Tag Archives: Hematology/Oncology

Diffused Alveolar Hemorrhage (DAH) AND Hemophagocytic Lymphohistiocytosis (HLH) 10/22/2018

October 22, 2018 vmcimchiefs Leave a comment

Thank you Charles for presenting this really interesting case. A 18 year old woman with a history of asymptomatic thrombocytopenia who presents with several days of non-specific fever, chills, malaise, mild shortness of breath and she was found to have acute anemia, thrombocytopenia, elevated transaminitis, and patchy bilateral pulmonary infiltrates on CXR during initial presentation. She became acutely ill with submassive hemoptysis and went into respiratory failure in 24-48 hours. She was found to have DAH on BAL. Her autoimmune and infectious work up came back negative, but her ferritin came back at 75776. Base on this and her constellation of symptoms, further work up revealed a 6/8 criteria for diagnosis of hemophagocytic lymphohistiocytosis!

DAH

Presentation

Dyspnea, cough fever, respiratory failure, acute anemia
Hemoptysis only in 2/3 of cases
Definition: Hemoptysis, diffuse alveolar infiltrates, acute anemia, and hypoxemic respiratory failure

Pathophysiology

Widespread damage to pulmonary small vessels, leading to blood within the alveoli eventually causing impaired gas exchange.
Causes: Autoimmune/connective tissue disease leading to pulmonary vasculitis (ANCA, anti-GBM), certain pulmonary infections, toxins, drug reactions, mitral stenosis in some cases
3 distinct histologic subtypes that can give hints to underlying pathology
- Most common: Pulmonary capillaritis: ANCA vasculitis, GPA, EPGA, pauci-immune, Goodpasture, HSP, SLE, RA, APLS, MCTD, Behcet, drug-induced, lung transplant rejection, etc.
  - Systemic vasculitis manifestation
- Bland pulmonary hemorrhage: Coagulopathy, mitral stenosis, toxin/inhalation, SLE, drugs, Goodpasture
  - Anti-GBM, SLE, no inflammation or destruction of capillaries but RBC leakage
- Diffuse alveolar damage: BM transplantation, radiation, ARDS, cytotoxic drugs, other causes

Diagnosis

CXR: Diffuse bilateral alveolar infiltrates, no pathognomonic findings
BAL: serial bloody aspirate with sequential sampling
CT: Non-specific GGO
Biopsy: Tissue biopsy of the lung is definitive in confirmation of DAH but underlying cause might not be revealed.

Management

Treat underlying cause
Respiratory support, most patients die from respiratory failure
High dose corticosteroids, i.e. methylprednisolone up to 500mg Q6H (up to 2g daily)
Other agents: Cyclophosphamide, azathioprine, MTX, mycophenolate, etanercept.
Plasmapheresis for Goodpasture or vasculitidies.
Key: Early identification and treatment

HLH

Epidemiology

Worldwide incidence is unknown, not enough data available, thought to be rare AND underrecognized but growing recognitive leads to higher incidence.
Familial types: more common to occur in pts < 18yo
Secondary HLH: any age

Pathophysiology

Uncontrolled hyperinflammatory response with dysregulated macrophage activity leading to excessive cytokine production
Primary: HLH due to an underlying genetic abnormality or without clear cause
- Autosomal recessive familial HLH
- Idiopathic
Secondary: Due to something else
- Retrospective study at Mayo in 2014:
  - Infection (34%), most commonly EBV
  - Autoimmune (8%), Macrophage activation syndrome (MAS), most often associated with AOSD, systemic juvenile idiopathic arthritis, or SLE.
  - Malignancy (52%) NHL, HL, acute leukemia
  - Idiopathic/Immune deficiency/other (6%)

Presentation

Fever, splenomegaly, cytopenias are most common
+ manifestation of the trigger

Complications: Infection, DIC, bleeding complications (reports of intracranial hemorrhage, GIB, DAH), end organ damage.

