Breast Cancer Metastasis in a Renal Carcinoma Pulmonary Metastasis: A Rare Example of Tumor-to-Tumor Metastasis

The tumor-to-tumor metastasis phenomenon remains fairly uncommon, with fewer than 100 cases described to present time. Virtually any tumor can be a donor or a recipient neoplasm. Nevertheless, renal carcinomas have been implicated as the most common malignant tumors to harbor metastasis, while lung and breast tumors are the most frequent donors. This article reports an extremely rare case of a breast cancer metastasis in a lung metastasis of clear cell type renal cell carcinoma that met all Campbell and coworkers' tumor-to-tumor metastasis criteria. Additionally, we present the literature case reports of breast cancer metastasis in renal cell carcinomas and try to discuss the mechanisms underlying its occurrence. Since this phenomenon identification will impact the therapeutic strategy and it is not easily detected by image, the anatomopathological study of any and all suspicious lesions is of crucial importance. To the best of our knowledge, this is the first report of a metastasis inside a metastasis.


Introduction
Tumor-to-tumor metastasis (TTM) is a term describing the presence of two histologically distinct tumors at one location, each with different morphologic and immunophenotypic features [1]. It is an extremely rare phenomenon in patients with multiple synchronous or metachronous primary malignancies. The most common metastatic donor neoplasms are lung and breast cancers, while meningioma is the most common recipient of metastasis among benign tumors and renal cell carcinoma among malignant tumors [2]. Although the lung is one of the organs most vulnerable to metastases, a lung carcinoma is one of the rarest recipients of TTM [3]. Furthermore, the phenomenon of a metastasis in another metastasis is still a rarer event.
Herein, we report a TTM case of a breast cancer metastasis in a pulmonary metastasis of clear cell type renal cell carcinoma (ccRCC).
This work has been approved by CHEDV's Ethics Committee, according to the Helsinki Declaration of the World Medical Association; also, the patient gave written informed consent to have her case used for this paper.

Patient History and Presentation.
We present a 57-yearold woman with a past medical history of stage IV ccRCC (pT3aR0cN0M1) diagnosed in August 2019. During diagnosis and staging evaluation, she was observed to have a 12 mm suspicious lesion on the left kidney and a 20 mm nonsuspicious solid nodule in the right adrenal; the multidisciplinary team (MDT) decided left radical nephrectomy, performed in September 2019, plus clinical and imagological surveillance of the right adrenal nodule. Follow-up exams revealed an increment of 2 mm of the right adrenal nodule without new lesions; MDT decided histological evaluation of the lesion, which revealed a ccRCC metastasis. Since this was a unique metastasis, a right adrenalectomy was performed in February 2020. In March 2020, the patient referred to having a palpable nodule in the left breast. The auxiliary diagnostic tests carried out revealed a stage III invasive ductal carcinoma (IDC) ER 100%, PgR negative, HER2 positive (FISH), and Ki67 > 30%, initially managed with neoadjuvant chemotherapy (CHT) with sequential anthracycline/taxane-based regime combined with dual anti-HER2 blockade (trastuzumab/pertuzumab), followed by surgery (cT3N+/ypT2N1 (3/15)cM0). In November 2020, the follow-up CT scan ( Figure 1) showed bilateral pulmonary nodules.

Diagnostic
Workup. The patient was asymptomatic, with a Karnofsky performance status (KPS) score of 100. No positive findings were encountered in the anamnesis on physical examination and/or other follow-up exams. PET/CT showed abnormal 18F-FDG uptake in the referred suspected pulmonary nodules, without other hypermetabolic changes that may suggest malignant involvement ( Figure 2).

Medical Management and Treatment.
Concerning the breast cancer, breast MDT proposed the patient, in November 2020, for adjuvant radiotherapy plus hormone therapy with anastrozole and dual anti-HER2 therapy with trastuzumab/pertuzumab (the anatomopathological confirmation of the breast cancer metastasis in the lung metastasis of the ccRCC occurred later in December). As for the ccRCC, urologic MDT proposed the patient, in January 2021, to pazopanib. An overview of patient clinical history and management is given in Figure 6.

