Silent familial isolated pituitary adenomas: histopathological and clinical case report.
ABSTRACT Familial isolated pituitary adenoma (FIPA) is a rare condition independent of Carney Complex or MEN1. An international multicenter study recently described 28 nonfunctioning pituitary adenomas in 26 families with only two homogeneous nonsecreting phenotype families consistent of silent GH and silent gonadotroph adenomas, respectively. We present the clinical, genetic, and morphological analysis of two silent pituitary adenomas occurring in a man and his daughter, and discuss the differential diagnosis associated with their histological, immunohistochemical, and ultrastructural features. The patients developed invasive nonsecreting macroadenomas manifesting only with compressive symptoms. Genetic analysis in the father showed no MEN-1 germ-line mutation. Tissue samples obtained after paraseptal trans-sphenoidal surgery were studied by immunohistochemistry for adenohypophyseal hormones, low molecular weight cytokeratins (CAM 5.2), proliferation markers, and anterior pituitary transcription factors (Pit-1 and SF-1) and by electron microscopy for secretory granules. The clinical, histological, and immunohistochemical features of the lesions posed a differential diagnosis between a null cell adenoma and a silent corticotroph adenoma (Type II); on the basis of immunohistochemical stains for cytokeratin and adenohypophysis cell lineage markers, tumor behavior and ultrastructural studies we concluded for the second. The reported cases represent an as yet undescribed example of homogeneous family with silent corticotroph adenomas (Type II). Our observations support the trend for more aggressive behavior in nonsecreting FIPAs as compared with sporadic adenomas.
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ABSTRACT: The diagnosis of double adenomas of the pituitary can be very complex and is usually suspected on histological assessment of a specimen and confirmed by immunohistochemical and ultrastructural studies. The most commonly applied technique is currently immunohistochemical staining to localize the six pituitary hormones. Application of this technique may fail to identify double adenomas when hormone immunoreactivity is weak or absent in one or both cell populations. We examined specimens from eight patients diagnosed with double adenomas over a 15-yr period. We tested the ability to detect the difference in the two adenomas in each case using three immunostains for the pituitary transcription factors Pit-1, T-pit, and SF-1. We conclude that immunohistochemical localization of the transcription factors Pit-1, T-pit, and SF-1 accurately detects and classifies the distinct cytodifferentiation of double adenomas of the pituitary.Endocrine Pathology 02/2005; 16(3):187-94. · 1.60 Impact Factor
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ABSTRACT: Postoperative management of clinically nonfunctioning pituitary adenomas (NFPA) presents difficult challenges. There are no good serum markers for presence or growth of the tumour, medical treatment is not effective and radiotherapy carries the risk of significant side-effects. The purpose of this study was to investigate the natural history and biological behaviour of surgically treated NFPA, with a special effort to identify characteristics indicative of a more aggressive course that could assist in the clinical decision-making process. Patients operated on at our institution for NFPA undergo uniform routine clinical follow-up at the endocrine clinic. Magnetic resonance imaging (MRI) studies are performed 3, 6 and 12 months after transsphenoidal surgery and yearly thereafter for the first 5 years. Subsequently, imaging is performed once every 2 years or as clinically indicated. From 1992 onwards, no patient received immediate postoperative radiation therapy. One hundred and twenty-two patients (78M/45F) operated on at our institution since 1989 and with a minimal follow-up of 1 year comprised the study group. Tumour size and characteristics were determined by MRI using a modification of Hardy's and Wilson's classifications. Maximal tumour height was also recorded and the information was routinely stored in a computerized database. Mean (+/- SD) follow-up was 51 +/- 31 months. Fourteen patients received postoperative radiation therapy. Subsequent tumour growth was observed in five of them, reduction in tumour size in four and no size changes in five. One hundred and eight patients did not receive postoperative radiation. Tumour