MEDICINE

Metastatic Renal Cell NeoplasmWithin a Papillary Thyroid Carcinomaas Incidental Finding in an Asymptomatic Patient: a Case Report

Maria-Rosa Bella-Cueto1& Mireia Pascua-Solé2 & Albert Cano-Palomares3 & M. Àngels Cabezuelo-Hernandez1 &

Maria-Rosa Escoda-Giralt1 & Santiago Barcons-Vilaplana4 & Paula Serret-Miralles1,5 & Carmen Caral-Vanaclocha1 &

Xavier Guirao-Garriga4 & Joan Prats-Lopez6 & Meritxell Medarde-Ferrer2 & Oscar Aparicio-Rodriguez2 &

Mario Prenafeta-Moreno7& Teresa Bonfill-Abella8 & Neus Combalia-Soriano1

Accepted: 11 May 2020# Springer Nature Switzerland AG 2020

AbstractTumor-to-tumor metastasis is a rare phenomenon affecting the thyroid gland. Otherwise, it is not unusual for a neoplasm to bedetected incidentally, without clinical symptoms. But what is exceptionally rare is that a malignant neoplasm debuts as anincidental finding in the form of a tumor-to-tumor metastasis. We contribute with the case of a previously healthy 41-year-oldwoman who presented an asymptomatic 39-mm-sized nodule on the left thyroid lobe in a routine health checkup. Ultrasound-guided fine needle aspiration cytology confirmed a papillary thyroid carcinoma. Because of the size, a total thyroidectomy wasperformed. In the surgical specimen, in addition to a classic papillary carcinoma with an extensive follicular pattern (pT2 pN0), asecond component was identified, consisting of a clear cell population with immunostaining profile of renal origin. Subsequentstudies found a 110-mm-sized left renal mass. A nephrectomy was performed and the pathological exam confirmed a renal cellcarcinoma, pT2 pNX pM1, with metastasis also to the adrenal gland. To our knowledge, this is the first case described of thisclinical presentation involving those two neoplasms. We present herein such an unusual clinical case along with a brief clinicaland pathological review on tumor-to-tumor metastasis, with special emphasis on renal-to-thyroid ones.

Keywords Tumor-to-tumormetastasis . Thyroid . Renal cell carcinoma . Incidental

Introduction

Metastasis to the thyroid gland is a well-known phenomenon,usually identified in autopsy series [1]. A special form of

metastasis is tumor-to-tumor metastasis (TTM), which is de-fined as a malignant neoplasm that metastasizes to anotherbenign ormalignant neoplasm [2]. Although this phenomenonis very rare, it has been described in the thyroid gland [3],

This article is part of the Topical Collection onMedicine

* Maria-Rosa Bella-Cuetorbella@tauli.cat

1 Department of Pathology, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònomade Barcelona, 08208 Sabadell, Spain

2 Department of Surgery, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònomade Barcelona, Sabadell, Spain

3 Department of Endocrinology, Parc Taulí Hospital Universitari,Institut d’Investigació i Innovació Parc Taulí (I3PT), UniversitatAutònoma de Barcelona, Sabadell, Spain

4 Unit of Endocrine and Head and Neck Surgery, Department ofSurgery, Parc Taulí Hospital Universitari, Institut d’Investigació iInnovació Parc Taulí (I3PT), Universitat Autònoma de Barcelona,Sabadell, Spain

5 Department of Pathology, Consorci Sanitari del Maresme,Mataró, Spain

6 Department of Urology, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònomade Barcelona, Sabadell, Spain

7 Department of Radiology, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònomade Barcelona, Sabadell, Spain

8 Department of Oncology, Parc Taulí Hospital Universitari, Institutd’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònomade Barcelona, Sabadell, Spain

https://doi.org/10.1007/s42399-020-00316-x

/ Published online: 29 May 2020

SN Comprehensive Clinical Medicine (2020) 2:978–984

where follicular or Hürthle cell adenomas are the most fre-quent receptors, while malignant neoplasms are hardly everfound [3].

Renal cell carcinoma (RCC), which often presents unpre-dictable metastatic behavior [4], is the most common origin ofthyroid metastases [5] and it has also been found as the me-tastasizing previously known neoplasm in cases of TTM to thethyroid [6].

