Malignant Pleural Effusion And White-Out!

Today we discussed a case of malignant pleural effusion causing complete opacification of a hemithorax. We learned the framework for subacute-chronic dyspnea, discussed the physical exam finding of clubbing, reviewed Light’s Criteria and discussed transudates and exudates. Here is a recap:

Subacute-Chronic Dyspnea DDx:

  • Pulmonary (malignancy falls into all of these categories)
    • Airway
      • bronchitis
      • COPD
      • Asthma
      • Bronchiectasis
      • Foreign body
    • Parenchyma
      • PNA
      • edema
      • atelectasis
      • ILD
    • Vasculature
      • PE
      • pHTN
      • AVMs (HPS can cause these)
    • Pleura
      • Pleural effusion
      • PTX
  • Cardiac
    • Arrhythmia
    • Ischemia
    • Valvular disease
    • Tamponade
    • Constrictive pericarditis
    • Myocarditis
  • Other
    • Anxiety
    • Anemia
    • Reduced PiO2
    • Hypoventilation
    • compensation for metabolic acidosis
    • pregnancy
    • Thyrotoxicosis

DDx for Clubbing:

  • 80% with underlying respiratory disorders
  • 10-15% with miscellaneous disorders
  • Congenital cyanotic heart disease, liver cirrhosis, chronic diarrhea, subacute endocarditis
  • 5-10% hereditary or idiopathic clubbing

Lights Criteria and Pleural Effusions (see this previous blog post for an excellent review)

https://scvmcmed.com/2017/04/17/am-report-32217-pleural-effusion/

DDx For Complete Opacification of a Hemithorax

  • Trachea pulled toward opacified side
    • Pneumonectomy
    • Total lung collapse
    • Pulmonary agenesis
    • Pulmonary hypoplasia
  • Trachea pushed away from the opacified side
    • Pleural effusion
    • Diaphragmatic hernia
    • Large pulmonary mass
  • Trachea remains central in position
  • Consolidation
  • ARDS/pulmonary edema
  • Pleural mass
  • Chest wall mass

SVC Syndrome with Complete Thrombotic Occlusion

This morning we presented a case of SVC syndrome with complete thrombotic occlusion.

SVC 101

  • What is it?
    • Obstruction of blood flow through the SVC
  • What are the three mechanisms by which this can happen?
    • Thrombosis
    • Invasion
    • Extrinsic Pressure
  • How does the body compensate?
    • Collateral veins develop to return blood to the heart

Causes of SVC Syndrome

CausesofSVCSyndrome.PNG

SVC Symptoms

  • Facial and neck swelling
  • Chest pain
  • Respiratory symptoms
  • Neurological manifestations such as head fullness, which may worsen by bending forward or lying own
  • Headaches, confusion, audiovisual disturbances
  • Cerebral edema can be fatal
  • Arm swelling
  • Onset of symptoms depends on whether collaterals had a chance to form

Physical Examination

  • May see distended chest wall veins
  • Pemberton’s sign may be positive
    • initially discovered in the context of a goiter, it can also be useful to identify other causes of SVC obstruction
    • have the patient raise their arms for two minutes and watch for increasing facial plethora (swelling and redness)

Treatment Options

  • Depends on urgency. If emergent, ABCs then straight to endovascular management with pharmacologic thrombolysis/balloon angioplasty/etc +/- stenting
  • If non-emergent, can obtain imaging and biopsy and plan treatment course with chemotherapy or radiation

Lastly, check out Radiopedia! It’s a great learning tool and really fun too.

https://radiopaedia.org/?lang=us

Hemolytic Uremic Syndrome

Today, we talked about the case of a middle aged woman with recent diagnosis of metastatic breast cancer on palliative Paclitaxel who was admitted with acute onset of bloody diarrhea found to have Shiga toxin and progression to HUS!  She developed neurologic manifestations for which she underwent PLEX and is now recovering in rehab.


Clinical Pearls

  • TTP and HUS present very similarly and are difficult to distinguish clinically.  HUS typically has worse renal failure than TTP and rarely has neurologic manifestations.
  • Because they are tough to tease apart, start PLEX early if TTP is on your differential for HUS because TTP has a high mortality rate.
  • Acute diarrhea requires work up in those with severe illness, inflammatory features, risk factors, persistent symptoms, or work in fields that are of public health related concern (food handlers, daycare workers, etc.)
  • The most common cause of acute bloody diarrhea worldwide is shigella.
  • Bloody diarrhea with a normal fecal leukocyte/lactoferrin count is highly suggestive of E. histolytica.
  • Majority of shiga toxin produced in adults is by E coli.
  • Avoid antibiotics if possible in a patient with bloody diarrhea due to shiga toxin as it can precipitate HUS.