enlargement occurred in 41 of 78 and in six of 30 patients with and without residual tumour after operation (P = 0.0024). The presence of cavernous sinus invasion before surgery [P = 0.02, odds ratio (OR) 2.72; confidence interval (CI) 1.1-6.43] and the extent of suprasellar extension in the postoperative tumour remnant (P = 0.0054 for presence of stage A, OR 4.4; 95% CI 1.5-12.5; and P = 0.012 for presence of stages B or C, OR 16.2; CI 1.8-144) were strong independent predictors of tumour enlargement. Our data may ease the selection of patients in whom radiation therapy is likely to be necessary for tumour control, and confirms that close postoperative follow-up is an adequate primary approach in low-risk patients.Clinical Endocrinology 07/2003; 58(6):763-9. · 3.40 Impact Factor
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ABSTRACT: The cases of gigantism sisters with somatotroph adenomas unrelated to multiple endocrine neoplasia (MEN) Type 1 are reported. The sisters grew rapidly since they were 5 or 6 years old and were diagnosed to have gigantism with pituitary adenoma by computed tomographic scan and magnetic resonance imaging. A serum endocrinological examination showed the elevated growth hormone values. After thyroxine-releasing hormone stimulation, growth hormone values exhibited a paradoxical rise. They were supposed to be unrelated to MEN Type 1, because analysis of the 11th chromosomes and the other endocrine functions were normal. They were operated on by the transphenoidal method. Immunohistochemical staining of both tumor specimens confirmed somatotroph adenomas. Pituitary adenoma associated with MEN Type 1 is a well-recognized entity. However, the sporadic occurrence of pituitary adenoma unrelated to MEN Type 1, especially in siblings, is extremely rare. Fifteen cases of pituitary adenomas in siblings were described in the literature. As for gigantism, only two brothers were reported. Our case of gigantism sisters is the second sporadic case. In our review of the isolated cases of pituitary adenoma in siblings described in the literature, 12 (70%) of 17 cases including ours are acromegaly or gigantism. This incidence is much higher than that of MEN Type 1 patients with pituitary adenomas. The cause of the familial occurrence of pituitary adenomas is still unclear, although autosomal recessive inheritance has been suggested. It has been stated that point mutations in codon 201 or 227 of the Gs alpha gene located in chromosome 20 were found in about 35 to 40% of somatotroph adenomas.(ABSTRACT TRUNCATED AT 250 WORDS)Neurosurgery 12/1994; 35(5):952-5; discussion 955-6. · 2.53 Impact Factor
Silent Familial Isolated Pituitary Adenomas:
Histopathological and Clinical Case Report
C. Villa & F. Magri & P. Morbini & A. Falchetti &
P. Scagnelli & E. Lovati & D. Locatelli &
F. R. Canevari & V. Necchi & E. Gabellieri &
G. Guabello & L. Chiovato & E. Solcia
Published online: 4 March 2008
# Humana Press Inc. 2008
Abstract Familial isolated pituitary adenoma (FIPA) is a
rare condition independent of Carney Complex or MEN1.
An international multicenter study recently described 28
nonfunctioning pituitary adenomas in 26 families with only
of silent GH and silent gonadotroph adenomas, respectively.
We present the clinical, genetic, and morphological analysis
of two silent pituitary adenomas occurring in a man and
his daughter, and discuss the differential diagnosis associated
with their histological, immunohistochemical, and ultrastruc-
tural features. The patients developed invasive nonsecreting
macroadenomas manifesting only with compressive symp-
toms. Genetic analysis in the father showed no MEN-1
germ-line mutation. Tissue samples obtained after paraseptal
trans-sphenoidal surgery were studied by immunohistochem-
istry for adenohypophyseal hormones, low molecular weight
cytokeratins (CAM 5.2), proliferation markers, and anterior
pituitary transcription factors (Pit-1 and SF-1) and by electron
microscopy for secretory granules. The clinical, histological,
and immunohistochemical features of the lesions posed a
differential diagnosis between a null cell adenoma and a silent
corticotroph adenoma (Type II); on the basis of immunohis-
tochemical stains for cytokeratin and adenohypophysis cell
concluded for the second. The reported cases represent an as
yet undescribed example of homogeneous family with silent
corticotroph adenomas (Type II). Our observations support
the trend for more aggressive behavior in nonsecreting FIPAs
as compared with sporadic adenomas.
