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Year : 2017  |  Volume : 60  |  Issue : 3  |  Page : 430-432
Metastasis within a metastasis to the thyroid: A rare phenomenon

1 Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
2 Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia

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Date of Web Publication22-Sep-2017


Metastatic disease involving the thyroid gland is uncommon. Solitary thyroid metastases from various primary sites particularly kidney, lung, and breast had been previously described. To the best of our knowledge, metastases from two topographically separate primary malignancies to the thyroid have never been documented hitherto. This is the first reported case of cancer-to-cancer metastasis involving an invasive breast carcinoma metastasized within a metastatic renal cell carcinoma in the nonneoplastic thyroid in a 58-year-old woman. Distinguishing a secondary thyroid metastases from a primary thyroid malignancy is utmost crucial as treatment differs. The possibility of tumor metastases from two separated primaries should always be considered in a tumor exhibiting malignant cell populations with two distinctive histomorphological appearances. The role of immunohistochemistry stains in equivocal cases cannot be overemphasized.

Keywords: Cancer-to-cancer metastases, clear cell renal cell carcinoma, invasive breast carcinoma, thyroid

How to cite this article:
Wong YP, Affandi KA, Tan GC, Muhammad R. Metastasis within a metastasis to the thyroid: A rare phenomenon. Indian J Pathol Microbiol 2017;60:430-2

How to cite this URL:
Wong YP, Affandi KA, Tan GC, Muhammad R. Metastasis within a metastasis to the thyroid: A rare phenomenon. Indian J Pathol Microbiol [serial online] 2017 [cited 2021 Jul 23];60:430-2. Available from: https://www.ijpmonline.org/text.asp?2017/60/3/430/215370

   Introduction Top

Secondary involvement of thyroid glands by a remote primary malignancy is uncommon despite it being a richly vascularized organ. It accounts for <4% of all thyroid malignancies identified in the clinical settings.[1] Frequently observed primary sites include kidney, breast, and lung malignancies.[1] To the best of our knowledge, metastases from two topographically separate primary malignancies to the thyroid have never been documented hitherto. Cancer-to-cancer metastasis occurring within a nonneoplastic thyroid gland is an exceptional finding. This is the first description of an intrathyroidal cancer-to-cancer metastasis from invasive breast carcinoma metastasizing into metastatic renal cell carcinoma (RCC) within a thyroid of a 58-year-old woman. Histological differential diagnosis and well-accepted hypothesis regarding the pathogenesis of this unusual phenomenon are briefly discussed.

   Case Report Top

The patient was a 58-year-old woman, with background history of concurrent invasive carcinoma of no special type (NST) of the left breast and clear cell RCC of the left kidney, presented to us with progressively enlarging anterior neck swelling 8 years postcurative surgery (mastectomy and nephrectomy) and chemotherapy. Sonography of the neck revealed multiple heterogeneous hypoechoic thyroid nodules in both lobes with solid and cystic areas. In the light of this findings and high clinical suspicion of malignancy, total thyroidectomy and selective node dissection were performed.

Grossly, the thyroid appeared lobulated on the surface, weighing 87 g. Serial sections revealed multiple yellowish firm tumor nodules in both lobes with measurement ranging from 5 to 55 mm in largest diameter. Adjacent unremarkable residual thyroid tissue was seen at the periphery [Figure 1]a.
Figure 1: Gross and histological section from thyroid nodule. (a) Yellowish firm tumor nodule with variegated cut surface with adjacent residual thyroid tissue at the periphery (arrow); (b) Sheets of malignant clear cells (arrow) with adjacent unremarkable colloid-filled thyroid follicles (H and E, ×40); (c) Malignant clear cells with round nuclei and inconspicuous nucleoli with abundant clear cytoplasm, arranged in nests separated by capillary-rich vascular network (H and E, ×200); (d) Occasional pseudofollicles filled with erythrocytes are seen (H and E, ×400); (e and f) Second distinct malignant component (asterisk) with adjacent malignant clear cell population, displaying moderate nuclear pleomorphism with prominent nucleoli and eosinophilic cytoplasm (H and E, ×200; ×600)

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Histopathological examination of the tumor nodules revealed two distinct populations of malignant cells with adjacent unremarkable colloid-filled thyroid follicles. The first population composed of malignant cells arranged in nested pattern separated by rich capillary vascular network [Figure 1]b. The malignant cells displayed hyperchromatic round nuclei with inconspicuous nucleoli, and abundant glycogen-rich cytoplasm [Figure 1]c confirmed with periodic acid-Schiff (PAS) with diastase digestion. Areas of erythrocytes-filled pseudofollicles are seen [Figure 1]d. Within them, a second population of malignant cells were noted, arranged in small clusters. They exhibited moderate nuclear pleomorphism, vesicular nuclei with prominent nucleoli, and eosinophilic cytoplasm [Figure 1]e and [Figure 1]f.

