Ultrastructural Pathology, 2014; 38(6): 430–437 ! Informa Healthcare USA, Inc. ISSN: 0191-3123 print / 1521-0758 online DOI: 10.3109/01913123.2014.937843
C ASE REPORT
Renal Cell Carcinoma Metastatic to a Pituitary FSH/LH Adenoma: Case Report and Review of the Literature
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Francesca Magnoli, MD1, Giovanna Finzi, PhD2, Cristina Riva, MD1, and Carlo Capella, MD1 1
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy and 2Department of Pathology, Ospedale di Circolo, Varese, Italy
ABSTRACT Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/ a-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma. Keywords: Clear cell renal cell carcinoma, electron microscopy, metastasis, pituitary adenoma
Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe [1]. A few cases of metastatic carcinoma to a pituitary adenoma have been described. In this condition, the metastasis can be the cause of a sudden enlargement of the neoplasm associated with worsening of symptoms of the mass. Herein, we report a case of a 76-year-old female with a clear cell renal cell carcinoma (CCRCC) metastatic to a gonadotroph cell adenoma. The peculiar morphologic features of this case are underlined and compared with those of the previously reported cases.
ptosis. Her past medical history was significant for recurrent nephrolithiasis, mild hypertension, and uterine prolapse surgically treated by hysterectomy when she was 50 years old. On admission, mitral valve regurgitation was diagnosed at physical cardiac examination and confirmed by echocardiography. Skull X-ray and brain CT scan showed a large intrasellar mass with suprasellar extension, highly suggestive of pituitary adenoma. Serum prolactin was 31 ng/mL (normal value: 3.3– 11.4 ng/mL). A trans-sphenoidal surgical approach was performed, and upon exposure of the sphenoid sinus extensive bone erosion was noted. Complete removal of all evident lesion was accomplished despite moderate tumor bleeding. The post-operative course was uneventful. Subsequent microscopic examination surprisingly revealed an intimate admixture of two distinct neoplasms: a FSH/LH/a-subunit pituitary adenoma and a grade II (according to Fuhrman) metastatic
CASE REPORT A 76-year-old Caucasian woman was admitted to Neurosurgery Department of our Hospital in November 1980, referring a 3-month history of diplopia, progressive loss of vision, and left eyelid
Received 29 May 2014; Accepted 18 June 2014; Published online 31 July 2014 Correspondence: Francesca Magnoli, MD, University of Insubria, Surgical and Morphological Sciences, via O. Rossi 9, Varese, 21100, Italy. E-mail: [email protected]
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Renal cell carcinoma metastatic to a pituitary adenoma CCRCC. The metastatic carcinoma consisted of large clear cells with sharply outlined membranes, growing in compact clusters, while the pituitary adenoma was made up of small to middle-sized cromophobic, periodic acid-Schiff (PAS) positive cells, arranged in a sinusoidal pattern with characteristic pseudorosettes formation around vessels. Individual cells exhibited no nuclear pleomorphism and mitosis were absent (Figure 1A and C). Immunohistochemistry was performed either manually or using an automated immunostainer (Benchmark XT, Ventana Medical Systems, Tucson, AZ) with the antibodies listed in Table 1. CCRCC cells were diffusely and intensely positive for CK AE1/ AE3, EMA, CD10, VEGF, VEGFR1, and vimentin; weakly and focally positive for CD31; negative for Melan-A, a-inhibin, SF1, ER, PgR, VEGFR2, CD34, Chromogranin A, a-subunit, ß-FSH, ß-LH, and SF1. The pituitary adenoma showed a diffuse immunoreactivity for Chromogranin A, DAX1, ER, and was partially positive for a-subunit, ß-FSH, ß-LH, a-inhibin, ER, PgR, SF1, DAX1, and VEGF and negative for GH, PRL, ACTH, and ß-TSH.
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Both components did not display any positivity for PTTG1, p53, CD34, and HIF-1a. The Ki-67 (MIB-1) proliferative index in the pituitary adenoma was 51% and in CCRCC was about 6% (Figure 1B and D). At the ultrastructural level, the CCRCC was characterized by cells arranged in compact clusters with close apposition of cell membranes or cells separated by slender clefts. The nuclei were round to irregular with prominent nucleoli. The cytoplasm was abundant and plentiful lipid vacuoles and glycogens were characteristically present. The mitochondria were numerous, large, pleomorphic, and distributed haphazardly in the cytoplasm. The FSH/LH/a-subunit (gonadotroph) cell adenoma consisted of polyhedral cells with uniform ovoid nuclei showing a finely dispersed light chromatin and spherical dark nucleolus situated close to the nuclear membrane. The cytoplasm contained stacks as well as dispersed profiles of well-developed rough endoplasmatic reticulum, numerous free ribosomes, and polysomes; and a conspicuous number of rod shaped, moderately dense mitochondria. The
FIGURE 1. (A, B) FSH/LH/a-subunit pituitary adenoma: (A) Small to middle-sized chromophobic cells, arranged in a sinusoidal pattern with characteristic pseudo-rosettes formation around vessels (200). (B) Immunoreactivity for ß-FSH (200). (C, D) Clear cell renal cell carcinoma: (C) Large clear cells with sharply outlined membranes, growing in compact clusters (200). (D) Immunoreactivity for CD10 (100). !
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432 F. Magnoli et al. TABLE 1. Antibodies and antisera used.
