Središnja medicinska knjižnica
Ulamec, M., Tomas, D., Perić-Balja, M., Spajić, B., Hes, O., Krušlin, B. (2008)
Neuroendocrine breast carcinoma metastatic to renal cell carcinoma and ipsilateral
adrenal gland. Pathology - research and practice, 204 (11). pp. 851-855.
University of Zagreb Medical School Repository
NEUROENDOCRINE BREAST CARCINOMA METASTATIC TO RENAL CELL
CARCINOMA AND IPSILATERAL ADRENAL GLAND
1Monika Ulamec, 1Davor Tomas, 1Melita Perić-Balja, 1Borislav Spajić,
2Ondrej Hes, 1Božo Krušlin
1 Ljudevit Jurak University Department of Pathology and Dpt of Urology, Sestre milosrdnice
University Hospital, Zagreb, Croatia
2 Sikl's Department of Pathology, Charles University, Medical Faculty Hospital, Pilsen,
Runing title: CANCER TO CANCER METASTASIS
Key words: renal cell carcinoma, breast cancer, neuroendocrine differentiation, cancer to
Božo Krušlin, M.D., Ph.D.
Ljudevit Jurak Department of Pathology,
Sestre milosrdnice University Hospital, Vinogradska 29, Zagreb, Croatia
phone: 3851 3787 177, fax: 3851 3787 244
We report a 60-year-old woman with neuroendocrine carcinoma of left breast
metastasizing to renal cell carcinoma (RCC) of the left kidney and to adrenal gland. A yellow,
well circumscribed tumor, 11 cm in largest diameter limited to the kidney was found.
Histopathology revealed RCC with foci of neuroendocrine differentiation. Solid sheets of
hyperchromatic epitheloid cells with high mitotic activity were found between typical clear
cells of RCC. These cells were CAM5,2 and E-cadherin focally positive, synaptophysin, and
NSE weakly positive, CK19 moderately positive, and AE1-AE3 and EMA strongly positive.
Chromogranin A, CD10, CK 14, CK 20, HER2 (score 1+), vimentin and HMB45 were
negative. The left adrenal gland contained multiple, separate foci of a tumor composed of
neuroendocrine component. Because of the biphasic tumor in the kidney, extensive clinical
examination and further analyses were recommended. Tumor in the left breast was revealed.
Two months later the patient underwent mastectomy with axillary lymph node dissection. The
tumor was histologically and imunohistochemically similar to neuroendocrine component
within RCC. All axillary nodes were positive.
To our knowledge this is the first case of neuroendocrine breast carcinoma with
metastasis to renal cell carcinoma and ipsilateral adrenal gland.
Breast cancer is the most common malignant tumor and the main cause of tumor-
related death in women. Its occurrence with other primary malignances, especially renal cell
carcinoma, is not a rare event. However, tumor metastatic to another neoplasm is rarely seen.
There are four cases of breast cancer metastasis to renal cell carcinoma described in the
literature [7,15,17,18]. We report the first case of breast carcinoma showing neuroendocrine
differentiation with metastasis to the renal cell carcinoma and ipsilateral adrenal gland.
A 60-year-old woman presented with painless macrohematuria persisting for several
months. Clinical examination including ultrasound, intravenous pyelography and CT scan
showed a well circumscribed tumor on the upper pole of the left kidney. The tumor of the left
breast was also found. Nephrectomy with ureterectomy was performed. During the same
operation, the left adrenal gland and spleen were removed. The patient underwent mastectomy
with axillary lymph node dissection two months later.
The patient received postoperative radiation therapy followed by hormonal treatment.
The patient is 18 months after second surgery well and without recurrence.