A panel of immunohistochemical stains were performed: CD10 [Figure 2]a, RCC marker [Figure 2]b, oestrogen receptor (ER) [Figure 2]c, mammaglobin [Figure 2]d, thyroid transcription factor-1 (TTF-1), and thyroglobulin. Immunoreactivity for CD10 and RCC marker was seen in the clear cell malignant component, while they displayed mammaglobin and ER immunonegativity suggestive of kidney in origin. On the other hand, the second malignant component exhibited mammaglobin and ER immunopositivity and was negative for CD10 and RCC marker, findings identical to those of primary breast malignancy. Both malignant cell populations demonstrated TTF-1 and thyroglobulin immunonegativity, excluding a primary thyroid neoplasm. The immunohistochemistry staining pattern confirmed the diagnosis of intrathyroidal cancer-to-cancer metastasis, involving invasive breast carcinoma, NST metastasizing into metastatic RCC within a nonneoplastic thyroid gland.
Figure 2: Immunohistochemistry staining pattern for intrathyroidal cancer-to-cancer metastasis (×400). The malignant clear cell component (asterisk) showed immunoreactivity for (a) CD10 and (b) renal cell carcinoma marker and were negative for (c) oestrogen receptor and (d) mammaglobin. A reverse staining pattern was observed in the second malignant component (CD10-, renal cell carcinoma marker-, oestrogen receptor+, mammaglobin+), consistent with primary malignancies from kidney and breast

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   Discussion Top

Metastasis from one malignant tumor to another, i.e., cancer-to-cancer metastasis (traditionally referred to as tumor-to-tumor metastasis) within the same individual is exceedingly uncommon, but a well-recognized entity. Cancer-to-cancer metastasis was first described by Berent in 1902 illustrating a case of metastatic squamous cell carcinoma from the jaw into RCC.[2] Since then, approximately 150 cases had been reported in the English literature thus far.

It is fundamental to distinguish cancer-to-cancer metastasis from collision metastasis, which is resultant from metastasis of two topographically separated tumors that successively collide and juxtapose with one another.[3] Diagnostic criteria for cancer-to-cancer metastasis that were asserted by Campbell et al.[2] to differentiate between these two entities are as follows: (i) coexistence of two or more independent primary malignancies; (ii) the recipient neoplasm must be a true neoplasm as defined by Robertson;[4] (iii) the donor neoplasm must be a true metastasis, not the result of direct contiguous spread; and (iv) exclude tumors that have metastasized to the lymphatic system.[2] Our case met these stringent criteria.

While lung adenocarcinoma reported being the most common donor tumor, followed by breast, prostate, and thyroid malignancies, clear cell RCC is the most frequent recipient encountered, followed by meningioma and thyroid neoplasms.[5] The pathogenesis of the occurrence of cancer-to-cancer metastasis to clear cell RCC remains debatable, due to lacking of detailed analysis on their occurrence. Two hypotheses have been proposed.[6] The “seed and soil” theory proposes that a lipid- and glycogen-rich recipient cell microenvironment (the “soil”) in clear cell RCC provides a “fertile” ground for the successful growth and propagation of metastatic tumor cells (the “seed”). The “anatomical-mechanical” theory postulates that the rich vascular architecture and high blood flow received by the recipient tumors (such as clear cell RCC) allow successful deposition of circulating metastatic tumor cells.[6]

In contrast, being one of the most richly vascularized organs, the low occurrence of secondary thyroid metastases is intriguing.[1] Primary thyroid neoplasm, a more common entity, needs to be excluded before considering a secondary thyroid metastasis. These include follicular adenoma, follicular carcinoma, and papillary carcinoma which sometimes display clear cell component.[7] Clear cell RCC characteristically shows the presence of neoplastic cells arranged in small nests and cords separated by prominent vascular stroma. Occasional pseudofollicular pattern filled with erythrocytes that is typically seen in RCC is helpful in making a distinction.[7] Demonstration of intracytoplasmic glycogen (PAS-positive, diastase-sensitive) and absence of mucin (PAS-positive, diastase-resistant) favor the diagnosis of RCC. On the contrary, thyroid tumors with clear cells do not display intracytoplasmic glycogen, but contain PAS-positive, diastase-resistant colloid material.[8]

