Multiple myeloma differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Haytham Allaham, M.D. [2]

Overview

Multiple myeloma must be differentiated from monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, and extramedullary plasmacytoma.^[1]

Differentiating Multiple Myeloma from other Diseases

The table below summarizes how to differentiate multiple myeloma from other conditions that cause similar presentation:^[1]

Plasma Cell Neoplasm	M Protein Type	Pathology	Clinical Presentation
MGUS	IgG kappa or lambda; or IgA kappa or lambda	<10% plasma cells in bone marrow	Asymptomatic, with minimal evidence of disease (aside from the presence of an M protein)
Isolated plasmacytoma of bone	IgG kappa or lambda; or IgA kappa or gamma	Solitary lesion of bone; <10% plasma cells in marrow of uninvolved site	Asymptomatic or symptomatic
Extramedullary plasmacytoma	IgG kappa or lambda; or IgA kappa or gamma	Solitary lesion of soft tissue in the nasopharynx, tonsils, or sinuses	Asymptomatic or symptomatic
Multiple myeloma	IgG kappa or lambda; or IgA kappa or gamma	Often multiple lesions of bone	Symptomatic

Another important differential diagnosis is that of widespread bony metastases. Findings that favor the diagnosis of bony metastases over that of multiple myeloma include:^[2]

Bone metastases more commonly affect the vertebral pedicles rather than vertebral bodies.
Bone metastases rarely involve mandible and distal axial skeleton.
Although both entities have variable bone scan appearances (both hot and cold) unlike multiple myeloma, extensive bony metastases rarely have a normal appearance.

Multiple myeloma must also be differentiated from other causes of bone pain and fatigue such as:

Waldenstrom Hypergammaglobulinemia
Bone fracture
Fibrous dysplasia
Enchondroma
Eosinophilic granuloma
Giant cell tumor
Osteoblastoma
Aneurysmal bone cyst
Solitary bone cyst
Hyperparathyroidism
Infection
Chondroblastoma
Chondromyxoid Fibroma
Reactive plasmacytosis
Macroglobulinemia
Osteoporosis (osteoporotic fracture)
Idiopathic transient osteoporosis of hip
Osteomalacia
Osteogenesis imperfecta
Multiple myeloma
Homocystinuria
Hypermetabolic resorptive osteoporosis.


Differential Diagnosis	Similar Features	Differentiating Features

Multiple myeloma	On physical examination, demonstrates diffuse bone pain and tenderness On imaging studies, demonstrates osteolytic lesions in the bones	-
Osteoporosis	On physical examination, demonstrates acute musculoskletal pain, if fracture happened On imaging studies, demonstrates severe decrease in BMD	On laboratory studies, not demonstrates monoclonal IgM overload in electrophoresis, and also Bence-Jones protein in urine
Idiopathic transient osteoporosis of hip	On physical examination, demonstrates acute hip pain On imaging studies, demonstrates sub-chondoral cortical loss and diffuse osteopenia of the femoral neck	On history, demonstrates mostly involvement of pregnant women and young men On history, demonstrates to be self-limiting in 6-8 months
Osteomalacia	On physical examination, demonstrates diffuse bone pain, fatigue, and fractures are the common symptoms On imaging studies, demonstrates low bone mineral density (BMD)	On imaging studies, demonstrate the brief bone mass loss in bones
Scurvy	On physical examination, demonstrates bone pain and frequent fractures due to brittle bone On imaging studies, demonstrates low bone mineral density (BMD)	On physical examination, demonstrates other mucosal disruption symptoms, such as bleeding gums On imaging studies, demonstrates normal bone mineral density (BMD)
Osteogenesis imperfecta	On physical examination, demonstrates Short stature, scoliosis, and propensity for fractures	On physical examination, demonstrates tooth defects, hearing defects, and blue sclera On laboratory studies, demonstrates near normal bone mineral density (BMD)
Homocystinuria	On physical examination, demonstrates diffuse bone pain and musculoskeletal symptoms	On physical examination, demonstrates visual impairment On laboratory studies, demonstrates high amounts of homocysteine in urine

Multiple myeloma must be differentiated from other causes of diabetes insipidus.

