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It’s difcult and challenging to recognize patients affected with THC2. Since
thrombocytopenia is usually asymptomatic, the low platelet count is frequently discovered only in adulthood. For this reason, physicians often do not suspect the
genetic origin of thrombocytopenia in patients with THC2. It has been previously
reported that this disorder may be misdiagnosed as immune thrombocytopenia
(ITP) and treated unnecessarily with immunosuppression or splenectomy [2, 4].
Here, we describe two unrelated cases of THC2 who were misdiagnosed with MDS
and treated with several courses of 5-azacytidine.
M. Mohammed
Clinical Case Presentation
Case 1
A 61-year-old man was referred in March 2016 for investigation of MDS presenting
with isolated thrombocytopenia. He had unremarkable medical history until the age
of 56 (March 2011) when thrombocytopenia came to attention upon blood examination performed for supercial phlebitis of the left leg. His platelet count was
25×109L−1 at that time, whereas his white blood cell (WBC) count and hemoglobin levels were normal.
At another medical center, the patient was diagnosed with ITP and treated
with prednisone and afterward with prednisone plus danazol for approximately
1year, without any improvement of his platelet count. In June 2013, the patient
underwent hematologic re-evaluation, and his platelet count was even lower at
20×109/L, his hemoglobin was normal, and his WBC count was at the upper
limit of normal. On account of the poor response to treatment, bone marrow aspirate and biopsy were performed and showed an increased number of megakaryocytes with prominent dysmegakaryopoiesis (plenty of small, underdeveloped,
hypolobulated megakaryocytes with typical micro-megakaryocytes) with no
other relevant changes. Cytomorphological analysis of bone marrow aspirate
showed that blast cells were 4%, and immunohistochemistry on bone marrow
biopsy identied 2% CD34+ blast cells. Bone marrow cytogenetics was unremarkable. Based on these ndings, a diagnosis of MDS, type refractory cytopenia with unilineage dysplasia (refractory thrombocytopenia), according to the
WHO 2008 classication of myeloid neoplasms [6], was made. Consequently,
the patient was treated with 12 courses of 5-azacytidine without any improvement. In December 2015, a follow-up bone marrow examination showed no
changes with respect to baseline.
In 2016, the patient’s platelet count was 20×109L−1 with no other abnormalities
of blood cell counts. He reported no symptoms and his physical examination was
unremarkable. Analysis of peripheral blood smears revealed no cytomorphological
abnormalities, except for a moderate reduction of platelet azurophilic granules.
40 Inherited Thrombocytopenia Misdiagnosed asMyelodysplastic Syndrome
285
Bone marrow examination conrmed dysmegakaryopoiesis without other signicant abnormalities. The family history revealed that both the patient’s brother and
father had chronic thrombocytopenia that had never come to medical attention
because it was asymptomatic. Therefore, a diagnostic workup for inherited thrombocytopenia (IT) was started [7]. Considering the picture of autosomal dominant,
non-syndromic thrombocytopenia with normal platelet size, the disorders caused by
mutations in ANKRD26, ETV6, RUNX1, or CYCS are considered7. A screening for
ANKRD26 was done rst because of the highest incidence of THC2 among these
conditions. Mutational analysis identied heterozygous substitution in the 5′UTR
of ANKRD26 [1], which segregated within the family, leading to the diagnosis of
THC2in the three affected individuals. All of them have stable isolated and asymptomatic thrombocytopenia and no peripheral cytomorphological abnormalities after
a 15-month follow-up.
Case 2
A 65-year-old man was admitted for acute pneumonia and hemoptysis in
November 2016. Blood cell count revealed low platelet count at 14×109L−1,
mild leukocytosis (WBCs 13.3×109L−1) with neutrophilia, and normal hemoglobin level. Blood smears showed normal platelet size, mildly reduced content
in platelet granules, and normal morphology of erythrocytes and leukocytes.
