A 61 year-old lady, a retired professor of mathematics, saw her doctor and asked to be investigated for diabetes mellitus. The reason she gave for this was that although she had no family history of diabetes a distant cousin and a colleague who had pain and tingling in their feet had been found to have a high blood sugar level and had been started on oral therapy for diabetes. On being asked why she thought she had diabetes and what symptoms she had, she gave the following information.
- She felt tired all the time. She had stopped going for her regular walks, now got her daughter to do her grocery shopping and asked her husband to fetch her books, tea, glass of water and reading glasses for her and he had been complaining about this. She had been very active and had done most of the household chores herself.
- She had painful tingling in her feet and legs, could not sleep at night because her legs felt “restless” all the time. Her slippers tended to fall off he feet and she now wore closed shoes whenever she left the house.
- Her legs felt as if they would not support her and she tended to support herself against the furniture when she walked and found stairs difficult to climb up and come down and had difficulty getting up from her low sofa. Her arms felt weak and she could not carry her shopping bags.
- She had lost her appetite, was eating less than half the quantity of the food she usually ate and had lost 3 kg of weight in 2 months. She was quite happy about this as she was overweight.
- Her fingers and toes felt cold all the time and she washed herself in warm water even in summer in Karachi.
What questions would you ask her in her history?
I think the most significant symptom is her spontaneous weight loss and poor appetite. Did she have other gastrointestinal symptoms like nausea, heartburn or epigastric pain linked to her food intake? Did she have difficulty in swallowing her food? Pain anywhere in her abdomen especially if it was persistent? Had her bowel habits altered in the last 3-4 months more than usual constipation or loose motions; bleeding per rectum or blood in her stools? Did her abdomen feel bloated or distended? The answer to all these questions was negative. Had she put herself on a “fad” diet like the cabbage soup diet or rice diet etc. No she ate her usual food which contained a fresh vegetable salad, lentils, eggs, cheese, a glass of lassi or some yogurt, chicken, meat and fish as well as rice and chapatis. She does not appear short of micronutrients (vitamins) in her diet though she may not be absorbing them. Possible vitamin B 12 deficiency, which is not linked to dietary intake nor to diarrhoea causing the malabsorption but rather to a deficiency of intrinsic factor in the stomach, Her tiredness could be due to anemia and feeling of weakness and painful tingling to motor and sensory neuropathy and subacute combined degeneration of the spinal cord from B12 deficiency. Well we will have to wait and see.
I would question her about her tiredness and weakness next. Is she breathless and does she tend to wheeze? No she has no respiratory symptoms and has never been a smoker, does not eat paan or tobacco. Is the tiredness linked to exercise? She wakes up fresh but becomes more and more tiredness during the day and by days end even her eyelids are drooping and her lips pouting? No. Does she have chest pain linked to exercise? No. Does she wake up late at night from sleep with chest tightness? No. HAs she recently started snoring or wakes up feeling tired and still sleepy and tends to fall asleep frequently during the day? Was she ever diagnosed as having sleep apnoea syndrome? No.
She did have her ECG and ETT done as part of the annual medical check up just before retiring from the university where she worked and had been given a clear bill of health for her heart and otherwise too.
So now we are dealing with a 61 year-old who has anorexia, weight loss, tiredness, possible sensory and motor neuropathy. Is she anemic too? These are very nonspecific symptoms and we will have to hope to pick up a clue on clinical examination and then rely on the investigations to make a diagnosis. (You can say this in the examination so that the examiner can follow your thought processes.)
On examination her weight was 81 kg against a recorded 88 one year ago in her last medical record. So she has been losing weight longer than she thinks. An indolent process? BP is 130/80 mmHg, pulse 73/min regular. She is clinically anemic but not jaundiced or cyanosed. She has a few bruises on her thighs and left shin. Her lymph nodes are not enlarged anywhere. Her thyroid is not enlarged visibly nor palpable to touch. There is no peripheral edema. The JVP is not raised. There is no cardiomegaly and the first and second heart sounds are audible. The lungs are clear. She has no evidence of free fluid in the abdominal cavity. The liver is palpable 5 cm below the costal margin and is firm. The spleen is palpable 6 cm below the costal margin and is firm. The kidneys are not palpable. She declined a rectal and vaginal examination. She has numbness on her feet and lower shins not conforming to any definite nerve distribution but more like a stocking pattern. There is some impaired sensation to fine touch on her fingers but she herself has not noticed this. There is 2/5 muscle weakness in the hip girdle muscles and in the shoulder girdle muscles. The tendon jerks in the upper limb are unremarkable as are the knee jerks. The plantar reflexes are downgoing. Her executive and cognitive mental functions are commensurate with her education and profession. Her cranial nerves were intact. When her hands are put in a bowl of iced water her fingers turned blue. on fundoscopy tortuous veins were seen in the retina.