Pituitary adenomas usually arise from a single-cell mutation
followed by clonal expansion, as demonstrated by X-allele
inactivation methods . In this process, dominant events,
like activation of oncogene function, or recessive events,
such as tumor suppressor inactivation, or both, play an
Endocr Pathol (2008) 19:40–46
C. Villa (*):P. Morbini:V. Necchi:E. Solcia
Department of Human and Hereditary Pathology, Pathology
Section, S. Matteo I.R.C.C.S. Foundation /University of Pavia,
Via Forlanini 14-16,
27100 Pavia, Italy
F. Magri:E. Gabellieri:L. Chiovato
U.O. of Internal Medicine and Endocrinology,
S.Maugeri I.R.C.C.S. Foundation, University of Pavia,
E. Lovati:G. Guabello
Endocrinology and Diabetology Unit,
S.Matteo I.R.C.C.S. Foundation,
Neuroradiology Unit, S.Matteo I.R.C.C.S. Foundation,
Neurosurgery Unit, S.Matteo I.R.C.C.S. Foundation,
F. R. Canevari
Otolaryngology/Head and Neck Surgery Unit,
S.Matteo I.R.C.C.S. Foundation,
Careggi Hospital (R.G.G.)/University of Firenze,
important pathogenetic role . Familial pituitary adeno-
mas are mainly part of multiple endocrine neoplasia type 1
(MEN1), a condition in which the prevalence of pituitary
adenoma is about 40% [3–6], which is associated with the
loss of a tumor suppressor gene on chromosome 11q13 .
Isolated familial somatotropinoma is another condition
depending on MEN1 germline mutations [8–11] or on loss
of heterozygosity over an extensive area of chromosome
11q13 . MEN1 gene mutations were also identified in
most cases of MEN1 syndrome , but not in cases of
familial isolated pituitary adenoma (FIPA) . FIPAs are
defined as two or more cases of pituitary adenomas in
single-family members in the absence of Carney Complex
or MEN1. FIPAs are rare and usually occur independently
of known genetic syndromes in a familial setting. Until
recently, mainly cases of familial growth hormone (GH)
secreting adenomas (clinically silent or functioning) and
prolactinomas have been described [10, 15–23].
In a recent international, multicenter, retrospective study,
FIPA showed a prevalence of 1.9–3.2% of the total pituitary
adenoma population . This series comprised 28 non-
functioning pituitary adenomas in 26 families, of which 24
were heterogeneous (with different tumor phenotypes in
affected family members); only two families presented the
same tumor phenotype (homogeneous), consistent of silent
GH and silent gonadotroph adenomas, respectively. Non-
secreting adenomas, identified using serum hormonal
and clinical data and by immunohistochemistry, were
subclassified as null cell and FSH/LH silent, GH silent,
β-endorphin/TSH β-subunit silent adenomas . Interest-
ingly, most (87.5%) nonsecreting FIPAs were invasive, a
behavior significantly different from that of sporadic cases
In this paper, we describe the clinical, genetic, and
morphological features of two familial isolated silent
adenomas, occurringin twosiblings presenting a particularly
aggressive behavior and discuss the differential diagnosis
associated with their histological, immunohistological, and
A 75-year-old male was referred to the Neurosurgery Unit
in April 2005 for an enlarging pituitary mass, as shown by
magnetic resonance imaging (MRI). The pituitary adenoma
was originally detected in 2001, when MRI, performed for
recurrent drop attacks, showed a pituitary mass 2 cm in
size. From 2001 to 2005, pituitary hormones assays and
visual field remained within normal limits. In February
2005, following a skull trauma, a new MRI documented a
pituitary mass 2.8 cm in size, grade 4d Wilson & Hardy
classification modified by Ouaknine  (Fig. 1a). A visual
field defect in the superior temporal quadrant of the right
eye became apparent.
