This is another reflection piece on the importance of haematology in seemingly non-haematological contexts. I have never really liked haematology, due to its relative complexity to other subspecialties in internal medicine. First, we've got the blood cells. Then, we need to know that they all arise from a common source - the one and only, haematopoietic stem cell. However, it doesn't stop here. Different blood cells can be differentiated by morphology (shape) and the variety of antigens (proteins) expressed on their cellular surfaces. We also have a broad array of diagnostic tests available, for both forming a working diagnosis prior to obtaining a bone marrow sample and a definite diagnosis afterwards. However, over the years, I've started to realise the importance of blood. After all, blood is the only organ which goes around the entire body. Therefore, if anything amiss occurs, it is likely to manifest in very non-specific ways. Chronic lymphocytic leukaemia, for instance, is a blood cancer which afflicts predominantly older patients and presents with non-specific, constitutional symptoms such as fatigue, night sweats, unexplained and significant weight loss, malaise, as well as more specific clues such as hepatosplenomegaly (liver and spleen enlargement). [1] Last time, I've described a case of hairy cell leukaemia, which is a blood cancer involving B cells which have developed 'hairy' processes radiating from the centre. It's a relatively rare disease. Now, I want to present a blood cancer which is significantly more common in elderly patients. This is why it gets confusing, since its clinical manifestations can sometimes be wrongly construed as other conditions elderly patients are prone to endure.
Its name, is MM.
Skull X-Ray showing Raindrop Skull - which is found in a patient with multiple myeloma; the skull contains numerous lytic lesions, as indicated by the darker (more hypodense) regions. (diagram extracted from https://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2018/nejm_2018.378.issue-20/nejmicm1714471/20180523/images/img_large/nejmicm1714471_f1.jpeg)
Our patient in this case is Sandy*, who is a 68-year old postmenopausal woman (G0P0) presenting with back pain. The patient is first seen (by me and my colleagues) at the general medical ward. A haematologist then gets involved. We've got the following clinical details so that you can also hop in and see what happened to this patient:
Back Pain (Chief Complaint)- has lasted for over 6 months, pain graded as 2/10 on visual analogue scale; persistent and relieved by resting; no morning stiffness; the pain is located over the lower back, at around L3-L5. It does not radiate to other parts of the body. The patient previously ignored the pain, dismissing it as an inevitable symptom of ageing. However, a few hours ago, the patient was doing housework, when suddenly she felt excruciating pain over the lower back and called an ambulance.
Associations of the Back Pain: No neural symptoms; no pain elsewhere; no urinary symptoms;
Associated Symptoms: malaise, fatigue, unexplained weight loss, non-specific nausea, depressed mood (all having lasted for over 2 months), palpitations (having first arisen three weeks ago), frothy urine (for over 2 months), pruritus (over abdomen) (for over 2 months), bruising (reported: over chest and flanks) (first emerged two weeks ago);
Past Medical History: recently (three weeks ago) treated for community-acquired pneumococcal pneumonia; according to medical records, she's had three events of pneumonia in the past four months; hospitalised two months ago for kidney stones; no diabetes or hypertension or any known cardiovascular diseases;
Past Surgical History: Received percutaneous nephrolithotomy for kidney stone (according to records, it was a staghorn calculus) (the inference being that recurrent urinary tract infections have been experienced [2]); appendectomy performed 3 years ago;
Drug History: Finished course of antibiotic treatment for pneumonia; occasional use of HRT (oestrogen formulation) for vaginal itchiness; no regular medication; no drug allergies; no recreational drug use (I know it's unlikely but we still need to ask);
Family History: Parents died of traumatic brain injury (car crash);
Autoimmune History: Unremarkable.
It has to be noted (again) that the patient is post-menopausal and has never given birth or had any pregnancies before. There are also no relevant gynaecological concerns, such as per-vaginal bleeding or pelvic pain and pressure;
Social History: Living alone, with relatives all living in Yorkshire; unremarkable dietary history; retired;
Travel History: Unremarkable.
After history-taking, we move on to physical examination. At this point, we're thinking more about mechanical back pain plus fractures, subjected to clarification of what she truly means when she says she has been doing 'housework'. Moreover, the absence of neurological symptoms, such as numbness and lower limb weakness, drives us away from vertebral prolapse. Myofascial pain (involving the spinal muscles and connective tissue) is thrown out of the window due to the index incident - acute exacerbation. The concurrence of myriads of non-specific, constitutional symptoms also seem to indicate that a larger issue is at play. It's not a confined, localised issue. What we're most curious about are the pruritus and bruising - how can they fit in the jigsaw puzzle?
Diagram showing Vertebral Prolapse - compression of the spinal cord and irritation of the spinal nerves; (extracted from http://3.bp.blogspot.com/-URd5oe7MqH4/UNkq_K_MbrI/AAAAAAAAADg/VsNSI1yo4Dw/s1600/mcdc7_herniated_disk.jpg)
We performed several physical examinations - the general examination, a spinal exam, an abdominal exam, lower limb neurological exam, and a cardiorespiratory exam.
