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\begin{document}

\title{Mimicking Multiple Myeloma: the importance of the differential diagnosis}



\author[1]{Daniele Derudas}%
\author[1]{Concu Claudia}%
\author[1]{Tania Durzu}%
\author[2]{Doloretta Piras}%
\author[1]{Sonia Nemolato}%
\author[1]{Annamaria Liguori}%
\author[1]{Maria Pina Simula}%
\author[1]{Giorgio La Nasa}%
\affil[1]{Ospedale Oncologico "Armando Businco"}%
\affil[2]{Ospedale San Michele di Alta Specializzazione e di Rilievo Nazionale}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
Here we describe the case of a caucasian man referred to our Center for
a suspicion of Multiple Myeloma which comprehensive work-up ruled out
the presence of plasma cells neoplasm and allowed us to perform a
diagnosis of brown tumor (BT).%
\end{abstract}%



\sloppy


\textbf{Mimicking Multiple Myeloma: the importance of the differential
diagnosis}

Daniele Derudas\textsuperscript{1}, Claudia Concu\textsuperscript{1},
Tania Durzu\textsuperscript{1}, Doloretta Piras\textsuperscript{2},
Sonia Nemolato\textsuperscript{3}, Anna Maria
Liguori\textsuperscript{1}, Maria Pina Simula\textsuperscript{1},
Giorgio La Nasa\textsuperscript{1}

\textsuperscript{1}Hematology Division and Bone Marrow Tranplantation
Center, Ospedale ``A. Businco'', Cagliari, Italy

\textsuperscript{2}Nephrology Division, Ospedale ``G. Brotzu'',
Cagliari, Italy

\textsuperscript{3}Pathology Department, Ospedale ``A. Businco'',
Cagliari, Italy

\textbf{Competing interests} : The authors have declared that no
competing interests exist

\textbf{Corrispondence} : Daniele Derudas\emph{daniele.derudas@aob.it}

\textbf{Written informed consent was obtained from the patient to
publish this report in accordance with the journal's patient consent
policy}

\textbf{Abstract} Multiple Myeloma (MM) is a malignant plasma cells
disorder that account for the 15\% of hematologic malignancies. The
clinical manifestation is defined by the presence of anemia, renal
failure, hypercalcemia and osteolytic bone lesions called with the
acronym CRAB. Here we describe the case of a caucasian man referred to
our Center for a clinical suspicion of MM. A comprehensive work-up,
including blood tests, radiological examinations and bone marrow biopsy
ruled out the presence of plasma cells neoplasm Further investigations
as CT guided-biopsy of a lytic lesion allowed us to perform a diagnosis
of brown tumor (BT), a tumor-like lesion due to the bone remodeling
process in prolonged hyperparathyroidism. This diagnosis was confirmed
by endocrinological evaluations followed by a parotidectomy with
resolution of the clinical manifestations. Our case outlines the
importance of an accurate differential diagnosis in the suspicion of MM,
because the concomitant occurrence of comorbidities and illnesses may
confound the evaluation, In particular the combination of anemia,
peripheral neuropathies and renal impairment could be associated to a
number of other causes and it is mandatory a thorough anamnesis,
clinical and instrumental examination and laboratory investigations to
rule out other etiologies.

\textbf{Introduction.}

Multiple Myeloma (MM) is a neoplastic disorder due to the proliferation
of clonal plasma cells that account for the 15\% of the hematological
neoplastic tumors\textsuperscript{1,2}. The symptomatic phase of this
neoplasm is characterized by the presence of one or more of the
following signs and/or symptoms: anemia (hemoglobin psitroalue of
\textless{} 2 g/dl below the lowest limit of normal, or a hemoglobin
value \textless{} 100 g/L), hypercalcemia (serum calcium \textgreater{}1
mg/dL higher than the upper limit of normal or \textgreater{} 11 mg/dL),
renal failure (creatinine cleareance \textless{} 40 mL per min or serum
creatinine \textgreater{} 2mg/dL) and bone lesions (one or more
osteolytic lesions on skeletal radiography, Computer Tomography (CT), or
Positron Emission Tomography-CT (PET-CT). This cohort of signs and
symptoms is historically defined with the acronym of
CRAB\textsuperscript{3}. However, particularly in the elderly patients,
these clinical manifestations are very frequent and could be caused by
other diseases than MM. The concomitant presence of other pathologic
conditions could led to a misdiagnosis with dramatic consequences for
the patients. Here we present the case of an adult Italian patient with
signs and symptoms coherent with suspicion of MM.