Material and methods
Specimens were fixed in 10% buffered formalin, embedded in paraffin, cut at 5 µm
thickness, and routinely stained with hematoxylin and eosin. Immunohistochemical staining
was performed following Microwave Streptavidin ImmunoPeroxidase (MSIP) protocol on
DAKO TechMate Horizon automated immunostainer using following primary antibodies
CK7, CK19, CK20, AE1-AE3, EMA, synaptophysin, S-100, chromogranin A, vimentin,
HMB45, Ki-67, ER, PR and HER2 (DAKO), CK14 (Novocastra) and CAM5.2 (Becton
Grossly, the kidney showed a yellow, well circumscribed tumor, 11 cm in largest
diameter, with elevated capsule but limited to the kidney (Fig. 1A). Histopathologic diagnosis
revealed typical renal cell carcinoma (RCC) with foci of solid sheets of hyperchromatic
epitheloid cells with high mitotic activity and apoptosis (Fig. 1B and C). Small foci of
necrosis were observed within the hyperchromatic epitheloid component. RCC component
was composed of atypical epithelial cells with clear cytoplasm and nuclei with nucleoli that
were seen under higher magnification. Tumor cells were arranged in alveolar structures and
solid nests. Hyperchromatic epitheloid cells were CAM5,2 and E-cadherin focally positive,
synaptophysin (Fig. 1D) and NSE weakly positive, CK19 moderately positive, and AE1-AE3
and EMA strongly positive. Estrogen (ER) was positive in approximately 60% of tumor cells
and progesterone (PgR) in almost all tumor cells. Chromogranin A, CD10, CK 14, CK 20,
HER2 (score 1+), vimentin and HMB45 were negative (Table 1). RCC cells were focally
positive for CAM5,2, weakly positive for EMA, strongly positive for vimentin, NSE and
CD10, and negative for CK14, CK19, CK 20, AE1-3, E-Cadherin, ER, PgR, HER2 (score
1+) as well as for HMB45, chromogranin A and synaptophysin. Ki-67 showed very low
activity in RCC (≤5%) but up to 15% of positive cells in the epitheloid component were found
(Table 1). Tumor microscopically infiltrated the kidney calyceal system but did not involve
renal blood vessels and ureter. Adjacent renal tissue was not affected by the tumor. Diagnosis
of RCC with foci of neuroendocrine component was established, and the tumor was staged as
T3N0M1 with nuclear grade 2 according to Fuhrman. Macroscopically and microscopically
adrenal gland contained multiple separate foci of a tumor composed of neuroendcrine
component similar to that described above. Spleen showed no significant changes. Two
months later the patient underwent mastectomy with axillary lymph node removal. Tissue of
the left breast and left axilla was obtained for histopathologic analysis. The tumor measured
up to 4.5 cm in largest diameter, with nipple and dermal infiltration. The tumor was composed
of solid areas of atypical epithelial cells with pronounced nuclear polymorphism and high
mitotic activity (more than 20 mitoses in 10 high power fields) (Fig. 1E). In a minor part the
tumor was composed of tubular formations. Histologically it appeared similar to the one
found within RCC. Immunohistochemically, tumor cells showed focally positive staining for
E-cadherin, vimentin and synapthophisin (Fig. 1F), weakly positive for NSE and CK19 and
strongly positive staining for AE1-AE3, EMA, CAM5,2. ER was positive in approximately
70% and PgR in approximately 85% of tumor cells. Other antibodies (CK14, CK20, CD10,
HER2 /score 1+/, and chromogranin A) were negative. Immunohistochemistry showed
reactions very similar to the neuroendocrine component of RCC (Table 1). Diagnosis of
invasive ductal carcinoma with neuroendocrine differentiation was made and classified as
poorly differentiated neuroendocrine carcinoma according to the WHO classification .
From axillary fat 2 conglomerates of lymphatic tissue measuring 3 and 4 cm in the largest
diameter and 9 lymph nodes were isolated and tumorous tissue identical to that described in
the breast was found in all nodes. The tumor of the breast was staged as T4N2M1 and G3.
On the basis of similar histology and imunohistochemical profile of neuroendocrine
cells in RCC and neuroendocrine cells in the breast carcinoma we concluded that breast
carcinoma metastasized to RCC; therefore, the initial diagnosis was changed in accordance to
The occurrence of multiple primary malignances is a rare but well-known
phenomenon. It has been reported in 2.3% of clinical and 8.1% of autopsy series . RCC is
the most common tumor found to coexist with other malignancies [1,10,12,13,14]. In
different studies the incidence of second primary malignancy associated with RCC is reported
to be 12%-27.4% [1,10,11,14]. About 19% of these tumors appeared synchronously . Other
primary malignant tumors most often associated with RCC are bladder, prostate, colorectal
and lung cancer [1,10,12,20]. Breast cancer is also one of the tumors known to coexist with
Tumor to tumor metastasis is a very rare event. Campbell et al.  established criteria
for metastatic carcinoma to a second primary carcinoma: evidence for the existence of more
than one primary tumor; the recipient tumor shown to be a true neoplasm; and evidence that
the second malignant neoplasm is a true metastasis with established growth or invasion in the
host tumor and not due to contiguous growth or embolism of tumor cells. By these criteria
less than 60 cases of tumor to tumor metastasis can be found in PubMed.
The first case of tumor to tumor metastasis was described by Berent in 1902 ; it was
a squamous epithelial cancer to an RCC. RCC is the most common recipient tumor (71.7%)
and the second is sarcoma (6.5%) . The most common donor cancers are lung, prostate
and thyroid . In co-existing malignancies with RCC, Sella and Ro  report on 15%
incidence of tumor to tumor metastasis. Three of these were female patients with
asymptomatic renal cell carcinoma that contained metastasis from the breast, colon and lung
cancer that was detected at autopsy .
Two mechanisms have been postulated to explain the phenomenon of metastasis to
1) Mechanical theory  is based on the fact that 25% of the minute volume flow goes
through the kidney and RCC, which is highly vascular. Because of this RCC is receiving a
large proportion of donor tumor emboli.