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Antibody a-Inhibin a-Subunit ACTH ß-FSH ß-LH ß-TSH CD10 CD31 CD34 CK AE1/AE3 Chromogranin A DAX-1 EMA ER GH HIF1a Ki-67 Melan-A p53 PgR PRL PTTG1 SF1 VEGF VEGFR1 VEGFR2 VIM
M (clone)/P M M P M M M M M M M M P M M M M M M M M P M P P P M M
(R1) (6E4) (C10) (3LH 5B6 YH4) (TSH01 + TSH02) (56C6) (JC/70A) (QBEnd/10) (AE1/AE3/PCK26) (LK2H10) (E29) (SP1) (54/9 2A2) (H1alpha67) (MIB1) (A103) (DO7) (1E2) (DCS-280.2)
(A-3) (V9)
Dilution Ready 1:100 1:250 1:30 1:250 1:100 Ready 1:20 Ready Ready Ready 1:200 Ready Ready 1:100 1:100 1:100 Ready Ready Ready Ready 1:50 1:1000 1:100 1:100 1:600 Ready
to use
to use to use to use to use to use to use
to to to to
use use use use
to use
Manufacturer Ventana (Tucson, AZ) Immunotech (Marseille, France) Dako (Carpinteria, CA) Dako (Carpinteria, CA) BioGenex (Fremont, CA) Thermo Scientific (Fremont, CA) Ventana (Tucson, AZ) Dako (Carpinteria, CA) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Santa Cruz Biotechnology (Dallas, TX) Ventana (Tucson, AZ) Ventana (Tucson, AZ) BioGenex (Fremont, CA) Novus Biologicals (Littleton, CO) Ventana (Tucson, AZ) Dako (Carpinteria, CA) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Novocastra (Newcastle upon Tyne, UK) Upstate biotechnology (Lake Placid, NY) Santa Cruz Biotechnology (Dallas, TX) Santa Cruz Biotechnology (Dallas, TX) Santa Cruz Biotechnology (Dallas, TX) Ventana (Tucson, AZ)
Note. M, monoclonal; P, polyclonal.
FIGURE 2. (A) FSH/LH/a-subunit pituitary adenoma: spherical and uniformly small secretory granules with a well evident limiting membrane (scale equals 2 mm). (B) Clear cell renal cell carcinoma: characteristic lipid vacuoles and glycogen and absence of neuroendocrine granules in the cytoplasm of CCRCC (scale equals 2 mm).
Golgi apparatus was well evident, but did not show a ‘‘honeycomb’’ appearance. The secretory granules were spherical and uniformly small (less than 200 nm), with a well-evident limiting membrane. They were distributed unevenly, being more numerous in the cytoplasmatic processes (Figure 2A and B). Following the histopathological diagnosis, the patient underwent renal radiologic investigations
which demonstrated the presence of a right kidney neoplasm. However, the patient refused any further surgical intervention and was discharged from hospital. Unfortunately, exactly one year later she was re-admitted for diffuse metastatic involvement of the skull base and died in November 1982. Post-mortem examination was not carried out. Ultrastructural Pathology
Renal cell carcinoma metastatic to a pituitary adenoma
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Review of well documented cases reported in the English literature, including the present case Table 2 summarizes the clinical presentation of the previously reported cases, most of them already reviewed by Noga et al. [2] and Hoellig et al. [3]. The mean age of the 23 patients was 66 years (range 44–88). Thirteen patients were females and 10 males. The most frequently reported symptoms were: declining visual acuity (63.5% of the cases), headache (36.3%), field vision defects (27.3%), cranial nerves (III, VI) palsy (18.1%). Endocrine hyperfunction was present in 34.7% of cases (four cases of hyperprolactinemia, three cases of acromegaly and one case of Cushing disease); 65.2% of cases were clinically nonfunctioning. Signs of partial or total hypopituitarism were present in 62.5% of cases in which an endocrinological evaluation was performed. In no case diabetes insipidus was reported. A history of carcinoma, present before appearance of symptoms due to sellar metastasis, was found in 43% of cases with a mean length of 3.7 years (range 6 months–10 years). A pituitary adenoma was present from 6 months to 31 years (mean 11.9 years) before the intradenomatous metastasis occurred, in 43% of the patients. The mean diameter of the pituitary tumor in cases in which it was registered by neuroradiologist, resulted to be 2.7 cm (range 0.5–5 cm); in 78% of cases the tumor was described as large, in 69.5% it was sellar and suprasellar/para-sellar and in 27% a sphenoid or cavernous sinus invasion was reported. Fifty-two percent and 26% of the patients underwent transphenoidal and transcranial surgical approach, respectively; 8.6% received palliative chemo and/or radiotherapy; in 11% of the cases the diagnosis was defined at autopsy. Lung neoplasms were the most frequent primary malignancies (21%), followed by breast and kidneyrenal pelvis (17% each), gastric (8.6%), pancreatic, prostatic, colonic, and mediastinal carcinomas (4.4% each). In 13% of the cases the primary neoplasm remained undiscovered. In 26% of the cases the metastasis was represented by a neuroendocrine neoplasm: a poorly differentiated neuroendocrine carcinoma (PDNEC) in 17% and a neuroendocrine tumor (NET) in 8.6%. The pituitary adenoma represented the only metastatic site in 26% of the cases, while in the majority (74%) metastases were present in multiple sites. The survival time after operation was reported in 18 cases. The median length of patients’ survival after surgery or different therapies was 5.4 months (range 2 days–21 months). Patients with metastasis limited to the pituitary adenoma had a median survival of 10.5 months versus 5 months of patients with multiple metastases. Eighty-two percent of the patients were dead at last follow-up, while the remaining 17.4% were alive. !