Metastatic clear cell adenocarcinoma from the lung potentially masquerades as RCC. Classically, they composed of cords and trabeculae of malignant clear cells separated by fibrovascular septae. However, these tumors can be easily discernible by their immunohistochemistry profile since clear cell lung adenocarcinoma is immunoreactive for TTF-1 and is negative for CD10 and RCC marker.[9]

Meanwhile, the second malignant component composed of poorly differentiated carcinoma, virtually indistinguishable from poorly differentiated primary thyroid malignancies. Immunohistochemistry stains allow precise determination of tumor origin, in the right clinical context. Given the history of breast carcinoma and RCC in the past as in the present case, we managed to accurately determine the site of tumor origin with a panel of immunohistochemistry stains (CD10, RCC marker, mammaglobin, ER, TTF-1, and thyroglobulin). The majority of RCCs typically show CD10 and RCC marker immunopositivity; breast carcinomas are immunoreactive for ER and mammaglobin and very occasionally for RCC marker, while thyroid neoplasms demonstrate TTF-1 and thyroglobulin immunoreactivity.[10]

Although it is generally agreed that multiple metastases to any system organs bring dismal prognosis, due to the rarity of such cases, their biological behavior remains uncertain. This also poses a considerable challenge in determining the most appropriate therapeutic approach in such patients.[11]

In summary, distinguishing a secondary thyroid metastases from a primary thyroid malignancy is utmost crucial as treatment differs. Although very rare, the possibility of tumor metastases from two separated primaries should always be considered in a tumor exhibiting bimodal histomorphological appearances. The role of immunohistochemistry stains in equivocal cases cannot be overemphasized.


We would like to thank all the laboratory staffs of Universiti Kebangsaan Malaysia Medical Center for their excellent technical support.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Hegerova L, Griebeler ML, Reynolds JP, Henry MR, Gharib H. Metastasis to the thyroid gland: Report of a large series from the mayo clinic. Am J Clin Oncol 2015;38:338-42.  Back to cited text no. 1
Campbell LV Jr., Gilbert E, Chamberlain CR Jr., Watne AL. Metastases of cancer to cancer. Cancer 1968;22:635-43.  Back to cited text no. 2
Anlyan FH, Heinzen BR, Carras R. Metastasis of tumor to second different tumor: Collision tumors. JAMA 1970;212:2124.  Back to cited text no. 3
Robertson HE. Tumor nomenclature – Suggestions for its revision. Am J Clin Pathol 1939;9:24-35.  Back to cited text no. 4
Gowda KK, Bal A, Agrawal P, Verma R, Das A. Tumor-to-tumor metastasis: Small cell carcinoma lung metastasising into a follicular adenoma of the thyroid. Indian J Pathol Microbiol 2017;60:133-5.  Back to cited text no. 5
[PUBMED]  [Full text]  
Mathot L, Stenninger J. Behavior of seeds and soil in the mechanism of metastasis: A deeper understanding. Cancer Sci 2012;103:626-31.  Back to cited text no. 6
Wieczorek TJ, Pinkus JL, Glickman JN, Pinkus GS. Comparison of thyroid transcription factor-1 and hepatocyte antigen immunohistochemical analysis in the differential diagnosis of hepatocellular carcinoma, metastatic adenocarcinoma, renal cell carcinoma, and adrenal cortical carcinoma. Am J Clin Pathol 2002;118:911-21.  Back to cited text no. 7
Mcmanus JF. Histological and histochemical uses of periodic acid. Stain Technol 1948;23:99-108.  Back to cited text no. 8
Kavunkal AM, Raju V, Shah SY, Cherian VK. Clear cell adenocarcinoma of the lung: The wolf in sheep's clothing. Indian J Thorac Cardiovasc Surg 2008;24:206-8.  Back to cited text no. 9
Lester SC. Special studies. In: Houston MJ, editor. Manual of Surgical Pathology. 2nd ed. Philadelphia: Elsevier; 2006. p. 103-40.  Back to cited text no. 10
Hayat MJ, Howlader N, Reichman ME, Edwards BK. Cancer statistics, trends, and multiple primary cancer analyses from the surveillance, epidemiology, and end results (SEER) program. Oncologist 2007;12:20-37.  Back to cited text no. 11

Correspondence Address:
Yin Ping Wong
Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_287_16

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