Diagnosis: Per the Histiocyte Society: 5/8 criteria for diagnosis. In case you cannot remember all 8, please refer here for the famous HLH Song by Dr. Eric Lau:

1. Fever
2. Splenomegaly
3. Peripheral cytopenia (> 2 cell lines)
4. Hypertriglyceridemia or Hypofibrinogenemia
5. Elevated ferritin > 500 (> 10000 = 90% sensitive and 96% specific for HLH)
6. Low NK cell activity
7. Elevated soluble CD25 (soluble IL2-R)
8. Hemophagocytosis in BM, spleen, or LN: Only seen in later course of the diseases and not required for the diagnosis, neither sensitive nor specific, can be seen in severe sepsis/critical illness)

Management

Like all things in medicine, treat the underlying cause
Current treatment is based on the HLH-94 study on pediatric population
- Induction: 8 weeks dexamethasone and etoposide.
- Maintenance: Cyclosporine, tacrolimus, dex pulses
- If MAS: Steroids alone, usually responsive.
- Hematopoietic stem cell transplant is refractory/relapsing.

For more information on HLH, please refer to this article by Dr. Schram and Dr. Berliner published in Blood (as in the journal) in 2015.

Morning Report

Small cell bladder cancer and hematuria- 10/17/18

October 17, 2018 vmcimchiefs Leave a comment

Thanks to Naina for presenting the case of an elderly man presenting with acute onset of n/v, and abdominal pain, found to have anemia and AKI, with work up revealing small cell cancer of the bladder causing ureteral obstruction with mets to the lymph nodes, liver, lung, and bone, hospitalization complicated by TLS prior to onset of chemo and contrast induced nephropathy.

Clinical Pearls

Bladder cancer is the most common malignancy of the urinary system and urothelial (transitional cell) carcinoma is the culprit >90% of the time. Less common subtypes include squamous, adeno, small cell (our patient), and sarcoma.
Unexplained hematuria in anyone >40 years is bladder cancer until proven otherwise!
CT urography is the diagnostic imaging of choice in the work up of hematuria.
Diagnosis of bladder cancer is often delayed due to similarity of symptoms with other benign disorders. However, majority of cases are still caught in stage 0-1 (muscle non-invasive disease) with overall good prognosis.

Bladder cancers:

Epidemiology
- Most common malignancy of the urinary system, 3-4 x more common in men but women are usually diagnosed with more advanced disease and have a higher mortality rate.
- Median age at diagnosis is ~70
- Incidence has increased by more than 50% during the past 20-30 years.
Types:
- Urothelial (transitional cell) carcinoma is the predominant histologic subtype in the US and Europe (>90% of all bladder cancers) and can arise in renal pelvis, ureter, or urethra
- Other: squamous, adeno, small cell, sarcoma
Degree of invasion:
- Superficial (non-muscle-invasive)
- Muscle-invasive
- Metastatic
Clinical presentation
- Painless hematuria
- Irritative voiding symptoms (frequency, urgency, dysuria) – only in 30% of patients
- Sometimes metastases cause the initial symptoms that lead to diagnosis (as in our patient)
- Most cancers eventually become symptomatic
Diagnosis: often delayed due to similarity of symptoms to other benign d/o
- Urine cytology >98% specific, 12-64% sensitive based on grade of tumor
- Imaging
  - CT favored over IVP
- TURBT done for diagnosis and staging
- DDx
  - Hematuria from enlarged prostate
  - Pregnancy
  - Cystitis
  - Prostatitis
  - Passage of renal calculi

Staging bladder cancer

Source: Nature Outlook.

Management
- Over 50% of people diagnosed with non-invasive disease develop recurrence
- Assess performance status with Karnofsky or Eastern Cooperative Oncology Group scales for older patients before deciding on chemotherapy
- Chemo regimens are often cisplatin-based which carry the side effects of nephrotoxicity, ototoxicity, and neuropathy

treatmetn of bladder cancer

Source: Nature Outlook

Hematuria

Refer to this thorough algorithm on UpToDate.

Incidence of malignancy in microscopic hematuria is ~2-5%
Incidence of malignancy in macroscopic hematuria is ~20%

Extra pearls on onset of hematuria during voiding:

Occurs at the beginning? Urethral source
Discharge noted between voidings or stain on undergarment? Urethral meatus or anterior urethra
Terminal hematuria? Bladder neck or prostatic urethra
Throughout voiding? Anywhere in the GU tract

Morning Report

Lymphocytic hypophysitis – 10/3/18

October 3, 2018 vmcimchiefs 1 Comment

Thanks to Sahar for presenting the interesting case of a middle-aged woman with metastatic melanoma recently started on ipilimumab who presented with a headache and fatigue, found to have hypothyroidism and adrenal insufficiency with work up consistent with hypopituitarism related to an adverse effect of ipilimumab: lymphocytic hypophysitis!

