Diagnosis

When a patient presents with a deep vein thrombosis (DVT) or pulmonary embolism (PE) and it is confirmed with appropriate diagnostic testing (Doppler Ultrasound of Lower Extremity, D-Dimer, V/Q Scan, CT chest with PE protocol), it is important to determine if this event was provoked or unprovoked. A full history and physical examination can help to determine the possible etiology of this event. It is important to rule out provoking factors, including but not limited to; prolonged travel (immobility on a plane or other mode of transportation), recent surgery (immobility), Oral contraceptive medications, hormone therapies, genetic predisposition due to a coagulopathy, as well as cancer.

Thus, a thorough investigation of a patient with a new DVT or PE should include appropriate cancer screening and work up.

Treatment

Low molecular weight heparin (LMWH) has been the treatment of choice in patients with CAT because it offers superior efficacy over warfarin. Other non-anticoagulant effects of LMWH (e.g. anti-inflammatory properties) may also make it more effective than warfarin in CAT. Recently, trials comparing anti-factor Xa direct oral anticoagulants (DOACs), including Apixaban, Edoxaban and Rivaroxaban, with LMWH have shown that these agents are reasonable alternatives to LMWH in many cases of CAT. The most common LMWH, Dalteparin, is indicated in cancer associated thrombosis (CAT). The therapeutic dosing for LMWHs are weight dependent. The therapeutic dosing for Dalteparin is 200 U/Kg daily for 1 month, then 150 U/Kg.

Apixaban: Initial LMWH is not required. Dosing is as usual at 10 mg twice daily for 1 week followed by 5 mg twice daily.

Edoxaban: After an initial 5-day treatment with therapeutic LMWH, edoxaban 60 mg once daily is given. The dose is reduced to 30 mg once daily in those who have creatinine clearance between 30 and 50 mL/min, weigh 60 kg or less, or are taking potent P-glycoprotein inhibitors (such as erythromycin, cyclosporine, dronedarone, quinidine, or ketoconazole).

Rivaroxaban: Initial LMWH is not required. Dosing is as usual at 15 mg twice daily for 3 weeks followed by a daily dose of 20 mg.

Patients should receive treatment for at least 3-6 months. Beyond this time frame, anticoagulation should be continued if;
- The patient is receiving systemic chemotherapy
- The patient has metastatic disease
- The patient has progressive or relapsed disease
- The patient has other risk factors that increase the risk of thrombosis

Thereafter, reassessments should be made every 3-6 months regarding need for anticoagulation therapy

Reference:
Thrombosis Canada, Clinical Guides - Cancer and Thrombosis (Version Aug 2020)
Key N, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2020;38(5):496-520.
Agnelli G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382(17):1599-1607.
Young AM, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of randomized trial (SELECT-D). J Clin Oncol 2018;36(20):2017-2023.
Raskob G, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615-624.

Multiple myeloma is a malignant neoplasm of the plasma cells found in the bone marrow.

Monoclonal Gammopathy of Undetermined Significance
This is a pre-cancerous condition of the plasma cells in the bone marrow. The incidence of MGUS is 1% for patients aged 50 or older, and 3% for patients older than 70.

Diagnostic Criteria:

• M-protein in serum <30g/L
• Bone marrow clonal plasma cells <10%
• No evidence of myeloma related organ or tissue impairment – Calcium remaining <2.75mmol/L, kidney function preserved with a creatinine <176umol/L, Hemoglobin remaining >100g/L, no lytic lesions or osteoporosis compression fractures

The rate of progression to multiple myeloma or another lymphoproliferative disorder (chronic lymphocytic leukemia, Waldenstrom Macroglobulinemia, Lymphoma) is approximately 1-1.5% per year.

Low Risk MGUS
- M-protein <15g/L
- The type of M-protein is IgG
- Free Light Chain ratio is normal

High Risk MGUS
- M-protein >15g/L
- The type of M-protein is IgA or IgM
- Abnormal Free Light Chain Ratio

Patients with MGUS do not need treatment. Patients with low risk MGUS can be followed annually with the following investigations:

• CBC
• Creatinine
• Calcium
• Serum and Urine Protein Electrophoresis
• Quantitative Immunoglobulins
• Free Light Chains
• Skeletal Survey

Smouldering (Asymptomatic) Myeloma
Diagnostic Criteria:

• M-protein >30g/L and/or
• Bone marrow plasmacytosis >10%
• No evidence of myeloma related organ or tissue impairment – Calcium remaining <2.75mmol/L, kidney function preserved with a creatinine <176umol/L, Hemoglobin remaining >100g/L, no lytic lesions or osteoporosis compression fracture
• No high risk features

Within this category, patients are classified into low risk, intermediate risk and high risk.

