Pleural effusion in hematological pathology
How to cite this article: Yerrapotu N, Rahman A, Gabali A, Shidham VB. Unusual presentation of chronic myelomonocytic leukemia as pleural effusion. CytoJournal 2021;18:3.
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A 51-year-old male with a history of chronic myelomonocytic leukemia-2 (CMML-2) presented with fatigue, night sweats, dyspnea, and right-sided chest pain exacerbated by deep breath. Computed tomography scan demonstrated right-sided pleural effusion with atelectasis. Pleural fluid cytology showed reactive mesothelial cells mixed with atypical cells [Figure 1]. The immunostains are performed using the SCIP approach. The atypical cells were immunoreactive for vimentin, CD68, and CD163, while non-immunoreactive for cytokeratin, calretinin, BerEP4, and MOC31.
Q1. What is the cytopathology interpretation here?
Small cell carcinoma of the lung
Answer to Q1: (e) The correct cytopathologic interpretation is myeloproliferative process.
Choice #(e): Myeloproliferative process involving pleural cavity is presented as this quiz case. The patient had a history of CMML-2. The cytology of pleural fluid shows atypical non-cohesive cells with various cells of myeloid series, including myeloblasts, monoblasts, promyelocytes, promonocytes, myelocytes, and metamyelocytes. Atypical cells were immunoreactive for vimentin, CD68, and CD163 and non-reactive for calretinin, BerEP4, and MOC31, consistent with monocytic lineage. The clinical history of CMML with cytomorphological and immunohistochemical features are consistent with CMML involving pleural cavity.
Option (a): On cytology, neoplastic cells of mesothelioma are cohesive groups seen as flat sheets, three-dimensional groups, and papillary or tubular acinar pattern. The mesothelioma cells are immunoreactive for calretinin (nuclear) and cytokeratin (CK) 7. The diagnosis of mesothelioma requires correlation with radiological findings, including pleural-based lesions/diffuse pleural thickening with a history of exposure to environmental factors such as asbestos.
Option (b): Metastatic melanoma may show singly scattered atypical cells with bizarre, hyperchromatic irregular nuclei with prominent nucleoli. Although most of the melanomas are amelanotic, some tumor cells may show melanin pigment.
Option (c): Metastatic adenocarcinoma shows loosely cohesive small nests/clusters of neoplastic cells with proliferation spheres. The cells may have intracytoplasmic targetoid vacuoles with secretion/foamy cytoplasm with peripherally pushed nuclei. Other features that can be identified are touching of the nucleus to the cell membrane, round to oval nuclei with fine to coarse chromatin, and sometimes prominent nucleoli. Some cases may show singly scattered cells. Adenocarcinoma cells usually are non-immunoreactive for vimentin with immunoreactivity for BerEP4 with characteristic immunoprofile of a particular primary site.
Option (d): Small cell carcinoma cells show atypical cells with high nuclear to cytoplasmic ratio, scant delicate basophilic cytoplasm, nuclear molding, diathesis, or necrosis, and granular (salt and pepper) chromatin. Although generally small cell carcinoma cells usually do not show easily detectable nucleoli, the metastatic small carcinoma cells in the serous effusion fluids may show an indistinct nucleolus.
ADDITIONAL QUIZ QUESTIONS
Q2. Which of the following is a feature of a myeloproliferative process?
TTF-1 positivity d. MPO cytoplasmic staining
Q3. Which of the following features favor an epithelial neoplasm over a hematological malignancy?
Q4. Which of the following features would favor a reactive lymphoproliferative process over lymphoma in pleural fluid?
Elevated Ki-67 proliferation index
A polymorphous population of lymphocytes
Cytoplasmic vacuoles with mucin (PAS-D and mucicarmine positive).
Answers to additional quiz questions
Q2. d, Q3. a, and Q4. b
BRIEF REVIEW OF CMML
Cellular specimen with non-cohesive cells
Variable cell morphology is seen, including rare myeloblasts, monoblasts, promyelocytes, promonocytes, myelocytes, metamyelocytes, bands, and segmented neutrophils. Eosinophils may show a full spectrum of maturation
Usually, a necrotic background is not present
Some of the cells may show granular cytoplasm.
Blood count shows marked leukocytosis, monocytosis, and organomegaly. The cells may show dysplastic changes
Around 80% of cases are de novo; 20% have a prior myelodysplastic syndrome, occasionally with monocytosis
Splenomegaly is present in 30–50% of cases, rarely causing a splenic rupture
May have a reactive aggregate of CD123+ benign plasmacytoid dendritic cells
More closely related to myelodysplastic syndrome than myeloproliferative neoplasms (the loss of heterozygosity evaluation).
