Adenomatoid tumour of the adrenal gland in a patient with germline SDHD mutation: a case report and review of the literature.
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ABSTRACT: The genes for the succinate dehydrogenase (SDH) subunits SDHA, SDHB, SDHC and SDHD are encoded in the autosome. The proteins are assembled in the mitochondria to form the mitochondrial complex 2, a key respiratory enzyme which links the Krebs cycle and the electron transport chain. Thirty percent of phaeochromocytoma and paraganglioma (PHEO/PGL) are hereditary and perhaps as many as half of these familial cases are caused by germline mutations of the SDH subunits. Negative immunohistochemical staining for the SDHB subunit identifies PHEO/PGL associated with germline mutation of any of the mitochondrial complex 2 components and can be used to triage formal genetic testing of all PHEO/PGL for SDH mutations. PHEO/PGL associated with SDHA mutation also show negative staining for SDHA as well as SDHB.A unique subgroup of gastrointestinal stromal tumours (GISTs) are driven by mitochondrial complex 2 dysfunction. These SDH deficient GISTs can also be definitively identified by negative staining for SDHB and show distinct clinical and morphological features including frequent onset in childhood and young adulthood, gastric location, a tendency to multifocality, absence of KIT and PDGFRA mutations, a prognosis not predicted by size and mitotic rate and a tendency to indolent behaviour of metastases. Some of these SDH deficient GISTs are driven by classical SDH mutations, but the precise mechanisms of tumourigenesis in many (including those associated with the Carney triad) remain unknown. Germline SDHB mutation is associated with a newly recognised type of renal carcinoma which commonly but not always demonstrates distinctive morphology and can also be recognised by negative staining for SDHB.Immunohistochemistry for SDHB therefore has emerged as a useful tool to recognise these distinct neoplasias driven by mitochondrial complex 2 dysfunction and to triage formal genetic testing for the associated syndromes.Pathology 04/2012; 44(4):285-92. · 2.66 Impact Factor
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ABSTRACT: Adenomatoid tumors (AT) are uncommon, benign tumors of mesothelial origination most frequently encountered in the genital tracts of both sexes. Their occurrences in the extragenital sites are much rarer and could elicit a variety of differential diagnosis both clinically and morphologically. With regard to the adrenal gland, to the best knowledge of us, only 31 cases of AT have been reported in the English literature. Several histologic growth patterns have been documented in AT, among which cystic type is the least common one. We herein present a further case of AT arising in the adrenal of a 62-year-old Chinese man with a medical history for systemic hypertensive disease. The tumor was incidentally identified during routine medical examination. An abdomen computed tomography scan revealed a solitary mass in the right adrenal. Grossly, the poorly-circumscribed mass measured 3.0 x 3.0 x 2.0 cm with a cut surface showing a gelatinous texture with numerous tiny cystic structures. Microscopic examination showed an infiltrated lesion with honeycomb appearance mimicking a lymphangioma, which composed predominantly of variably sized and shaped anastomosing small cystic spaces lined by flattened endothelial-like cells, without any epithelioid or signet-ring like components present. Foci of extraadrenal tumor extension, lymphoid aggregates with occasional germinal centre formation, intralesional fat tissue, stromal myoid proliferation and ossification were also observed. Immunohistochemical analyses confirmed the mesothelial differentiation of this tumor and indicated a diagnosis of cystic lymphangiomatoid AT of the adrenal.International journal of clinical and experimental pathology 01/2013; 6(5):943-50. · 2.24 Impact Factor
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ABSTRACT: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma (PCC)/ paraganglioma (PGL) tumors in SDH-x mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinico-pathological phenotype and even causal relatedness to SDH-x mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centres. SDHA/SDHB immunohistochemistry (IHC), SDH-x mutation analysis and loss of heterozygosity analysis of the involved SDH-x gene were performed on all tumors. A cohort of 348 tumors of unknown SDH-x mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas and adenomatoid tumors, was investigated by SDHB IHC.Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the wild-type allele, indicating bi-allelic inactivation of the germline mutated gene. Out of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.These findings strengthen the aetiological association of SDH-x genes with pituitary neoplasia, while provide evidence against a link between PTC and SDH-x mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDH-x alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.European Journal of Endocrinology 10/2013; · 3.14 Impact Factor
Adenomatoid tumour of the adrenal gland in a
patient with germline SDHD mutation: a case
report and review of the literature
Adenomatoid tumour, a benign neoplasm, is seen most com-
monly in the male and female genital tract including epididy-
mis, uterus and fallopian tubes.1,2Adenomatoid tumours of the
adrenal gland are rare and often an incidental finding. In some
cases, clinical suspicion of phaeochromocytoma leads to resec-
tion of the adrenal gland. Thus far, the tumour has not been
described in association with syndromic or genetic conditions.
