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\begin{document}

\title{Paramedullary plasmacytoma originating from the first cervical vertebra
(C1) in an 8-month-old warmblood weanling with tetraparesis: Clinical
and pathological findings}



\author[1]{Vivien Schiffbauer}%
\author[1]{Anna Pelli}%
\author[2]{Simone Della Tommasa}%
\author[1]{Reiner Ulrich}%
\author[1]{Anja Reinert}%
\author[1]{Kerstin Gerlach}%
\author[1]{Iris Voelker}%
\affil[1]{Leipzig University}%
\affil[2]{University of Leipzig Faculty of Veterinary Medicine}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
To the authors' \selectlanguage{english}knowledge there is only one report in the literature,
dealing with paramedullary plasmacytomas in horses as so-called ``break
out lesions'', originating from the bone marrow of a vertebra and
invading the epidural space (Drew and Greatorex 1974). Our case report
describes the clinical and patho-morphological findings of such a case.
The affected 8-month-old warmblood weanling colt exhibited acute
tetraparesis thus, a spinal cord lesion in the cervical column was
suspected. Computed tomography revealed osteolytic lesions in C1 and a
heterogeneous mass within the respective segment of the vertebral canal.
By means of patho-morphological examination, with the aid of
transmission electron microscopy, a plasmacytoma was identified, that
had grown out of the bone marrow of C1 into the epidural space, locally
compressing the spinal cord. In tetraparetic, young horses traumatic
spine cord injuries, cervical vertebral malformations and infectious
diseases of the central nervous system represent common differentials.
However bone-dissolving tumours such as paramedullary plasmacytomas
should be considered as a further possible cause in the presence of
severe neurological deficits.%
\end{abstract}%



\sloppy


\textbf{Title}

Paramedullary plasmacytoma originating from the first cervical vertebra
(C1) in an 8-month-old warmblood weanling with tetraparesis: Clinical
and pathological findings

Anna Pelli\emph{\textsuperscript{+α}}\selectlanguage{greek} , \selectlanguage{english}Vivien
Schiffbauer\emph{\textsuperscript{++α}}\selectlanguage{greek} , \selectlanguage{english}Simone della
Tommasa\textsuperscript{+}, Reiner Ulrich\emph{\textsuperscript{++}} ,
Anja Reinert\selectlanguage{ngerman}\emph{\textsuperscript{§},} Kerstin
Gerlach\selectlanguage{english}\emph{\textsuperscript{+}} , Iris
Volker\selectlanguage{english}\emph{\textsuperscript{++}*}

\selectlanguage{english}\textsuperscript{+}Department for Horses, Faculty of Veterinary
Medicine, Leipzig University, Germany; and \selectlanguage{english}\textsuperscript{++}Institute
of Veterinary Pathology, Faculty of Veterinary Medicine, Leipzig
University, Germany; and \textsuperscript{SS}Institute of Anatomy,
Histology and Embryology, Faculty of Veterinary Medicine, Leipzig
University, Germany

\textsuperscript{*}Corresponding author email: Iris.Voelker@outlook.com

\selectlanguage{greek}\textsuperscript{α}\selectlanguage{english}shared first authorship

\textbf{Summary}

To the authors' \selectlanguage{english}knowledge there is only one report in the literature,
dealing with paramedullary plasmacytomas in horses as so-called ''break
out lesions'', originating from the bone marrow of a vertebra and
invading the epidural space. Our case report describes the clinical and
patho-morphological findings of such a case. The affected 8-month-old
warmblood weanling colt exhibited acute tetraparesis thus, a spinal cord
lesion in the cervical column was suspected. Computed tomography
revealed osteolytic lesions in C1 and a heterogeneous mass within the
respective segment of the vertebral canal. By means of
pathomorphological examination, including transmission electron
microscopy, a plasmacytoma was identified, that had grown out of the
bone marrow of C1 into the epidural space, locally compressing the
spinal cord. In tetraparetic, young horses traumatic spine cord
injuries, cervical vertebral malformations and infectious diseases of
the central nervous system represent common differentials. However
bone-dissolving tumours such as paramedullary plasmacytomas should be
considered as a further possible cause in the presence of severe
neurological deficits.