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DISCUSSION The patient described in our report had some peculiar clinico-pathological features. First of all, the CCRCC was asymptomatic at the start and was diagnosed after detection of the pituitary metastasis. In addition, the metastasis of CCRCC involved a FSH/LH/ a-subunit adenoma, a finding which was not previously well documented in the English literature. In fact, two cases of CCRCC metastatic to pituitary adenomas have been described [4,5]: in both cases the pituitary tumor was diagnosed as an adenoma without any immunohistochemical expression of pituitary hormones. Although most of the non-functioning, non-hormone producing pituitary adenomas are now considered to belong to the family of FSH/LH/ a-subunit tumors, the two above-mentioned cases cannot be undoubtedly located in this category of tumors. In addition, the two previously reported CCRCCs differ from the case here reported, having been associated with a long history (9 years and 4 years, respectively) of a previously resected CCRCC. CCRCC metastases to the pituitary may be difficult to distinguish from other clear cell carcinomas and from pituitary adenomas with interspersed adrenal cortical cells [6]. In our case, the diagnosis of metastatic CCRCC was based on the presence of solid alveoli composed of large cells with clear cytoplasm, intensely immunoreactive for EMA, CD10, and CK AE1/AE3. The absence of immunoreactivity for Melan-A, SF1, and a-inhibin excluded the possibility of an adenoma with interspersed adrenocortical cells. Electron microscopy (EM), which was not performed in the previously reported cases [5,7], showed abundant glycogen and lipid droplets in the cytoplasm of metastatic cells, confirming the diagnosis of CCRCC. In addition, EM documented the presence, in pituitary adenomatous cells, of small secretory granules characteristic of gonadotroph cells [8]. CCRCC has a variable and complex biologic behavior [9]. The most important prognostic factor is the presence or absence of metastatic disease. Common metastatic sites for CCRCC are the lung, bone, liver, adrenal, and brain. Unusual sites are also registered and are sometimes discovered at the same time of the primary tumor. These include pituitary, thyroid, orbit, nasal structures, paranasal sinuses, vagina, gallbladder, pancreas, subungueal tissues, and soft tissue of distal extremities [10]. Metastatic renal cell carcinoma to the pituitary gland is extremely rare: in a clinico-pathologic review of 88 cases of carcinoma metastatic to the pituitary gland no CCRCC metastases were reported [11], while they were present in 2.6% of cases in a review of 360 pituitary metastases reported in the literature [12]. A recent study reviewing 23 cases of pituitary metastases from CCRCC demonstrated that these tumors behave
72 M
66 F
66 F
56 F
61 F
77 M
Age & Presentation gender (duration of symptoms) 67 M nr
50 F
4 [4]
5 [24]
6 [24]
7 [25]
8 [26]
9 [27]
10 [27]
Case
11 [28]
12 [28]
46 F
75 M
3 [23]
14 [30]
78 M
2 [22]
76 M
73 F
1 [7]
13 [29]
70 F
Case (reference)
Endocrine symptoms
Nausea, lethargy, decreased vision (nr) H, blurred vision, hemianopsia (3m)
Exophtalmus (nr)
Vision loss and hemianopsia in the LE (7y) Fever, nausea, diarrhea (2d) Visual field impairment (3w) NIII palsy, vision loss, BH (nr) H, nausea (40y) sudden blindness of the LE H, disturbed vision (42y), sudden blindness of the LE H, nausea, vomiting, bil NVI palsy (3w) H, disturbed vision (3y) H, loss of vision, bil NIII palsy, SIADH (2w)
HP
Acromegaly
L, SSe, ISe
L, SSe
1.52.52, SSe
L, SSe, ISe
L, ISe, PSe
L, SSe
2
nr
L, SSe
5
PA size (cm or descriptiozn)
TS
TS
4.5, SSe
L, SSe, ISe
Enlarged sella
Treatment Pituitary tumor ize (cm)/ extension None 0.5
TS, RT
TS
RT
TCS
TCS
TS, RT
TS
none
TCS
TCS, RT
Treatment
Truncal and RT, CT facial obesity
No
Endocrine symptoms
No
No
No
HP
HP
No
No
No
No
H, left hemiparesis No (nr)
Age and gender
Presentation (duration of symptoms)
TABLE 2. Summary of previously reported cases of metastases to pituitary adenoma.
Lung
Unknown
Breast (1y)
Stomach (A)
Stomach (A)
Lung (1y)
Pelvis and ureter (A) Kidney (9y)
Breast (3y)
Breast (15y)
Site and history of primitive ca
Yes (15y)
Yes (6m)
Yes (5y)
died after 4m; MM: bone, lung, liver, brain died after 28d; MM
Further clinical course; metastases
Further clinical course
died; MM
(continued )
mts prostatic ca in died; MM: bone, liver, hormone neg PA lymph nodes mts pancreatic PDNEC died after 7m; MM in ACTH Crooke’s cell PA mts lung adk in GH PA died; MM
Histopathologic findings
died 3w after admission (lung mts); MM mts ca in non functioning alive; SM ACTH PA mts lung NSSC in onco- died 6m after TS; MM cytic PA
mts breast ca in FSH/ LH/GH PA
mts SCC in hormone died 1m after TS; MM neg PA mts gastric mucin died 2d after TS producing ca in (sepsis); MM PRL PA mts gastric mucin prodied 12d after TS ducing adc in PRL cell (sepsis); MM PA
mts transitional cell ca in died after 5w; nr PA mts CCRCC in hormone unknown; SM neg PA
mts breast G3 ca in chromophobe PA
mts breast G3 ca in acidophil PA
Histopathologic findings
Mediastinum (1y) mts NET in PRL PA
Lung
Pancreas (6m)
History of Site and history pituitary of primitive ca adenoma No Prostate (9y)
No
Yes (2y)
No
Yes (17y)
Yes (18y)
No
Yes (25y)
No
No
Yes (8m)
History of pituitary adenoma
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434 F. Magnoli et al.
Ultrastructural Pathology
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2014 Informa Healthcare USA, Inc.