We report one case of adrenal adenomatoid tumour in a patient
with a personal and family history of succinate dehydrogenase
complex subunitD (SDHD)
The patient was a 24-year-old man who was referred for an
adrenal mass. He had an unremarkable medical history. His
father was found to have cervical paragangliomas and upon
genetic testing a germline P81L mutation in SDHD was
detected. Site-specific predictive genetic testing confirmed
the presence of the family-specific germline mutation in SDHD
in the patient. The patient did not report any blood pressure
problems or other symptoms worrisome for phaeochromocy-
toma. His biochemical workup showed a 24h urine norepi-
nephrine of 59mg (normal 15–100), epinephrine 4mg (normal
2–24), dopamine 249mg, (normal 52–480), metanephrine
180mg (normal 25–222), and normal potassium 309mmol
(normal 40–412). His creatinine collection was 1.8mg/dL and
potassium was 3.9mmol/L. Computed tomography (CT) of his
chest, abdomen and pelvis showed no intrathoracic pathology
and a 30?20mm mass, originating from the left adrenal gland.
Magnetic resonance imaging (MRI) of the abdomen around the
30?20?25mm. Additionally MRI of the neck showed bilat-
eral carotid body masses measuring 25?26mm on the left and
22?15mm on the right. The patient elected to undergo adre-
nalectomy, after which he was going to consider removal of the
carotid body masses. After adrenalectomy, the patient was
instructed to return in 6 months for a metanephrine level.
The specimen received in pathology measured 77?35?
gland was stretched over a 36?33?18mm tumour mass that
seemed to arise from the adrenal cortex. On gross examination,
the tumour was a solitary well-circumscribed solid mass with a
small foci of haemorrhage, but no necrosis was noted (Fig. 1).
On microscopic examination, the tumour was composed of
variably sized anastomosing tubules and channels (Fig. 2A)
lined by bland cuboidal to epithelioid cells, some of which
contained intracellular vacuoles (Fig. 2B). The tumour cells
had low nuclear/cytoplasmic ratios, with no appreciable
mitotic activity or nuclear pleomorphism. Scattered aggregates
of mature lymphocytes were seen throughout the lesion.
The tumour cells surrounded the adrenal cortical or medullary
tissue, imparting an appearance of an infiltrative growth
pattern. Focal involvement of adrenal capsule and extension
into periadrenal fat was noted.
By immunoperoxidase staining, the tumour was diffusely
positive for cytokeratin AE1/3 (Fig. 2C), calretinin (Fig. 2D)
and WT-1 (Fig. 2E), focally positive for S-100 protein, and
negative for synaptophysin, chromogranin, CD31 and CD34,
supporting the diagnosis of adenomatoid tumour. CD31 and
CD34 immunostain underlined the presence of vessels.
We performed immunohistochemistry for SDHB (1:250;
Sigma-Aldrich, USA) on the adenomatoid tumour and found
a weak diffuse cytoplasmic blush (Fig. 3A), lacking definite
granularity. The adjacent adrenal gland (positive control)
showed granular cytoplasmic staining in a mitochondrial
pattern (Fig. 3A, arrows, and 3B).