Past medical history was signicant for lung emphysema, and thrombocytopenia was discovered when he was in his 50s. In 2010 and at another institution, a
hematologic workup including bone marrow aspirate and biopsy showed an
increased number of megakaryocytes and dysmegakaryopoiesis (small, hypolobulated megakaryocytes and micro- megakaryocytes) without other relevant
changes. Blast cells were 3%. On this basis, a diagnosis of MDS was made and
therefore chemotherapy treatment was started. After eight courses of azacytidine, re-evaluation showed no hematological response, and chemotherapy was
discontinued. The patient didn’t develop any bleeding symptoms before or after
chemotherapy treatment. In 2014, a follow-up bone marrow aspirate and biopsy
were performed and demonstrated the same changes. Upon admission for pneumonia in 2016, the patient was rst considered as having ITP and hence treated
with intravenous immunoglobulins and prednisolone, in addition to antibiotic
and antifungal treatment, without any increase in platelet count. But shortly
after that, family history revealed that three of his six children and two of his six
siblings had thrombocytopenia. Consequently, a diagnostic workup for inherited thrombocytopenia (IT) was started. The non-syndromic thrombocytopenia
with normal platelet size and the dominant inheritance strongly suggested mutation of the ANKRD26 gene. Screening for the 5′UTR of ANKRD26 identied a
heterozygous substitution. This variant is segregated with thrombocytopenia
286
within the patient’s family. After the pneumonia is resolved, the patient is
asymptomatic with platelet count at 30–40 ×109/L with no other blood count or
cytomorphological abnormalities.
M. Mohammed
Differential Diagnosis
1. Myelodysplastic syndrome
2. Immune thrombocytopenic purpura
What WasMisdiagnosed inThis Case andWhy?
Myelodysplastic Syndrome
In both cases, patients developed thrombocytopenia and a prominent picture of
dysmegakaryopoiesis (small, hypolobulated megakaryocytes and micromegakaryocytes) upon bone marrow examination without further alterations.
Consequently, a diagnosis of MDS was made and the patients received needless
chemotherapy treatment.
Discussion
Although thrombocytopenia 2 is rare, it’s one of the most prevalent forms of IT: in
a series of 274 consecutive pedigrees with familial thrombocytopenia, THC2
accounts for 17% of the cases with a denite molecular diagnosis [8]. This disorder
is underdiagnosed like other forms of IT. Low platelet count frequently comes to
attention only in adulthood since patients with THC2 have no or mild bleeding tendency in addition to the normal size of platelets [9]. These features often lead to
overlooking the genetic origin of the disorder. Therefore, patients with THC2
(including these two cases described here) are often misdiagnosed as having ITP
and receive unnecessary immunosuppressive treatments, including splenectomy
[1]. Misdiagnosis as ITP is rather frequent also in other forms of inherited thrombocytopenia with mild bleeding tendency [10]. The two cases described here demonstrate that THC2 patients can be misdiagnosed with MDS as well and hence can be
subjected to undue myelosuppressive treatments. In both cases, the feature leading
to misdiagnosis was the nding of prominent dysmegakaryopoiesis upon bone marrow examination, which is a constant nding in all THC2 patients and appears to be
very similar to that present in MDS.Moreover, dysmegakaryopoiesis with similar
features has been reported also in other forms of inherited thrombocytopenia,
including those caused by mutations in ETV6, RUNX1, and FLI1 [11–14]. Therefore,
patients with these disorders also are at risk of being misdiagnosed as having MDS.
40 Inherited Thrombocytopenia Misdiagnosed asMyelodysplastic Syndrome
287
Plan of Action, the Points Clinician Should Consider, Pitfalls to Avoid, and Pearls of Knowledge to Consider
Inherited thrombocytopenias are rare disorders. However, recent observations
revealed that MDS presenting with isolated thrombocytopenia and bone marrow
dysplasia limited to the megakaryocyte lineage (refractory thrombocytopenia
according to the WHO 2008 classication) is very rare too. For example, a multicenter study of 1145 patients with MDS and unilineage cytopenias found only 1
patient presenting the criteria for refractory thrombocytopenia [15], and Marinier
etal. identied 6 cases of refractory thrombocytopenia in a single-center series of
293 consecutive MDS patients [16]. Therefore, when dysmegakaryopoiesis is demonstrated in a patient with isolated thrombocytopenia, MDS should not be considered the most likely diagnosis. In contrast, inherited thrombocytopenia should be
regarded as the most likely diagnosis.
If Misdiagnosed, WasIt Realized Later? How WasIt
Rectied? Were There Any Legal Ramications?
Yes, it was realized later because of two factors:
1. Failure of treatment:
The rst patient was misdiagnosed as having MDS and received 12 courses of
5-azacytidine with no improvement.
The second patient was misdiagnosed rst as having MDS and hence also
received chemotherapy treatment (azacytidine) without any improvement.