\textbf{Keywords:} horse; tetraparesis; vertebra; spinal cord; tumour

\textbf{Introduction}

In horses spinal cord dysfunction can have several causes, including
traumatic injury, cervical vertebral stenotic myelopathy or malformation
and infectious diseases such as protozoal or viral myeloencephalitis
(MacMillan \emph{et al.} 2021). Neoplastic disease is considered a
further differential, however, especially in young horses, tumours
originating from the cervical vertebrae represent a rare event. To date,
there is only one report in the literature of a plasmacytoma with
invasion of the vertebral canal (Drew and Greatorex 1974). The aim of
this case report was to describe clinical, imaging and pathological
features of a paramedullary plasmacytoma in a young horse, in
distinction to other variants of this neoplastic disease.

\textbf{Case history}

An 8-month-old warmblood weanling colt was presented to the Department
for Horses of the University of Leipzig for acute non-ambulatory
tetraparesis. Four days before presentation, the foal was found in the
stable with neck asymmetry, which was deviated mildly to the right. The
colt was standing but unable to extend the neck and to grab the hay from
the ground. On the right cranial side of the neck, a swelling was
noticed by the owner. A trauma was suspected. The foal was treated for
two days by the referring veterinarian with antibiotic (Cefquinom, 1
mg/kg body weight (BW) q. 24h) and non-steroidal anti-inflammatory drugs
(Flunixin meglumine, 1.1mg/kg BW q. 24h). On the morning of referral to
the Department for Horses of the University of Leipzig the foal was
found lying down in the stable and was unable to rise.

\textbf{Clinical findings}

On presentation the foal was bright, alert and responsive, but in
lateral recumbency and unable to stand. The colt was classified with
grade 5/5 ataxia based on a modified grading system for cervical spinal
cord disorders (Mayhew \emph{et al.} 1978; DeLahunta and Glass 2009).
The foal presented with a body temperature of 37.8\selectlanguage{ngerman}°C, a heart rate of 52
beats/min and a respiratory rate of 22 breaths/min. He was able to eat
and drink food and water within his reach. He made several unsuccessful
attempts to rise but settled quickly and did not require sedation.

His neck appeared to deviate mildly to the right in the proximal neck
region, and there was a diffuse swelling at the level of the third to
fifth cervical vertebra (C3--C5). The swelling showed increased warmth
and was painful to palpation. Increased muscle tone of the neck was
present and the cervicofacial reflex of the left cervical side was
decreased. The foal showed volitional movement of the forelimbs and
weaker volitional movement of the hindlimbs. Examination of spinal
reflexes revealed slight hyperreflexia of both patellar reflexes and
slightly decreased tail tone. The foal was continent and had been
passing both urine and faeces. His response to pain stimulus was
inconsistent in both hindlimbs when the skin was tapped with a needle.
Clinical findings suggested a focal spinal cord lesion located between
C1 and C5.

Haematological and biochemical blood analysis included the following
findings: mild increase in erythrocytes (10.66 T/l, reference interval
7.4--10.2 T/l), mild increase in segmented neutrophils (70\%, reference
interval 30.4\%--65.4\%), mild hypocalcaemia (2.68 mmol/l, reference
interval 2.72--3.15 mmol/l), mild hypophosphatemia (1.08 mmol/l,
reference interval 1.40--2.16 mmol/l), severe sideropenia (3.2 \selectlanguage{greek}µ\selectlanguage{english}mol/l,
reference interval 20.66--47.67 \selectlanguage{greek}µ\selectlanguage{english}mol/l), mild increase in fibrinogen
(4.4 mmol/l, reference interval 2--4 mmol/l), mild hypoalbuminemia (22.9
mmol/l, 24.8--32.7 mmol/l), mild hypocreatinemia (64 mmol/l, reference
interval 80.7--125.7 mmol/l), mild increase in creatin kinase (457
mmol/l, reference interval 151--374 mmol/l).

In an attempt to reduce inflammation and improve clinical symptoms, the
colt was administered flunixin meglumine intravenously (1.1 mg/kg BW).
Medication did not improve the clinical symptoms and the owner agreed to
further diagnostic tests. A computed tomography (CT) examination of the
head and cranial cervical spine was performed.