We now have an elderly lady who has been losing weight, for a year, who is anemic, tired, anorexic, has some bruising so bleeding tendency, peripheral sensory and motor neuropathy. Her liver and spleen are enlarged, with a possible Raynaud’s phenomenon and tortuous retinal veins. She has no bone tenderness. What is the differential diagnosis?
- Waldenstrom’s macroglobulinemia.
- Monoclonal gammopathy.
- Multiple myeloma.
- Non-Hodgkin’s lymphoma
I have obtained the information for this blog from Medscape and I am pasting the link address for your convenience.
(You may choose to discuss chronic lymphoid leukemia first in the examination if you wish.)
Waldenström macroglobulinemia (WM) is a rare B lymphocytic subtype of non-Hodgkin lymphoma. Approximately 2800 cases of WM are diagnosed each year in the United States. Worldwide, WM is estimated to have an incidence of approximately 3-4 million patients per year. Although the exact etiology of WM is unknown, reports have linked this chronic, slowly evolving malignant hematologic disease to genetic, environmental, and viral factors.
WM typically presents in elderly patients; the median age at diagnosis in the United States is 65 years though it can present in younger patients. WM is more common in men than women, and the disease disproportionately affects white, non-Hispanic patients. Thanks to newer therapies, the median survival rate of patients with symptomatic WM is > 7-10 years.
Although WM has an indolent disease course, disease progression can lead to serious sequelae from hyperviscosity syndrome (HVS); coagulation abnormalities; peripheral neuropathy; increased risk for infection; and organ damage from immunoglobulin M (IgM) deposits in the skin, gastrointestinal tract, kidneys, spleen, and other organs.
Unfortunately, the nonspecific clinical presentation of weakness, anorexia, and weight loss associated with WM can prevent timely diagnosis and treatment in this vulnerable patient population.
The REAL and WHO classifications define WM as a rare, chronic, slowly progressive lymphoplasmacytic lymphoma due to a mutation in B lymphocytes. This mutation causes an overproduction of IgM, resulting in HVS and lymphoplasmacytic infiltrate in the bone marrow.
Clinical presentation of WM are similar to those of MM (eg, fatigue, weakness, weight loss, anemia). However, there are other signs and symptoms that help clinicians differentiate WM from MM. Organomegaly, a common presenting sign of patients with WM, is an uncommon presentation in patients with MM. Conversely, lytic bony and renal diseases are common presentations in patients with MM but are uncommon in patients with WM.
It is important to note that approximately 25% of patients with WM are asymptomatic. In this patient population, WM is often an incidental finding—one typically discovered through blood work performed for a routine physical exam.
WM should be considered in patients presenting with weakness, anorexia, weight loss, and symptoms of Raynaud phenomenon. Common physical exam findings of WM include hepatosplenomegaly, lymphadenopathy, purpura, and neuropathy.
In patients with WM, central nervous system infiltration by the B-cell clone often results in altered mental status, including lethargy and coma. Malignant lymphoplasmacytic cell involvement can also lead to Bing-Neel syndrome, a rare disease manifestation of WM that causes confusion, memory loss, disorientation, and motor abnormalities. Bing-Neel syndrome can develop in patients with known WM and in previously undiagnosed patients—even in the absence of systemic progression. Signs and symptoms of life-threatening HVS include abnormal bleeding, dizziness, headache, blurry vision, and hearing or vision disturbances.
Onset is insidious and nonspecific. Many patients are asymptomatic at presentation and are diagnosed incidentally from routine blood work. Weakness, anorexia and weight loss are the most common symptoms. Merlini et al reported the frequency of presenting features in 215 patients with Waldenström macroglobulinemia, as follows :
Weakness – 66%
Anorexia – 25%
Peripheral neuropathy – 24%
Weight loss – 17%
Fever – 15%
Raynaud phenomenon – 11%; Raynaud phenomenon is due to cryoglobulinemia and may precede other serious symptoms by several years
Mental status changes, including lethargy, stupor, or even coma, can occur. Infiltration of the central nervous system by the malignant clone can cause a syndrome of confusion, memory loss, disorientation, and motor abnormalities called the Bing-Neel syndrome.
Symptoms due to hyperviscosity syndrome, which can be life threatening, include the following :
Hearing or visual problems
Visual changes, such as blurred vision or double images, and spontaneous bleeding with minor trauma can be presenting features. Patients often present with a history of abnormal bleeding. Gastrointestinal (GI) findings may include malabsorption, GI bleeding, and diarrhea.
The physical findings result from tissue infiltration by the malignant clone, the hyperviscosity state caused by antigen-antibody reactions triggered by the paraprotein, and derangement of the hemostatic system by the paraprotein. Hepatosplenomegaly and lymphadenopathy are common. Merlini et al reported the following occurrences of symptoms in 215 patients evaluated for Waldenström macroglobulinemia:
Hepatomegaly – 20%
Splenomegaly – 19%
Lymphadenopathy – 15%
Purpura – 9%
Hemorrhagic manifestations – 7%
Papilledema, ie, sausage-shaped (distended and tortuous) retinal veins, and hemorrhages may be evident on funduscopic examination.