Indications for work up of acute diarrhea:

  • Age >65
  • Immunocompromised
  • Significant volume depletion
  • Blood in stool
  • Fever
  • Severe abdominal pain
  • Recent antibiotics
  • Known or suspected IBD
  • Food handler, daycare worker, healthcare worker
  • Recent travel

DDx for acute bloody diarrhea:

  • IBD
  • Ischemic colitis
  • Invasive infections
    • Shigella (most common)
    • EHEC and EIEC (most commonly associated with shiga toxin)
    • Campylobacter
    • Nontyphoidal salmonella
    • Entamoeba histolytica
    • Schistosoma (more common in resource limited settings)

Work up for acute bloody diarrhea:

  • Enteric pathogen panel (NAAT):
    • Campylobacter, salmonella, shigella species, vibrio, yersinia, shiga toxins, norovirus, and rotavirus
  • Stool culture
    • Grows campylobacter, Shigella, Salmonella, and E coli strains. If suspecting other organism, must specifically request that culture from lab
  • Stool leukocytes or lactoferrin
    • More helpful if negative to rule in amebiasis.

Shiga toxin mediated hemolytic uremic syndrome

  • Characterized by the triad of MAHA, thrombocytopenia, and acute renal failure. Rare neurologic manifestations can occur as in our patient.
    • Other clinical symptoms ⇒ bloody stools, absence of fever, WBC>10k, and abdominal pain.
    • 23-47% require hospitalization
  • 6-9% of people infected with EHEC (O157:H7 and O104:H4) can go on to developing HUS and it is much more common in children.
  • Pathophys
    • Ingestion of undercooked beef and E coli
    • Shiga toxin produced by E coli binds to vascular endothelial cell surface, thereby inhibiting protein synthesis, generating lots of cytokines and chemokines, and causing end organ damage and thrombosis.
  • Clinical course
    • HUS develops 5-10 days after onset of diarrhea
    • Up to 50% of patients require dialysis and 39% have long term renal injury.
    • Mortality is 3-5%
  • Treatment:
    • Supportive care is the mainstay
    • Some data from an outbreak in Germany suggests there may be benefit to plasma exchange (PLEX) via removal of shiga toxin and prothrombotic factors from the body
    • Eculizumab ⇒ beneficial in patients with complement-mediated HUS (not shiga-toxin mediated)

TTP: 

  • Main distinguishing features from HUS
    • Renal failure can often be mild
    • Neurologic impairment is more common
    • Mortality rates are much higher
    • Confirmatory test is ADAMTS13
    • Mainstay of treatment is PLEX!

Moral of this story: start PLEX while you’re waiting to decide if it’s HUS or TTP!

Hydralazine-induced ANCA associated vasculitis!

Thanks to Jen for presenting the case of a middle-aged lady with h/o HTN on hydralazine and PE noted to have progressively worsening glomerulonephritis and a discoid skin rash, with anti-MPO and anti-histone antibody positive serologies concerning for drug-induced ANCA associated vasculitis!


Clinical Pearls

  • Many cases of drug-induced lupus are actually drug-induced ANCA vasculitis!
  • Medications associated with drug induced ANCA-vasculitis include hydralazine (most common and most severe presentation), followed by methimazole/PTU, and minocycline.
  • Drug-induced vasculitis tends to present with anti-histone antibody positivity (sensitive but less specific).  Drug-induced ANCA vasculitis can be anti-MPO positive especially in the case of hydralazine.
  • Treatment involves witholding the offending agent.  In the case of hydralazine induced ANCA-vasculitis, steroids and additional immunosuppressive therapy (cytoxan or rituxan) are also indicated to reduce progression to ESRD.

Eosinophilia

  • Severity:
    • >500 eos ⇒ eosinophilia
    • > 1500 eos ⇒ severe eosinophilia
    • > 5000 eos ⇒ severe eosinophilia at risk of end organ damage
  • Etiology (NAACP-P)
    • Neoplasms
      • Monoclonal leukemias (eosinophil proliferation)
      • Polyclonal: T cell lymphomas, Hodgkin lymphoma, some solid organ tumors (cervical, ovarian, gastric, colon, urotherlial, and squamous cell carcinomas)
    • Allergies
    • Adrenal insufficiency (super rare)
    • CTD
      • EGPA, RA
    • Parasites/bugs
      • Parasites: remember that only multicellular parasites can cause eosiniphilia
      • Other bugs: ABPA, cocci, HIV
    • Primary eosinophilic syndromes