Since clinical testing revealed a germline SDHD P81L
mutation, we sought to determine if a second somatic ‘hit’
could have occurred in the tumour. PCR-based direct Sanger
sequencing of genomic DNA extracted from the paraffin
embedded, formalin fixed adenomatoid tumour was performed
per routine of Neumann et al.3Sequencing of the promoter and
all four exons (and flanking intronic regions) of the SDHD
gene revealed only the germline heterozygous missense
mutation P81L (c.242C>T) (Fig. 4). We then sought to
determine if somatic deletion of the remaining wildtype
allele occurred. Because the tumour was microdissected
and contained 100% tumour, we were able to validly inspect
the sequencing chromatogram which revealed two clear
heterozygote peaks, i.e., no deletions were present (Fig. 4).
Approximately 34 other adrenal adenomatoid tumours
have been reported in the literature.1,4,5These tumours are
usually asymptomatic and found incidentally on radiology or
at autopsy.1,5Adenomatoid tumours have been described in
other sites such as heart, intestinal mesentery, omentum,
uterus, pancreas and pleura. The tumour has been reported
in association with AIDS and disseminated coccidioido-
mycosis, micronodular adrenal cortical hyperplasia and in a
vascular cyst of an adrenal gland, but has never been described
in association with Carney’s complex.6The reported mean
age is 41 years (range 31–64) with a male predominance for
adrenal adenomatoid tumours,1differing slightly from our
patient who is a younger (24-year-old) male. While other
studies reported symptoms associated with the tumour such
as syncope and hypertension, in the majority of cases the
tumour is non-functional.1,6Histogenesis is thought to be
related to entrapment of primitive mesenchymal cells associ-
ated with the mu ¨llerian tract in the adrenal or to the dislodge-
ment of mesothelial inclusions.1,6,7
Histologically, four patterns have been described: adenoidal,
angiomatoid, cystic, and solid, and more then one pattern can
be seen in a specimen. The most common pattern consists of
variably sized tubules and fenestrated channels arranged in
ring-like cells are seen. Lymphoid nodules are often present.4,5
Adrenal adenomatoid tumours display an immunophenotype
similar to that of the genital tract.2,5,7,8The tumours are
strongly reactive for calretinin, cytokeratin AE1/3, CAM
5.2, CK5/6, WT-1, D2–40 and caldesmon. Calretinin, D2–40
and WT-1 have shown a higher sensitivity then CK5/6 and
The differential diagnosis can be broad and includes: primary
Pathology (August 2011) 43(5), pp. 495–498
C O R R E S P O N D E N C E
Print ISSN 0031-3025/Online ISSN 1465-3931#2011 Royal College of Pathologists of Australasia
lymphangioma, angiosarcoma, primary as well as metastatic
adenocarcinoma, malignant mesothelioma, and adrenal cyst.
Lymphangioma is the most common mimic of adrenal angio-
matoid tumour. Lymphangioma is positive for endothelial
markers and negative for cytokeratin and mesothelial markers
and the opposite is true of adrenal adenomatoid tumour.1
Epithelioid angiosarcomas can present as complex cystic-solid
and mitosis are common findings. These tumours are very
rare and the cells are positive for endothelial markers (CD31,
CD34, and factor VIII).5,6An adrenal cyst can be considered in
the differential diagnosis when cystic structures are prominent.
If signet ring cells seem to be prominent, metastatic carcinoma
needs to be ruled out.6Multicystic mesotheliomas may
demonstrate focal areas of adenomatoid-like change which
occur in the peritoneum of young to middle-aged women.5
The genes for various familial tumour syndromes associated
with phaeochromocytoma have been identified, such as
the proto-oncogene RET [associated with multiple endocrine
neoplasia type 2 (MEN 2)], the tumour suppressor gene VHL
yellow bulging cut surface.
Well-circumscribed adrenal adenomatoid tumour with solid grey-
intracellular vacuoles. Tumour cells show positive immunostaining for (C) cytokeratin AE1/3, (D) calretinin and (E) WT-1.
cortical tissue (A, arrows, B).