- General Examination: patient fatigued and rather thin (not cachexic, which is usually a term describing cancer patients); pulse rate around 72 bpm (rhythm and magnitude normal), respiratory rate around 16 bpm. There is no lymphadenopathy.
More important points are listed below:
Pallor Present;
Peripheral Oedema up to the shins (bilateral);
Uraemic Complexion (this remains uncertain and is subjected to bias; according to my colleagues, this is likely to be uraemic since the patient's facial skin shows a shade of unhealthy brown which contrasts the lighter skin tone elsewhere).
- Spinal Examination: Tenderness over the region L3-L5; no overlying skin changes; movement limited by tenderness;
- Abdominal Examination (indicated due to history of kidney stones and nausea): Lanz incision (transverse) observed in RLQ; Bruising over the chest, flanks and hypogastrium (four bruises in total, all sized at roughly 3 cm x 2 cm); Scratch Marks over the right lower quadrant; no abdominal tenderness or mass; liver edge smooth and no hepatomegaly; all liver signs negative (e.g. spider angioma, Dupuytren's contracture); spleen normal; kidneys non-ballotable; normal abdominal aorta and bowel sounds.
- Lower Limb Neurological Examination: Unremarkable.
- Respiratory and Cardiovascular Examination (indicated due to history of pneumonia): Unremarkable.
We have also checked the patient's blood pressure and did urine dipstick at the bedside. The blood pressure is 132/94 mmHg, which falls within the normal range given the patient's age. Urine dipstick shows 3+ proteinuria and no haematuria.
The full panel of investigations and their results are presented below. Note that numerical values are not recorded (because my brain has limited RAM space and I processed those values for the benefit of convenience):
Tests:
Blood Tests (basic): Full Blood Count, Clotting Profile (we are concerned about the bruising, since they are not located at spots normally inflictable by trauma), Liver and Renal Function Tests, U&E, ESR and CRP (inflammatory markers), Spot Urine (Urine Albumin-Creatinine ratio) test;
Haematology-specific Screening Tests for Multiple Myeloma: Serum Electrophoresis (Protein), M-protein measurement in Urine;
Imaging: Spinal X-Ray (for back pain), Chest X-Ray (to see if the pneumonia is fully resolved). A full skeletal survey has been subsequently performed for the purposes of completeness.
As recommended by the consultant, MRI is also performed in deeper investigation of the spinal fracture.
Results (most remarkable findings):
Anaemia, Thrombocytopenia (FBC);
Normal inflammatory marker levels;
Hypercalcaemia, High Creatinine, High Urea, low eGFR (equivalent to Stage 3 Chronic Kidney Disease);
Urine albumin-creatinine ratio is high (above 300 mg/g) and Albumin/Globulin Ratio < 0.8; Very high gamma-globulin, reflective of high risk of multiple myeloma;
Serum M-protein level > 30 g/L;
Spinal Fracture - L4 (identified first on X-Ray; reduced height of the vertebra and slight mal-alignment- maybe subjected to bias) --> on MRI, we can clearly see the fracture, which is very likely to be pathological;
Multiple lytic lesions are seen along the spine as well.
Spinal X-Ray (Lateral View) showing lytic lesions over postero-superior aspects of L2 and L3, and the antero-inferior aspect of T12. This film is not the patient's. (It is extracted from: http://www.stritch.luc.edu/lumen/MedEd/Radio/curriculum/Neurology/Spine_plain_xray_2013.htm)
In light of the aforementioned findings, we have decided to proceed in the direction of multiple myeloma. Our current suspicions are as follows:
The patient has active multiple myeloma; this requires further tests (hence our lovely haematologist) including a bone marrow biopsy (trephine) (to assess the percentage of clonal cell infiltration of the bone marrow) and serum immunofixation (for further delineation of clonality); calculation of serum free light chain ratio is also done (normal range: usually 0.26-1.65);
The patient has chronic kidney disease which can be attributed to active multiple myeloma; this can be achieved through a multitude of mechanisms, including the rise of chronic kidney stones (high calcium content), formation of tubular casts, hyperviscosity. [8] Pruritus, anaemia, thrombocytopenia and bruising can be due to impaired kidney function. Anaemia and thrombocytopenia are frequently seen due to lower concentrations of erythropoietin and thrombopoietin. [9]
The patient suffers from hypercalcaemia, which can lead to a number of symptoms. Relevant to this patient, it can be responsible for the progressive bone weakness (thereby culminating into a fracture of the L4), depression and chronic renal calculi. [10-11]
The patient also experiences recurrent infections, including pneumonia and urinary tract infections (hence the staghorn calculus, which often spans recurrent events). Multiple myeloma compromises the immune system.