Clinical Pearls

Remember that adrenal insufficiency and hypothyroidism are causes of elevated ADH levels.
Red flags for obtaining head imaging for headache include age >55, sudden onset, positional, onset after trauma or exercise, fever, focal neuro findings, and immunosuppression.
Pituitary adenomas can have three manifestations: mass effect, hormonal hypersecretion, and hypopituitarism. When imaging shows a pituitary mass, your work up should address each of these categories.
The most sensitive test to assess hypothalamic-pituitary access function is LH/FSH!
Immunotherapies are commonly associated with a flare of autoimmune diseases. A more rare side effect of CTLA-4 inhibitors (like ipilimumab) is lymphocytic hypophysitis (inflammation of the pituitary gland)
- This condition commonly presents with headache out of proportion to neurologic findings and preferential decline in ACTH and TSH though other hormones can also be impacted.
For hypopituitarism, remember to always treat adrenal insufficiency first before replacing thyroid hormone. Failure to do so can precipitate adrenal crisis!

Indications for imaging a patient with headache:

Age >55
Sudden onset
Worse with lying down or wakes patient from sleep
Rapid onset after trauma or exercise
Fever
Focal neurologic findings
New headache in immunosuppressed patient

Pituitary adenoma:

Evaluate for the following
- Mass effect: visual field deficit, headache
- Hormonal hypersecretion
  - Prolactin ⇒ galactorrhea, amenorrhea, infertility
  - GH ⇒ Acromegaly
  - TSH ⇒ hyperthyroidism
  - ACTH ⇒ Cushing disease
  - ADH ⇒ SIADH
- Hyposecretion:

Capture

Hypophysitis:

Inflammation of the pituitary
Four categories based on histologic findings:
- Lymphocytic
  - Most common form
  - Seen in late pregnancy and post-partum period
  - Also associated with ipilimumab as our patient here!
- Granulomatous
  - Idiopathic or secondary to GPA, sarcoid, TB
- Plasmacytic (IgG4-related)
- Xanthomatous (most rare)
Clinical presentation
- Headache out of proportion to exam findings
- Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
Prognosis:
- Pituitary size eventually normalizes but pituitary loss of function is often permanent.

Hyponatremia:

Lastly, refer to this algorithm from our recent morning report to help you think through hyponatremia.

Morning Report

Elevated Alk Phos… Only Clue to Breast Cancer 9/20/2018

September 20, 2018 vmcimchiefs Leave a comment

Sarah presented a middle age woman with a history of schizophrenia, HFpEF, possibly COPD, who presented from her Board and Care facility due to inability to ambulate. She was able to provide much of a history but her exam was normal. Her labs were notable for alk phos in the 700-1000 range, and mildly elevated AST/ALT in the 60-70s. An abdominal US revealed hepatic steatosis but really nothing else… Her medical history was also obscure since she receives her care from multiple institutions.

She was incidentally found to have a breast mass on exam, and subsequent work up for her elevated alk phos unfortunately revealed metastatic breast cancer.

Elevated Alk Phos

Background: Alk Phos is derived from mainly bone and liver, higher in men, varies with age (higher in kids, thought to be due to physiologic osteoblastic activity)

GGT (gamma glutamyl transpeptidase): liver specific, can be used to verify if alk phos elevation is due to biliary disease if GGT is also elevated.

Alk Phos

Breast Cancer

Most common tumor in women

Risk

> 50
Personal Hx
Strong family Hx of pre-menopausal breast cancer
Genetic BRCA 1 & 21
Personal hx or ovarian or endometrial cancer
Dense breasts
OCP use for > 15 years
Late menopause

Screening:

Screen F > 50 or < 5-10 yrs prior to age in 1^st degree relative with breast cancer, and then Q2yr
More frequent screening recommended for specific mutations, i.e. BRCA, TP53, then MRI Q year
How about F with breast implants? MRI, CT, or mammogram? The recommendation is still mammogram but with multiple views

Common Scenarios:

