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\begin{document}

\title{A PARATHYROID CANCER WITH SOPOROUS STATE, DEPRESSION AND SEVERE
COGNITIVE DECLINE IN ACUTE RENAL FAILURE}



\author[1]{Federica Vultaggio}%
\author[1]{Barbara Martino}%
\author[2]{Letizia Nitro}%
\author[3]{Emanuela Fuccillo}%
\author[1]{Giovanni Felisati}%
\author[4]{Loredana De Pasquale}%
\affil[1]{Universita degli Studi di Milano}%
\affil[2]{University of Milan}%
\affil[3]{ASST Santi Paolo e Carlo}%
\affil[4]{Azienda Ospedaliera San Paolo}%


\vspace{-1em}



  
  \date{June 02, 2024}


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\textbf{INTRODUCTION}

Parathyroid carcinoma (PC) is a rare endocrine cancer {[}1,3{]} and the
most uncommon cause of primary hyperparathyroidism (pHPT). It usually
induces elevated serum calcium and parathyroid hormone (PTH) levels and
the clinical presentation is often characterized by severe symptoms of
hypercalcaemia. The diagnosis is not always immediate, especially if
there is no evidence of a neck mass which may suggest this kind of
disease.

The aim of this work is to describe the peculiar clinical presentation
of a case of PC and to highlight the importance of suspecting a
malignant parathyroid disease in the presence of a pHPT associated with
peculiar biochemical and clinical features. The suspicion is essential
to perform an adequate intervention at first surgical approach, as which
affects the subsequent prognosis.\textbf{~}

\textbf{CASE REPORT}

Here we present a male patient in his 80s with a negative family history
of endocrine diseases. In the past he received a diagnosis of anxiety
disorder, mild cognitive impairment, essential hypertension and hearing
impairment.

He went to our Emergency Department, because of a soporous state
associated with worsening of cognitive impairment. According to clinical
reports, general examination did not describe the presence of a neck
mass. Therefore, he was hospitalized at the Medicine Department to
conduct medical care.

Haematological investigations revealed an important rise of the serum
calcium level at 19,29 mg/dL (normal range for age 8,4 -- 10,2 mg/dL),
an extremely high value of PTH at 2146 pg/ml (normal range for age 8,7
-- 7,6 pg/mL) and phosphorus level at 1,7 mg (normal range for age 2,5 -
4,5 mg/dl). The first suspicion was a pHPT.

During his first day of hospitalization, the urinary calcium
concentration recorded was 400 mg/24h (normal range for age \textless{}
300 mg/24h). After few days, the patient underwent a neck ultrasound
that pointed out a symmetrical thyroid gland with normal size and
morphology. Behind the right thyroid lobe a 28 mm solid, iso-hypo-echoic
with anechoic gaps inside, rounded nodule was found: it was described as
indissociable from the thyroid lobe {[}see figure 1{]}.

A parathyroid Technetium-99m sestamibi scan was performed after a week.
This exam revealed a persistent hot-spot of Technetium 99m in the lower
part of the right thyroid lobe and also in the posterior area, near
oesophagus and trachea {[}see figure 2{]}.

A subsequent neck CT scan executed after one day confirmed a mass of
31x21x31 mm characterized by irregular enhancement. This mass was in
close contact with the right thyroid lobe and with the wall of the
oesophagus and the trachea, without evidence of a clear cleavage plane
from the oesophagus {[}see figure 3{]}.

To verify the oesophageal infiltration, a trans-oesophageal
ultrasound-endoscopy was performed and it pointed out an uncertain
infiltration of its muscularis tunic. We could verify during the
surgical treatment that the oesophagus muscolaris tunic was not
infiltrated.

First of all, in the presence of severe hypercalcaemia, it is necessary
to distinguish whether primary pHPT, malignant diseases or
para-neoplastic syndrome causes it.

In case of primary pHPT, a high PTH serum concentration will be found.
Actually, the elevation of serum calcium is due to PTH-mediated
activation of osteoclasts, leading to increased bone resorption. Other
causes of elevated serum calcium concentration are solid tumours,
metastasis or leukaemia: they may be the cause of high serum calcium
level due to the activity of some cytokines and interleukin-1. Finally,
an autonomous production of parathyroid hormone-related protein (PTHrP)
can be found in the para-neoplastic syndromes: the final result is the
elevation of PTH level and consequently calcemia.