\textbf{Case report.}

\emph{Clinical history:} He suffered from hypertension, well controlled
with medical therapy

\emph{Case presentation:} In the April 2020 a 57 years Caucasian old man
was referred to our Hematologic Center by a nephrologist for anemia,
renal failure, hypercalcemia and bone lesions with the suspicion of MM.
The past medical history of patient reported fatigue, night swears and
weight loss from January 2018. In the February 2018 it is documented a
mild and progressive hypochromic-normocytic nemia (Hb 10,6 gr/dl) with
hyperferritinemia, low iron blood levels and low count of reticulocytes.
A colonoscopy showed two intestinal polyps with a high grade dysplasia.
In the December 2019 it was performed a radiography of lumbar spine
because of onset of pain with the finding of multiple lytic lesions.
From January 2020 the patient was followed with blood tests with the
documentation of a progressive anemia (Hgb 8,5 gr/dl), renal failure
(serum creatinine 1,57 mg/dl, glomerular filtration 43 ml/min according
to Modification of diet in renal disease (MDRD ), glycosuria (with
normal value of glycemia and glycated hemoglobin). He was referred to
Nephrology Center for a comprehensive evaluation. It was confirmed the
anemia and renal failure with a slight glomerular proteinuria (0,95
gr/24 hour). Blood tests showed hypercalcemia (serum calcium 12,9
mg/dl), normal serum albumin. A skeletal survey and total body CT
confirmed the multiple bone lysis interesting the whole skeleton and
particularly the pelvis, bilateral femurs, dorsal vertebrae with erosion
of the bone cortical. Notably it was described a lesion of the left lobe
of the thyroid gland.

\emph{Initial work-up:} In the first hematological examination the
patient complained fatigue and diffuse skeletal pain. There were not
remarkable clinical signs. The blood test confirmed the mild
normocytic-normochromic anemia, hypercalcemia, high levels of serum
calcium and a mild renal failure. We performed investigation focused on
definition of MM diagnosis . But, no monoclonal component was detected
by serum and urine protein electrophoresis, serum and urine
immunofixation. The levels of serum immunoglobulins and free light
chains were normal according with renal function. Bone marrow biopsy and
aspirate did not show a monoclonal plasma cell infiltrate. The patient
underwent treatment with fluid hydration and Zoledronic acid to correct
(with a reduction of dosage according with glomerular filtrate).

\emph{Differential diagnosis:} After excluding a monoclonal gammopathy
our attempts were aimed to discover other neoplastic or endocrine
diseases that could cause the clinical manifestations of our patient.

\emph{Further examination:} A FDG PET-TC was performed to rule out
further pathologic finding. This evaluation showed a diffuse
hypercaptation of bone marrow and different bone sites, particularly the
jaw, bilateral ribs, dorsal and lumbar vertebral vertebrae, pelvis and
bilateral femurs. A CT-guided biopsy of the third dorsal vertebra was
performed: the histologic examination was coherent with a ``brown
tumor'' (fig.1a, 1b,1c).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Fig.1a HE 10X and 1B HE 20X giant cell tumor uniformly distributed in
the biopsy.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Fig.1b HE 20X giant cell tumor uniformly distributed in the biopsy.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Fig 1c: HE 40X multinucleated giant cell embedded with mononuclear ovoid
to spindled neoplastic cell.

\emph{Final diagnosis:} High elevated levels of serum parathyroid
hormone (PTH) and urine calcium and phosphorus, confirmed the diagnosis
of hyperparathyroidism. The patient performed an ultrasound of the
thyroid with the finding of a ovoidal mass, highly vascularized, in the
left lobe. Referred to an endocrinologist it was performed an
parathyroidectomy for the presence of adenoma with resolution of the
pathologic manifestations and improving of the clinical outcome.