2) The "seed and soil" theory  is based on the provision of a fertile environment in which
compatible tumor cells could proliferate. The theory was introduced by Stephen Paget
 in 1889 year in his seminal paper in Lancet. He proposed that the processes of
metastasis did not occur by chance but, rather, that certain favored tumor cells with
metastasis activity (the “seed”) had a special affinity for the growth-enhancing
milieu within specific organ (the “soil”) . Extensive research into chemokines and
their receptors has elucidated and confirmed this theory [4,8]. Muller et al. 
showed that the chemokine receptors CXCR4 and CCR7 are highly expressed in
human breast cancer cells, malignant breast tumors and metastases. Their respective
ligands CXCL12 and CCL21 exhibit peak levels of expression in organ representing
the first destination of breast cancer metastasis. Similar model was discovered for
other tumors where adhesion molecules and chemokines also represent the
navigation system for circulating tumor cells to metastasize in an organ-specific
Breast carcinoma is known to coexist and metastasize more often to intracranial meningeoma
. In the literature there are only 4 cases of breast carcinoma metastasizing to RCC
[6,15,17,18]. Two cases are described in living patients with known metastatic breast cancer
including metastasis to RCC [7,18]. In the report by Sella and Ro, it was discovered at
autopsy . It can be expected that cases like this may be more often discovered in living
patients because of the widespread use of ultrasonography and computer tomography in
imaging of the kidneys as part of abdominal evaluation of other diseases .
To our knowledge, the case presented is the first case of breast carcinoma with
neuroendocrine differentiation metastatic to RCC reported in the literature. In our case, RCC
was found first and then other malignancy was suspected and actually diagnosed almost
synchronously. Neuroendocrine breast carcinoma is quite uncommon, accounting for 2%-5%
of breast carcinomas . In the differential diagnosis, a primary neuroendocrine tumor of the
kidney, especially carcinoma should be considered. Neuroendocrine carcinoma of the kidney
accounts for much less than 1% of all epithelial renal malignant tumors . Gross and
microscopic features are similar to the same tumor type occurring at other, more typical
locations. A concomitant urothelial carcinoma is common . We revealed an overlap in
the immunohistochemical expression of neuroendocrine markers (NSE) and
cytokeratins in primary breast cancer and neuroendocrine component that was
observed within clear cell RCC. Similar pattern of immunoreactivity was found in the
adrenal gland metastasis. However it is well known that NSE is quite nonspecific and
unreliable marker. Described foci within RCC and adrenal gland metastasis also showed
similar morphologic features to primary neuroendocrine carcinoma of the breast.
In summary, multiple synchronous primary malignances are rare but may be
occasionally seen. One should be especially careful in patients with RCC where the incidence
is even higher. A newly diagnosed renal tumor next to an existing cancer is challenging since
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Table 1. Immunohistochemistry of primary and metastatic breast cancer to renal cell
carcinoma, renal cell carcinoma (RCC) and adrenal gland metastasis of breast cancer
AE1-AE3 - +++ +++ +++
CAM 5.2 +/- +/- +++ +/-
CK14 - - - -
CK19 - ++ + +
CK20 - - - -
EMA + +++ +++ +++
PgR - 100% 85% 80%
ER - 60% 70% 60%
HER2 - (score 1+) - (score 1+)- - (score 1+) - (score 1+)
CD10 +++ - - -
E-cadherin - +/- +/- +/-
NSE +++ + + +
Chromogranin A - - - -
Synaptophysin - + +/- +
Vimentin +++ - +/- -
HMB45 - - not analyzed not analyzed
Legend: - negative; +/- focally positive; + weakly positive; ++ moderately positive;
+++ strongly positive
Figure 1. a) Gross photograph of kidney with well circumscribed tumor measuring up to 11
cm at the upper pole, b) histology revealed renal cell carcinoma with foci of neuroendocrine
component (HEx40), c) neuroendocrine component was composed of solid sheets of
hyperchromatic epitheloid cells with high mitotic activity (HEx400) d) positive
immunostaining for synaptophysin in neuroendocrine component of renal cell carcinoma
(RCC), (x200), e) breast carcinoma was composed of solid areas and pseudotubular formation
of atypical epithelial cells histologically similar to neuroendocrine cells in RCC (HEx400) f)
immunohistochemistry showed similar reactions for synaptophysin in breast carcinoma like
neuroendocrine component within RCC, (x400)
The complete names and addresses of 4 experts to serve as possible authors for the
accompanying “Critical Commentaries“:
1. 1. Zoran Gatalica, Professor of Pathology
Director of Anatomic Pathology
Dpt of Pathology
Creighton University School of Medicine
601 North 30th Street
Omaha, NE 68131-2197
2. Gregor Mikuz, Prof, Dr.
Institut für Pathologie
3. Rodolfo Montironi, Prof, Dr
Unit of Pathological Anatomy, United Hospitals,
Polytechnic University of the Marche Region (Ancona),
School of Medicine,
Via Conca 71,
I-60020 Torrette, Ancona,
4. Vincenzo Eusebi, Prof, Dr
Department of Pathology, Bellaria Hospital,
University of Bologna,
Via Altura 3
40139 Bologna, Italy