With evidence of elevated serum calcium and PTH values, a diagnosis of
pHPT can be made. Subsequently, clinicians should differentiate the
PC-induced pHPT and the pHPT due to benign diseases. As reported in
literature, PC is a rare cause of primary hyperparathyroidism,
accounting for less than 1\% of cases. It should be suspected that
elevated calcium and PTH serum levels, in the presence of a neck mass,
or infiltration and symptoms of surrounding organs, for example
dysphonia, would appear if the cancer invades recurrent laryngeal nerves
{[}1,2{]}.

After diagnosis of severe hypercalcaemia due to pHPT, the patient
started an intravenous treatment with hydration, diuretic, clodronate,
calcimimetic and steroids in accordance with the nephrologist's
indications. Because of the persistence of severe hypercalcaemia and
worsening of renal function, he was transferred to the Intensive Care
Unit (ICU) for monitoring: after nephrological re-evaluation, a CVC was
placed to start dialysis. Subsequently, he was admitted to the Internal
Medicine Unit for medical therapy. Following a new increase of serum
calcium, another dialysis session was performed, and the therapy with
zoledronate (4mg iv) and cinacalcet was increased (from 60 to 120 mg/day
iv). After that treatment, the calcemia level returned to the normal
range with complete restoration of his cognitive functions.

Once the diagnostic process had been completed, the patient was admitted
to our Surgery Unit where he underwent a surgical treatment about 2
weeks after the onset of symptoms: en-bloc resection of the pathologic
inferior right parathyroid with the right thyroid lobe and the superior
macroscopically normal parathyroid. During the surgery we found a
cleavage plan between oesophagus and the mass, so there was
no-infiltration of muscolaris tunic, unlike the ultrasound-endoscopy
first impression. Neuromonitoring was used during the entire procedure.
The ipsilateral cervical lymphadenectomy was not executed. The
intraoperative values of PTH went from 749,5 pg/ml pre-incision to 67,6
pg/ml ten minutes after the removal of the pathologic gland.

A part from the surgery no medical therapies were performed. Routine
haematological investigations in the first post-surgery day revealed a
serum calcium level of 8,1 mg/dl and a serum PTH value of 9,1 pg/ml.
After removing the pathologic gland, a transient condition of
hypoparathyroidism was observed, but the serum level of calcium and PTH
returned to the normal range after three months of oral calcium therapy.

Macroscopically, the pathological parathyroid gland had a diameter of
3,2 cm {[}see Figure 4{]}. The weight was not defined because of the
en-bloc resection with the right thyroid lobe. Histological examination
revealed the presence of a PC.

The follow-up was executed at 3, 6, 9, 12 and 24 months with
haematological examination; at 6, 12 and 24 months a neck ultrasound was
also made. At 2-year check-up, the patient was disease-free: the neck
ultrasound showed no signs of local recurrence, and serum calcium and
PTH values were within the normal ranges, respectively 10,2 mg/dl and 21
pg/ml. Nowadays, the patient is still alive and in good conditions and
regained all his cognitive functions.



\textbf{DISCUSSION}

The PC is an extremely rare endocrine malignancy{[}3{]}. Its incidence
is less than 1-2\% of pHPT patients, which is usually caused by a
parathyroid adenoma and sometimes by primary parathyroid hyperplasia.
From 1988 to 2003, 224 patients with parathyroid tumour were identified
by the Surveillance, Epidemiology and End Results (SEER) cancer registry
data: the incidence of PC increased from 3.58 to 5.73 per 10 million
population{[}4{]}.

The aetiology of the tumour remains unclear, but molecular analysis
studies recognize several genes that play a central role in the
molecular pathogenesis of PC, such as HRPT2 gene, germ-line missense
variants of the parathyroid transcription factor gene GCM2{[}7,8{]} and
the somatic alteration of PI3K/AKT/MTOR pathway{[}9,10{]}. Cyclin D1
amplification{[}11{]} is also involved in the pathogenesis.

There is no difference between males and females, and the mean age of
presentation is 44-54 years.

Clinical presentations are investigated in different small studies: the
most common sign (65-75\%) is the elevation of serum calcium
concentration above 14 mg/dl. Other signs are: elevation of serum PTH
concentrations, neck mass (34-52\%), bone (34 - 73\%) and renal disease
(32-70\%), pancreatitis (0-15\%), no symptoms (2-7\%) and symptoms of
local and adjacent structure invasion in case of a not functioning PC
(rare form). Completely asymptomatic PC has also been described
{[}1,2,12,13{]}.