Breast

Local disease in situ	No malignancy beyond basement membrane	Lumpectomy + RT, or mastectomy. If ER +, use tamoxifen/aromatase inhibitors
Lobular carcinoma in situ (LCIS)	Isolated to lobule, within basement membrane, not exactly cancer yet but high risk	ER+ use tamoxifen/AI to dec risk of development into invasive breast cancer. NSABP-P1 trial: Pt with LCIS tx with tamoxifen dec risk of invasive breast cancer, but inc risk of endometrial cancer esp in > 50yo
Infiltrating ductal carcinoma, LN negative	Spread beyond BM, need to sample sentinel LN, if negative, no further need for dissection.	Wide excision of mass with free margins + RT, adjuvant chemo for size > 1cm. Tamoxifen/AI if ER +
Infiltrating ductal carcinoma with LN positive	Same as above but LN +, warrants further LN dissection, automatic adjuvant chemo	Wide excision (modified radical mastectomy), RT + adjuvant chemo + Tamoxifen/AI if ER+.
Local invasive dz involving skin or chest wall		Chemo followed by mastectomy, + tamox/AI if ER+

Lymph node positivity is the most important prognostic factor, followed by tumor size, then receptors, and then grade.

For diagnosis, always get excision biopsy for dx, FNA has low sensitivity, hence even if negative, always follow by excisional bx.

Receptors and Management

	ER+	ER-	HERR2+
Pre-menopausal	Chemo + tamoxifen	Chemo	+ trastuzumab
Post-menopausal	Aromatase inhibitors + chemo	Chemo	+ trastuzumab

Tamoxifen: Use for 10 years if ER/PR+. Dec risk of new breast cancer and effective for metastatic dz of receptor positive.

Down side: inc risk of endometrial cancer 3x, inc thromboembolic risk.

Aromatase inhibitors: Watch out for osteoporosis

Morning Report

92% blasts… Fever… AND a rash?! 9/19/2018

September 19, 2018 vmcimchiefs Leave a comment

Narges presented a case of a middle age woman without any prior medical history, presenting with 1 week of bruising, epistaxis, and bleeding from her gums. Her initial lab work was notable for a WBC of 52.2 with 92% blasts, later confirmed to be AML. She developed a fever and a rash over the next few days… She had neutropenic fever, and around the same, time, developed AML-associated Sweet’s Syndrome!

AML: A quick overview

Accounts for 80% of acute leukemias in adults

Risk Factors

Benzene exposure
Radiation exposure, commonly 7-10 years after exposure
Prior tx with alkylating agents and topoisomerase II inhibitors like doxorubicin, etoposide.
Age: greatest risk factor, older = at high risk, median age 65
CML, MDS, and myeloproliferative syndromes have a chance to evolve into AML.

Initial presentation

Bruising, gum bleeding, epistaxis from thrombocytopenia
SOB, DOE, fatigue from anemia
Pyogenic infections of the skin
HSM found in 1/3 of pts
50% might have gingival hyperplasia as first signs of the disease
Small subset might have concurrent HLH on presentation
If fever, almost always infection

Diagnosis

Buzz words: blasts on smears, Auer rods (peroxidase stain)
> 20% blasts cells
Flow cytometry
- CD117, CD33 most common
- CD19, if seen, suggests lymphoblastic origins
Subtypes
- M3 (Acute promyelocytic leukemia), t(15; 17), prone to DIC, responsive to ATRA and potentially can be cured.
  - If pt receiving ATRA +/- Arsenic trioxide develop pulmonary sx think of an entity called Differentiation Syndrome, can be life threatening, stop treatment and give steroids.
- Non APL: Everything else

Management:

Induction, consolidation (after complete remission, assess induction response via BM bx) via HiDAC high dose cytarabine, or autologous CT, or allogeneic HCT, maintenance (usually not needed but can be beneficial in some types of AML)
APL: ATRA +/- ATO
Non-APL: 7 day course of cytarabine and 3 day course of an anthracycline. For older pts with more comorbidities, can use a milder regimen with azacytidine or decitabine.

Neutropenic fever

Definition: T > 38.3 or > 38 sustained over 1 hour, with neutropenia (ANC < 500)

Determine high risk or low risk

Low Risk: Anticipated neutropenia < 7 days, clinically stable, NO medical comorbidities
- IDSA: Can consider outpatient antibiotics, Cipro + Augmentin and able to tolerate PO, otherwise inpatient management
High Risk: Anticipated neutropenia > 7 days, clinically unstable, any medical comorbidities
- Automatically inpatient management
- Monotherapy with pseudomonal coverage initially is recommended by IDSA
  - Cefepime: 2g Q8H, higher dose than usual
  - Meropenem 1g Q8H
  - Imipenem
  - Zosyn 4.5g Q6-8
  - Ceftazidime increasingly avoided.
- If history of MRSA, e/o catheter infection, skin infection, pneumonia, or unstable, add Vancomycin/MRSA coverage
- PCN allergy: Can consider using Aztreonam, cipro
- If recurrent of persistent fever after 4-7 days: Add an empiric antifungal, most of the time cover for candida since it’s the most common cause of invasive fungal infection.
  - Echinocandin is favored i.e. caspofungin, increasing azole resistance in candida.
  - Think aspergillus if e/o pulmonary nodules, ampho B and voriconazole then are preferred