\textbf{Computed tomography examination and findings}

The CT examination was done at the Department for Horses of the
University of Leipzig, using a multi-detector row CT unit (Mx8000 IDT 16
CT scanner, Philips Medical-Systems DMC GmbH, Hamburg, Germany). The
colt was sedated with Romifidine (0.08 mg/kg IV) and Butorphanol (0.08
mg/kg IV) and general anaesthesia was induced with Ketamin (2.2 mg/kg
IV) and Diazepam (0.08 mg/kg IV). Anaesthesia was maintained with an
intravenous continuous rate infusion (CRI) of triple drip (Guaifenesin
100 mg/ml; Romifidine 0.1 mg/ml, Ketamine 2.2 mg/ml) at a rate of 2.2
ml/kg/h (Davidson 2008). The colt was placed in ventral recumbency with
the head and neck in an extended position. For image acquisition the
following settings were used: tube voltage 120 kV, tube current 234 mAs,
rotation time 0.75 s, pitch 0.438 and 1 mm slice thickness with a
spacing between the slices of -0.5. The window width was set at 2000 HU
(Hounsfield units) and the window level at 500 HU with a 512 \selectlanguage{ngerman}× 512
matrix.

The CT scan (Figure 1) showed changes consistent with osteolysis of both
cortical and cancellous bone of the right condyle of the occiput as well
as the left side of the vertebral body of C1 (Figure 1A), including the
left part of the arcus dorsalis (Figure 1B). Moreover, thickening of the
cortical plate and new bone formation was observed at the proximal
aspect of the left ala atlantis (Figure 1C). The transverse plane images
also revealed the presence of a heterogeneous mass in the vertebral
canal, causing right dorsal deviation of the spinal cord (Figure
1B--1C). The mass showed a radio density of approximately 33--44 HU,
hereby showing lower CT numbers measured for surrounding muscle tissue
(HU 52--61). The permeative character of the described bone lesions, led
to the diagnosis of a pathologic fracture due to osteomyelitis or
neoplasia. The presence of a tumour, an abscess or rather a hematoma
were considered plausible differentials for the mass located within the
cervical canal. Because of the poor prognosis, the colt was humanly
euthanized.

\textbf{Pathological examination and findings}

During necropsy, the gross examination revealed an approximately 3.5 ×
2.5 × 0.7 cm, wine-red to beige coloured, tightly elastic, intraspinal
epidural neoplasm, located dorsolaterally with orientation to the left
on the dura mater at the level of C1 (Figure 2A). Locally, the spinal
cord showed mild, acute, multifocal to confluent, subdural hemorrhage.
After maceration of C1, moderate to severe, multifocal to confluent
osteolysis with destruction of the regional bone in the left dorsal
arch, partly in the transition to the left ventral arch and the left
cranial articular fovea was determined (Figure 2B).

Histologically, the neoplasm was unencapsulated, infiltrative and
moderately cell rich. It consisted of predominantly loosely packed round
cells within moderate amounts of a pre-existing fibrovascular stroma
(Figure 2C). The neoplastic cells were round to oval, average 15 \selectlanguage{greek}µ\selectlanguage{english}m in
diameter, had distinct cell boundaries and predominantly small amounts
of an amphophilic, homogeneous cytoplasm. The round to oval cell nuclei
were eccentrical and had finely stippled, hypochromatic chromatin and up
to two distinct nucleoli. Within the tumour cell population, there was
moderate anisocytosis and anisokaryosis, the ratio of nucleus to
cytoplasm was shifted to the nucleus, and there were individual giant
cells containing up to four random arranged nuclei. The mitotic rate was
up to six, sometimes bizarre, mitoses per 2.37 mm\textsuperscript{2}.
Small proportions of the neoplastic cells were infiltrating the
surrounding area. There were areas of hemorrhage and
hemosiderin-containing macrophages and also a mild, acute, multifocal,
purulent inflammation. By methyl green pyronine stain single cells
showed low to moderate amounts of intracytoplasmic ribonucleic acids.