75 F
87 M
60 M
62 F
44 F
71 M
55 F 66 M
Case (reference)
15 [31]
16 [31]
17 [2]
18 [5]
19 [32]
20 [3]
21 [33] 22 [34]
Loss of vision, NIII palsy (2w) Leg pain (nr) H (nr)
Bitemporal anopsia (nr)
bil visual decline (nr) bil visual decline, optical atrophy (nr) Loss of vision, hemianopsia, left hemiparesis (9m) H, visual loss (4m)
Presentation (duration of symptoms)
Acromegaly HP
No
Acromegaly
No
No
No
No
Endocrine symptoms
TS, RT None
TS
TS
TCS
TCS
TS
TS
Treatment
Yes (4y)
3.4 3, SSe 321.6, PSe, SSe No enlarged pituitary No
No
No
No
Yes (31y)
No
History of pituitary adenoma
2.6, SSe, CS
L, SSe
5, CS
L, SSe
L, SSe
PA size (cm or descriptiozn)
Unknown Lung (A)
Lung (6m)
Lung (7y)
Kidney (4y)
Probably rectum
Unknown
Breast (3y)
Site and history of primitive ca
Further clinical course; metastases
mts CCRCC in hormone neg PA mts GHRH producing atypical carcinoid in GH cell hyperplasia/ PA mts SCC in hormone neg PA mts NEC in GH PA mts NSCC in PRL PA
mts adc in hormone neg PA
died after 21m; MM died after few days; MM
died after 3d; MM
alive with disease 3m after TS; MM
died after 8m; MM
died shortly after TCS; MM
mts breast ca in FSH/LH alive 18m after TS; SM PA mts ca in FSH/LH PA alive 6m after TS; SM
Histopathologic findings
Note. A, at autopsy; adc, adenocarcinoma; BH, bitemporal hemianopsia; bil, bilateral; ca, carcinoma; CS, cavernous sinus; CT, chemotherapy; d, days; F, female; H, headache; HP, hyperprolactinemia; ISe, intrasphenoidal extension; L, large; LE, left eye; m, months; M, male; MM, multiple metastases; mts, metastatic; neg, negative; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; nr, not reported; NSSC, non-small cell carcinoma; PA, pituitary adenoma; PDNEC, poorly differentiated neuroendocrine carcinoma; PSe, para-sellar extension; RT, radiation therapy; SCC, small cell carcinoma; SM, sole metastasis; SSe, suprasellar extension; TCS, transcranial surgery; TS, transphenoidal surgery; w, weeks; y, years.
Age and gender
Table 2. Continued.
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Renal cell carcinoma metastatic to a pituitary adenoma 435
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436 F. Magnoli et al. differently from other metastatic malignancies, involving more commonly the anterior pituitary and causing more severe visual dysfunction and hypopituitarism, while diabetes insipidus is less frequent [13]. In reality, the majority of metastatic tumors to the pituitary involve the posterior lobe of the gland [14], due to the fact that the posterior lobe receives a direct systemic arterial blood supply, while the anterior pituitary is mainly vascularized by the hypophyseal portal system. Consequently, diabetes insipidus is the most frequent symptom associated with metastases to the pituitary gland, while visual disturbances and hypopituitarism are reported in a small percentage of cases [13,14]. The case described in this study as well as the 22 cases previously reported in the literature represent examples of tumor-to-tumor metastasis. It is still unclear why a neoplasm can be a host for a secondary neoplasm. At least two hypotheses try to explain this phenomenon [15,16]. The ‘‘mechanical’’ theory proposes that metastatic patterns depend on the quantity of viable neoplastic cells reaching the target organ. Pituitary adenomas have been shown to possess direct arterial supply from carotid and capsular vessels [17]. As a consequence, circulating neoplastic cells may bypass portal vessels, vascularizing the normal anterior pituitary, and generate metastases within the adenoma from the systemic circulation. The rich vascularization of the adenomas may render them more accessible to metastatic tumor cells in the circulating blood. Thus, the vascular network might act as a filter to metastatic emboli in the blood stream [18]. In this context, an interesting finding is that in the majority (65.5%) of cases of metastasis to pituitary adenomas, the recipient was represented by a nonfunctioning adenoma (identified as FSH/LH/a-subunit or gonadotroph adenoma in more recent cases, including ours). Moreover, FSH-expressing (gonadotroph) adenomas showed the highest vascular density evaluated with the use of factor VIII-related antigen [19]. The second theory, ‘‘seed and soil’’, proposes tentatively that tumor cells (seed) possess biological features apt to be implanted and to proliferate in a fertile environment [15,16]. In this context, the intradenomatous renal cell carcinoma metastasis may be due to acquisition by neoplastic renal cells of factors interacting with endothelial cells and with perivascular stroma. Interesting findings in the case here reported were that CCRCC metastatic cells highly expressed both VEGF and VEGFR1, and focally expressed CD31. VEGF was also detected in gonadotroph adenomatous cells. The presence of this growth factor and of the relative receptor suggests that they could drive tumor growth promoting vasculogenesis [20,21] and favor the interactions between adenomatous and carcinomatous cells, possibly through direct binding between growth factors and corresponding receptors.