(A) Adenomatoid tumour showing a diffuse cytoplasmic blush (weak diffuse staining) in contrast to the true granular cytoplasmic staining of adjacent adrenal
CORRESPONDENCE Pathology (2011), 43(5), August
(associated with von Hippel-Lindau disease) and NF1
(associated with type 1 neurofibromatosis). A recently ident-
ified heritable form of paraganglioma-phaeochromocytoma
caused by germline mutations in the genes encoding succinate
dehydrogenase (SDH) complex has been described. A broad
spectrum of germline mutations of the genes encoding
various subunits SDH (SDHB, SDHC, and SDHD) have been
discovered (reviewed by Eng 2010).9
the mutations associated with familial head and neck para-
ganglioma usually need to be followed for development of
phaeochromocytoma. It has been shown that 20–30% of
apparently non-syndromic phaeochromocytoma cases harbour
germline mutation.10,11Clinical parameters such as age
<45years, multiple phaeochromocytoma,
location, and previous head and neck paraganglioma can
predict for mutation carriers and prioritise gene testing in
individuals without a personal or family history of head and
neck paraganglioma to reduce costs.10
Hereditary head and neck paragangliomas (HNP) are nearly
exclusively associated with germline mutations of at least three
succinate dehydrogenase subunit genes (SDHx).11Neumann
and colleagues recently analysed clinical parameters as
potential predictors for finding germline mutations in HNP
and found that family history, previous phaeochromocytoma,
multiple HNP, age?40 years and male gender were predictors
family history, male and young age and was found to have a
germline SDHD mutation by predictive testing. Interestingly,
the adenomatoid tumour did not undergo loss or mutation of
the remaining wild-type allele. SDHD is maternally imprinted
which means that the allele inherited from this patient’s mother
would be silenced throughout the germline. So in effect, there
of the remaining wild-type allele would not be necessary.
Recently, van Nederveen and colleagues proposed that
negative immunostaining for SDHB is highly specific for
phaeochromocytomas and paragangliomas associated with
SDHB, SDHC, or SDHD gene mutations.12All tumours with
a germline SDH mutation (36 SDHB, 5 SDHC and 61 SDHD)
were negative for SDHB immunohistochemistry. In four SDH-
mutated tumours, the authors reported a weak and diffuse
cytoplasmic SDHB immunoreactivity in the tumour cells.
Similar to our case, the staining pattern was clearly distinct
from the strong speckled pattern present in the normal cells of
the intratumoural fibrovascular network. Since independent
tumour samples with the same mutation were clearly negative
for SDHB immunoreactivity, the weak cytoplasmic staining in
the tumour cells was considered to be a non-specific back-
ground artefact and scored as negative.12Previous studies have
shown that immunohistochemistry for SDHB can be used to
triage genetic testing.12,13Gill and colleagues13have found that
completely absent staining is more commonly found with
SDHB mutations, whereas weak diffuse staining, as in our
case, often occurs with SDHD mutation.
While there are reports of increased risk of renal tumours,14
thyroid tumours, and gastrointestinal stromal tumours (GISTs),
there are no reports indicating the association of adenomatoid
tumour with mutations of the SDHB and SDHD genes.15
Mutation analysis for the SDHD gene was performed in the
current adrenal gland tumour and a heterozygous germline
mutation wasdetected,confirming that the adenomatoid tumour
reported in our patient was a SDHD mutated tumour. Germline
mutations affecting encoding subunits of SHDx may predispose
individuals to different tumours in different organs and other
mutation types or other as yet unidentified phaeochromocytoma
predisposing genes might exist. Adenomatoid tumour of
the adrenal gland is a rare tumour and has never been
previously reported in association with phaeochromocytoma
and/or HNP. The current case report should inspire further
interest in this unusual tumour, especially in the setting of
Abberly Lott Limbach*
*Pathology and Laboratory Medicine Institute, Department of
Cleveland Clinic Lerner Research Institute, Cleveland, Ohio,
Contact Dr C. Magi-Galluzzi.
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sequence in the codon 81 region compared to (B) heterozygous P81L SDHD
mutation identified in the tumour-derived DNA. Note that this reflects the
germline mutation in tumour tissue. Because the DNA was extracted from a
region with 100% tumour (without normal tissue), theclear heterozygote pattern
showing the germline mutated allele and the wildtype allele excludes a somatic
deletion (loss of heterozygosity).
Sequencing chromatograms of SDHD mutation. (A) Wild-type
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CORRESPONDENCEPathology (2011), 43(5), August