Sweet’s Syndrome

Uncommon, inflammatory disorder, usually affects pts ages 30-60. Older = more likely malignancy associated

Presentation:

Abrupt, painful, edematous (juicy), erythematous papules/plaques/nodules + fever and leukocytosis.
Rare mucosal/oral involvement.
Can also rarely causes inflammation of a particular organ system, i.e eye, liver, heart, CNS, kidney, even bone.

Image adapted from Derm 101

Types

Classic
- Idiopathic, majority of cases
- Associations: Infections (URI, GI) 1-3 weeks after infection
- IBD
- Pregnancy
- HIV, TB, hepatitis, autoimmune conditions
- Possible inc risk of malignancy
Malignancy associated
- AML is the malignancy most associated with Sweet’s Syndrome.
- Risk:
Drug-induced (long list but some of the potential ones we used more commonly are):
- Bactrim, Macrobid, AED, hydralazine, clozapine, PTU, GCSF, Mirena, Lasix, Azathioprine, ATRA

Dx Criteria: both majors and 2 minors are required

Majors
- Abrupt onset of painful erythematous plaques or nodules
- Histopath evidence of dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis
Minor:
- > 38C
- Underlying malignancy, IBD, pregnancy, or recent upper resp, GI infection, or vaccination
- Steroid responsive
- Labs: ESR > 20, CRP elevated, leukocytosis > 8000 with > 70% neutrophils)

Biopsy: Dense, neutrophilic infiltrate in the dermis, w/o e/o vasculitis.

Morning Report

Aplastic Anemia 9/12/2018

September 12, 2018 vmcimchiefs Leave a comment

Today our Doctor-in -Training, Emma, presented a case of a middle age woman with no significant medical or family history coming in with a month of fatigue, menorrhagia, and gum bleeding. She was incidentally found to be pan-cytopenic. Bone marrow biopsy revealed hypocellularity with no abnormal morphologies, which is consistent with aplastic anemia!

Aplastic anemia

Epidemiology
- Rare, 2 per million per year, higher incidence amongst Asians, can occur in all ages but most of the time in the first 1st-4th decades.
Pathophysiology
- Big picture: Think of it this way. Aplastic anemia is similar to a factory not working due to not enough workers (stem cells). Compare and contrast this with MDS, which is basically a loss of quality control (mutation in the stem cells) leading to bad products that get worse over time (leading eventually to pancytopenia, leukemia).
  - Causes
    - Primary (rare), most of the time acquired
    - Infectious: CMV, Parvo, EBV, HIV, hepatitis, TB
    - Toxins: Benzene, glue vapors, solvents, pesticides
    - Autoimmune: SLE, eosinophilic fasciitis, graft v host,
    - Other: Pregnancy, paroxysmal nocturnal hemoglobinuria, thymoma, irradiation
    - Medications: NSAIDS, Bactrim, Lasix, Gold, Allopurinol, penicillamine, phenothiazines, AEDS, anti-psychotics
  - Association
    - PNH: CD55 & CD59 abnormalities can be sen in up to 50% of patients with aplastic anemia!
  - Presentation
    - S/S of anemia
    - S/S of thrombocytopenia (menorrhagia, petechiae)
    - Recurrent infections
  - Diagnosis
    - Bone marrow biopsy most definitive, helps distinguish AA from other causes of pancytopenia
    - BM finding
      - Hypocellular, marrow space mostly fat cells and marrow stroma.
      - Remaining cells are morphologically normal
      - No fibrosis, no e/o malignancy
    - Severe AA criteria
      - BM cellularity < 25 + 2 of ANC < 500, plt < 20k, retic < 20k
    - Very Severe AA criteria
      - ANC < 200
    - Mgx: Severe AA require treatment
      - Under age 20: Early allogeneic HCT as soon as possible. If HCT not possible, immunosuppressives
      - 20 – 50: HCT also recommended if no contraindications, immunosuppressives (Anti-thymocyte globulin, cyclosporine for example) + eltrombopag (thrombopoietin agonist) otherwise.
      - > 50:
        
        Transplantable: Early hematopoietic cell transplantation
        
        Older, not candidates for HCT: Immunosuppressive, less intense preferred as age increases.
      - Treat other underlying/reversible causes in all cases.