\textbf{Diagnostic report.} The diagnosis of symptomatic MM is based on
the demonstration of clonal bone marrow plasma cells [?] 10\% or
biopsy-proven bony or extramedullary plasmacytoma and any one or more of
the myeloma defining events as anemia, hypercalcemia, bone lytic lesions
and renal failure\textsuperscript{3}. These events are caused by a
direct activity of the monoclonal plasma cells (anemia, hypercalcemia
and bone lysis) or the paraprotein (renal failure). Anemia is usually
normochromic-normocytic and is present in roughly the 75\% of patients
at diagnosis. The main causes are massive bone marrow myeloma
infiltration, induction of apoptosis of erythroblast by myeloma cells,
chronic anemia disorder (due to a functional iron deficiency),
erythropoietin deficiency in patients with renal failure,
paraprotein-induced hemodilution for increasing of plasma
volume\textsuperscript{4}. The bone lesions are detected in up to 80\%
at diagnosis and 100\% in advanced stage. They can affect all bones but
more of 60\% involve the spine. The most frequent clinical and
radiological pictures are represented by lithic lesions and diffuse
osteoporosis, pathological fractures, cord spinal compression, bone pain
and neoplastic hypercalcemia. Myeloma bone disease is characterized by
significant deregulation of the physiological interaction among
osteocytes, osteoblast, immune cells and the bone matrix with a
consequent increasing of osteoclast activity and suppressed osteoblast
function. Different aberrant molecular pathway can lead to the bone
loss: the RANK/RANKL and Notch signaling pathwayss are involved in the
osteoclast activation and the Wingless-type (Wnt) and beta-catenin
pathway as regulator of bone homeostasis and osteoblast
differentiation\textsuperscript{5,6}. The whole-body low-dose CT
constitutes the current standard for the diagnosis and assessment of
multiple myeloma-related bone disease. PET-CT and whole-body MRI are
also useful imaging modalities for multiple myeloma-related bone disease
evaluation and PET-CT is the gold standard for the follow-up of
MM-related bone disease and assessment of metabolic response to therapy,
including detection of residual disease after
treatment\textsuperscript{7}. Hypercalcemia is the most common metabolic
complication of MM but its pathogenesis remains unclear The primary
cause of the hypercalcemia is myeloma bone resorption that leads to
efflux of calcium into the extracellular fluid. However the pathobiology
of hypercalcemia is more complex in this setting: for example this
finding is most common in those myeloma patients who have the greatest
tumor volume, irrespective of serum parathyroid hormone-related protein
(PTHrP) status. The myeloma patients have frequently irreversible
impairment in renal function with increased renal tubular calcium
reabsorption. In this case the capacity of the kidneys to clear excess
calcium load from the circulation effectively is overwhelmed, resulting
in elevated serum calcium levels. The hypercalcemia related to MM
differs from the elevated calcium levels in patients with solid tumors
because the latest one is due to excessive secretion of PTHrP. The
myeloma hypercalcemia is almost always associated with renal failure and
increased serum phosphate that lead to a decreased glomerular filtration
rate. Moreover, unlike the solid tumors, the Myeloma patients usually
respond very rapidly to steroids because of the quick suppression of
tumor plasma cells growth. The clinical findings are dependent on the
calcium level: patients may be asymptomatic ([?] 12mg/dl) or they may
present with symptoms such as dry mouth, anorexia and vomiting,
polyuria, polydipsia, depression, or confusion (12 to 16 mg/dl). Rarely,
patients may develop a life-threatening `hypercalcemic crisis' ([?] 16
mg/dl) and a state of coma\textsuperscript{8}. In case of hypercalcemia
is mandatory to rule out other causes of elevated levels of calcium:
pseudo-hypercalcemia (increase in circulating proteins like M-protein),
primary hyperparathyroidism (the first cause of hypercalcemia,
especially in elderly people), paraneoplastic hypercalcemia (local
production of OAF-type cytokines, systemic production of PTH-like
peptide or calcitriol), hypervitaminosis D (pharmacological overdose,
overproduction of neoplasms or granulomatous diseases), drugs
(milk-alkalin syndrome, lithium, thiazides), tertiary
hyperparathyroidism (renal failure), hypocalciuric familial
hypercalcemia (rare autosomal dominant disease with calcium-sensing
receptor alteration characterized by asymptomatic hypercalcemia since
childhood and family history of hypercalcemia). In newly diagnosed MM
patients, 20\% to 30\% will present with estimated glomerular filtration
rates (GFRs) \textless{} 30 mL/min/1.73 m\textsuperscript{2} at the time
of diagnosis. Dialysis is required in up to 5\% of patients. However
these patients may develop decreased GFRs during the disease course,
usually in case of relapse. The most common cause of decreased GFR in
patients with multiple myeloma is light chain cast nephropathy. This
clinical-pathology manifestation occurs when serum monoclonal free light
chains (FLCs) bind and precipitate with Tamm-Horsfall protein in the
distal nephron. The formation of the casts causes tubular obstruction
(typically distal) that leads to intense immune response, resulting in a
giant cell reaction around the casts and interstitial inflammation. The
tubular obstruction causes a rapid kidney injury. Some medications
frequently taken by these patients, as nonsteroidal anti-inflammatory
drugs for bone pain, may aggravate or even precipitate the kidney
injury. Other drugs that may be associated with light chain cast
nephropathy include angiotensin- converting enzyme inhibitors and
angiotensin receptor blockers. Intravenous contrast can represent a
associated risk for cast nephropathy, although recent studies found the
association to be less significant. Monoclonal immunoglobulin deposition
disease (MIDD), amyloidosis, and rarely, kidney infiltration by myeloma
cells or acquired adult Fanconi syndrome represent other renal
pathologies in patients with MM. The diagnostic work-up in case of
suspicion of MM needs to rule out other causes for these symptoms and
signs\textsuperscript{9,10}. In fact all of these events are
non-specific and could be associated with other diseases. Particularly
MM represents a disease strongly related to age: roughly the 70\% of
newly diagnosed Myeloma patients are older than 65 years and 40\% older
than 75 year. The establishment of the diagnosis in this setting of
patients can be challenging because comorbidities and illnesses may
confound the valuation. For example anemia, peripheral neuropathies and
renal impairment could be associated to a number of other causes and it
is mandatory a thorough anamnesis, examination and laboratory
differential diagnosis to rule out other etiologies (\textbf{Tab.1} )

