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

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

Lymphocytic hypophysitis – 10/3/18

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.

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

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 1st 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

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

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.

Sweet.jpgImage 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.

Aplastic Anemia 9/12/2018

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).Capture
      • 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.

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

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 anemiasSchistocytes 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:

Picture1

 

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

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