Article Type : Short commentary
Authors : Bajaji A
Keywords : Case Reports & Images
Exceptional neoplasia
with perivascular clear cell and epithelioid cell differentiation are diverse
and constituted by angiomyolipoma, clear cell “sugar tumour” of pulmonary and
extra pulmonary sites, clear cell myomelanocytic tumour of falciform ligament
or ligamentum teres and lymphangioleiomyomatosis on account of distinctive
histological manifestations. Variable genetic and malignant biological
behaviour is exemplified within perivascular epithelioid cell tumours.
Perivascular epithelioid
cell tumour (PEComa) is a contemporary neoplasm of mesenchymal origin emerging
within diverse sites while representing a classified group with distinctive
histology and immune histochemical staining. The tumefaction is composed of
epithelioid cells which demonstrate dual properties of smooth muscle and
melanocytes with pertinent immune reactivity. Cellular component tends to
aggregate around and circumscribe blood vessels, thus engendering the acronym
“PEComa”.
Perivascular epithelioid
cell tumour was initially described by Bonetti et al in 1992 [1]. Zamboni et al
in 1996 documented perivascular epithelioid cell tumour of the pancreas and
denominated the neoplasm as “sugar tumour” on account of clear, glycogen rich,
cytoplasm imbued within perivascular epithelioid cells. A normal counterpart of
perivascular epithelioid cell tumour is absent [2].
Perivascular epithelioid
cell tumour occur within head and neck, nasal sites, gynaecological soft tissue
as uterus, diverse cutaneous locations, soft tissue, bone, abdominopelvic
sites, retroperitoneal sites as the kidney, orbit or skull base, although no
site of tumour emergence is exempt. Perivascular epithelioid cell tumour occurs
in the absence of tuberous sclerosis [3]. Perivascular epithelioid cell tumour
of cervical region is an extremely exceptional mesenchymal neoplasm of unknown
biological behaviour. Mean age of tumour emergence is 41 years although the
neoplasm can appear within 24 years to 67 years. Uterine perivascular
epithelioid cell tumour demonstrates a mean age of emergence at 51 years. The
neoplasm depicts a female predilection wherein an estimated 80% to 90% of
incriminated individuals are females and commonly appears in middle aged women
[3].
The neoplasm can be
benign or of uncertain malignant potential or malignant. Malignant neoplasms
depict cogent features such as tumour magnitude exceeding >5 centimetres,
infiltrative pattern of tumour evolution, enhanced nuclear grade, enhanced
cellularity, mitotic activity exceeding >1 per 50 high power fields, necrosis
and vascular invasion. An estimated 9% of gynaecological perivascular epithelioid
cell tumours are associated with tuberous sclerosis complex along with a
history of childhood seizures, are aptly treated with lobectomy and demonstrate
radiographic features of angiomyolipoma or sclerotic bone lesions [3]. Distinctive
classification systems describe the neoplasm as “benign”, “malignant” or of
“uncertain malignant potential” in order to appropriately prognosticate the
tumours.
Classification system
developed by Folpe et al proposes diagnostic criterion of malignant neoplasms
as tumour magnitude exceeding >5 centimetres, mitotic activity ? 1 per 50
high power fields, necrosis, elevated nuclear grade and an infiltrative tumour
architecture [4]. Classification system suggested by Schoolmeester et al
demonstrates diagnostic criterion as tumour magnitude ? 5 centimetres, mitotic
index ? 1 per 50 high power fields, significant nuclear atypia, necrosis and
lympho-vascular invasion [5].
· Absence
of aforesaid criterion -benign cervical neoplasm
· One
to three criterion – tumour of uncertain malignant potential
· Four
or more criterion – malignant neoplasm [4,5]
Malignant perivascular epithelioid cell
neoplasm can demonstrate localized tumour invasion within petrous or occipital
bone, clivus, foramen magnum, spinal canal and pulmonary parenchyma [3].
The neoplasm demonstrates
a varied clinical representation and can be discovered incidentally or display
chronic pain or vaginal bleeding. The neoplasm can masquerade as a postpartum
retained placenta or induce spontaneous haemo-peritoneum.