Neuropathy is typically slowly progressive, distal, symmetrical, and sensorimotor. Other variants, including a chronic ataxic neuropathy known as Miller-Fisher syndrome (a variant of Guillain-Barré syndrome), have been described. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) also may be associated with Waldenström macroglobulinemia.
Skin manifestations include the following:
Purpura (see the image below)
Bullous skin disease
Papules on extremities
Cutaneous plaques and nodules
Chronic urticaria (Schnitzler syndrome)
Purpura from Waldenström macroglobulinemia is evident in the forearm of a 65-year-old man who presented with a purpuric rash on all of his extremities. Although the patient had a history of hepatitis C, the possibility of hepatitis C cryoglobulinemia was excluded because the rash extended well beyond the hands and feet, and blood testing identified a type I cryoglobulinemia. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.
Pulmonary involvement is rare (3-5%), with nodules, masses, parenchymal infiltrates, or pleural effusion.
Elevated IgM (confirmed with immunofixation), elevated blood viscosity, and lymphoplasmacytic infiltrate on bone marrow biopsy are diagnostic criteria for WM. In addition, WM cells are often positive for the biomarkers CD19, CD20, CD22, and CD79a. Because MYD88L265P mutations are present in approximately 90% of patients with WM, genetic studies can help differentiate WM from MM and other types of lymphoma.
The monoclonal antibody rituximab , given in combination with the alkylating agent bendamustine or a proteasome inhibitor (eg, bortezomib, carfilzomib [off-label use]; ixazomib [for patients with WM cells resistant to ibrutinib]), is the typical treatment for WM.
Other therapies for WM include alkylating agents, purine nucleoside analogues, immunomodulatory medications, mammalian target of rapamycin inhibitors, and monoclonal antibodies.
In 2015, ibrutinib (Imbruvica) was the first therapy approved by the
U.S. Food and Drug Administration (FDA) specifically for patients
with Waldenström macroglobulinemia. There are many other drugs
that can be used to manage this disease, alone and/or in various
combinations, including the following:
• Bendamustine (Treanda) • Cladribine (Leustatin)
• Bortezomib (Velcade) • Fludarabine (Fludara)
• Chlorambucil (Leukeran) • Rituximab (Rituxan)
Other agents used alone or in combination for primary treatment
are cyclophosphamide (Cytoxan), carfilzomib (Kyprolis), and
For patients whose disease relapses (returns after treatment) or
becomes refractory (does not respond to treatment), secondary
therapies may be successful in providing additional remissions.
Some of the previous therapies discussed can be used or reused
depending on a patient’s age, length of remission, stem cell transplant
eligibility, and previous toxicities encountered. Additional therapies
to treat relapsed/refractory Waldenström macroglobulinemia
• Everolimus (Afinitor)
• Ofatumumab (Arzerra) for patients who are intolerant to
• High-dose chemotherapy followed by an autologous (patients
receive their own stem cells) or allogeneic (patients receive
stem cells from a donor) stem cell transplant in select patients
Corticosteroids and various antineoplastic medications (tyrosine kinase inhibitor, alkylating, antimetabolite, anthracycline, proteasome inhibitors, and monoclonal antibody) are also treatment options for WM.
Some of the clinical manifestations are similar to those of Multiple Myeloma (eg, fatigue, weakness, weight loss, anemia). However, there are other signs and symptoms that help clinicians differentiate WM from MM. Organomegaly, a common presenting sign of patients with WM, is an uncommon presentation in patients with MM. Conversely, lytic bony and renal diseases are common presentations in patients with MM but are uncommon in patients with WM.
Hematopoietic stem cell transplant (HSTC) should be considered for young patients with WM who have chemosensitive disease at the time of their first or second disease relapse and also for newly diagnosed patients with very high-risk WM.
A study by Cornell and colleagues demonstrated significantly improved outcomes of patients with WM 5 years after allogeneic HSCT, most notably progression-free survival of 42% and overall survival of 52%. Patients with chemosensitive WM whose pretransplant status was more stable before allogeneic HSCT experienced significant increase in overall survival.
A risk assessment using the International Prognostic Scoring System for WM should be performed in all patients before HSCT
Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes (see the histologic sample in the image below). CLL is the most common form of leukemia found in adults in Western countries.  Some patients die rapidly, within 2-3 years of diagnosis, because of complications from CLL, but most patients live 5-10 years.
See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.
Signs and symptoms
Patients with CLL present with a wide range of symptoms and signs. Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be asymptomatic at time of presentation.
Signs and symptoms include the following:
Enlarged lymph nodes, liver, or spleen
Loss of appetite or early satiety
Abnormal bruising (late-stage symptom)
Patients with CLL have a higher-than-normal white blood cell count, which is determined by complete blood count (CBC). Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of CLL. Other tests that may be helpful for diagnosis include bone marrow biopsy and ultrasonography of the liver and spleen. Immunoglobulin testing may be indicated for patients developing repeated infections.