Surgical excision is the cardinal treatment. The use of intraoperative
PTH (IOPTH) testing is debated: according to Medas F. et al.{[}14{]} it
plays an important role, especially in patients with pHPT and normal PTH
level. Instead, Sartori P.V. et al.{[}15{]} strongly suggest
reconsidering the role of IOPTH monitoring during parathyroidectomy in
patients with concordant preoperative ultrasonography and nuclear
scanning.

Only after the surgical resection is it possible to have a definitive
diagnosis by the analysis of the microscopic anatomy of the excised
specimen.

Although this pathology is rare, it's important to suspect the diagnosis
of PC pre-operatively to undertake the best treatment for patients.

The case described in this report had an unusual clinical presentation,
making the diagnosis challenging. First of all, the lack of a neck mass
made the suspicion of PC less immediate. Depression and cognitive
impairment are symptoms that certainly do not immediately raise
suspicion of PC. Literature does not include these two among the most
common symptoms of PC. Thanks to the biochemical examinations, it was
possible to think about a parathyroid gland disease, which was confirmed
by the neck ultrasound, the CT scan and the parathyroid-thyroid
scintigraphy. Definitive diagnosis of malignancy was made after the
surgical treatment and after microscopically examination.

The gold standard procedure is the en-bloc resection, which means
removing the parathyroid cancer with the surrounding soft tissue, the
ipsilateral thyroid lobe and the adjacent structure involved by the
carcinoma. This type of surgery seems to be associated with a lower rate
of recurrence and death. Actually, in patients treated with complete
tumour resection during the initial surgical procedure, survival rates
improve to 90\% and 67\% at five and ten years respectively{[}16{]}. In
our case, there was no evidence of disease relapse during the follow up
performed at 3-6-9-12 and 24 months. An ipsilateral cervical
lymphadenectomy can also be performed, but there is no unique opinion
about that: some authors recommend it{[}17,18{]}, but not all agree with
this{[}19{]}.

The patient's excellent prognosis may also be due to his classification
as a low-risk tumour, according to the Risk Schulte System{[}20{]},
which is based on histopathological criteria and was proposed by Talat
and Shulte in 2010. It represents an important tool to predict the
survival and the recurrence of the PC. The system classifies pathologies
as low or high risk. Low risk tumours invade the capsule and adjacent
soft tissues, while high risk ones involve vascular structures and vital
organs.

The good prognosis of our patient has a limit: the follow-up period was
not extremely long, but according to the studies of W.C Gao{[}21{]} and
B. J. Wilkins and J. S. Lewis Jr.{[}22{]}, the highest rate of
recurrence occurs within the first 2-5 years from the initial treatment.



\textbf{ACKNOWLEDGMENTS}

Not applicable.

\textbf{DATA AVAILABILITY STATEMENT}

Data sharing is not applicable to this article as no datasets were
generated or analyzed during the current study.

\textbf{AUTHOR CONTRIBUTION}

Federica Vultaggio wrote the clinical report

Federica Vultaggio, Loredana De Pasquale and Emanuela Fuccillo collected
the medical data and critically revised the manuscript.

Loredana De Pasquale, Barbara Martino, Emanuela~Fuccillo, and
Giovanni~Felisati~were involved in drafting the manuscript and helped in
the acquisition of data.

Giovanni~Felisati~, Loredana De Pasquale and Barbara Martino conceived
the publication and revised the manuscript.

All authors listed gave final approval of the version to be published
and agreed to be accountable for all aspects of the work.

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\end{enumerate}

\textbf{FIGURE LEGENDS}

\emph{Figure 1}\textbf{.} ~Iso-hypo-echoic with anechoic gaps inside
rounded nodule.

\emph{Figure 2}\textbf{.} ~Persistent hot-spot of Technetium 99m in the
lower part of the right thyroid lobe.

\emph{Figure 3}\textbf{.} ~Mass in contact with right thyroid lobe, wall
of oesophagus and trachea without cleavage plan..

\emph{Figure 4}\textbf{.} ~En-bloc resection of pathologic inferior
right parathyroid with right thyroid lobe.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Neck-Ultra-Sound-2/Neck-Ultra-Sound-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/thyroid-parathyroid-scintigraphy-2/thyroid-parathyroid-scintigraphy-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Neck-CT-Scan-2/Neck-CT-Scan-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Surgical-Specimen-2/Surgical-Specimen-2}

\end{center}
\end{figure}

\selectlanguage{english}
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