With the immunohistochemical markers CD3 (T lymphocytes; A0452, Agilent
Technologies, Santa Clara, USA), CD79a (B lymphocytes; clone HM57,
MCA2538H, Bio-Rad Laboratories, Inc., Hercules, USA), CD 20 (B
lymphocytes; PA5-16701, Thermo Fisher Scientific, Waltham, USA), MUM-1
(plasma cellular multiple myeloma oncogene 1; clone MUMp1, M7259,
Agilent Technologies, Santa Clara, USA), kappa light chain (\selectlanguage{greek}κ \selectlanguage{english}side chain
of immunoglobulins; A0191, Agilent Technologies, Santa Clara, USA) and
lambda light chain (\selectlanguage{greek}λ \selectlanguage{english}side chain of immunoglobulins; clone BIg501E,
BIG501E, VMRD, Inc., Pullman, USA), the neoplastic tumour cell
population was predominantly indistinct to immuno-negative (not shown).

By means of a transmission electron microscopic examination (TEM), the
tumour cells showed a plasma cell morphology at the ultrastructural
level. Pleomorphic, large cells with an eccentrical nucleus and
sometimes moderate amount of cytoplasm were determined (Figure 2D). Most
of the nuclei were large and irregular in shape, some of them contained
prominent nucleoli. In addition, the tumour cells contained abundant
amount of rough endoplasmic reticulum (Figure 2D). Often, dilated
cisternae of rough endoplasmic reticulum were detected, so that the
tumour cells as a whole had a vacuolated appearance (Figure 2D). The
dilated cisternae of the endoplasmic reticulum showed a flocculent
material, which can be assumed to be consistent with globulin
precipitates, a feature of antibody-producing plasma cells.

\textbf{Discussion}

Various terms for malignant neoplastic processes, originating from
plasma cells exist in the literature. It is a heterogeneous tumour
disease group with many variants. Only few descriptions are available,
especially for young horses.

Most of the knowledge of this special tumour entity derives from human
medicine, but it is unclear to what extent the classification and
diagnostic criteria for human plasma cell tumours are applicable to the
horse (Edwards \emph{et al.} 1993).

Basically, the following variants can be distinguished depending on the
organs affected: Multiple myeloma is a malignant neoplastic process
originating from the plasma cell and is characterized by multifocal to
diffuse growth pattern within the bone marrow and destruction of the
affected bone (Edwards \emph{et al.} 1993; McConkey \emph{et al.} 2000).
However, in addition to this medullary form, extramedullary forms can be
distinguished in which the bone marrow is not affected (McConkey\emph{et
al.} 2000). In the horse, extramedullary plasmacytomas have been
described, for example, in lymph nodes, spleen, lung, liver, kidney,
brain, orbit, pituitary gland, adrenal cortex, tongue muscles, as well
as in nervous and connective tissue (Markel and Dorr 1986; Edwards
\emph{et al.} 1993; McConkey \emph{et al.} 2000).

Some authors also distinguish tumours characterized by a single lytic
bone lesion and call these ''solitary plasmacytoma of bone''
(Frassica\emph{et al.} 1989; Edwards \emph{et al.} 1993). However, there
is controversy as to whether this is just an early form of multiple
myeloma or whether it represents a distinct variant of the disease
(Frassica\emph{et al.} 1989).

Further variants derived from human medicine exist such as ''smoldering
(asymptomatic) multiple myeloma'', which is an asymptomatic plasma cell
proliferation disorder associated with a high risk of developing
symptomatic multiple myeloma (Kyle \emph{et al.} 2007).

When single or multiple osteosclerotic bone lesions are present, it is
also referred to as ''osteosclerotic myeloma'' (Kyle and Greipp 1988).

In addition, leukemic forms of the disease are rarely described
(Edwards\emph{et al.} 1993). Plasma cell leukemia is present when the
number of neoplastic plasma cells in the blood is >\selectlanguage{english}2,000/\selectlanguage{greek}µ\selectlanguage{english}L and when
they account for at least 20\% of the differential blood count
(Bernasconi \emph{et al.} 1989; Edwards \emph{et al.} 1993).

Furthermore, in humans a distinction between secretory and non-secretory
tumour forms exists, whereby in the secretory form monoclonal antibodies
are produced by the tumour cells and paraproteins are detectable in
serum or urine (Kyle and Greipp 1988; Edwards \emph{et al.} 1993;
McConkey \emph{et al.} 2000).