The tumor was resected by direct paraseptal trans-
sphenoidal approach. Surgical excision proved difficult
because the tumor was firm with dense vascularization.
Before surgery, serum pituitary hormone levels (i.e., thyroid
stimulating hormone [TSH], prolactin, follicle-stimulating
hormone [FSH], luteinizing hormone [LH], adrenocortico-
tropic hormone [ACTH] and growth hormone [GH]), as
well as thyroid hormones, testosterone, cortisol, insulin-like
growth factor [IGF I], parathyroid hormone [PTH] and
gastrin were in the normal range for age and sex, but during
the follow-up a progressive hypopituitarism developed
(TSH<0.01 mU/L, prolactin<0.5 ng/mL; FSH 0.10 U/L,
LH 0.10 U/L, ACTH<5 pg/mL, and GH<0.01 ng/mL)
and specific hormone replacement therapy was started.
Subnormal responses of cortisol to synthetic ACTH (Syn-
acthen, 1 mcg) and of GH after stimulation with growth
hormone-releasing hormone (GHRH) and arginine (GHRH
arginine test) were also detected (cortisol peak response after
Synacthen test=10.7 mcg/dL and GH response after GHRH+
Arginin < 0.10 ng/mL).
A follow-up MRI performed 3 months after surgery
showed the presence of residual tumor in the pituitary
region. On June 2007, the residual tumor had reached a size
of 2.8 cm.
A 47-year-old female, the single daughter of the above-
described patient, experienced the abrupt onset of visual
field defect with homonymous hemianopsia in January
2005. MRI documented the presence of a pituitary mass,
3.6 cm in size, grade 4d Wilson & Hardy classification
modified by Ouaknine , with suprasellar and right
laterosellar extension and compression of the optic chiasm
(Fig. 2a). The pituitary mass obliterated the suprasellar
cistern and reached the third ventricle, left deviated,
extending to the cavernous sinus. In basal conditions,
pituitary hormone values (TSH 1.6 mU/L, prolactin
12 ng/mL, FSH 6 U/L, LH 5.8 U/L, ACTH 18.2 pg/mL,
GH 0.52 ng/mL) and peripheral hormone levels (thyroid
hormones, cortisol, IGF I, PTH, and gastrin) were within
the normal range, with the exception of the 17-β estradiol,
which was low for the early luteal phase of the cycle
(estradiol 13.3 ng/mL). The patient’s history documented
two pregnancies and regular menses.
On April 2005, the patient underwent tumor resection by
direct paraseptal trans-sphenoidal surgery. Surgery was
complicated by for the presence of fibrous adhesions and
firm tumor tissue, and for abundant bleeding from
numerous intratumoral small vessels. For these reasons,
Endocr Pathol (2008) 19:40–464141
Fig. 2 Case 2 images. a
Contrast enhanced coronal
T1-weighted MRI (TSE
sequences): 3.6 cm lesion with
cavernous sinus invasion, grade
4d Wilson & Hardy classifica-
tion modified by Ouaknine. b
H&H ×20: papillary/sinusoidal
growth pattern with abundant
composed of chromophobic cells.
c CAM5.2 immunostaining ×40:
diffuse cytoplasmic pattern. d
Electron microscopy (original
magnification ×16,000): sparsely
granulated adenoma character-
ized by secretory granules
variable in shape and density
(110–290 nm in diameter)
Fig. 1 Case 1 images. a
T1-weighted MRI (TSE
sequences): 2.8 cm lesion with
cavernous sinus invasion, grade
4d Wilson & Hardy classification
modified by Ouaknine.
b H&H ×20: chromophobic
pituitary adenoma with
and pseudorosettes formation.
c CAM5.2 immunostaining ×40:
with patchy distribution.
d Electron microscopy (original
magnification ×16,000): sparsely
granulated adenoma with
spherical, electron-dense secreto-
ry granules (140–460 nm in
42 Endocr Pathol (2008) 19:40–46
the tumor was only partially removed. In the immediate
postoperative period, the patient developed a cerebrospinal-
fistula in the left chiasm optic region with subsequent
Two further trans-sphenoidal explorations were then
performed at days 20 and 27 after the first surgical
procedure. During this period, the patient underwent a
progressive deterioration of consciousness resulting in a
coma status due to brain ischemic damage documented by
MRI. Three months after surgery the patient developed
acute renal failure and died. Autoptic examination of the
brain was performed.