Not infrequently, metastases are the first manifestation of amalignant neoplasm. However, the thyroid gland is seldomthe target organ where metastasis appears as a guiding signof a primary non-previously diagnosed neoplasm [4, 7].Whilethyroid nodules are often found at neck palpation in routinephysical examinations [8, 9], the detection of a TTM of anoccult neoplasm is also highly improbable. To our knowledge,we present the first description in the literature of a TTM of anoccult RCC over a papillary thyroid carcinoma (PTC) detect-ed as an incidental finding at neck palpation.

Case Report

A 41-year-old woman was referred to our hospital for thestudy of a palpable thyroid nodule, which was detected duringa routine health checkup. Ultrasound (US) showed a 39 ×17 mm solid lump in the left lobe, with areas of cystic degen-eration (Fig. 1). A fine needle aspirative (FNA) cytology wasperformed. Cytological smears and cell block disclosed epi-thelial cells arranged in plates, papillae, and follicles, withnuclear hypochromasia and clefts (Fig. 2), consistent withthe diagnosis of PTC (Bethesda VI category).

A total thyroidectomy with lymph node dissection of thecentral compartment was performed. The thyroid weighed23.4 g and measured 7 × 5 × 2.5 cm. The nodular lesion mea-sured 3.7 × 2.5 cm. It was partially encapsulated, and it pre-sented a solid and cystic pattern. It was brown in color and

elastic in consistency, with a central whitish and violet area(Fig. 3). In the remaining parenchyma, another non-encapsulated solid brown nodule of 0.6 cm was discovered.

At the microscopic study, the largest lesion correspondedto a well-delimited and partially encapsulated classic PTCwith predominant follicular architecture (90%). Additionalareas constituted by cells with broad plant-like clear cyto-plasm and large nuclei with contour irregularities were detect-ed. The larger ones corresponded to the whitish and violetareas identified macroscopically, while others were less than1 mm in size (Fig. 4). No areas with clear cells were observedin the rest of the thyroidal parenchyma.

The 6-mm nodule turned out to be a papillary thyroidmicrocarcinoma. The two lymph nodes found in the centrallymphadenectomy were free of disease.

The immunohistochemical study disclosed positivity forthyroid transcription factor 1 (TTF-1), thyroglobulin, and

Fig. 1 Thyroidal US showing a solid and cystic nodule in the left lobemeasuring 39 × 17 mm

Fig. 2 Cell block of the FNA showing a follicular-patterned proliferationof follicular cells with optically clear nuclei. Hematoxylin-eosin, × 400

Fig. 3 The lesion was well-delimited, without a definite capsule, andmeasured 37 × 25 mm in its larger dimensions. It was solid and cystic,fleshy colored, with a purple-black focus near the cystic area

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cytokeratin 19 in the PTC component, and positivity forCD10, and RCC marker in the areas of clear cells (Fig. 5).

The definitive diagnosis confirmed a PTC (pT2m pN0),and metastasis of clear RCC inside the largest nodule.

The patient underwent a computed tomography (CT)–pos-itron emission tomography scan which revealed a hypermet-abolic renal mass of 110 mm in the left kidney with extensionto the adrenal gland (Fig. 6a). The patient was submitted to aradical left nephrectomy with adrenalectomy. The pathologyreport certified a nuclear grade IV/IV of Führman clear RCC(Fig. 6b), with involvement of the renal capsule and a metas-tasis of 30 mm in the adrenal gland (pT2pNXpM1). Renalvein and margins of resection were free of neoplasm.Afterwards, adjuvant ablative treatment with I131 wasperformed.

The CT scan performed in the third month of follow-upruled out renal recurrence, but demonstrated a significantgrowth of a previously known but indeterminate nodular im-age (from 10 to 11 mm) at the upper external quadrant of theleft breast. The mammography showed a well-defined en-hanced lump at the upper external quadrant. Metastatic clearRCC was confirmed by core needle biopsy. The lesion wasconsidered an isolated metastasis and the treatment chosen

was surgery and adjuvant chemotherapy. Lumpectomy guid-ed by radio-guided occult lesion localization (ROLL) wasperformed, and metastatic renal cell carcinoma was con-firmed. Since then, the patient is receiving treatment withpazopanib. Forty-six months after the first surgery, the patientnoticed a 10-mm nodule in the parotid gland that was con-firmed by FNA cytology as metastasis of renal cell carcinomaand resected by parotidectomy with free margins. Currently,she is free of disease after 48 months of follow-up from thefirst surgery.