Fun Fact: Blood transfusion can lead to falsely elevated iron studies within the first 24-36 hours.

Morning Report

Adrenal insufficiency, lupus flare, and mixed AIHA- 9/6/18

September 6, 2018 vmcimchiefs Leave a comment

Thanks to Becky for presenting the case of a middle-aged woman with h/o SLE and Evans syndrome who presenting with subacute onset of fatigue after her prednisone dose was reduced, found to have iatrogenic adrenal insufficiency, lupus flare, and mixed autoimmune hemolytic anemia!

Clinical Pearls:

Evans syndrome describes AIHA + ITP, a rare condition associated with SLE and often precedes the diagnosis of SLE by a few years.
Hematologic manifestations of SLE are many and include the following
- Anemia (chronic disease, iron deficiency, medication-induced, warm AIHA>>cold AIHA, pure red cell aplasia, MAHA, and pernicious anemia)
- Leukopenia
- Thrombocytopenia
- Pancytopenia
- Evans syndrome
Smear findings can be very helpful in diagnosing different types of hemolytic anemias. Schistocytes are a very specific for MAHA, valve disorders, AVMs, APLS whereas AIHA would result in spherocytes.
- The negative predictive value of spherocytes is low. So a smear without spherocytes does not rule out AIHA!
Lastly, the most common cause of adrenal insufficiency (AI) is iatrogenic.
- General rule of thumb for when risk of AI is high and you should taper steroids slowly is if someone is on prednisone > 20 mg for > 3 weeks. Keep in mind that people with smaller BSA would be more susceptible to AI and at risk with even lower doses.

Hemolytic anemia work up

Check smear

Schistocytes
- MAHA: TTP, HUS, HELLP, DIC, HTN
- Valve disorder
- AVMs
- APLS
No schistocytes (+ spherocytes)
- Intrinsic RBC defect
  - Enzyme deficiency (G6PD)
  - Hemoglobinopathy (sickle cell)
  - Membrane defect (hereditary spherocytosis)
- Extrinsic RBC defect
  - Liver disease
  - Splenic sequestration
  - Infections (clostridium perfringens, babesia, malaria, bartonella)
  - Meds/toxins (dapsone, nitrites, lead, copper, snake venom)
  - AIHA (warm and cold)
- Intravascular
  - Transfusion reaction
  - Infections
  - PNH

Lab findings in AIHA:

↑ retic
↑ indirect bili
↑ LDH
↓ haptoglobin
+ DAT (but keep in mind that DAT can be negative in 3% of patients with WAIHA)
+ spherocytes

Summary of AIHAs:

Morning Report

Suspiciously High Protein Gap… MM? 8/23/18

August 23, 2018 vmcimchiefs Leave a comment

An elderly lady presented to the ED with what seems like orthostatic hypotension… Found to be anemic but otherwise no complaints. Her lab work incidentally revealed anemia, low anion gap, and grossly elevated protein gap (11.3), but otherwise nothing else! What’s going on?

Low Anion Gap:

Definition: Less than 3
Most common cause: Lab error!
Other causes: hypoalbuminemia, severe hyperchloremic metabolic acidosis, lithium intoxication, hyperklameia, hypercalcemia, hypermagnesemia…
Could also be a hint of presence of weird proteins!

Elevated Protein Gap:

Recall: Protein gap = Serum Protein – Serum Albumin, greater than 4 = elevated
Non-specific finding but can be caused by any processes that leads to an increase in non-albumin serum proteins, again could be a hint of presence of weird proteins??

Her peripheral blood smear revealed presence of Rouleaux, which is another hint of elevated levels of serum protein (but we already know that!). Hematology was consulted and the top differential at this point is some sort of gammopathy, with Waldenstrom’s Macroglobulinemia and Multiple Myeloma highest on the possibilities:

	MM	Waldenstrom macroglobulinemia
Presentation	Fatigue, anemia, Bsx, bone pain, rarely has hyperviscosity	Fatigue, anemia, Bsx, neurologic sx (hyperviscosity, more common)
M-protein	IgG, IgM is very very rare	IgM
Bone-marrow	>10% clonal plasma cells, CD56 positive	Lymphoplasmacytic infiltration, CD 19, CD 20 positive. CD56 negative.