\textbf{Tab.1 : differential diagnosis of signs and symptoms of}

\textbf{Multiple Myeloma}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Clinical features of myeloma} & \textbf{Alternate diagnoses that
can mimic myeloma}\tabularnewline
\midrule
\endhead
\emph{Hypercalcemia} (13\% at diagnosis) Increased osteoclastic bone
resorption Increased renal tubular calcium resorption &
\emph{Hypercalcemia} Primary hyperparathyroidism Tertiary
hyperparathyroidism (CKD, vitamin D deficiency) Malignancy (e.g. bone
metastases) Drugs (e.g. thiazides, lithium, vitamin D, vitamin A)
Endocrine conditions (e.g. thyrotoxicosis, Addison's disease)
Granulomatous conditions (e.g. sarcoidosis, tuberculosis) Other (e.g.
prolonged immobilization, milk-alkali syndrome)\tabularnewline
\emph{Renal failure} (19\% at diagnosis) Light chain cast nephropathy
Hypercalcemia Monoclonal immunoglobulin deposition disease Plasma cell
infiltration of the kidneys Concurrent amyloidosis Drug-induced (NSAIDs,
bisphosphonate) & \emph{Renal failure AKI} (acute kidney injury)
Prerenal causes (e.g. dehydration, sepsis) Renal causes (e.g
drug-induced, infections) Postrenal causes (e.g. acute urinary
retention) \emph{CKD} (chronic kidney disease)( 60\% of \textgreater{}80
year old) Age-related decrease in eGFR Hypertension Diabetic nephropathy
Drug-induced (eg diuretic, NSAIDs) Obstructive uropathy (e.g. due to
BPH) Glomerulonephrities\tabularnewline
\emph{Anemia} (35\% at diagnosis) Bone marrow infiltration by plasma
cells Cytokine-mediated suppressive effect on erythropoiesis Renal
failure (decreased erythropoietin production) & \emph{Anemia} (25\% of
\textgreater{}80 year old) Anemia of chronic disease Iron deficiency
(dietary and/or blood loss) Vitamin B12 or Folate deficiency Chronic
kidney disease Myelodysplasia Others (e.g. hemolytic anemia,
thalassemia)\tabularnewline
\emph{Bone pain} (58\% at diagnosis) Increased osteoclast activity
causing lytic bone lesions, osteoporosis, pathological fractures
Plasmocytomas affecting the bone & \emph{Bone Pain Nonmalignant causes}
Osteoporosis Osteomalacia Osteomyelitis Paget's disease Injury (e.g.
fractures) \emph{Malignant causes} Primary bone cancer Bony metastases
(e.g breast, prostate, lung, thyroid, kidney, testicular,
ovarian)\tabularnewline
\bottomrule
\end{longtable}