Regarding the typical punched-out lytic bone lesions of the C1, the
intraspinal tumour mass and the pathomorphologic findings, especially
considering the ultrastructure of the tumour cells, the presence of a
malignant neoplasm originating from plasma cells is diagnosed. The
immunohistochemical examination in the present case was inconclusive. A
probable reason for this could be the different stages of
differentiation of the tumour cells.

Only based on the CT findings (lytic bone lesions) and the cell
morphology, a ''nonproductive osteoblastic osteosarcoma'' should be
considered primarily for differential diagnosis. However, due to the
lack of evidence of osteoid, which should be found in small amounts even
in a ''nonproductive osteoblastic osteosarcoma'' (Thompson and Dittmer
2017b), as well as the rather atypical localization for the horse
(Bush\emph{et al.} 2007; Thompson and Dittmer 2017b), this seems
unlikely. In particular, the tumour cell invasion into the vertebral
canal (Thompson and Dittmer 2017a) as well as the morphology typical for
plasma cells on an ultrastructural level such as an eccentric nucleus,
much cytoplasm with abundant rough endoplasmic reticulum with partially
dilated cisternae (Curtis \emph{et al.} 1975) suggest a plasma cell
tumour as cell of origin.

The peculiarity of this case report is the age of the affected horse (8
months old), the localization (C1) and the associated clinical symptoms
(tetraparesis) as well as the manifestation of the disease
(paramedullary plasmacytoma). To the authors' knowledge, the term
''paramedullary plasmacytoma'' used in human medicine (Hameed \emph{et
al.} 2020) has received little attention in veterinary medicine to date,
although it fits well to characterize the growth of the tumour
throughout the compacta of the vertebral body with invasion into the
vertebral canal. To date, there is only one other case report in the
literature describing the invasion of a plasma cell tumour into the
vertebral canal in a horse (Drew and Greatorex 1974). Therefore, in the
present case, a solitary localization of the tumour in the C1 is most
likely but with residual uncertainty. Maybe the lesions found here can
be regarded as the initial stage of multiple myeloma. Whether there are
further lytic bone lesions remains unclear, because a full body CT scan
was not feasible in the weanling colt. However, based on the blood count
and serum chemistry, there were no indications of a systemic disease
like a secretory active multiple myeloma.

\textbf{Conclusions}

In veterinary medicine the term ''paramedullary plasmacytoma'' is also
suitable for affected horses to describe a particularly rare form of
this tumour disease. Rarely, young animals under one year of age may be
affected. Especially in young animals, not only common trauma to the
spine should be considered causative for signs of paresis. In terms of a
pathological fracture or bone lesion, also neoplasia such as para- or
medullary plasmacytomas with concurrent osteolysis, may be an important
differential diagnosis. These can be well visualized with advanced
imaging methods such as CT and confirmed by consecutive necropsy.

\textbf{Author' declaration of interests}\selectlanguage{english}

No conflicts of interest have been declared.

\textbf{Ethical animal research}

No experimental animals were used in this case report.

\textbf{Source of funding}

No funding was provided for this study.

\textbf{Acknowledgements}

The authors thank Lars Riesche for macroscopical preparation.

\textbf{Authorship}

All the authors participated in the article preparation and have
approved the final version.

\textbf{References}

Bernasconi, C., Castelli, G., Pagnucco, G. and Brusamolino, E. (1989)
Plasma cell leukemia: a report on 15 patients. \emph{Eur. J. Haematol.
Suppl.} \textbf{43(51)} , 76-83.

Curtis, S.K., Propp, R., Cowden, R.R. and Tartaglia, A.P. (1975)
Ultrastructure of a human malignant IgA-producing
plasmacytoma.\emph{Exp. Mol. Pathol.} \textbf{22} , 386-399.

Davidson, G.S. (2008) Equine anesthesia: triple drip. \emph{Int. J.
Pharm. Compd.} \textbf{12} , 402-404.

DeLahunta, A. and Glass, E. (2009) Large animal spinal cord disease. In:
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Elsevier, St. Louis. pp 285-318.

Drew, R.A. and Greatorex, J.C. (1974) Vertebral plasma cell myeloma
causing posterior paralysis in a horse. \emph{Equine Vet. J.}\textbf{6}
, 131-134.