Informed consent was obtained from the patient forpublication.

Discussion

Metastases to the thyroid gland are uncommon—up to 3%of thyroidal tumors [4, 7, 10, 11]. The most frequent or-igins are melanoma, RCC, breast and lung carcinoma,hematological cancer, or head and neck malignant neo-plasms [3, 4, 7, 12, 13]. It is noticeable that RCC metas-tasis to the thyroid can appear as a solitary lesion, mim-icking a primary thyroid tumor [2].

Fig. 4 a Papillary carcinoma with a follicular pattern and desmoplasticstroma (hematoxylin-eosin stain). b, c Areas of clear cells close topapillary carcinoma component (hematoxylin-eosin stain). d Cystic area

covered by papillary carcinoma cells, with clear cell component below(hematoxylin-eosin stain)

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TTM is a rare phenomenon. The most common malignantrecipient of metastases is RCC [2–4, 8, 11, 13–19]), and themost frequent donor is lung carcinoma [1, 15, 17]. Some the-ories are suggested in order to explain the TTM-related path-ogenesis. It is claimed differences in blood supply, expressionof adhesion molecules, or slow growth of the recipient neo-plasm [2, 6, 11, 13].

TTM in the thyroid is extremely rare. In fact, we havefound only 36 cases previously described in the literature.RCC is the most common donor, followed by lung and breastcarcinoma [2, 6, 11, 20]. The commonest recipient for thyroidneoplasm is follicular adenoma [3, 7, 11, 17], and the mostfrequent thyroid malignant condition able to be invaded bymetastasis is the follicular variant of PTC, followed by classic

Fig. 5 Immunohistochemical studies. a Thyroglobulin. b TTF-1. c Renal cell carcinoma marker. d CD10. Papillary thyroid carcinoma cells expressthyroglobulin and TTF-1, while clear cells metastatic from renal cell carcinoma express renal cell marker and CD10

a b

Fig. 6 Renal cell carcinoma. a Computed tomography image showing the renal mass. b Histological aspect of the renal clear cell carcinoma(hematoxylin-eosin stain)

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PTC, Hürthle cell carcinoma, follicular thyroid carcinoma,and medullary thyroid carcinoma [15, 17, 21, 22].

Palpable thyroid nodule is an exceptional first manifesta-tion of a TTM [4, 11]. As the use of imaging techniques isincreasing, TTM can be found incidentally, for example, in anUS study of carotid arteries [3]. In our case, the palpation of anasymptomatic thyroid nodule was the first finding of an un-known RCC and a synchronous PTC.

The diagnosis of TTM may challenge the pathologist bothat FNA cytology and at histopathological study of core biopsyand thyroidectomy—intraoperative and definitive. It shouldbe suspected when a dimorphic pattern with cellular popula-tions of different architectural, nuclear, and cytoplasmic char-acteristics is observed in a unique lesion [1]. It justifies theneed of a wide sampling of neoplastic lesions at the histopath-ological study [23].

However, a dimorphic pattern found in a thyroid lesion isnot exclusive of TTM. Eloy et al. [24] identified an area ofbasaloid morphology within a follicular carcinoma, in whichthe absence of a known primary tumor together with the mor-phology, immunohistochemical profile, and molecular studiessuggested an origin from solid cell nest or cellularity derivedfrom the last branchial arch.

A careful review of patient data—mainly surgical proce-dures and pathology reports—may be helpful to clarify thediagnosis of TTM, particularly in cases whose morphologyis similar to the primary malignancy [1, 16]. In addition, itmust be kept in mind that a primary thyroid neoplasm and amalignancy of another origin may appear synchronically ormetachronically, being this situation more often found due tothe increasing use of positron emission tomography (PET)–CT [25].

The intraoperative studymay not identify the TTMbecauseof its lower accuracy compared with the definite diagnosis.Moreover, clinical information during this procedure can belimited [1].

Some histopathological criteria, such as multicentricity andabsence of host reaction (desmoplasia, inflammation, oredematous or myxoid stroma), have been mentioned as warn-ing signs for TTM, although cases with a single focus havealso been described [11].

