Keywords
Disseminated malignancy - microangiopathic hemolytic anemia - thrombocytopenia - thrombotic
thrombocytopenic purpura
Introduction
Disseminated malignancy can rarely present with microangiopathic hemolytic anemia
and thrombocytopenia clinically similar to TTP, but does not respond to plasma exchange.
TTP carries a grave prognosis if plasma exchange is delayed. In patients presenting
with microangiopathic hemolytic anemia and thrombocytopenia, if the malignancy is
not clinically apparent plasma exchange may be started thinking as TTP. So, early
recognition of cancer-associated microangiopathic hemolytic anemia with thrombocytopenia
is important to avoid inappropriate plasma exchange and delay in cancer-specific chemotherapy.[1]
Case Reports
Case 1
A 56-year-old man was admitted with high-grade fever, myalgia, and generalized body
ache for 20 days. He was on medications for diabetes since 20 years. He had pallor,
was icteric and had no other signs. His hemoglobin was 6.9 g/dl (normocytic, normochromic),
total white blood cell (WBC) count 6900/μl, platelet count 0.11 × 109/L, erythrocyte sedimentation rate (ESR) 65 mm in 1 h. Peripheral smear showed normocytic
normochromic anemia with evidence of microangiopathic hemolysis and severe thrombocytopenia
[Figure 1]a. His corrected reticulocyte count was 5%, serum lactate dehydrogenase (LDH) 1594
U/L and the direct and indirect Coombs tests were negative. Prothrombin time and partial
thromboplastin time were normal. Urinalysis showed no albuminuria with 6–8 leukocytes/high
power fields. Chest X-ray and electrocardiogram were normal. Biochemical parameters
revealed normal blood sugars, renal function tests, and serum electrolytes. Liver
function tests showed indirect hyperbilirubinemia with normal enzymes. Ultrasonography
of abdomen showed mild prostatomegaly, minimal right pleural effusion, and mild ascites.
He was started on plasma exchange therapy since according to the revised diagnostic
criteria thrombotic thrombocytopenic purpura (TTP) must be considered in the presence
of thrombocytopenia and microangiopathic hemolytic anemia alone. Etiological work
up including dengue, leptospira, Rickettsia, Epstein Barr virus, HIV, hepatitis B
and C serologies, and antinuclear antibody were negative. Test for malarial parasite
was negative and blood cultures did not reveal any growth. Since the platelet count
showed no improvement after few cycles of plasma exchange a bone marrow study was
done which showed metastasis from poorly differentiated adenocarcinoma [Figure 1]b. The workup for primary did not reveal anything, and despite all efforts, he succumbed
to his illness few days later.
Figure 1: (a) Peripheral smear showing microangiopathic hemolysis in case 1 (Leishman
stain, ×100). (b) Bone marrow showing sheets of large tumor cells in case 1 (H and
E, ×40)
Case 2
A 58-year-old housewife was admitted with altered sensorium and yellowish discoloration
of eyes for 10 days. She had infiltrative ductal carcinoma of the right breast treated
with modified radical mastectomy followed by 10 cycles of chemotherapy with docetaxel
and radiotherapy, following which she was on daily tamoxifen. She was known to have
diabetes for 4 years and hypothyroidism for 1 year on thyroxine supplementation. She
was drowsy, had pallor, jaundice, and had no other signs. Her hemoglobin was 7.9 g/dl
(normocytic, normochromic), total WBC count 14,000/μl, platelet count 0.6 × 109/L, ESR 44 mm in 1 h. Peripheral smear showed evidence of microangiopathic hemolysis
and thrombocytopenia [Figure 2]a. Her corrected reticulocyte count was 3%, serum LDH 794 U/L and the direct and
indirect Coombs tests were negative. Prothrombin time and partial thromboplastin time
were normal. Urinalysis showed no albuminuria with 4–6 leukocytes/high power fields.
Urine culture grew E. coli. Chest X-ray and electrocardiogram was normal. Biochemical parameters revealed normal
blood sugars, thyroid, and renal function tests with mild hyponatremia. Liver function
tests showed indirect hyperbilirubinemia with normal enzymes. Computed tomography
of the head was normal. A bone marrow study was done which showed infiltration with
malignant cells [Figure 2]b. Tamoxifen was discontinued and she was given piperacillin and tazobactam for urinary
tract infection. She became conscious few days later but was not willing for further
management and got discharged.
Figure 2: (a) Peripheral smear showing microangiopathic hemolysis in case 2 (Leishman
stain, ×100). (b) Bone marrow showing clusters of atypical cells in case 2 (H and
E, ×10)
Microangiopathic hemolytic anemia can be associated with a variety of diseases including
thrombotic TTP, hemolytic uremic syndrome, disseminated intravascular coagulation
(DIC), preeclampsia, eclampsia, malignant hypertension, drugs and autoimmune disorders.
Clinical, hematologic, biochemical parmeters helps to differentiate between them.
TTP carries very high mortality rate if inappropriately treated.[2] Patients presenting with microangiopathic hemolytic anemia and thrombocytopenia
are likely to suffer from TTP; hence, they are treated with plasma exchange immediately.
Early plasma exchange allows more than 80% of patients with idiopathic TTP to achieve
remission. Rarely, microangiopathic hemolytic anemia and thrombocytopenia can be the
predominant presenting clinical features in patients whose systemic malignancy is
not initially apparent causing diagnostic dilemmas. Hence, clinicians must be aware
that patients with clinically diagnosed TTP may have an occult systemic malignant
disorder.[3]
Patients presenting with microangiopathic hemolytic anemia and thrombocytopenia due
to malignancy often have widely disseminated cancer. Even though treatment success
may be limited, prompt diagnosis is important for appropriate management. The risks
of plasma exchange can be avoided if the malignancy is recognized promptly.
Differentiating acute disseminated cancer from acute TTP using baseline clinical and
laboratory characteristics is challenging.[4] Certain features may suggest the presence of an occult systemic malignancy including;
presenting symptoms of dyspnea, cough, and pain other than abdominal pain.[1] Extremely elevated serum LDH may suggest tumor lysis, even if increased levels are
seen in TTP patients. The presence of many nucleated red cells and immature granulocytes
in the marrow may also suggest metastatic malignancy. Many patients with systemic
malignancy causing microangiopathic hemolytic anemia and thrombocytopenia may have
DIC, but the absence of evidence for DIC does not exclude the possibility of malignancy.
Case 1 did not show any of aforementioned features, and a bone marrow study clinched
the diagnosis. Patients who have a history of malignancy favor the possibility of
disseminated malignancy.[1] One of our patients (case 2) had a history of malignancy which helped us in the
diagnosis and avoiding the risks of plasma exchange. Failure to respond to plasma
exchange in patients with a diagnosis of TTP also favors disseminated malignancy.
Case 1 described above did not show any improvement after few cycles of plasma exchange
which made us think of an occult malignancy.
Even though the optimal therapy for malignancy causing microangiopathic hemolytic
anemia and thrombocytopenia is unknown, immediate initiation of an effective antineoplastic
treatment is of utmost importance. Plasma exchange therapy is the treatment of first
choice for TTP, but its benefit in disseminated malignancy remains highly controversial.[4],[5],[6] We hope the cases described here may help readers to be aware of disseminated malignancy
when evaluating patients presenting with microangiopathic hemolytic anemia and thrombocytopenia.