Edwards, D.F., Parker, J.W., Wilkinson, J.E. and Helman, R.G. (1993)
Plasma cell myeloma in the horse. A case report and literature
review.\emph{J. Vet. Intern. Med.} \textbf{7} , 169-176.

Frassica, D.A., Frassica, F.J., Schray, M.F., Sim, F.H. and Kyle, R.A.
(1989) Solitary plasmacytoma of bone: mayo clinic experience. \emph{Int.
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Hameed, M., Sandhu, A., Soneji, N., Amiras, D., Rockall, A., Messiou,
C., Wallitt, K. and Barwick, T.D. (2020) Pictorial review of whole body
MRI in myeloma: emphasis on diffusion-weighted imaging. \emph{Br. J.
Radiol.} \textbf{93} , 20200312.

Kyle, R.A. and Greipp, P.A. (1988) Plasma cell dyscrasias: Current
status. \emph{Crit. Rev. Oncol. Hematol.} , \textbf{8} , 93-152.

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P.J., Hodnefield, J.M., Larson, D.R., Plevak, M.F., Jelinek, D.F.,
Fonseca, R., Melton, L.J., III and Rajkumar, S.V. (2007) Clinical course
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Engl. J. Med.} \textbf{356} , 2582-2590.

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a cervical vertebral epidural haematoma. \emph{Equine Vet.
Educ.}\textbf{33(6)} , e177-e180.

Markel, M.D. and Dorr, T.E. (1986) Multiple myeloma in a horse. \emph{J.
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Mayhew, I.G., deLahunta, A., Whitlock, R.H., Krook, L. and Tasker, J.B.
(1978) Spinal cord disease in the horse. \emph{Cornell
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plasmacytoma in a horse with ptyalism and dysphagia. \emph{J. Vet.
Diagn. Invest.} \textbf{12} , 282-284.

Thompson, K.G. and Dittmer, K.E. (2017a) Tumors of bone: Multiple
myeloma. In: Tumors in domestic animals, fifth edn., Ed: D.J. Meuten,
John Wiley \& Sons Inc., Ames, Iowa. pp 412-414.

Thompson, K.G. and Dittmer, K.E. (2017b) Tumors of bone: Osteosarcoma.
In: Tumors in domestic animals, Fifth edition edn., Ed: D.J. Meuten,
John Wiley \& Sons Inc., Ames, Iowa. pp 374-394.

\textbf{Figure legends}

Fig. 1: Transverse plane computed tomography images (right is to the
left) of an 8-month-old warmblood colt with acute onset of
non-ambulatory tetraparesis. An artefact caused by damaged detectors is
marked with asterisks. A) Focal, well defined osteolytic lesions at the
right ventral aspect of the right condylus occipitalis (white arrow) at
the level of the atlanto-occipital joint. B--C) Concurrent bone
destruction with ``moth-eaten'' pattern, involving the arcus dorsalis of
C1 (white arrow) and periosteal new bone formation at the proximal
aspect of the left ala atlantis of C1 (black arrow). Note right dorsal
displacement of the spinal cord (white circle) caused by a mass located
within the vertebral canal.

Fig. 2: 8-month-old warmblood colt suckling with paramedullary
plasmocytoma

originating from the bone marrow of C1 with invasion of the epidural
space. A) Intraspinal epidural neoplasm (oval), dorsolaterally left on
the spinal cord (black arrow). Segment detached from the vertebral canal
at the level of C1. B) Macerated C1 with destruction of the local bone
especially in the left dorsal arch (black arrow), partly in the
transition to the left ventral arch (white arrow). C) Loosely packed
round cells, with moderate anisocytosis and anisokaryosis. Note the
eccentric and huge nuclei in relation to the cytoplasm, the binuclear
cells (circle), sometimes a ``halo'' (arrow) and the bizarre mitoses
(arrowhead). Haematoxylin and eosin, scale bar = 50 \selectlanguage{greek}µ\selectlanguage{english}m. D) A tumour cell
on the ultrastructural level. Note the abundant amount of rough
endoplasmic reticulum (arrow) with dilated cisternae (arrowhead)
containing flocculent material. TEM Libra 120 (Zeiss, Oberkochen,
Germany), 80 keV. Scale bar = 2500 nm.

\textbf{Hosted file}

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