Individuals may be
asymptomatic or manifest symptoms such as functional abdominal pain, abdominal
mass, occasional diarrhoea. Perivascular epithelioid cell tumour can infiltrate
the uterine myometrium. Perivascular epithelioid cell tumour can expand rapidly
during gestation, thereby ensuring a subacute elevation of intrauterine
pressure which may induce a rupture of the uterine wall [6]. Pelvic masses with
aberrant vaginal bleeding can be concurrent to the genetic condition of
tuberous sclerosis complex which is characterized by mental retardation,
seizures and benign neoplasia such as cutaneous angiofibromas [6]. Perivascular
epithelioid cell tumour typically enunciates benign biological behaviour
although tumour relapse and malignant metamorphosis is documented at several
primary sites wherein metastasis can commonly ensue to cutaneous locales or
orbit [6].
As the clinical
representation of perivascular epithelioid cell tumour is nonspecific and
imaging evaluation such as ultrasound, magnetic resonance imaging (MRI) and
positron emission computerized tomography (PET CT) scan may be inconclusive,
assessment of cogent tissue specimen with pertinent immune histochemical assay
is mandated and diagnostic [6,7].
Grossly, the neoplasm is
well circumscribed, encapsulated and spherical. Cut surface is homogenous and
light brown, circumscribed by an uninvolved, lobular parenchyma. Characteristically,
the tumour demonstrates spindle-shaped or epithelioid cells disseminated around
vascular articulations. Perivascular epithelioid cell tumour is typically
comprised of epithelioid cells with clear or eosinophilic, granular cytoplasm
demonstrating melanocytic and smooth muscle differentiation, possibly derived
from perivascular epithelioid cells [7].
Perivascular epithelioid
cell tumour demonstrates distinct histological features such as epithelioid to
spindle-shaped cells with clear, granular and eosinophilic cytoplasm, spherical
to elliptical nucleus and inconspicuous nucleoli [7]. Perivascular epithelioid
cell tumour is composed of flattened sheets of epithelioid cells with minimal
cellular and nuclear pleomorphism, cytoplasmic pigmentation and a minimal
mitotic index below <1 per 50 high power fields [7]. Perivascular tumour
cells demonstrate a radial configuration with peri-luminal arrangement,
epithelioid cells which abut blood vessels and spindle-shaped cells which are
distant from blood vessel. Cells with clear to granular, eosinophilic
cytoplasm, miniature, centric, spherical or elliptical nuclei with miniature
nucleoli are discerned. Multinucleated giant cells are frequent and may exhibit
features of malignant metamorphoses such as predominant cellular and nuclear
atypia, mitotic activity and tumour necrosis [7,8]. “Pecosis” may accompany the
neoplasm denominated by a continuous layer of clear, perivascular cells which
appears away from sites of tumour transitioning into invasive cell nests. Cells
of perivascular epithelioid cell tumour appose and appear in direct contact
with abluminal surface of capillary basal lamina [7]. “Pecomatosis” can be
discerned which is designated as a perivascular aggregation of clear to
eosinophilic cells, a phenomenon which may simulate a mesothelioma.
The neoplasm can appear as an organizing haematoma enveloped by sheets of spindle- shaped cells with eosinophilic cytoplasm, elliptical nuclei, miniature nucleoli and minimal mitotic activity [7,8]. The tumefaction consists of sheets of uniform, epithelioid, spindle- shaped cells imbued with abundant, granular, eosinophilic cytoplasm and distinctive, prominent nucleoli [8]. On cytogenetic analysis, significant genomic aberrations are discerned in a majority of instances wherein frequent imbalances appear within chromosomes 19-, 16p-, 17p-, 1p-, 18p-, X+, 12q+, 3q+, 5+, 2q+. Deletion within chromosome 16p- is indicative of loss of TSC2 gene.
Figure 1: Peripheral epithelioid cell tumour depicting accumulation of plump spherical cells with abundant eosinophilic cytoplasm and circumscribing mature adipose tissue cells.
Figure
2: Peripheral epithelioid cell tumour exhibiting
fascicles of spindly cells with ample, eosinophilic cytoplasm and uniform
nuclei.
On
ultrastructural examination, the cells are incorporated with abundant
cytoplasmic glycogen, pre-melanosomes, thin, attenuated filaments with
occasional occurrence of dense bodies, hemi-desmosomes and inadequately
configured cellular junctions [7-10] (Figures 1 and 2).