As an additional note, tubular casts are formed due to the excessive production of serum light chains in multiple myeloma, whereby existing mechanisms for their excretion and breakdown (catabolism) are insufficient. Light chains combine with uromodulin, forming such casts. As these casts are formed, they can lead to distal tubular obstruction and thickening of the ascending Loop of Henle. There is thus progressive deterioration of renal function. [8]
Diagram showing the typical serum protein electrophoresis results of Multiple Myeloma - note the spike over gamma-globulin (extracted from https://healthjade.net/wp-content/uploads/2019/11/Multiple-myeloma-serum-protein-electrophoresis.jpg)
Final Diagnosis: (active, symptomatic) Multiple Myeloma;
Serum free light chain ratio exceeds 1.65 and displays clonality. Moreover, the skeletal survey displays numerous lytic lesions in the axial skeleton, especially the ribs.
Due to the age and physical condition of the patient, the haematology team decides that she is not eligible for haematopoietic stem cell transplant. Therefore, the following treatment plan is organised:
Chemotherapy Regimen: Prednisolone (corticosteroid), Melphalan (alkylating agent), Bortezomib (26S proteasome inhibitor);
Supportive Treatment: Angiotensin-converting Enzyme Inhibitor (ACEI) and Statins for Chronic Kidney Disease; Bisphosphonates (Zoledronic Acid), Bone pain control, Vertebral Augmentation (for vertebral fracture), creams for soothing pruritus; blood transfusion per protocol due to anaemia.
Bortezomib is deemed as a special agent in chemotherapy for multiple myeloma. It has been discovered that myeloma is more reliant on the ubiquitin-proteasome system, which is important in removing undesirable proteins. These chiefly include misfolded proteins. In multiple myeloma, due to the rapid production of immunoglobulins, it's only fair to improve the invasion process by amplifying a process which eliminates misfolded proteins - the weaklings of the herd. Moreover, proteasomes also activate the NF-kB signalling pathway which triggers the creation of an ideal microenvironment for the growth of aberrant plasma cells. Bortezomib, as a 26S proteasome inhibitor, puts a halt in front of the process. [13]
So, there you have it. A patient with back pain which turns out to have a blood disease. It suffices to say that as clinicians we need to be more vigilant and open to possibilities. It transpires that even if you shy away from haematology, you can't avoid haematology knocking on your door.
*This case is not real (haha). Actually, I don't want to admit this but I've written this very typical case on multiple myeloma because many of my colleagues seem to struggle with it. They struggle most when coming up with differential diagnoses regarding back pain. However, awareness towards haematological malignancies must be promoted. We need to know that simply because the symptom starts from the back, it doesn't necessarily follow that the pathology is right over there.
[1] Hallek, M. (2019). Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 94: 1266– 1287. https://doi.org/10.1002/ajh.25595.
[2] Diri A, Diri B. (2018). Management of staghorn renal stones. Renal failure, 40(1), 357–362. https://doi.org/10.1080/0886022X.2018.1459306.
[3] O'Connell TX, Horita TJ, Kasravi B. (2005). Understanding and Interpreting Serum Protein Electrophoresis. Am Fam Physician 71(1):105-112.
[4] Carroll MF, Temte JL. (2000). Proteinuria in Adults: A Diagnostic Approach. Am Fam Physician. 62(6):1333-1340.
[5] Prakash V. (2020). L4 vertebral body pathological fracture secondary to myeloma | Radiology Case | Radiopaedia.org. Radiopaedia.org. Retrieved 23 November 2020, from https://radiopaedia.org/cases/l4-vertebral-body-pathological-fracture-secondary-to-myeloma-1.
[6] Smith D, Yong K. (2013). Multiple myeloma. BMJ (Clinical research ed.), 346, f3863. https://doi.org/10.1136/bmj.f3863.
[7] Bird JM, Owen RG, D’Sa S, et al. (2011), Guidelines for the diagnosis and management of multiple myeloma 2011. British Journal of Haematology, 154: 32-75. https://doi.org/10.1111/j.1365-2141.2011.08573.x.
[8] Dimopoulos M, Kastritis E, Rosinol L. et al. (2008). Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 22, 1485–1493. https://doi.org/10.1038/leu.2008.131.
[9] Dorgalaleh A, Mahmudi M, Tabibian S, et al. (2013). Anemia and thrombocytopenia in acute and chronic renal failure. International journal of hematology-oncology and stem cell research, 7(4), 34–39.
[10] Carroll MF, Schade DS. (2003). A Practical Approach to Hypercalcemia. Am Fam Physician. 67(9):1959-1966.
[11] Tanaka M, Yamazaki S, Hayashino Y. (2007). Hypercalcaemia is associated with poor mental health in haemodialysis patients: results from Japan DOPPS. Nephrology Dialysis Transplantation. 22(6), 1658-1664. https://doi.org/10.1093/ndt/gfm008.
[12] Palumbo A, Anderson K. (2011). Multiple Myeloma. New England Journal Of Medicine, 364(11), 1046-1060. https://doi.org/10.1056/nejmra1011442.
[13] Role of Proteasome in Multiple Myeloma. Myeloma Revealed. (2020). Retrieved 23 November 2020, from https://www.myelomarevealed.com/proteasome-multiple-myeloma/.