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\begin{document}

\title{Primary epithelioid hemangioendothelioma of the Spine: A first in
Africa. A case report and literature review}



\author[1]{Bakang Kgaodi}%
\author[1]{Jed  Lazarus}%
\author[2]{Brendon Price}%
\author[1]{Stefan Kruger}%
\author[1]{Crispin Thompson}%
\affil[1]{University of Cape Town Faculty of Health Sciences}%
\affil[2]{National Health Laboratory Service}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{Introduction}

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumour that
originates from vascular endothelial or pre-endothelial cells. Its
demographic characteristics are unclear and there is no racial and sex
predilection\textsuperscript{,8}The overall incidence of EHE is 0.230
per 1000000 person-years.\textsuperscript{8} EHE in general affects
patients in the age range 16-74 years but EHE of the bone is more
prevalent in the third and fourth decade of
life.\textsuperscript{2,3,5}EHE can develop in any part of the body but
is reported to more frequently in the liver (34\%), lungs (21\%), bone
(19\%) and other sites (26\%). \textsuperscript{1.,2} It was first
described and named in 1982 by Weiz and Enzinger and is classified in
the 2020 WHO classification of bone tumours as a low-to-intermediate
grade neoplasm.\textsuperscript{2.,3} Malignant vascular bone tumours
are rare and constitute less than 1\% of primary bone
tumours.\textsuperscript{3} Bone involvement usually involves the lower
extremity (62\%), upper extremities (14\%) and vertebra
(10\%)\textsuperscript{3.} As such primary EHE of the spine is very
uncommon, with the thoracic spine most likely to be involved followed by
cervical, lumbar, and sacral levels in order of decreasing
frequency\textsuperscript{3.}

Here we report on a 26-year-old female with thoracic T2 and T3 lesions
in keeping with primary EHE of the spine, her clinical presentation,
work up including laboratory, immunohistopathological and imaging
studies. We also conclude on her management and current condition. There
are currently no prior clinical case reports on primary EHE of the spine
in South Africa or Africa as a whole.

\textbf{Statement of Ethics}

Informed consent and assent were obtained from the patient to proceed
with writing and publishing this report. Every effort has been made to
exclude information that may identify her.

\textbf{Case Presentation}

\textbf{History}

A 26-year-old female, born as twin A of a set of twins, presented from a
peripheral hospital with a 2-month history of progressive lower limb
weakness. She had initially mobilised with crutches with gradual
deterioration and at time of review was wheelchair bound with associated
bladder and bowel incontinence. She had no known medical comorbidities,
no prior history of trauma or fever.

\textbf{Examination}

On general exam, patient noted to have a thyroid nodule and hirsutism.
She was well oriented with intact cranial nerves and normal upper limb
function. She however had features of thoracic myelopathy with increased
lower limb reflexes, clonus, hypertonia, Babinski sign and paraparesis
(worse on right side). There was a T4 sensory level and diminished anal
sphincter tone and peri-anal sensation. No obvious tenderness or steps
on her back and nor features of sepsis or inflammation.

\textbf{Initial imaging: Computed Tomography (CT) Scan}\selectlanguage{english}
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\textbf{Figure 1. A. B}

Coronal(A) and axial (B) CT images showing expansile osteolysis and
collapse of T3 and T4 vertebral bodies with residual bony trabeculae,
sclerotic rim and segmental kyphosis.

NB Surveillance CT scans of the chest (including neck), abdomen and
pelvis did not show any primary. A solitary thyroid nodule was noted. On
thyroids ultrasound: TIRADS classification of 5.

\textbf{Magnetic Resonance Imaging (MRI) findings}\selectlanguage{english}
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\textbf{Figure 2: A B}

Sagittal(A) and axial (B) views T2 and T3 vertebral body collapse with
involvement of posterior elements and high-grade cord compression.
Lesions are T1 isointense to grey matter and slightly T2 hyperintense
and enhance with gadolinium contrast.