Drug-induced lupus:

  • M:F is 1:1 but hydralazine induced lupus is more common in women
  • Mechanism is poorly understood and genetic predisposition may play a role. More likely to happen in patients who are slow acetylators
  • Autoantibodies:
    • Anti-histone antibodies: 95% sensitive
    • Other antibodies are uncommon
  • Drugs: long list!
    • Procainamide, hydralazine, chlorpromazine, quinidine, minocycline, PTU, statins, anti-TNF agents, IFN, methyldopa
    • Weaker associations: AEDs, antimicrobials, beta blockers, lithium, HCTZ, amiodarone, cipro etc.
  • Treatment:
    • Stop offending agent
    • Joint symptoms: NSAIDs
    • Skin symptoms: topical steroids
    • Hydral-induced vasculitis: need cytotoxic or other immunosuppressive therapy. Treatment similar to ANCA positive vasculitis
  • Prognosis:
    • Resolution of symptoms weeks to months

Drug induced ANCA positive vasculitis:

  • Patients typically present with constitutional symptoms, arthralgias/arthritis, and cutaneous vasculitis
  • Strongest association with hyperthyroidism meds, hydralazine, and minocycline (hydral is the most common)
  • Rare, but should be aware of this association because it impacts management and because it is often not diagnosed until too late in the disease course.  In fact, many cases of drug induced lupus are actually drug induced ANCA-associated vasculitis
  • In a small case series of hydral-induced ANCA-associated vasculitis of 10 patients, 90% had renal involvement of whom 7 recovered at 6 month follow up (though one required HD).
    • Hydralazine-induced ANCA vasculitis is generally p-ANCA pattern with anti-MPO positivity (might also have anti-lactoferrin or anti-elastase)
    • Treatment involves immunosuppression with steroids and cytoxan or rituxan.
  • Non-hydralazine drug-induced ANCA vasculitis is typically treated with stopping the offending agent and has a better prognosis than its hydralazine-induced counterpart. In fact, ANCA positivity without clinical vasculitis is common especially in cases involving PTU.

Hepatocellular Carcinoma 5/6/2019

Katie presented an elderly man presenting with few weeks of unintentional 40lbs weight loss and abdominal pain, found to be jaundiced on exam with notable hepatomegaly. Labs notable for mild hepatitis and mix conjugated and unconjugated hyperbilirubinemia with mild coagulopathy. He was ultimately diagnosed with cirrhosis and extremely likely HCC with “numerous” masses of varying size (largest one was 10 cm) with portal vein invasion.


Please refer to this previous post on etiology of hyperbilirubinemia.

Please refer to this other post on hepatitis serologies made ridiculously simple.


Hepatomegaly and jaundice: Think infiltrative/malignant process!

For patients with cirrhosis and abdominal distension, palpating and percussing the liver can be challenging.

A strategy we went over during the last physical exam round was the scratch test, which relies on the principle of the different of sound transmission through materials of various densities.

To perform the scratch test, place your stethoscope over the RUQ just above the costal margin or just below the xiphoid, and from the RLQ, lightly scratch the patient horizontally and then slowly move superiorly toward the costal margins until the sound intensities. The location of sound intensification marks the inferior edge of the liver.

Small study re: accuracy of using the scratch test.


Hepatocellular Carcinoma

Epidemiology

  • Most of the time a complication from liver cirrhosis
  • Risk Factors
    • Cirrhosis, any etiology
    • Chronic HBV even without cirrhosis (oncogenic virus)
    • HCV with cirrhosis
    • Fungal aflatoxins
  • Higher prevalence in East and SE Asia + Sub-Saharan African nations
  • HBV inc risk by 100x

Presentation

  • Variable initial presentation
    • Asx
    • Decompensated cirrhosis
    • Jaundice, abd pain, B-sx, +/- palpable pass
    • Variceal hemorrhage
    • Tumor rupture leading to acute hemorrhagic shock
    • Obstructive jaundice due to biliary tree invasion
    • 10-15% with metastatic dz at time of dx.
      • Most common sites: Lung, lymph nodes, adrenal glands.
    • Paraneoplasic: Hypoglycemia (adv HCC), erythrocytosis, hypercalcemia, diarrhea