Low Risk
A patient is low risk if they have both of these features:
- You have <10% plasma cells in the bone marrow
- M-protein level in the blood is 30g/L or more.

Intermediate Risk
A patient is intermediate risk if they have both of these features:
- Plasma cells make up 10% or more of cells in the bone marrow
- M-protein level in the blood is less than 30g/L.

High Risk
A patient is high risk if they have both of these features:
- Plasma cells make up 10% or more of cells in the bone marrow
- M-protein level in the blood is 30g/L or more.

Very High Risk
A patient is considered very high risk if they have all of the following features:
- Plasma cells make up 60% or more of cells in the bone marrow
- The Serum Free Light Chain Ratio is >100.
- An MRI scan shows >1 area of bone or bone marrow destruction

If patients have high-risk or very high-risk features, they are considered as having overt myeloma, and are treated as such.
Patients with smouldering myeloma do not require treatment. They should be followed every 3-6 months and monitored for myeloma-related symptoms (CRAB) or end organ damage.

Multiple Myeloma
Diagnostic Criteria:

• M-Protein detected in serum and/or urine through Serum protein electrophoresis, urine protein electrophoresis or free light chain assay
• Clonal bone marrow plasma cells or plasmacytoma
• Evidence of organ dysfunction – Calcium >2.75mmol/L, Creatinine >176umol/L, Hemoglobin <100g/L, bone lesions or osteopenia with compression fracture
• High risk features including bone marrow plasmacytosis >60%, t(4;14) or p53 deletion, 2 or more lytic lesions, or FLC ratio >100

Staging:
International Staging System

Stage I – The beta-2 microglobulin is <3.5mg/L, and albumin is >35g/L or more.

Stage II – The beta-2 microgloublin is <3.5mg/L, and albumin is less than 35g/L.
OR The beta-2 microglobulin is >3.5mg/L but less than 5.5mg/L.

Stage III – The beta-2 microglobulin is >5.5mg/L.

Treatment
Once a diagnosis of Multiple Myeloma is made, your treatment will ensue at Windsor Regional Hospital Cancer Center. The treatment may include chemotherapy, radiation, bisphosphonates, surgery, stem cell transplantation or plasmapheresis.
Treatment for Multiple Myeloma is not curative, but can cause cancer to regress, and go away for some time.

References: http://www.albertahealthservices.ca/assets/info/hp/cancer/if-hp-cancer-guide-lyhe003-multi-myeloma.pdf
American Cancer Society – Multiple Myeloma, Canadian Cancer Society

Lymphadenopathy refers to lymph nodes, which are abnormal in size, number or consistency. In general, lymphadenopathy can be divided into two major categories for evaluation; localized or generalized. Localized lymphadenopathy occurs when lymph nodes are enlarged in only one area of the body. Generalized lymphadenopathy occurs when lymph nodes are enlarged in two or more noncontiguous areas of the body. Upon initial assessment of lymphadenopathy, a detailed history and physical examination are of utmost importance to help narrow the differential diagnosis.

Tips for history taking regarding lymphadenopathy:

• Are there any systemic/constitutional symptoms of fevers, chills, sweats, fatigue, and weight loss?
• What medications is the patient taking?
• Has there been any recent travel, occupational exposure, animal exposure, high-risk behaviors, etc. recently?
• Are there any localized signs of infection or malignancy surrounding the enlarged lymph node?

If lymph nodes are detected during physical examination, there are five characteristics that should be noted;

1. Size – Lymph nodes >1cm are considered abnormal.
2. Tenderness – If a lymph node grows inside quickly, pain is experienced due to stretching of the capsule. However, rapid growth can occur in both benign inflammatory or infection causes, as well as malignancy. Thus, the presence of tenderness does not help to differentiate a benign versus malignant lymph node.
3. Texture/Consistency – Typically, lymph nodes that are smooth and relatively soft are benign in nature. Lymph nodes that are hard, firm, rubbery and irregular shape are more likely associated with malignancy.
4. Mobility – A fixed or matted lymph node is more likely to be associated with a malignancy. Freely mobile lymph nodes are more likely related to a benign process.
5. Location – The location of lymphadenopathy can be helpful for the differential diagnosis. For example, mononucleosis is associated with cervical adenopathy whereas some sexually transmitted diseases are associated with inguinal adenopathy. In generalized adenopathy, physical examination and history should focus on systemic illnesses. The finding of supraclavicular lymphadenopathy is the most worrisome and is highly suspicious for malignancy.