Subsequently, he was diagnosed with ITP and treated with intravenous immunoglobulins and prednisolone, but no hematological response was detected.
2. Family history:
In both cases, collection of family history revealed that family members had
thrombocytopenia. Following that, a diagnostic workup for IT was started and
mutation of ANKRD26 gene was identied.
Conclusion
The clinical picture of thrombocytopenia 2in addition to other forms of ITs can be
very similar to that of MDS.Whenever a patient presents with isolated thrombocytopenia and bone marrow examination shows only dysmegakaryopoiesis, inherited
thrombocytopenia should always be thought of regardless of the patient’s age at
presentation. Systematic collection of family history is very important and is a costeffective tool to avoid misdiagnosis with MDS, ITP, or other causes of
288
M. Mohammed
thrombocytopenia. The correct diagnosis of patients with inherited thrombocytopenia is crucial to avoid undue treatment with steroids and potentially harmful chemotherapy and also essential for them to receive the proper management and
counseling.
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Landolt-Marticorena C, Hunger S, Heller P, etal. Germline mutations in ETV6 are associated
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14. Poggi M, Canault M, Favier M, Turro E, Saultier P, Ghalloussi D, Baccini V, Vidal L,
Mezzapesa A, Chelghoum N, Mohand-Oumoussa B, Falaise C, Favier R, Ouwehand WH,
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Part VIII
Infectious Diseases
Chapter 41
Hematogenous Disseminated Tuberculosis
Misdiagnosed asMetastatic Lung Cancer
AkhilAnsary
Learning Objectives
By the end of this case report and discussion, the clinician will be able to:
1. Create an appropriate differential diagnosis in patients presenting with the symptomatology suspect for hematogenous disseminated tuberculosis by considering
all relevant details of the medical history together with the physical examination
of the patient.
2. Evaluate the different components of medical history and physical examination
needed to reach a denitive diagnosis.
3. Analyze the characteristics of hematogenous disseminated tuberculosis and differentiate it from metastatic lung cancer.
4. Apply the correct initial diagnostic and conrmatory test to prevent misdiagnosis of hematogenous disseminated tuberculosis and also to emphasize the value
of biopsy and 18F-FDG-PET in distinguishing TB and cancer.
5. Discuss and analyze the consequences of a misdiagnosis or delay in reaching a
correct diagnosis for the individual patient prognosis, tuberculosis transmission,
and public health.
6. Recognize a probable hematogenous disseminated tuberculosis the moment the
patient presents through a complete medical history and appropriate physical
examination, choose the correct tuberculosis diagnostic tools, and interpret the
tests correctly, especially in the light of true or false test results.
A. Ansary (*)
St. Martinus University Faculty of Medicine, Willemstad, Curacao
e-mail: akhil.ansary@martinus.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_41
293
294
A. Ansary
Introduction
Tuberculosis (TB) is recognized as a diagnostic chameleon that can mimic cancer.
TB can cause pulmonary inltrates and mediastinal lymphadenopathy in the thorax
[1]. Every year, over ten million people get tuberculosis worldwide. According to the
World Health Organization (WHO), Mycobacterium tuberculosis is present in around
a quarter of the world’s population [2, 3]. Despite well-documented and widely pub-
licized techniques of prevention and cure, tuberculosis remains a global problem [4,
5]. Lung cancer is the leading cause of death among males worldwide [6]. The chal-
lenge of proper tuberculosis and malignancy diagnosis has been exacerbated by a
constant increase in admissions to tuberculosis hospitals of malignant diseases associated with or imitating tuberculosis. Both disorders share the same symptoms and
characteristics. This complicates the diagnosis. Lung cancer patients who wait longer
to be diagnosed and treated have a worse prognosis and survival rate [7].
Clinical Case Presentation
A 73-year-old man was admitted to the hospital after suffering 2 months of chest
pain, low-grade fever, asthenia, anorexia, and weight loss. The patient has a medical
history of type 2 diabetes, for which he is being treated with gliclazide regularly.