Discussion
Metastasis from one neoplasm (the donor) to another neoplasm (the recipient) has been described in the literature for many years since Fried published the first documented case of bronchogenic carcinoma metastatic to a meningioma in 1930 [4,5]. In 1968, Campbell and coworkers proposed the following basic criteria for the diagnosis of TTM: (i) diagnosis of more than one primary tumor; (ii) extravascular metastasis existence; (iii) confirmation that it has not resulted from direct contiguous spread nor from tumor cell embolization; and (iv) in the presence of generalized lymphatic or hematological malignancy, exclusion of those tumors that metastasized to the lymphatic system [1]. During the decades that followed, some authors reported TTM phenomenon, with the donor neoplasm arising from a variety of sites, including the breast. Although the lung is one of the rarest recipients of TTM [3], renal neoplasms, and particularly ccRCC, are the most common tumor metastasis recipient. Additionally, there have been few cases previously reported of metastatic breast cancer within ccRCC (Table 1).
We reported an extremely rare case of breast cancer metastasis in a lung metastasis of ccRCC that met all Campbell and coworkers' TTM criteria.
Although the exact mechanism by which TTM occurs is yet to be understood, two major theories have been described to explain this phenomenon [12][13][14][15]. The first one, the  Case Reports in Oncological Medicine metabolic theory, argues that metastatic tumor cells would preferentially grow in microenvironments with abundant micronutrients, while the second one, the mechanical/anatomic theory, proposes that tumor metastasis is mainly determined by hemodynamic factors of the vascular and lymphatic system, as these factors are most important for successful delivery of metastatic tumor cells. The ccRCC is highly vascularized due to the inactivation of the von Hippel Lindau tumor suppressor gene, which increases hypoxiainducible factor, leading to increased vascular endothelial growth factor [16]. This, in addition to the fact that kidneys receive approximately 20% of the cardiac output, makes ccRCC a hemodynamically favorable recipient, from a mechanistic perspective [17]. Moreover, and from a metabolic standpoint, ccRCC has increased glycogen and lipid content, which may account for its favorable microenvironment [18]. With this in mind, it is easy to understand why renal cell carcinoma, and in particular ccRCC, is such a frequent recipient of TTM. Awareness of the TTM phenomenon is important to avoid an incorrect diagnosis and to select the appropriate treatment when unusual malignancies are encountered. In this case, due to their distinct biological behavior, there is not a single effective treatment for both HER2+ breast and ccRC metastatic cancers. Therefore, and since this patient has a good KPS score, both neoplasms were addressed separately. The change of the breast cancer stage led to the alteration of the anti-HER2 treatment strategy, with the initiation of dual blockade, as indicated by Cleopatra trial results for HER2+ metastatic disease [19]. Concerning the ccRCC treatment, our patient was in the International Metastatic Renal Cell Carcinoma Database Consortium (IMRCCDC) favorable risk group. The results of Keynote 426 and of Check-Mate 9ER trials support the use of pembrolizumab plus axitinib or nivolumab plus cabozantinib, respectively, as the first-line treatment in metastatic disease for all IMRCCDC risk groups, being the preferred choices in the favorable risk group, but neither of them are reimbursed by the Portuguese

Case Reports in Oncological Medicine
Medicines and Heath Care Products Authority (INFARMED), which justify the option of pazopanib administration for this case therapeutic strategy (noninferior to sunitinib in the COMPARZ trial with better quality of life) [20][21][22].
We report this case for its rarity. To date, literature reported only six cases of metastasis of breast cancer in renal cell carcinomas. Nevertheless, and to the best of our knowledge, this is the first report of a metastasis inside a metastasis.  Chest wall and regional nodal irradiation (EBRT) 08-09/2019 01/2021 12/2020 11/2020 10/2020 03/2020 02/2020