In conclusion, metastases to pituitary adenomas are rare. The clinical symptoms do not differ substantially from those of patients with simple pituitary adenomas, but the prognosis of patients with metastasis to a pituitary adenoma is poor. The majority of adenomas harboring metastases are non-functioning adenomas often expressing FSH/LH/a-subunit. Immunohistochemistry and electron microscopy play a major role in defining the two components present in the neoplastic mass. The origin of metastasis is more frequently from neoplasms of the lung, followed by the breast and the kidney. Neuroendocrine neoplasms both well differentiated (NET) or poorly differentiated (PDNEC) represent a significant proportion of metastatic tumors within pituitary adenomas.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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C ASE REPORT
Renal Cell Carcinoma Metastatic to a Pituitary FSH/LH Adenoma: Case Report and Review of the Literature
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Francesca Magnoli, MD1, Giovanna Finzi, PhD2, Cristina Riva, MD1, and Carlo Capella, MD1 1
Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy and 2Department of Pathology, Ospedale di Circolo, Varese, Italy
ABSTRACT Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/ a-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma. Keywords: Clear cell renal cell carcinoma, electron microscopy, metastasis, pituitary adenoma
Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe [1]. A few cases of metastatic carcinoma to a pituitary adenoma have been described. In this condition, the metastasis can be the cause of a sudden enlargement of the neoplasm associated with worsening of symptoms of the mass. Herein, we report a case of a 76-year-old female with a clear cell renal cell carcinoma (CCRCC) metastatic to a gonadotroph cell adenoma. The peculiar morphologic features of this case are underlined and compared with those of the previously reported cases.
ptosis. Her past medical history was significant for recurrent nephrolithiasis, mild hypertension, and uterine prolapse surgically treated by hysterectomy when she was 50 years old. On admission, mitral valve regurgitation was diagnosed at physical cardiac examination and confirmed by echocardiography. Skull X-ray and brain CT scan showed a large intrasellar mass with suprasellar extension, highly suggestive of pituitary adenoma. Serum prolactin was 31 ng/mL (normal value: 3.3– 11.4 ng/mL). A trans-sphenoidal surgical approach was performed, and upon exposure of the sphenoid sinus extensive bone erosion was noted. Complete removal of all evident lesion was accomplished despite moderate tumor bleeding. The post-operative course was uneventful. Subsequent microscopic examination surprisingly revealed an intimate admixture of two distinct neoplasms: a FSH/LH/a-subunit pituitary adenoma and a grade II (according to Fuhrman) metastatic
CASE REPORT A 76-year-old Caucasian woman was admitted to Neurosurgery Department of our Hospital in November 1980, referring a 3-month history of diplopia, progressive loss of vision, and left eyelid
Received 29 May 2014; Accepted 18 June 2014; Published online 31 July 2014 Correspondence: Francesca Magnoli, MD, University of Insubria, Surgical and Morphological Sciences, via O. Rossi 9, Varese, 21100, Italy. E-mail: [email protected]
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Renal cell carcinoma metastatic to a pituitary adenoma CCRCC. The metastatic carcinoma consisted of large clear cells with sharply outlined membranes, growing in compact clusters, while the pituitary adenoma was made up of small to middle-sized cromophobic, periodic acid-Schiff (PAS) positive cells, arranged in a sinusoidal pattern with characteristic pseudorosettes formation around vessels. Individual cells exhibited no nuclear pleomorphism and mitosis were absent (Figure 1A and C). Immunohistochemistry was performed either manually or using an automated immunostainer (Benchmark XT, Ventana Medical Systems, Tucson, AZ) with the antibodies listed in Table 1. CCRCC cells were diffusely and intensely positive for CK AE1/ AE3, EMA, CD10, VEGF, VEGFR1, and vimentin; weakly and focally positive for CD31; negative for Melan-A, a-inhibin, SF1, ER, PgR, VEGFR2, CD34, Chromogranin A, a-subunit, ß-FSH, ß-LH, and SF1. The pituitary adenoma showed a diffuse immunoreactivity for Chromogranin A, DAX1, ER, and was partially positive for a-subunit, ß-FSH, ß-LH, a-inhibin, ER, PgR, SF1, DAX1, and VEGF and negative for GH, PRL, ACTH, and ß-TSH.
431
Both components did not display any positivity for PTTG1, p53, CD34, and HIF-1a. The Ki-67 (MIB-1) proliferative index in the pituitary adenoma was 51% and in CCRCC was about 6% (Figure 1B and D). At the ultrastructural level, the CCRCC was characterized by cells arranged in compact clusters with close apposition of cell membranes or cells separated by slender clefts. The nuclei were round to irregular with prominent nucleoli. The cytoplasm was abundant and plentiful lipid vacuoles and glycogens were characteristically present. The mitochondria were numerous, large, pleomorphic, and distributed haphazardly in the cytoplasm. The FSH/LH/a-subunit (gonadotroph) cell adenoma consisted of polyhedral cells with uniform ovoid nuclei showing a finely dispersed light chromatin and spherical dark nucleolus situated close to the nuclear membrane. The cytoplasm contained stacks as well as dispersed profiles of well-developed rough endoplasmatic reticulum, numerous free ribosomes, and polysomes; and a conspicuous number of rod shaped, moderately dense mitochondria. The
FIGURE 1. (A, B) FSH/LH/a-subunit pituitary adenoma: (A) Small to middle-sized chromophobic cells, arranged in a sinusoidal pattern with characteristic pseudo-rosettes formation around vessels (200). (B) Immunoreactivity for ß-FSH (200). (C, D) Clear cell renal cell carcinoma: (C) Large clear cells with sharply outlined membranes, growing in compact clusters (200). (D) Immunoreactivity for CD10 (100). !
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432 F. Magnoli et al. TABLE 1. Antibodies and antisera used.