\textbf{Laboratory work up:}

\begin{itemize}
\tightlist
\item
  CEA (Carcinoembryonic antigen) negative, Anti-nuclear antibodies (CTD)
  negative, HIV negative
\item
  Normal: Thyroid hormones (TSH/T4/T3), Parathyroid hormone, CA-125, CA
  19-9, Full blood count, urea and electrolytes, Erythrocyte
  sedimentation rate, glycated haemoglobin, liver enzymes, and lactate
  dehydrogenase.
\item
  Urine electrophoresis: normal urine creatinine, protein \textless{}
  0.04g/L, Bence-jones protein 0
\end{itemize}

\textbf{Clinical Course -- Treatment and Outcome}

Patient initially taken for CT guided biopsy of the thoracic lesion as
well as fine needle biopsy of the thyroid nodule.

\textbf{Ultrasound guided thyroid nodule FNA:}

Atypical epithelial cells with microfollicular arrangement. These cells
also show nuclear inclusions, nuclear irregularity, and nuclear grooves.
These features are in keeping with papillary thyroid carcinoma.

\textbf{CT guided biopsy of thoracic lesion for immunohistopathology} :\selectlanguage{english}
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\textbf{FIGURE 3: A} , H\&E image of EHE with plump neoplastic atypical
vascular endothelial cells (inset 1, arrow) compared to admixed normal
benign flattened and spindle endothelial cells (inset 2,
star).\textbf{B.} CD31 immunostain highlighting membranes of neoplastic
cells. C, FLI-1 immunostain highlighting large irregular nuclei of
neoplastic cells. A horseradish peroxidase-diaminobenzidine (HRPO-DAB)
detection system was used. Original magnification of A-C (400x).

A wide panel of antibodies was employed to further characterise this
lesion. CD34, CD31 and FLI-1 immunopositivity confirmed vascular
endothelial origin. Metastatic carcinoma was ruled out by negative
staining for AE1/AE3 and Cam5.2 (cytokeratins). In light of thyroid
nodule, additional TTF-1 and PAX8 stains were employed to rule out
metastatic PTC; these were both negative. They are crucial for thyroid
organogenesis and differentiation and are thus invariably positive in
the presence of thyroid metastasis\textsuperscript{9.} Less likely
entities such as epithelioid sarcoma and haemangioblastoma were excluded
by negative immunostaining results for INI-1 and inhibin, respectively.

As the lesion showed well-formed vessels as opposed to the more classic
blister cells and myxohyaline stroma, a TFE3 antibody was employed to
assess for the presence of a YAP1-TFE3 gene fusion which is
characteristic in this subset of EHE. The TFE3 results were,
unfortunately negative.

There is no locally available FISH platform to assess the presence of
the WWTR1-CAMTA1 gene fusion nor is there a locally available fusion
specific antibody.

Overall the architectural, cytomorphological atypia and
immunohistochemical features are that of an atypical vascular lesion.
The features are more atypical than that haemangioma but fall short of
the significant atypia of angiosarcoma. Therefore a consensus diagnosis
of EHE was reached.

\textbf{Surgical plan:}

Patient was taken for T2 and T3 separation surgery with C7 to T6
posterior instrumented fusion. Intra-operatively a highly vascular
reddish-brown tumour that was encountered. Post operative MRI showed
adequate tumour debulking. The histopathology examination was identical
to that following the CT guided biopsy and in keeping with an
Epithelioid hemangioendothelioma.

On follow up review, patient is recovering well and ambulating
independently. She was discussed at a multi-disciplinary meeting with
pathology, radiology, radiation-oncology and neurosurgery and a
collective decision to offer radiation therapy was decided upon. She has
done the pre-radiation planning and will receive a total of 54Gy in 30
fractions over 6 weeks.

She is due to follow up with the endocrine surgical service for the
thyroid papillary carcinoma at their outpatient service and is planned
for elective thyroid lobectomy.

