Fig 1c: HE 40X multinucleated giant cell embedded with mononuclear ovoid
to spindled neoplastic cell.
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.
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 failure3. 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
volume4. 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
differentiation5,6. 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
treatment7. 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 coma8. 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) < 30 mL/min/1.73 m2 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
signs9,10. 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 (Tab.1 )
Tab.1 : differential diagnosis of signs and symptoms of