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Antibody a-Inhibin a-Subunit ACTH ß-FSH ß-LH ß-TSH CD10 CD31 CD34 CK AE1/AE3 Chromogranin A DAX-1 EMA ER GH HIF1a Ki-67 Melan-A p53 PgR PRL PTTG1 SF1 VEGF VEGFR1 VEGFR2 VIM
M (clone)/P M M P M M M M M M M M P M M M M M M M M P M P P P M M
(R1) (6E4) (C10) (3LH 5B6 YH4) (TSH01 + TSH02) (56C6) (JC/70A) (QBEnd/10) (AE1/AE3/PCK26) (LK2H10) (E29) (SP1) (54/9 2A2) (H1alpha67) (MIB1) (A103) (DO7) (1E2) (DCS-280.2)
(A-3) (V9)
Dilution Ready 1:100 1:250 1:30 1:250 1:100 Ready 1:20 Ready Ready Ready 1:200 Ready Ready 1:100 1:100 1:100 Ready Ready Ready Ready 1:50 1:1000 1:100 1:100 1:600 Ready
to use
to use to use to use to use to use to use
to to to to
use use use use
to use
Manufacturer Ventana (Tucson, AZ) Immunotech (Marseille, France) Dako (Carpinteria, CA) Dako (Carpinteria, CA) BioGenex (Fremont, CA) Thermo Scientific (Fremont, CA) Ventana (Tucson, AZ) Dako (Carpinteria, CA) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Santa Cruz Biotechnology (Dallas, TX) Ventana (Tucson, AZ) Ventana (Tucson, AZ) BioGenex (Fremont, CA) Novus Biologicals (Littleton, CO) Ventana (Tucson, AZ) Dako (Carpinteria, CA) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Ventana (Tucson, AZ) Novocastra (Newcastle upon Tyne, UK) Upstate biotechnology (Lake Placid, NY) Santa Cruz Biotechnology (Dallas, TX) Santa Cruz Biotechnology (Dallas, TX) Santa Cruz Biotechnology (Dallas, TX) Ventana (Tucson, AZ)
Note. M, monoclonal; P, polyclonal.
FIGURE 2. (A) FSH/LH/a-subunit pituitary adenoma: spherical and uniformly small secretory granules with a well evident limiting membrane (scale equals 2 mm). (B) Clear cell renal cell carcinoma: characteristic lipid vacuoles and glycogen and absence of neuroendocrine granules in the cytoplasm of CCRCC (scale equals 2 mm).
Golgi apparatus was well evident, but did not show a ‘‘honeycomb’’ appearance. The secretory granules were spherical and uniformly small (less than 200 nm), with a well-evident limiting membrane. They were distributed unevenly, being more numerous in the cytoplasmatic processes (Figure 2A and B). Following the histopathological diagnosis, the patient underwent renal radiologic investigations
which demonstrated the presence of a right kidney neoplasm. However, the patient refused any further surgical intervention and was discharged from hospital. Unfortunately, exactly one year later she was re-admitted for diffuse metastatic involvement of the skull base and died in November 1982. Post-mortem examination was not carried out. Ultrastructural Pathology
Renal cell carcinoma metastatic to a pituitary adenoma
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Review of well documented cases reported in the English literature, including the present case Table 2 summarizes the clinical presentation of the previously reported cases, most of them already reviewed by Noga et al. [2] and Hoellig et al. [3]. The mean age of the 23 patients was 66 years (range 44–88). Thirteen patients were females and 10 males. The most frequently reported symptoms were: declining visual acuity (63.5% of the cases), headache (36.3%), field vision defects (27.3%), cranial nerves (III, VI) palsy (18.1%). Endocrine hyperfunction was present in 34.7% of cases (four cases of hyperprolactinemia, three cases of acromegaly and one case of Cushing disease); 65.2% of cases were clinically nonfunctioning. Signs of partial or total hypopituitarism were present in 62.5% of cases in which an endocrinological evaluation was performed. In no case diabetes insipidus was reported. A history of carcinoma, present before appearance of symptoms due to sellar metastasis, was found in 43% of cases with a mean length of 3.7 years (range 6 months–10 years). A pituitary adenoma was present from 6 months to 31 years (mean 11.9 years) before the intradenomatous metastasis occurred, in 43% of the patients. The mean diameter of the pituitary tumor in cases in which it was registered by neuroradiologist, resulted to be 2.7 cm (range 0.5–5 cm); in 78% of cases the tumor was described as large, in 69.5% it was sellar and suprasellar/para-sellar and in 27% a sphenoid or cavernous sinus invasion was reported. Fifty-two percent and 26% of the patients underwent transphenoidal and transcranial surgical approach, respectively; 8.6% received palliative chemo and/or radiotherapy; in 11% of the cases the diagnosis was defined at autopsy. Lung neoplasms were the most frequent primary malignancies (21%), followed by breast and kidneyrenal pelvis (17% each), gastric (8.6%), pancreatic, prostatic, colonic, and mediastinal carcinomas (4.4% each). In 13% of the cases the primary neoplasm remained undiscovered. In 26% of the cases the metastasis was represented by a neuroendocrine neoplasm: a poorly differentiated neuroendocrine carcinoma (PDNEC) in 17% and a neuroendocrine tumor (NET) in 8.6%. The pituitary adenoma represented the only metastatic site in 26% of the cases, while in the majority (74%) metastases were present in multiple sites. The survival time after operation was reported in 18 cases. The median length of patients’ survival after surgery or different therapies was 5.4 months (range 2 days–21 months). Patients with metastasis limited to the pituitary adenoma had a median survival of 10.5 months versus 5 months of patients with multiple metastases. Eighty-two percent of the patients were dead at last follow-up, while the remaining 17.4% were alive. !