SPEP revealed monoclonal IgG spike, and bone marrow revealed > 60% plasmacytosis, hence pt has multiple myeloma!

Do not be tricked! If SPEP revealed polyclonal protein elevation, it could be due to a systemic inflammatory process or infection (Hep C, HIV for instance!)

MM Spectrum

Multiple Myeloma

Diagnosis
- SPEP/UPEP for immune proteins
- Smar: > 50% Rouleaux formation, seen with elevated serum proteins
- BM Bx: Looks at % of plasma cells in the marrow, also can do cytogenetics
- Xrays: Lytic lesions (Bone Survey, not a bone scan)
- Other: Cr, calcium, albumin, beta 2 microglobulin (levels help determine staging with prognostic differences)
- > 60% plasma cells on BM has poor prognosis
- UA picks up albumin, NOT light chains
- Light chain: Normal kappa/Lambda FLC ratio is 0.26 – 1.65, MM would have one that’s grossly elevated
MM Presentation
- Almost all pts will have M-protein spike
- 73% with anemia, 66% with lytic bone lesions, 29% with renal insufficiency.
- Fatigue and normocytic anemia are common findings, blood smear might reveal rouleaux.
- Might cause pancytopenia
MM Types: based on the kind of abnrl protein
- IgG: 55% of the time, followed by IgA (25%), least common is IgM (0.5%). 20% are light chains only, lacking expression of the immunoglobulin heavy chain.
- Cytogenetics determine high risk vs standard risk myeloma
  - High risk = Del 17P, t(14; 16), t(14;20) on FISH
Management:
- Smouldering: Watch
- Active: treat
  - Chemo: 3 drug regimen preferred
    - VRd: Bortezomib, lenalidomide, dexamethasone
    - VCd/CyBorD: Bortezomib, cyclophosphamide, dexamethasone
    - VTd: Bortezomib, thalidomide, dex
  - Hematopoietic cell transplantation (HCT): High dose chemo followed by autologous HCT is standard of care if eligible.
  - US: case by case, but if pt meets one of the following, they are not eligible for transplant:
    - Age > 77
    - Cirrhosis
    - Poor performance status
    - NYHA 3-4

Morning Report

GI Kaposi Sarcoma – 8/20/18

August 20, 2018 vmcimchiefs Leave a comment

Thanks to Wendy for presenting a case of an elderly man with h/o remote renal transplant presenting with chronic progressive DOE, lower extremity edema, and upper and lower GI bleed, found to have AIDS-related GI kaposi sarcoma and associated protein-losing enteropathy!

Clinical Pearls:

Keep a broad differential for patients on immunosuppression
Incidence of KS is higher with CD4 counts <200 but it can be seen in CD4>500 as well.
Prognosis is generally good with treatment. Poorer prognosis is associated with visceral involvement (as opposed to cutaneous), multiple opportunistic infections, and CD4<200
Mainstay of therapy is anti-retrovirals. Chemotherapy can be used for ARV unresponsive disease, significant edema, extensive organ involvement, or IRIS. Studies on chemo + ARV vs ARV alone showed no survival benefit with the former.
Thanks to Dr. Szumowski for the clinical pearl on use of sirolimus in renal transplant recipients with KS (article here).

Differential for odynophagia:

Infectious
- HSV
- CMV
- Fungal
  - Candida ⇒ risk factors include dentures, immunosuppression (AIDS, chemo), radiation to head and neck, recent antibiotics
  - Others: crypto, histo, blasto, aspergillus
- Mycobacteria
Medication-induced
Less common
- Reflux esophagitis
- Crohn’s

Kaposi Sarcoma:

Vascular tumor associated with HHV-8
Four different epidemiologic forms:
1. AIDS-related: most common type in US
  - Higher incidence with CD4 <200 but can be seen with CD4 >500 as well.
2. Endemic/African
3. Organ transplant-associated (higher incidence after solid organ transplant)
4. Classic (indolent cutaneous proliferative disease in older men of Mediterranean or Jewish descent)

KS in the GI tract:

