Laine S, Mattila J. 1994 Thyroid antibodies in association with thyroid malignancy. Simultaneous occurrence of thyroiditis and thyroid malignancy. APMIS. 102:390–394.[Medline]
  19. Juhasz F, Boros P, Szegedi G, et al. 1989 Immunogenetic and immunologic studies of differentiated thyroid cancer. Cancer. 63:1318–1326.[CrossRef][Medline]
  20. Allen CA, Hogg N. 1987 Association of colorectal tumor epithelium expressing HLA-D/DR with CD8 positive T-cells and mononuclear phagocytes. Cancer Res. 47:2919–2923.[Abstract/Free Full Text]
  21. van Ravenswaay Claasen HH, Kluin PM, Fleuren GJ. 1992 Tumor infiltrating cells in human cancer. On the possible role of CD16+ macrophages in antitumor cytotoxicity. Lab Invest. 67:166–174.[Medline]
  22. Factor SM, Biempica L, Ratner I, Ahuja KK, Biempica S. 1977 Carcinoma of the breast with multinucleated reactive stromal giant cells. Virchows Arch. 374:1–12.
  23. Hashimoto H, Koga S, Watanabe H, Munetobe E. 1980 Undifferentiated carcinoma of the thyroid gland with osteoclast-like giant cells. Acta Pathol Jpn. 30:323–324.[Medline]
  24. Gaffey MJ, Lack EE, Christ ML, Weiss LM. 1991 Anaplastic thyroid carcinoma with osteoclast-like giant cells. A clinicopathologic, immunohistochemical and ultrastructural study. Am J Surg Pathol. 15:160–168.[Medline]
  25. Matsubayashi S, Kawai K, Matsumoto, et al. 1995 The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland. J Clin Endocrinol Metab. 80:3421–3424.[Abstract]
  26. Fidler IJ. 1985 Macrophages and metastases-a biological approach to cancer therapy: presidential address. Cancer Res. 45:4714–4726.[Free Full Text]
  27. Belfiore A, Garofalo MR, Giuffrida D, et al. 1990 Increased aggressiveness of thyroid cancer in patients with Graves’ disease. J Clin Endocrinol Metab. 70:830–835.[Abstract]
  28. Farid NR, Shi Y, Zou M. 1994 Molecular basis of thyroid cancer. Endocr Rev. 15:202–232.[CrossRef][Medline]



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