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DISCUSSION The patient described in our report had some peculiar clinico-pathological features. First of all, the CCRCC was asymptomatic at the start and was diagnosed after detection of the pituitary metastasis. In addition, the metastasis of CCRCC involved a FSH/LH/ a-subunit adenoma, a finding which was not previously well documented in the English literature. In fact, two cases of CCRCC metastatic to pituitary adenomas have been described [4,5]: in both cases the pituitary tumor was diagnosed as an adenoma without any immunohistochemical expression of pituitary hormones. Although most of the non-functioning, non-hormone producing pituitary adenomas are now considered to belong to the family of FSH/LH/ a-subunit tumors, the two above-mentioned cases cannot be undoubtedly located in this category of tumors. In addition, the two previously reported CCRCCs differ from the case here reported, having been associated with a long history (9 years and 4 years, respectively) of a previously resected CCRCC. CCRCC metastases to the pituitary may be difficult to distinguish from other clear cell carcinomas and from pituitary adenomas with interspersed adrenal cortical cells [6]. In our case, the diagnosis of metastatic CCRCC was based on the presence of solid alveoli composed of large cells with clear cytoplasm, intensely immunoreactive for EMA, CD10, and CK AE1/AE3. The absence of immunoreactivity for Melan-A, SF1, and a-inhibin excluded the possibility of an adenoma with interspersed adrenocortical cells. Electron microscopy (EM), which was not performed in the previously reported cases [5,7], showed abundant glycogen and lipid droplets in the cytoplasm of metastatic cells, confirming the diagnosis of CCRCC. In addition, EM documented the presence, in pituitary adenomatous cells, of small secretory granules characteristic of gonadotroph cells [8]. CCRCC has a variable and complex biologic behavior [9]. The most important prognostic factor is the presence or absence of metastatic disease. Common metastatic sites for CCRCC are the lung, bone, liver, adrenal, and brain. Unusual sites are also registered and are sometimes discovered at the same time of the primary tumor. These include pituitary, thyroid, orbit, nasal structures, paranasal sinuses, vagina, gallbladder, pancreas, subungueal tissues, and soft tissue of distal extremities [10]. Metastatic renal cell carcinoma to the pituitary gland is extremely rare: in a clinico-pathologic review of 88 cases of carcinoma metastatic to the pituitary gland no CCRCC metastases were reported [11], while they were present in 2.6% of cases in a review of 360 pituitary metastases reported in the literature [12]. A recent study reviewing 23 cases of pituitary metastases from CCRCC demonstrated that these tumors behave
72 M
66 F
66 F
56 F
61 F
77 M
Age & Presentation gender (duration of symptoms) 67 M nr
50 F
4 [4]
5 [24]
6 [24]
7 [25]
8 [26]
9 [27]
10 [27]
Case
11 [28]
12 [28]
46 F
75 M
3 [23]
14 [30]
78 M
2 [22]
76 M
73 F
1 [7]
13 [29]
70 F
Case (reference)
Endocrine symptoms
Nausea, lethargy, decreased vision (nr) H, blurred vision, hemianopsia (3m)
Exophtalmus (nr)
Vision loss and hemianopsia in the LE (7y) Fever, nausea, diarrhea (2d) Visual field impairment (3w) NIII palsy, vision loss, BH (nr) H, nausea (40y) sudden blindness of the LE H, disturbed vision (42y), sudden blindness of the LE H, nausea, vomiting, bil NVI palsy (3w) H, disturbed vision (3y) H, loss of vision, bil NIII palsy, SIADH (2w)
HP
Acromegaly
L, SSe, ISe
L, SSe
1.52.52, SSe
L, SSe, ISe
L, ISe, PSe
L, SSe
2
nr
L, SSe
5
PA size (cm or descriptiozn)
TS
TS
4.5, SSe
L, SSe, ISe
Enlarged sella
Treatment Pituitary tumor ize (cm)/ extension None 0.5
TS, RT
TS
RT
TCS
TCS
TS, RT
TS
none
TCS
TCS, RT
Treatment
Truncal and RT, CT facial obesity
No
Endocrine symptoms
No
No
No
HP
HP
No
No
No
No
H, left hemiparesis No (nr)
Age and gender
Presentation (duration of symptoms)
TABLE 2. Summary of previously reported cases of metastases to pituitary adenoma.
Lung
Unknown
Breast (1y)
Stomach (A)
Stomach (A)
Lung (1y)
Pelvis and ureter (A) Kidney (9y)
Breast (3y)
Breast (15y)
Site and history of primitive ca
Yes (15y)
Yes (6m)
Yes (5y)
died after 4m; MM: bone, lung, liver, brain died after 28d; MM
Further clinical course; metastases
Further clinical course
died; MM
(continued )
mts prostatic ca in died; MM: bone, liver, hormone neg PA lymph nodes mts pancreatic PDNEC died after 7m; MM in ACTH Crooke’s cell PA mts lung adk in GH PA died; MM
Histopathologic findings
died 3w after admission (lung mts); MM mts ca in non functioning alive; SM ACTH PA mts lung NSSC in onco- died 6m after TS; MM cytic PA
mts breast ca in FSH/ LH/GH PA
mts SCC in hormone died 1m after TS; MM neg PA mts gastric mucin died 2d after TS producing ca in (sepsis); MM PRL PA mts gastric mucin prodied 12d after TS ducing adc in PRL cell (sepsis); MM PA
mts transitional cell ca in died after 5w; nr PA mts CCRCC in hormone unknown; SM neg PA
mts breast G3 ca in chromophobe PA
mts breast G3 ca in acidophil PA
Histopathologic findings
Mediastinum (1y) mts NET in PRL PA
Lung
Pancreas (6m)
History of Site and history pituitary of primitive ca adenoma No Prostate (9y)
No
Yes (2y)
No
Yes (17y)
Yes (18y)
No
Yes (25y)
No
No
Yes (8m)
History of pituitary adenoma
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434 F. Magnoli et al.
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2014 Informa Healthcare USA, Inc.