As RCC is one of the neoplasms with more erratic meta-static behavior [4], the presence of clear cell morphology atthe pathological examination may suggest TTM.Nevertheless, other neoplasms with clear cell morphologyshould also be considered in the differential diagnosis. In fact,plenty of primary thyroid tumor cells can present with a clearcytoplasm, both benign (follicular adenoma, Hürthle cell ad-enoma) and malignant (papillary carcinoma, follicular carci-noma, Hürthle cell carcinoma, medullary carcinoma), as wellas paraganglioma [4, 15]. Moreover, other carcinomas withmetastatic potential (such as lung or salivary gland carcino-mas) can also present clear cell morphology [4].

In our case, the immunohistochemical study was definitive.According to the histopathological image, different organ-identifying antibodies may be indicated: cytokeratin 20 andCDX-2 to disclose colonic origin; CD10, RCC marker, andracemase for kidney; mammaglobin, GCDFP-15, estrogen,and progesterone receptors for breast; or S-100 and Melan-Afor melanoma [1, 2, 4, 11]. It is important to note that immu-nohistochemical markers are not pathognomonic of a uniqueorgan. For instance, TTF-1 is positive in lung and thyroidneoplasms, cytokeratin 20 and CDX-2 are positive in the co-lumnar cell variant of PTC, PAX-8 can be positive in thyroidand renal carcinomas, and CEA can be positive in metastaticcolonic adenocarcinoma, in metastatic lung adenocarcinoma,and in medullary thyroid carcinoma [17]. In order to confirmlung origin, Napsin-A can be useful, since it is usually positivein adenocarcinoma of pulmonary origin, whereas it is negativein primary thyroid neoplasms [26]. A weak positivity can alsobe observed due to diffusion of thyroglobulin in the limitsbetween primary and metastatic neoplasms [2]. Likewise, un-differentiated thyroid carcinoma usually loses the expressionof thyroglobulin and TTF-1 [27], and occasionally PAX-8remains as the only marker of thyroid origin [28].

Search for somatic gene alterations described in primarythyroid neoplasms, such as point mutations in BRAF orRAS, may contribute to identify the primary thyroid compo-nent [17, 27, 29]. In addition, fluorescence in situ hybridiza-tion (FISH) studies may be useful, by determining RET-PTCor PAX8-PARgamma rearrangements in primary thyroid tu-mors, and EGFR amplifications and ALK rearrangements inprimary lung neoplasms [29].

Other more advanced techniques can be helpful in thesecases. Some studies have relied on ploidy analysis to discrim-inate between the receptor and donor components in TTM[17]. With regard to RCC, loss of heterozygosity for theVHL gene would favor renal origin [17]. For more complexcases, microarray techniques or next-generation sequencing(NGS) studies have been proposed to determine the doublecomponent in compound neoplasms [30, 31].

At the thyroid FNA cytology, TTM should be consideredwhen two significantly different populations are found [32].We have only identified two reports in which it was possibleto diagnose TTM by FNA cytology: a metastasis of breastcarcinoma in a follicular variant of PTC and a metastasis ofRCC in a Hürthle cell carcinoma [2, 17]. In contrast, in anoth-er case, the metastatic component of a lung small cell carci-noma was considered suspicious of anaplastic thyroid carci-noma [29].

The fact that these lesions are not usually diagnosed byFNA cytology, as in our case, determines that they are usuallytreated following the protocols of primary thyroid neoplasms.

In relation to the treatment in single metastasis, thyroidec-tomy is considered the appropriate procedure with good prog-nosis. However, in cases of advanced neoplasia, surgery can

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be indicated just to palliate the symptoms [7]. Overall, thetreatment should consider the stage and grade of the primarytumor, the extent of the thyroid lesion, and the general condi-tion of the patient [29].

In conclusion, we provide a unique observation of TTM ina PTC discovered incidentally by palpation in a routine check-up as the first manifestation of a RCC. TTM is an exceptionalform of metastasis, and it is even rarer as the first sign of amalignant neoplasm. Although in our case the typical mor-phology of both entities allowed an easy diagnosis, sometimesit can be a challenge. As it has been reviewed, the currentmultiple complementary techniques can be of help to obtainan accurate diagnosis. However, the first approach of suspi-cion should still be based on morphologic and clinical criteria.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict ofinterest.

Ethical Approval Ethical approval by the local Committee of Ethics andClinical Research was waived.

Informed Consent The patient has given informed consent for publica-tion of the case.

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