The body temperature was 36.7° C, the pulse rate was 96 beats per minute, the
blood pressure was 133/83mmHg, the respiratory rate was 20 breaths per minute,
the oxygen saturation was 96%, and the skin and sclera were yellow. The respiratory, cardiovascular, neurological, and abdominal systems were all normal. Anemia
(hemoglobin 114g/L), abnormal liver function (alanine aminotransferase 57U/L,
aspartate aminotransferase 48U/L, glutamyl transpeptidase 818U/L, alkaline phosphatase 671 U/L, total bilirubin 44 mol/L), and elevated cancer antigen 19-9
(CA19-9, 165U/ml) were discovered during the examination. The interferon release
assay resulted in a negative result. Lacunar infarction in the bilateral basal ganglia
was found on computed tomography (CT) skull scan. On a thorax CT scan, multiple
rounds or round-like nodules of varying sizes were found across both lungs, indicating metastatic lung disease. The pancreatic head had a tumor. The pancreatic duct
and intrahepatic bile duct showed dilation on abdominal enhanced CT.The testing
results strongly suggested lung metastases originating from the pancreatic head or
the intestine. However, TB infection could not be completely ruled out. The patient
declined a second biopsy and instead elected to try rifampin and isoniazid as an
experimental anti-TB treatment. A month later, a chest CT revealed that the lung
lesions had not been absorbed. CA19-9 levels in the blood grew dramatically, reaching 1167 U/ml in a lab test. A sputum smear showed negative acid-fast bacilli
(AFB). The doctor ruled out tuberculosis and suggested gastrointestinal malignant
tumors with lung metastasis. After 3 months, his daughter convinced the patient to
have a second opinion. Hyperbilirubinemia (total bilirubin 70mol/L) and CA19-9
41 Hematogenous Disseminated Tuberculosis Misdiagnosed asMetastatic Lung Cancer
295
of 832 U/ml, cancer antigen 125 141 U/ml, neuron-specic enolase 22.98ng/ml,
angiotensin-converting enzyme 178U/L, and serum (1,3)—D-glucan 235 pg/ml
were all discovered in the laboratory. The lung, liver, pancreas, spleen, and gallbladder neck showed a high uptake on 18F-uorodeoxyglucose positron-emission
tomography (18F-FDG-PET) scans, indicating benign illness. The patient agreed to
undergo endoscopic retrograde cholangiopancreatography to treat hyperbilirubinemia induced by bile duct obstruction. A biopsy of a brushed biliary cell revealed no
malignant growth. The lump in the left upper lobe was biopsied using a CT scanguided transthoracic needle biopsy, and the histology revealed coagulative necrosis
with granulomatous inammation. Periodic acid-Schiff staining was negative,
whereas AFB staining was positive. Meanwhile, qPCR for MTB DNA in the sputum revealed 4900 copies per milliliter. As a result, the diagnosis of tuberculosis
infection was conrmed. The patient then agreed to a 3-month course of isoniazid
(300mg/QD), rifampicin (450 mg/QD), ethambutol (750 mg/QD), pyrazinamide
(1500mg/QD), and levooxacin (600mg/QD), followed by 9 months of isoniazid
(300 mg/QD) and rifampicin (450 mg/QD). The thorax CT 4 months following
admission to our hospital demonstrated that the lung lesions were signicantly
absorbed. After a year of treatment, the patient discontinued the medications due to
continued clinical and radiological improvement. At the 6-month follow-up after
discontinuation, the patient was symptom-free.
Differential Diagnosis
1. Pulmonary tuberculosis
Mycobacterium tuberculosis is the infectious species that causes pulmonary
tuberculosis (TB) . M. tuberculosis frequently goes dormant in people before
becoming active TB.Although TB most frequently affects the lungs and is contagious in this form, it can also affect nearly any organ system, including the
lymph nodes, central nervous system, liver, bones, genitourinary tract, and gastrointestinal tract.
2. Gastrointestinal cancer metastasis to the lung
The greatest cause of death for both men and women globally is lung cancer.
The majority of lung cancer cases are discovered late in the disease. It could be
challenging to differentiate between intrapulmonary metastases and pulmonary
tuberculosis (especially when the tumor histologies are similar). The common
clinical appearance of lung cancer makes it possible to mistake it for tuberculosis.
3. Miliary tuberculosis
Miliary tuberculosis (TB) is characterized by microscopic tubercles visible
on gross pathology that resemble millet seeds in size and shape. Miliary TB
results from a large lymphohematogenous spread of Mycobacterium tuberculo-
sis bacilli. Miliary TB can present with a wide range of nonspecic clinical
symptoms. The diagnosis is frequently delayed by an unusual clinical presentation. Miliary TB is frequently misdiagnosed as widespread metastasizing cancer.