75 F
87 M
60 M
62 F
44 F
71 M
55 F 66 M
Case (reference)
15 [31]
16 [31]
17 [2]
18 [5]
19 [32]
20 [3]
21 [33] 22 [34]
Loss of vision, NIII palsy (2w) Leg pain (nr) H (nr)
Bitemporal anopsia (nr)
bil visual decline (nr) bil visual decline, optical atrophy (nr) Loss of vision, hemianopsia, left hemiparesis (9m) H, visual loss (4m)
Presentation (duration of symptoms)
Acromegaly HP
No
Acromegaly
No
No
No
No
Endocrine symptoms
TS, RT None
TS
TS
TCS
TCS
TS
TS
Treatment
Yes (4y)
3.4 3, SSe 321.6, PSe, SSe No enlarged pituitary No
No
No
No
Yes (31y)
No
History of pituitary adenoma
2.6, SSe, CS
L, SSe
5, CS
L, SSe
L, SSe
PA size (cm or descriptiozn)
Unknown Lung (A)
Lung (6m)
Lung (7y)
Kidney (4y)
Probably rectum
Unknown
Breast (3y)
Site and history of primitive ca
Further clinical course; metastases
mts CCRCC in hormone neg PA mts GHRH producing atypical carcinoid in GH cell hyperplasia/ PA mts SCC in hormone neg PA mts NEC in GH PA mts NSCC in PRL PA
mts adc in hormone neg PA
died after 21m; MM died after few days; MM
died after 3d; MM
alive with disease 3m after TS; MM
died after 8m; MM
died shortly after TCS; MM
mts breast ca in FSH/LH alive 18m after TS; SM PA mts ca in FSH/LH PA alive 6m after TS; SM
Histopathologic findings
Note. A, at autopsy; adc, adenocarcinoma; BH, bitemporal hemianopsia; bil, bilateral; ca, carcinoma; CS, cavernous sinus; CT, chemotherapy; d, days; F, female; H, headache; HP, hyperprolactinemia; ISe, intrasphenoidal extension; L, large; LE, left eye; m, months; M, male; MM, multiple metastases; mts, metastatic; neg, negative; NEC, neuroendocrine carcinoma; NET, neuroendocrine tumor; nr, not reported; NSSC, non-small cell carcinoma; PA, pituitary adenoma; PDNEC, poorly differentiated neuroendocrine carcinoma; PSe, para-sellar extension; RT, radiation therapy; SCC, small cell carcinoma; SM, sole metastasis; SSe, suprasellar extension; TCS, transcranial surgery; TS, transphenoidal surgery; w, weeks; y, years.
Age and gender
Table 2. Continued.
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Renal cell carcinoma metastatic to a pituitary adenoma 435
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436 F. Magnoli et al. differently from other metastatic malignancies, involving more commonly the anterior pituitary and causing more severe visual dysfunction and hypopituitarism, while diabetes insipidus is less frequent [13]. In reality, the majority of metastatic tumors to the pituitary involve the posterior lobe of the gland [14], due to the fact that the posterior lobe receives a direct systemic arterial blood supply, while the anterior pituitary is mainly vascularized by the hypophyseal portal system. Consequently, diabetes insipidus is the most frequent symptom associated with metastases to the pituitary gland, while visual disturbances and hypopituitarism are reported in a small percentage of cases [13,14]. The case described in this study as well as the 22 cases previously reported in the literature represent examples of tumor-to-tumor metastasis. It is still unclear why a neoplasm can be a host for a secondary neoplasm. At least two hypotheses try to explain this phenomenon [15,16]. The ‘‘mechanical’’ theory proposes that metastatic patterns depend on the quantity of viable neoplastic cells reaching the target organ. Pituitary adenomas have been shown to possess direct arterial supply from carotid and capsular vessels [17]. As a consequence, circulating neoplastic cells may bypass portal vessels, vascularizing the normal anterior pituitary, and generate metastases within the adenoma from the systemic circulation. The rich vascularization of the adenomas may render them more accessible to metastatic tumor cells in the circulating blood. Thus, the vascular network might act as a filter to metastatic emboli in the blood stream [18]. In this context, an interesting finding is that in the majority (65.5%) of cases of metastasis to pituitary adenomas, the recipient was represented by a nonfunctioning adenoma (identified as FSH/LH/a-subunit or gonadotroph adenoma in more recent cases, including ours). Moreover, FSH-expressing (gonadotroph) adenomas showed the highest vascular density evaluated with the use of factor VIII-related antigen [19]. The second theory, ‘‘seed and soil’’, proposes tentatively that tumor cells (seed) possess biological features apt to be implanted and to proliferate in a fertile environment [15,16]. In this context, the intradenomatous renal cell carcinoma metastasis may be due to acquisition by neoplastic renal cells of factors interacting with endothelial cells and with perivascular stroma. Interesting findings in the case here reported were that CCRCC metastatic cells highly expressed both VEGF and VEGFR1, and focally expressed CD31. VEGF was also detected in gonadotroph adenomatous cells. The presence of this growth factor and of the relative receptor suggests that they could drive tumor growth promoting vasculogenesis [20,21] and favor the interactions between adenomatous and carcinomatous cells, possibly through direct binding between growth factors and corresponding receptors.
In conclusion, metastases to pituitary adenomas are rare. The clinical symptoms do not differ substantially from those of patients with simple pituitary adenomas, but the prognosis of patients with metastasis to a pituitary adenoma is poor. The majority of adenomas harboring metastases are non-functioning adenomas often expressing FSH/LH/a-subunit. Immunohistochemistry and electron microscopy play a major role in defining the two components present in the neoplastic mass. The origin of metastasis is more frequently from neoplasms of the lung, followed by the breast and the kidney. Neuroendocrine neoplasms both well differentiated (NET) or poorly differentiated (PDNEC) represent a significant proportion of metastatic tumors within pituitary adenomas.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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