Materials and Methods
The surgical samples were fixed in formalin and embedded
in paraffin. Five-micrometer-thick sections were stained
with hematoxylin–eosin (H&E), periodic acid-Shiff (PAS)
and reticulin for light microscopy. Immunohistochemistry
for pituitary hormones was performed with the following
antibodies: anti-PRL (COR910 Ylem Rome, Italy; poly-
clonal, rabbit, working dilution 1:1200), anti-GH (COR905
Ylem; polyclonal, rabbit, working dilution 1:1200), anti-α
subunit (0375 Immunotech Marseille, France; monoclonal,
mouse, working dilution 1:50), anti-FSHβ (ORM918
Ylem; monoclonal, mouse, working dilution 1:100), anti-
LHβ (ORM928 Ylem; monoclonal, mouse, working
dilution 1:100), anti-TSH (ORM913 Ylem; polyclonal,
rabbit, working dilution 1:10), anti-ACTH (ORM900
Ylem; monoclonal, mouse, working dilution 1:20) using
streptavidin–biotin peroxidase complex method (LSAB,
Dako Cytomation, Carpinteria, CA, USA) and diamino-
benzidine tetrahydrochloride (Dako liquid DAB, Dako
Cytomation) as chromogen substrate. No antigen retrieval
procedures were required for the immunostains.
The Ki-67 antigen was detected with monoclonal mouse
MIB-1 antibody (Dako Cytomation; working dilution 1:50)
after microwave pretreatment (15’×600 MW in pH 6 citrate
buffer). The vascular density was assessed with CD34
antibody (Ylem; working dilution 1:100). Low molecular
weight cytokeratin (CAM 5.2, Becton Dickinson; working
dilution 1:200) and chromogranin A (Dako Cytomation,
working dilution 1:5,000) expression were also evaluated
The P53 expression was evaluated with monoclonal
mouse antibody (Dako Cytomation, working dilution
1:5,000) after microwave pretreatment (15’× 600 MW in
pH 6 citrate buffer).
The main pituitary transcription factors Pit-1 and SF-1
were also assessed [25, 26].
Pit-1 polyclonal rabbit antibody (which identified
(Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA;
working dilution 1:200) and SF-1 polyclonal rabbit anti-
body (which identified gonadotroph differentiation)
(Abcam, Cambridge-UK; working dilution 1:400) were
used after microwave pretreatment (20’× 600 MW in pH
9.9 EDTA) and endogenous avidin/biotin block (avidin/
biotin blocking kit, Dako Cytomation). Normal pituitary
tissue present in the samples was used as positive internal
control. Negative control reactions were obtained in each
test series by omission of the primary antibody.
Samples for the ultrastructural study were obtained from
paraffin blocks microdissection. The specimens were
dewaxed and rehydrated through graded alcohols, postfixed
in osmium tetraoxide and embedded in Epon Araldite
mixture. Ultrathin sections (~600 Å) were stained with lead
citrate and uranyl acetate and examined with 902 Zeiss
electron microscope. Morphometric measurements were
performed with NIH Image J software (1.26).
Genetic Screening for MEN-1 Gene Mutations
Genomic DNA was extracted from peripheral blood
leukocytes of patient 1, using a microvolume extraction
method, QIAamp DNA Mini Kit (Qiagen GmbH, Hilden,
Germany) according to the manufacturer’s instructions.
Exons 2–10 of the MEN1 gene and their boundaries were
amplified by polymerase chain reaction (PCR), and
sequenced . Sequencing products were analyzed with
the ABI Prism 3100 genetic Analyzer (Applied Biosystems,
Foster City, CA, USA). The sequences obtained were
compared to wild-type reference sequence of the MEN1
gene (sequence no.U93237) .