Type of DI	Subclass	Disease	Defining signs and symptoms	Lab/Imaging findings
Central	Acquired	Histiocytosis	Bone lysis and fracture Purulent otitis media Diabetes insipidus and delayed puberty Maxillary, mandibular, and gingival disease Rash and maculoerythematous skin lesions Scaly, erythematous scalp patches Lung involvement GI bleeding Lymph node enlargement^[3]	CD1a and CD45 + Interleukin-17 (ILITA) Skull x-ray of a patient with Langerhan's histiocytosis showing lytic lesions - Case courtesy of Dr Hani Salam, Radiopaedia.org, rID: 9459
		Craniopharyngioma	Headache Endocrine dysfunction Diabetes insipidus Hypothyroidism Adrenal failure Diabetes insipidus (e.g., excessive fluid intake and urination) Growth failure and delayed puberty	Suprasellar calcified cyst on MRI Brain MRI showing suprasellar mass consistent with the diagnosis of craniopharyngioma - Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 16812
		Sarcoidosis	Systemic complaints Fever Anorexia Arthralgias Pulmonary complaints Dyspnea on exertion Cough Chest pain, Hemoptysis (rare) Diabetes mellitus	Hypercalcemia Hypercalciuria (noncaseating granulomas) Elevated alkaline phosphatase Serum amyloid A (SAA) ACE levels may be elevated Contrast-enhanced patches in a patient previously diagnosed with lung sarcoidosis - Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 10930
	Congenital	Hydrocephalus	Cognitive deterioration Headaches Neck pain Blurred vision Unsteady gait Incontinence such as polyuria	Dilated ventricles on CT and MRI Obstructive hydrocephalus showing dilated lateral ventricles - Case courtesy of Dr Paul Simkin, Radiopaedia.org, rID: 30453
	Congenital	Wolfram Syndrome (DIDMOAD)	Diabetes Insipidus Diabetes Mellitus Optic Atrophy Deafness	Negative islet cell antibodies Optic atrophy on electroretinogram Deafness on audiogram Atrophy of brain stem on MRI
Nephrogenic	Acquired	Drug-induced (demeclocycline, lithium)	Polyuria Polydipsia Nocturia	Urine osmolality <100 mmol/ Arginine vasopressin level >4.6 pmol/ Little or no response to administration of exogenous arginine vasopressin
		Hypercalcemia	Polyuria Polydipsia Gastrointestinal disturbances Pathological fractures Confusion Palpitations and cardiac arrhythmias	Ca levels greater than 11 meq/L
		Hypokalemia	Polyuria Hyporeflexia Palpitations and cardiac arrhythmias	K levels less than 3meq/L on CBC
		Multiple myeloma	Pathologic bone fractures Bleeding Hypercalcemia leading to polyuria Infection Hyperviscosity Anemia	IgG or IgA spike on serum protein electrophoresis Monoclonal M spike Disordered plasma cell proliferation on bone marrow biopsy Skeletal survey in a patient with multiple myeloma showing multiple lytic lesions - Case courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 7682
		Sickle cell disease	Chronic pain Anemia Aplastic crisis Splenic sequestration Infection Isosthenuria presenting with polyuria	Hemoglobin level is 5-9 g/dL Hematocrit is decreased to 17-29% Peripheral blood smears demonstrate target cells, elongated cells, and characteristic sickle erythrocytes MRI can demonstrate avascular necrosis of the femoral and humeral heads Blood film showing the sickle cells - By Dr Graham Beards - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18421017
Primary polydipsia		Psychogenic	Polyuria Polydipsia Nocturia	Dry mucus membrane History of psychiatric disorders
Gestational diabetes insipidus			Polyuria Polydipsia Nocturia Pregnancy	Dry mucus membranes Pregnancy
Diabetes mellitus			Polyuria Polydipsia Nocturia Weight gain	Elevated blood sugar levels >126 Elevated HbA1c > 6.5