Diagnosis

  • Imaging: Sensitivity generally dec with small lesions, but imaging alone to establish dx of HCC without a biopsy in certain patient populations.
    • Contrast enhanced CT (triphasic)
      • Arterial phase hyperenhancement: Characteristic of HCC lesions but not specific, can be small hemangiomas, focal nodular hyperplasia, atypical focal fibrosis, non-HCC malignancy
      • Venous phase Washout: Again characteristic of HCC but not specific, cirrhosis nodules can be similar.
      • Capsular appearance: Pretty specific for HCC
      • All 3 of the above = diagnostic of HCC, very specific not but as sensitive.
      • Highest PPV for pts with cirrhosis with lesions > 2cm
    • MRI
      • Contraindicated in GFR < 30, Nephrogenic systemic fibrosis
      • More sensitive than CT, ~ specificity,
    • US: Can be use as diagnosis but cannot evaluate disease burden, transplant candidacy, operator dependent. 90% sensitive and 97% specifc
    • LIRADS
      • Should only be applied to pts with cirrhosis, chronic HBV, lesions identified on surveillance US for HCC, current or prior dx of HCC.
      • Should NOT be applied to: no risk factors for HCC, < 18, cirrhosis secondary to congenital hepatic fibrosis or vascular etiology.
    • LIRADS definitions for hepatocellular carcinoma based on ACR v2017:
      • LR-1: Definitely benign
      • LR-2: Probably benign
      • LR-3: Intermediate probability for HCC
      • LR-4: Probably HCC
      • LR-5 – Definitely HCC
      • LR-5V: Definitely HCC with tumor in vein
      • LR-M: Probably malignancy, not specific for HCC
      • LR-TR Viable: Treated, probably or definitely viable HCC
      • LT-TR Nonviable: Treated, probably or definitely not viable
      • LR-TR Equivocal: Treated, equivocally viable
      • LR-TR Nonevaluable: TReated, response not evaluable
  • Labs
    • Alpha-fetoprotein: Elevated in 40-65% of patients with HCC
      • Normally produced during gestation, not during adulthood.
      • Levels do not correlate well with degree of disease
      • Sensitivity: 60%, spec: 80%, not good as a screening tool.
      • Higher levels > 400 are very specific for HCC.
      • May be seen in chronic liver disease so not very sensitive.
      • Elevated levels are associated with advanced fibrosis, pregnancy
  • Biopsy: Reserved for indeterminate nodules that do not meet radiologic criteria for HCC.
    • Not recommended for LR1, LR2, LR3, or LR5 lesions
    • Risk: spread of tumor along needle track, sampling error (false negative), usual surgical risk (bleeding, infection, etc)
  • Staging:
    • TNM
    • Barcelona Clinic Liver Cancer staging system

Management

  • Surveillance for at risk patients:
    • Cirrhosis or HBV: Q6mo liver US
  • Resection
    • Preferred therapy for localized disease
    • Sufficient liver reserve, can’t be worse than Child Pugh A cirrhosis
    • 5 year survival rate as high as 90%
    • Stage IIIB, IVA, and IVB are incurable by resection (any invasion of a major portal or hepatic vein, other organs, visceral peritoneum, nodal mets)
  • Antiviral
    • Recommended for those with active viral infection and HBV related HCC.
  • Liver transplantation
    • Milan criteria widely accepted, to be considered a candidate for transplant, pt must meet all criteria
      • Solitary tumor < 5cm or up to 3 tumors all < 3cm
      • No evidence of regional nodal or distant mets
      • No evidence of vascular invasion
  • Ablation
    • Radiofrequency or microwave or localized ethanol/acetic acid/cryo localized ablation
    • Best outcomes for tumor size < 4 cm
    • Cirrhosis: Restricted to Child Class A or B
    • Can be used to bridge to liver transplant
  • TACE
    • Disruption of HCC supply, usually derived from the hepatic artery
    • Leads to tumor necrosis from ischemia.
    • Usually used for tx of large unresectable HCC not amenable to other tx i.e. resection or RFA.
    • Best candidates: No vascular invasion or extrahepatic spread, Child Puph A or B
    • Relative contraindication:
      • bili > 2
      • LDH > 425
      • AST > 100
      • Tumor > 50% of liver
      • Untreated EV
      • Significant medical comorbidities
  • Radiation
    • Localized external radiation vs radioembolization, HCC is radiation sensitive.
  • Systemic chemo
    • Sorafenib
      • SHARP trial, prolongs survival over supportive care in pts with adv HCC)
      • Might be more beneficial for HCC related to viral etiology
    • Other agents: Regorafenib, Lenvatinib
    • Complication during tx
      • Reactivation of viral hepatitis

Prognosis

  • 10-20% of cases are curable (resectable disease)
  • 5-yr survival rates of about 5% or less if beyond stage III (portal vein invasion)
  • Some evidence that sorafenib improves survival by around 3 months but it is a costly medication (60 tablets can cost up to $9000 after discount!)