Differential Diagnosis Based on Location of Lymphadenopathy

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Generalized Lymphadenopathy
If a patient presents with generalized lymphadenopathy, it is most likely related to a systemic illness. The following are conditions and investigations appropriate to complete to determine a cause for generalized lymphadenopathy:

• EBV – Monospot testing, EBV serology
• CMV – CMV serology
• Toxoplasmosis – IgM toxoplasma antibody
• HIV – HIV serology
• Tuberculosis – PPD (TB skin test), CXR
• Hepatitis B and C – Hepatitis serology (for type B and C), LFTs
• Systemic Lupus Erythematosus – ANA, complement levels, also evaluate for clinical criteria
• Rheumatoid Arthritis – RF, anti-CCP
• Lymphoma – CBC with differential and peripheral smear, biopsy of lymph node
• Leukemia – CBC with differential and peripheral smear, bone marrow aspiration and biopsy
• Sarcoidosis – Serum ACE, biopsy of lymph node

It may also be reasonable to order an abdominal ultrasound, to assess for splenomegaly.
If a definitive etiology or diagnosis that explains the generalized lymphadenopathy cannot be made, a biopsy will be completed. An excision lymph node biopsy will be carried out (trying to target the largest, most abnormal node that is reasonably accessible).

Localized Lymphadenopathy
When a patients presents with localized lymphadenopathy, it is again important to explore a thorough history and physical examination to determine a likely etiology for the lymphadenopathy. If a definitive etiology or diagnosis that explains the localized lymphadenopathy cannot be made, the patient may need to proceed with further testing and excisional biopsy.

Often times, a physician can obtain an ultrasound of the abnormal localized lymph node. Certain characteristics of lymph nodes on ultrasound indicate an abnormal lymph node including; loss of fatty hilum, focal necrosis, or cystic necrotic nodes. Furthermore, a node may be classified as abnormal on ultrasound based on size criteria, however this varies based on location.

However, if the patient has a benign clinical history, no constitutional or worrisome symptoms, and an unremarkable physical examination demonstrating a non-suspicious lymph node (see criteria above), it is reasonable to wait 4 weeks and re-examine the patient to see if the lymph node has regressed or disappeared.

References: Lymphadenopathy: Differential Diagnosis and Evaluation. ROBERT FERRER, M.D., M.P.H.,University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
Am Fam Physician. 1998 Oct 15;58(6):1313-1320.
BMJ Best Practice – Assessment of Lymphadenopathy.

A = Asymmetry – If a mole or skin lesion is symmetric, it is more likely benign. If a mole is asymmetrical, it is more suspicious for malignancy.
B = Borders – A mole is more suspicious for malignancy if the borders are irregular, notched or scalloped
C = Colour – Most benign moles are all one colour. If a mole has a variety of colours, possibly different tans, browns, or blacks, this is a warning sign.
D = Diameter – Moles with a diameter >6mm are more suspicious for malignancy.
E = Evolving – If a mole starts to change or evolve, in size, shape, colour, etc., this is a warning sign of malignancy.

A skin biopsy is required to confirm the diagnosis and determine the histologic subtype of malignancy. Although the malignant skin lesions such as Squamous Cell Carcinoma, Basal Cell Carcinoma and Melanoma have certain features on physical examination that give a practitioner suspicion for the diagnosis, tissue is always required for diagnosis. Depending on the characteristics of the lesion, a shave biopsy, excisional biopsy or punch biopsy may be chosen.

Biopsy Type

Shave Biopsy – This biopsy is performed with a small surgical blade. The physician will scrape the top layers of skin to obtain a tissue sample. This type of biopsy is chosen for skin lesions when the likelihood of melanoma is very low. This is not the ideal biopsy type to diagnose melanoma because it may not measure how deeply melanoma has invaded the tissue.

Punch Biopsy – A punch biopsy allows for a tissue sample to be obtained in deeper layers of the skin. The punch biopsy tool is placed on the skin, and repetitively rotated until the tool has cut through all layers of the skin. The sample is removed and the skin is often stitched together.

Incisional & Excisional Biopsy – These biopsies are performed using a surgical knife, cutting through all layers of the skin, and removing a wedge of tissue. The edges of the biopsy are then sutured together. An incisional biopsy is when only partial tumor removal is completed. An excisional biopsy is when the entire tumor is removed. This is the preferred biopsy type if the physician is suspicious of melanoma.

www.cancercare.org/cancer/skincancer-melanoma/