Histopathology and Immunoprofile
By light microscopy, case 1 showed trabecular/sinusoidal
architecture with formation of pseudorosettes around blood
vessels. The cells had scant chromophobic cytoplasms
(Fig. 1b). Small fragments of adenohypophysis and
neurohypophysis were present in the surgical sample.
The immunoreactions for anterior pituitary hormones
and PAS stain were completely negative. Chromogranin A
was diffusely expressed on tumor tissue and CAM 5.2
showed a perinuclear/cytoplasmic expression with patchy
distribution (Fig. 1c). Ki-67 labeling index was 7% with
Endocr Pathol (2008) 19:40–46 4343
mitotic activity lower than 1 in 10 high-power fields. P53
was completely negative. The transcription factors Pit-1 and
SF-1 were identified in the fragment of adenohypophysis
with nuclear expression in mammosomatotroph-lactotroph-
thyrotroph and gonadotroph cells, respectively, while the
tumor resulted negative [25, 26].
Case 2 showed a papillary/sinusoidal growth pattern
with abundant pseudorosettes, mainly composed of chro-
mophobic cells (Fig. 2b). The immunostains for anterior
pituitary hormones were negative. Tumor cells showed a
moderate chromogranin A expression and strong, diffuse
cytoplasmic CAM 5.2 immunoreactivity (Fig. 2c). Tumor
growth fraction was 5% (Ki67 index), with a single mitosis
in 10 high-power fields; P53 was completely negative. The
immunohistochemical reactions for transcription factors
Pit-1 and SF-1 were negative.
The immunohistochemical profile observed in the two
cases could fit with only two members of silent pituitary
adenoma classification: null cell type adenoma (with
unexpected cytokeratins expression) or silent corticotroph
adenoma (Type II) (with the absence of both ACTH-
expression and PAS stain) [25, 29, 30].
The ultrastructural study of formalin-fixed paraffin embedded
samples was technically limited by the poor preservation of
the cellular detail, and only allowed the analysis of secretory
granule diameter and cytoplasmic distribution.
Case 1 showed rare, spherical, electron-dense, cytoplasmic
secretory granules ranging from 140 nm to 460 nm in
diameter (mean 290 nm) (Fig. 1d).
Case 2 ultrastructural features were suggestive of a
sparsely granulated adenoma with variability in size, shape,
and density. The size ranged from 110 nm to 290 nm (mean
180) (Fig. 2d).
These observations did not allow a conclusive charac-
terization of tumor type, but the size of the granules was
more consistent with a silent corticotroph adenoma (Type
II) since their granules are usually bigger (150–400 nm,
according to different authors) than those of null cell
adenoma (100–250 nm, according to different authors) [25,
In both patients and in their relatives (i.e., a sister of patient
1 and the offspring of patient 2), covering three generations,
clinical and biochemical evaluation for MEN 1-related
tumors (serum calcium, parathyroid hormone, and gastrin)
were negative. The family history did not reveal other cases
of pituitary adenomas or pertinent syndromes, including
acromegaly or gigantism.
Genetic analysis for MEN 1 mutations, performed on the
75-year-old patient, showed no MEN-1 germ-line mutation.
We described two cases of familial silent pituitary adenoma
occurring in a father and in his daughter. Molecular studies
of Case 1 for MEN 1 gene showed no association with
menin mutation. On the basis of the clinical, histological
and immunohistochemical features of the two lesions, the
differential diagnosis was limited to null cell adenoma or a
silent corticotroph adenoma (Type II). Although the lack of
immunoreactivity for anterior pituitary hormones was
suggestive for a null cell type adenoma, the remaining
features, such as cytokeratin expression and the absence of
immunoreactivity for lineage cytodifferentiation markers
like Pit-1 and SF-1 transcription factors, sustained the
final diagnosis of silent corticotroph adenomas (Type II)
[25, 29, 31].