Hypercalcemia of malignancy

Thanks to John for presenting the case of a middle-aged woman with metastatic renal cell carcinoma who presented with subacute diffuse weakness and constipation, found to have symptomatic hypercalcemia, treated with IV fluids and zoledronic acid.


Clinical Pearls

  • A third of patients with malignancy develop hypercalcemia in their disease course.  Hypercalcemia of malignancy is associated with very poor prognosis (~50% 30 day mortality).
  • Constipation plus polyuria is the most specific symptom combination for hypercalcemia
  • Denosumab is superior to zoledronic acid in treating hypercalcemia of malignancy and is safe to use in renal failure.
  • One way to quickly determine the etiology of hypercalcemia from your chemistry panel is to look at the chloride to phosphate ratio.  A ratio > 33 is highly suggestive of a PTH or PTHrP mediated process.

Hypercalcemia ddx:

Hypercalcemia algorithm

** Primary hyperPTH is the most common cause of hypercalcemia in the outpatient setting.  Malignancy is the most common cause of hypercalcemia in the inpatient setting.

Treatment of hypercalcemia:

Ca <12

  • No treatment if asymptomatic
  • Avoid exacerbating factors

Ca 12-14

  • If chronic/asymptomatic ⇒ same tx as Ca <12
  • If acute/symptomatic ⇒ same tx as Ca 14-18

Ca 14-18

  • IVF – lots!
  • Lasix only if concurrent renal/heart failure
  • Calcitonin
  • Bisphosphonate (zoledronic acid >>pamidronate if malignancy. Denosumab if refractory to ZA or severe renal impairment)

Ca >18

  • Above PLUS
  • Hemodialysis

Hypercalcemia treatment chart

Leukostasis

Thanks to Grace for presenting the case of a middle aged man who presented with chronic weight loss, acute SOB, and splenomegaly on exam, found to have a WBC of 188 on work up and chest imaging concerning for leukostasis.


Clinical Pearls

  • Most common cause of splenomegaly is portal HTN.  But the ddx is broad (see schema below).
  • Most common cause of a WBC 25k-75k is infection (C diff)
  • WBC >100k is leukemia until proven otherwise.
  • Leukostasis is symptomatic hyperleukocytosis, most commonly associated with AML.
  • Management involves lowering the WBC by leukapharesis, hydrea, and TKIs (if CML) and preventing TLS.

Splenomegaly DDx

  • ↑ Water: portal HTN (most common cause)
  • ↑ Cells:
    • RBCs
      • Hemolysis ⇒ Thalassemias, hereditary spherocytosis, malaria, babesia
    • WBCs
      • Infection
        • Mono ⇒ EBV, CMV, HIV
        • Tick-borne ⇒ Rickettsia, anaplasmosis, ehrlichiosis
        • Granuloma ⇒ TB, histo, leishmaniasis
      • Autoimmune
        • Sarcoid
        • Still’s
        • Felty
      • Lymphoma
      • Myeloproliferative d/o
        • Polycythemia vera
        • Essential thrombocythemia
        • CML
  • ↑ Molecules:
    • Amyloidosis
    • Other (lysosomal and glycogen storage diseases)

Leukostasis:

  • Defined as symptomatic hyperleukocytosis and is a hematologic emergency!
  • Mortality rate can be as high as 40% within the first week of presentation.
  • Clinical manifestations of ischemia primarily in CNS, MI, 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), generally if in myeloid blast crisis
    • 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
      • Uric acid lowering therapy
    • In hemodynamically stable patients AVOID TRANSFUSION – it’s like adding fuel to the fire and can worsen ischemia. Platelet transfusion is less dangerous than RBCs and you may have to do it before trialysis line placement.

TLS:

  • ↑K, ↑Phos, ↑uric acid, ↑creatinine, ↓calcium
  • Occurs in bulky or chemosensitive tumors with high proliferative rate (Burkitt’s lymphoma, acute leukemias, small cell lung cancer)
  • Allopurinol takes 1-2 days to show effect and does not reduce preexisting elevated uric acid levels so use rasburicase if uric acid already high or preemptively if TLS risk is high or if there is kidney injury.
  • HD if concern for renal damage

Causes of pseudohyperkalemia

  • Technique of blood drawing (tourniquets and fist pumping)
  • Thrombocytosis
  • Leukocytosis (>120k)