\textbf{Discussion}

EHE is a rare low grade malignant neoplasm with potential for
metastasis. Only 20\% of the cases present with
metastasis\textsuperscript{1.,5.} It originates from vascular
endothelial or pre-endothelial cells. Although it can develop anywhere
in the body it most reported in the liver, lungs and bone. Primary EHE
of the bone is rare constituting only 1\% of all malignant tumours of
the bone\textsuperscript{1,2,5.}, as such primary involvement of the
spine in EHE is very rare \textsuperscript{5.} Spinal EHE has a
non-specific clinical presentation, usually with pain (mostly radicular
or mechanical in nature) or neurological deficits attributable to
compression of the spinal cord and/or nerve roots. There is a paucity of
literature on EHE in Africa with only a few case reports on pulmonary,
hepatic and pleural EHE and none for primary EHE of the
Spine\textsuperscript{6,7.} It occurs equally in both males and females
with no racial predilection\textsuperscript{1.}Weissferdt et al
describes better overall survival for unicentric tumour as compared to
multifocal disease (89\% and 50\% respectively) and a mortality rate of
20\%. The median survival is at 1.3 years and 5-year survival of 33\%
after disease progression\textsuperscript{5.}

Although EHE of the spine has no pathognomic features that are specific
enough to be used as the sole means of diagnosis, most if not all cases
show an expansile osteolysis with bony trabeculae and lack a sclerotic
margin. There is usually vertebral body collapse with segmental kyphotic
deformity\textsuperscript{1,2,3,4,5.} On MRI the lesions are usually
isointense to grey mater on T1 weighted imaging, slightly hyperintense
on T2 weighted imaging with increased uptake of contrast on contrasted
sequences\textsuperscript{1.} Chen P et al., suggests
that\textsuperscript{18}F-FDG PET/CT scan may be of some use in
difficult cases (especially those with multifocal disease) with
hypermetabolism, but this is not pathognomic and as such cannot be used
in solitude to confirm diagnosis of EHE or its
dissemination\textsuperscript{2.}

Macroscopically the tumour a reddish-brown mass with tendency to bleed.
The diagnosis of EHE rests mostly on the histopathological analysis.
Microscopically the tumour cells appear as round, polygonal or fusiform
with a central nucleus and intracytoplasmic vacuolations but with the
absence of increased mitotic activity or
necrosis\textsuperscript{2,3,4,5,8.} Immunohistochemically EHE stains
positive for CD31, CD34, EGR, Factor VIII related antigen and
FLI-1\textsuperscript{2,3,4,5,8.} Cytogenetic analysis can be used to
show chromosomal translocation involving chromosomes 1 {[}t(1;3) and 3
(p36.3;q25) that results in WWTRI-CAMTAI fusion. This is present in
approximately 90\% of the cases with EHE\textsuperscript{2,3.} A subset
of patients with EHE may show YAP-1 TFE 3 fusion\textsuperscript{10.}

The mainstay of treatment for patients with EHE of the spine seems to be
multimodal with surgery, total resection where feasible, as the
centrepiece.\textsuperscript{2,3,5} Pre-operative embolization to reduce
the vascularity of the tumour and radiation and chemotherapy are also
described. Given the rarity of EHE, especially EHE of the spine, there
currently exists no universally accepted treatment guidelines with
clearly defined outcomes.

\textbf{Conclusion}

Our case is the first ever described case of spinal EHE in Africa. Our
patient shows the previously described features in EHE of the spine. The
clinical presentation, radiological features, microscopic and
immunohistochemical features are congruent with those of the other cases
of spinal EHE described from elsewhere. EHE remains a rare entity and
EHE of the spine ultra-rare. The treatment modalities though not
standardised, show that multimodality treatment with surgery and
adjuvant radiotherapy remain the most plausible.

\textbf{Author contributions}

Bakang Kgaodi: Conceptualization, data curation, formal analysis,
investigation, methodology, project administration, writing and editing
of manuscript.

Jed Lazarus: Conceptualization, formal analysis, review and editing.

Brendon Price: Formal analysis, methodology, writing and review.

Stefan Kruger: Investigation, methodology, project administration,
reviewing of manuscript.

Crispin Thompson: Conception and supervision of case write up process.

\textbf{References}

\begin{enumerate}
\tightlist
\item
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\item
  Chen P., Lin Q. et al., Epithelioid hemangioendothelioma of spine: A
  case report with review of literatures. Radiology case reports
  15(2020) 2687:2692. https://doi.org/10.1016/j.radcr.2020.10.24
\item
  Weissferdt A \& Moran C., Epithelioid hemangioendothelioma of the
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  254-259, July 2014. DOI:10.1097/PAP.0000000000000027
\item
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\item
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\item
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\item
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\end{enumerate}

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