In both adenomas, we observed diffuse reactivity for
CAM5.2 antibody, specific for cytokeratin 8 and 18 [29,
32]. According to the morphological classification of
pituitaryadenomasproposedbyAsa, diffuse cytoplasmic
CAM5.2 expression is typically identified in corticotroph
adenomas while null cell adenomas are negative. Silent
corticotroph adenomas (Type II) resemble the histological
features of functioning sparsely granulated corticotroph
adenomas and are generally much more aggressive than
other silent adenomas and more prone to recurrence [25, 33].
Thus, the negativity for PAS stain, the strong immunoreac-
tivity for cytokeratin and the aggressive behavior of our two
cases supported the diagnosis of silent corticotroph adenomas
(Type II) in spite of the absence of even weak immuno-
reactivity for ACTH (and other POMC-derivated peptides)
[25, 29, 30].
Immunohistochemical detection of the three transcription
factors Pit-1, SF-1, and Tpit [25, 26] that regulate the three
main pathways of cell differentiation and hormonal secre-
tion of adenohypophysis has been proposed to allow a
differential diagnosis among the three adenoma families:
and corticotroph [25, 30]. Tpit in the present cases would
have been useful to confirm the corticotroph lineage,
according to the assumption that a hormone-negative,
Tpit-positive silent adenoma is as aggressive as ACTH-
reactive silent corticotroph adenomas with similar thera-
peutic implications . Unfortunately, as stated by
Al-Brahim and Asa in a recent review , as yet no
effective antiserum or antibody for formalin-fixed paraffin-
embedded samples is commercially available for Tpit, as
confirmed by our dismal results with several commercial
products against Tpit. Further and more specific investigation
44Endocr Pathol (2008) 19:40–46
for ACTH, POMC, T-pit o Neuro D1 mRNA, could not
be performed due to the small amount of tissue available and
to the lack of frozen samples. However, in both cases, Pit-1
and SF-1 reactions were negative with appropriate positive
controls and consequently a mammosomatotroph-lactotroph-
thyrotroph and gonadotroph origin could be excluded. In
particular, we could exclude a null cell adenoma, since most
classified as members of gonadotroph adenoma family
According to the current World Health Organization
(WHO) classification  based on clinical and immuno-
histochemical hormone production patterns, the described
tumors should be classified as null cell type adenomas,
which are however usually less aggressive and less prone to
recurrence than the present cases . In our opinion,
cytokeratin production and cell lineage marker expression
could help to define those lesions that do not perfectly fit in
WHO categories. To this purpose, we evaluated CAM5.2
expression in a series of 39 clinically nonsecreting immuno-
negative pituitary adenomas with mean follow-up of
24 months . Our preliminary results showed a significant
predictive value of CAM 5.2 expression for tumor recurrence
(P=0.037) and a weaker correlation with invasion (P=0.004)
(personal communication). Most of CAM 5.2 positive cases
were negative for Pit-1 and SF1 (unpublished data).
On the basis of all the above considerations, our final
diagnosis was that of silent corticotroph adenomas (Type II).
In the present report, we add to the previously described
FIPA series  two invasive nonsecreting pituitary
adenomas, describing for the first time a homogeneous
FIPA family displaying two silent corticotroph adenomas
(Type II). Interestingly, nonfunctioning adenomas in the
recently reported FIPA series were more frequently macro-
adenomas and showed increased invasive attitude than
sporadic cases . Our observations support the trend for
more aggressive behavior in FIPAs as compared with
sporadic adenomas and suggest that CAM5.2 may play an
important role in silent pituitary adenomas classification
and prognostic evaluation.
As far as the genetics of familial pituitary adenomas is
concerned, recent studies show new perspectives in p27 or
AIP gene germline mutations, which have been identified in
GH-oversecreting FIPA [35–37]. However, only one subject
with a nonsecreting tumor belonging to a heterogeneous
family was found to carry a mutation in AIP gene so far .
Further studies are needed to define the background beyond
MEN-1, although the heterogeneity of FIPAs could make the
identification of genes involved in single families more
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