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