Can occur in the absence of cutaneous disease
Symptoms range from asymptomatic to weight loss, abdominal pain, n/v, UGIB/LGIB, malabsorption, diarrhea
Inflammatory cytokine syndrome:
- Systemic inflammation in AIDS-related KS
- Symptoms:
  - Fever
  - Edema
  - Neuropathy
  - GI/respiratory symptoms
  - Hypoalbuminemia (can occur in the absence of the who syndrome)
    - Secondary to protein losing enteropathy (check stool clearance of alpha-1 antitrypsin)
  - Thrombocytopenia
  - Splenomegaly

Staging of KS:

Extent of tumor (T): limited to skin with minimal oral cavity involvement is good. Visceral involvement has poor prognosis.
Immune status (I): Degree of immunosuppression from HIV. CD4 <200 has worse prognosis
Severity of systemic illness (S): poor prognosis a/w h/o OI, thrush, B symptoms, etc.
Endoscopy and bronchoscopy are only done if initial stool test and CXR are abnormal

Treatment:

Goal: palliation, prevention of disease progression, and shrinkage of tumor to alleviate edema, organ compromise, and psychological distress
Systemic
- Treatment with potent ART
  - IRIS can occur within 3-6 weeks of initiation
- Chemo: for patients with advanced KS and rapid progression
  - Indications
    - >25 lesions
    - Unresponsive to local treatment or ART alone
    - Extensive edema
    - Symptomatic visceral involvement
    - IRIS
  - Agents:
    - Pegylated liposomal doxorubicin or daunorubicin
    - Paclitaxel, bleo, vinblastine, vincristine, etoposide
- Chemo + ART or ART alone? While response rates are higher with the former, no survival benefit
Local symptomatic therapy
- Intralesional chemo (vinblastine)
- Radiation therapy
- Topical alitretinoin

Morning Report

CML, leukocytosis, and leukostasis – 8/14/18

August 14, 2018 vmcimchiefs Leave a comment

Yours truly presented a case of a middle aged man admitted for traumatic rib fracture overnight and found to have a WBC of 368k with cytogenetics consistent with CML!

Clinical Pearls

WBC > 100k is most consistent with leukemia.
WBC up to 75k can be seen with C diff infection.
Leukostasis is most commonly associated with AML > ALL > CML > CLL and defined as hyperleukocytosis with evidence of end-organ damage (CNS, renal, pulm)
- Hematologic emergency!
- Treatment is three-fold:
  - cytoreduction: leukapharesis, hydroxyurea, TKI (especially for CML), induction chemo (with other malignancies)
  - FLUIDS
  - prevention of tumor lysis syndrome (another heme emergency): allopurinol, FLUIDS

Differential for leukocytosis:

Blood Cell Lineage

Neutrophilia (most common, >7000/mm^3)
- Infections
- Stress/trauma
- Chronic inflammation
- Meds
- Leukemias
Lymphocytosis (>4500/mm^3)
- Pertussis
- Syphilis
- Viral infections
- Hypersensitivity reactions
- Leukemias/lymphomas
Monocytosis (>880/mm^3)
Eosinophilia (>500/mm^3):
- Neoplasm
- Adrenal insufficiency
- Asthma/atopy
- Collagen vascular disease
- Parasites

CML:

Refer to this and this prior posts on the blog for all the details!
Some details to highlight
- Smear tends to show lots of immature myeloid cells from many different stages of maturation (some blasts, metamyelocytes, myelocytes, bands, and mature neutrophils)
- If >20% blasts, then think AML

Leukostasis:

Defined as symptomatic hyperleukocytosis and is a hematologic emergency!
Mortality rate is can be as high as 40% within the first week of presentation.
Clinical manifestations of ischemia primarily in CNS, lungs, and kidneys. Can also see limb ischemia and priapism.
Malignancies at highest risk of leukostasis in order of prevalence:
- AML (WBC >50k)
- ALL (WBC >100k, though tends to present with TLS and DIC much more commonly than leukostasis)
- CML (WBC >100k)
- CLL (WBC >400k)
Treatment:
- FLUIDS, lots and lots of fluids
- Cytoreduction: lowers the WBC
  - Leukapharesis: not readily available as it requires a dialysis line and trained nursing staff
  - Hydroxyurea: to lower the WBC
  - Tyrosine kinase inhibitors (especially for CML related leukostasis)
  - Induction chemo (for non-CML related leukostasis)
- Prevent tumor lysis syndrome:
  - FLUIDS
  - Allopurinol
- In hemodynamically stable patients AVOID TRANSFUSION – it’s like adding fuel to the fire and can worsen ischemia.