Immune reactivity to
myogenic and melanocytic markers is observed. Perivascular epithelioid cell
tumour is intensely immune reactive to human melanoma black -45 (HMB-45)
antigen, cathepsin-K, smooth muscle markers desmin and actin and weakly immune
reactive to melan-A [3]. The neoplasm is immune reactive to melanocytic markers
human melanoma black-45 (HMB-45)(92%) antigen, melan-A(72%), microphthalmia
transcription factor (50%), NKI/ C3, tyrosinase, S100 protein (33%) and smooth
muscle markers such as Myo D1, smooth muscle actin (SMA) (80%), desmin (40%),
calponin and vimentin (80%). The tumour is immune non-reactive to cytokeratin,
CD117/ c-kit and CD34. Also, reactivity to desmin and H-caldesmon is less
frequent. A subset of tumours are immune reactive to TFE3 and depict a TFE3
chromosomal rearrangement [6,7]. Tumour cells are immune non reactive to
synaptophysin, chromogranin A, pan cytokeratin CK20, CK7 and S100 protein [7].
Perivascular epithelioid
cell tumour requires a differentiation from neoplasms clear cell or oxyphilic
carcinoma which is immune reactive to cytokeratin. Epithelioid or clear cell
smooth muscle tumours are immune non reactive to human melanoma black -45
(HMB-45) antigen. Malignant melanoma is intensely immune reactive to S100
protein. Undifferentiated or high grade sarcoma which depicts morphological
features of malignancy such as cellular and nuclear pleomorphism, atypia,
nuclear hyperplasia or hyperchromasia and prominent mitotic (Figures 3-6).
Cervical perivascular epithelioid cell tumour necessitates segregation from primary and secondary cervical malignant melanoma. However, minimal cellular and nuclear pleomorphism with minimal mitosis favours a perivascular epithelioid cell tumour [6,7]. Perivascular epithelioid cell tumour of pterygopalatine fossa requires segregation from lesions such as epidermoid cyst, meningocoele, mucosal carcinoma, schwannoma, chordoma, teratoma or neurofibroma. Majority of aforesaid masses are benign although localized tumour invasion can ensue [6,7]. Histological differentiation of pancreatic perivascular epithelioid cell tumour is required from pancreatic neuro-endocrine tumour (NET), malignant metastasis and carcinoma pancreas. Segregation is also mandated from pseudo-papillary neoplasm, gastrointestinal stromal tumour (GIST), acinar cell carcinoma of pancreas, metastasis of clear cell renal cell carcinoma (CCRCC) or malignant melanoma [7,8].
Figure 3: Peripheral epithelioid cell tumour with fascicles of spindle-shaped cells with abundant clear to eosinophilic cytoplasm and regular nuclei.
Figure
4: Peripheral epithelioid cell tumour with accumulation
of plump, spindle-shaped cells with eosinophilic cytoplasm, uniform nuclei and
indistinct nucleoli.
Figure 6: Perivascular epithelioid cell tumour delineating nests of spherical
cells with abundant eosinophilic cytoplasm, uniform nuclei and indistinct
nucleoli.