BPH: benign prostatic hypertrophy, NSAIDs: nonsteroidal
anti-inflammatory drugs; eGRF: estimated glomerular filtration rate

This case demonstrates the importance of the differential diagnosis
because the events described above are associated to a case of
hyperparathyroidism mimicking the signs and symptoms coherent with a
suspicion of MM. Particularly, the diagnostic journey for this patient
led to a evidence of a brown tumor (BT), a pathologic expression of
``osteitis fibrosa cystica'' associated to an uncontrolled
hyperparathyroidism. This skeletal manifestation was first described by
Recklinghausen in 1891 and is the result of the overproduction of PTH in
primary or secondary hyperparathyroidism: osteoblasts will increase
RANKL expression, which binds to its corresponding RANK receptor on
osteoclasts and promotes osteoclast activity. PTH also reduces
osteoprotegerin (PG) levels, preventing RANKL and RANK interactions and
thus inhibiting bone resorption. Based on this process, this tumor-like
lesion represents the terminal stage of the bone remodeling process with
an overall incidence of 2--3\%\textsuperscript{11}. BT can involve in
any part of the skeleton, but most frequently they are found in the
jaws, ribs, clavicles, extremities, and pelvic girdle and although the
lack of malignant potential, it may be invasive. Clinical manifestations
include swelling, pathological fracture diffuse skeletal pain and in
case of multiple bones these lesions can mimic metastatic disease. The
pathology features are characterized by non-neoplastic reactive tissue
associated to an extensive osteoclastic bone resorption and
osteoclast-like multinucleated giant cells, osseous microfractures, and
hemorrhage as well as hemosiderin depositions The term brown tumor
refers to an accumulation of hemosiderin pigment, giving the lesion its
macroscopically brown appearance The radiological examination shows
osteolytic lesions with well-defined borders and differential diagnosis
includes primarily bone metastasis, Multiple Myeloma, amyloid cysts,
chondroma, aneurysmal bone cyst, osteosarcoma, and giant cell
tumor\textsuperscript{12}. Hyperparathyroidism (HPT) is the third most
common endocrine disease after diabetes and thyroid disorders. HPT can
be can be primary, secondary, or tertiary. Primary HPT occurs when [?]1
parathyroid glands produce too much PTH; the main causes of this
clinical condition are a solitary adenoma in 80--85\% of patients,
multiple adenomas in 5\%, parathyroid hyperplasia in 10--15\%, and
carcinoma in less than 1--5\%. Secondary HPT occurs when the increased
PTH secretion is due to an organic cause (such as kidney, liver, or
bowel disease causing hypocalcemia and a subsequent increase in PTH
secretion). Tertiary HPT is a consequence of persistent parathyroid
stimulation (such as long-standing secondary hyperparathyroidism), which
results in autonomous (unregulated) PTH function.

In this clinical case the overlap of symptoms makes the diagnosis very
challenging because not only the signs and symptoms were very suspicious
for MM but also the blood test and the radiological findings were
typical for the plasma cells disease. Particularly the whole-body CT and
PET-CT mimicked the myeloma bone disease. The refractoriness to the
therapy with Zoledronic Acid, the absence of monoclonal protein and
pathologic bone marrow plasma cells and the arising of PTH led us to
consider an alternative cause of the clinic manifestations and only the
histopathologic examination helped us to achieve a diagnosis. A prompt
endocrinology evaluation and surgery therapy were essential to resolve
the patient's symptoms with an improvement of his outcome and
quality-of-life.

\textbf{Conclusions.} Our case reminds clinicians they should always
consider multiple differential diagnosis when face a cohort of signs or
symptoms coherent with a suspicion of MM not confirmed by investigations
because, particularly in elderly patients, the CRAB could be
non-specific and associated with different non-neoplastic diseases.

\textbf{Authorship and Disclosures} . DD and MP reviewed the literature
and wrote the paper. CC, TD, DP, SN and AML followed the patient and
wrote the paper. GLS supervised the work.

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