Appropriate evaluation of
tissue specimen obtained from incriminated sites as pterygopalatine fossa is
indicated to eliminate malignant metamorphoses, except in prominently vascular
juvenile nasopharyngeal angiofibroma [9]. Mild anaemia or elevated levels of
chromogranin A may be discerned. The exceptional perivascular epithelioid cell
tumour of pancreas can be pre-operatively discerned by endoscopic, ultrasound
guided fine needle aspiration cytology (FNAC) [6,7]. Endoscopic ultrasound
guided fine needle aspiration (EUS FNAC) is a superior imaging modality for
obtaining tissue specimens for assessment. Ultrasound of the tumefaction
demonstrates a spheroidal, well defined, hypoechoic mass. Pancreatic neoplasm
depicts a well-defined, heterogeneous, predominantly hypoechoic mass with
lateral shadow extending into homogenous, circumscribing pancreatic tissue and
an absence of dilatation of pancreatic duct. Aforesaid manifestations can be
confirmed upon computerized tomography (CT) and magnetic resonance imaging
(MRI) [9,10]. On ultrasonography, a hypoechoic tumefaction is observed. Colour
Doppler demonstrates a certain degree of internal vascular flow. Uterine
neoplasms can be isointense, in contrast to encompassing myometrial tissue,
upon T1 and T2 weighted imaging. Antenatal diagnosis is challenging as
pregnancy associated pelvic magnetic resonance imaging is performed in the
absence of gadolinium contrast. Several neoplasms depict oestrogen receptors
(ER) and progesterone receptors (PR) which contribute to tumour evolution in
context to hormonal alterations during pregnancy [9,10]. Diverse imaging
techniques such as abdominal or endoscopic ultrasound, computerized tomography
(CT) or magnetic resonance imaging (MRI) display a well circumscribed,
spherical to elliptical mass with normal circumscribing soft tissue and lack of
tumour infiltration. On colour Doppler or contrast- enhancement, arterial hyper-vascularity
is observed. Elastography demonstrates a hard lesion with lateral shadowing,
thus indicating an encapsulated tumour. Aforesaid features can simulate a
neuro-endocrine tumour (NET). Contrast enhancement within an endoscopic
ultrasound (EUS) may differentiate the lesion from NET. In contrast, an
adenocarcinoma displays a poorly defined, infiltrative, hypodense tumefaction
[9,10]. Magnetic resonance imaging (MRI) depicts a nodule of intermediate
signal intensity. Positron emission computerized tomography (PET-CT) of the
incriminated zone depicts a soft tissue mass with significant uptake of nuclear
contrast, indicative of a malignant neoplasm. The tumour can be in proximity to
abutting viscera although direct tumour invasion is absent. Tumour metastasis
or abnormal, infiltrated lymph nodes are absent. In situ hybridization may or
may not be able to discern EWS and TFE3 genomic rearrangements, features which
support the diagnosis of conventional perivascular epithelioid cell tumour
[9,10]. Nodules of pterygopalatine fossa can be detected with nasal endoscopy,
computerized tomography (CT) and contrast- enhanced magnetic resonance imaging
(MRI) [10] (Figures 7 and 8).
The neoplasm is usually benign although certain instances can demonstrate malignant metamorphoses and recapitulate a high grade sarcoma. Factors associated with inferior prognosis are tumour magnitude exceeding > 5 centimetres to 8 centimetres, infiltrative tumour articulation, enhanced nuclear grade with mitotic figures exceeding > 1 per 50 high power fields or atypical mitotic figures and coagulative cell necrosis [7,8].
Figure 7: Perivascular epithelioid cell tumour displaying fascicles of spindle-shaped cells with eosinophilic cytoplasm and regular nuclei.
Figure
8: Perivascular epithelioid cell tumour depicting
aggregates of spindle shaped epithelioid cells with clear cytoplasm and uniform
nuclei.
Comprehensive surgical
resection of the neoplasm is generally curative due to benign biological
behaviour. Cervical perivascular epithelioid cell tumour is appropriately
treated with total hysterectomy. Prognostic outcomes are superior than a
uterine neoplasm. Localized surgical excision is accompanied by disease
reoccurrence in around 8.3% of cervical lesions and nearly 21.5% of uterine
neoplasms [3].
Radical surgical excision
of the neoplasm is contingent to tumour histology. As pancreatic perivascular
epithelioid cell tumour is imbued with a malignant potential, cogent surgical
extermination as pancreatectomy with splenectomy can be adopted. Neoplastic
occurrence may be absent within the tumour perimeter, abutting viscera and
resected lymph nodes. Surgical extermination is recommended for solid
pancreatic tumefaction exceeding >2 centimetre magnitude or neuro-endocrine
tumour. Nevertheless, clinical signs and symptoms, location of tumour, evidence
of malignant metamorphoses and individual comorbidities are critical factors in
selecting cogent therapeutic options [9,10]. Majority of pancreatic
perivascular epithelioid cell tumours are benign and associated with superior
prognosis as the tumefaction is devoid of relapse or distant metastasis.
Nevertheless, the neoplasm can delineate a potential for malignant
metamorphoses. Hepatic metastasis can occur and malignant features such as
tumour infiltration, necrosis or tumour magnitude exceeding > 5 centimetres
can ensue. Adjuvant chemotherapy with epirubicin and ifosfamide can be adopted
for metastatic lesions [9,10]. Radiation therapy can be therapeutically
employed in instances with significant tumor progression. Nevertheless,
established indications for adjuvant radiation are as yet undescribed [10].