WHO diagnostic criteria (2016 WHO classification)
Persistent peripheral blood monocytosis >1 × 109/L or monocytes accounting for > 10% of WBC
WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, primary myelofibrosis, polycythemia vera, and essential thrombocythemia are not met
No rearrangement of PDGFRA, PDGFRB, or FGFR1 and no PCM1- JAK2 present
<20% blasts (includes myeloblasts, monoblasts, and promonocytes) in blood and bone marrow.
Type 0: About <2% blasts in the blood and <5% in the bone marrow, no Auer rods.
Type 1: About 2–4% blasts in blood or 5–9% blasts in the bone marrow and no Auer rods.
Type 2: About 5–19% blasts in blood, 10–19% blasts in bone marrow, or Auer rods present with any number of blasts.
If blasts and/or promonocytes (blast equivalents) are 20% more in bone marrow differential count or blood, it is classified as acute myeloid leukemia (AML).
Peripheral blood may have dysplastic changes typical of myelodysplasia in one or more myeloid lineages
In case of minimal or absent myelodysplasia, the diagnosis can be established in the presence of acquired or clonal genetic abnormality or if persistent monocytosis of >3 months and after excluding reactive causes for monocytosis.
Most of the cases have increased WBC count because of monocytosis and neutrophilia. However, sometimes, the number is slightly decreased. In general, the monocytes appear normal but may have abnormal granulation, more nuclear convolutions, and denser chromatin than promonocytes (termed as abnormal monocytes).
Hypercellular marrow with mildly increased monocytes (this is not diagnostic by itself) and increased granulocytes; may have increased reticulin fibers; variable dysplastic changes in erythroid cells, myeloid cells, and megakaryocytes. Cases with eosinophilia need screening for PDGFRA, PDGFRB, and FGFR1 gene abnormalities.
Variable immunoreactivity for CD68, CD163, CD64, and CD14 is observed [Figures 2 and 3]. CD64, CD68, and CD163 are markers of monocytic differentiation. CD163 is also the marker of histiocytic differentiation. The cells are immunoreactive for myelomonocytic markers such as CD13 and CD33. When an increased number of CD34 immunoreactive cells are present, evolving acute leukemia should be considered.
Mutational analysis is beneficial when benign cases of monocytosis cannot be ruled out
In most cases, a clonal abnormality can be identified in one of the following nine genes: SRSF2, ASXL1, CBL, EZH2, JAK2, KRAS, NRAS, RUNX1, and TET2.
Abnormalities in 20–40% of cases, including trisomy 8, monosomy 7, monosomy 5, deletion 12p, and deletion 20q.
The absence of the Philadelphia chromosome, BCRABL-1 fusion gene, PDGFRA, PDGFRB, or FGFR1 rearrangements.
Flow cytometry is generally considered non-specific. The neoplastic monocytes in CMML have the same immunophenotypic expression as mature monocytes with bright expression of CD45, CD11b, CD11c, CD13, CD14, CD64, and CD15. Aberrant phenotypes including dim/variable CD14, CD13, HLA-DR, CD64, and overexpression of CD56 are also observed in majority of cases
Abnormal antigen expression of two or more antigens plus 20% of marrow monocytes showing moderate CD14 expression is found to be 100% specific for CMML versus reactive monocytosis
Monocytes show no expression of stem cell markers, including CD34 and CD117.
Median survival is 20–40 months. Progression into acute leukemia occurs in 15–30% cases, which is the most crucial factor conferring a poor prognosis. Various clinical factors, including but not limited to, lactate dehydrogenase, splenomegaly, and blast count, are included in the CMML-specific prognostic scoring system.
Differential diagnosis in this case
Tumor cells with occasional cytoplasmic brown pigment, with bizarre; hyperchromatic, irregular nuclei with prominent nucleoli
Necrosis and occasional mitotic figures can also be seen
Immunoreactive for S100 protein, HMB45, and MelanA/ MART1.
The effusion fluid is usually highly cellular
Cohesive flat sheets with papillary or tubular/acinar patterns are common
The nuclei are centrally or near centrally located
Binucleation or multinucleation is common
The nuclei show a varying degree of pleomorphism, but nuclear to cytoplasmic ratio remains relatively consistent
Immunoreactive for calretinin (nuclear immunostaining), D2-40 (membranous/microvillous immunostaining), and CK 5/6.
Small cell carcinoma
High nuclear to cytoplasmic ratio
Scant delicate basophilic cytoplasm
Diathesis or necrosis
Granular (“salt and pepper”) chromatin
Cells are approximately 1.5 times the size of mature lymphocytes
Immunoreactive for pan-keratin (dot-like pattern), TTF-1, chromogranin, and synaptophysin.
Adenocarcinoma of lung
Tightly cohesive small nests/clusters of neoplastic cells arranged in the form of glandular architecture
Proliferation spheres may be present
Intracytoplasmic vacuoles/foamy cytoplasm, displacing nuclei at the periphery (rhabdoid appearance)
Neoplastic cells have large round to oval nuclei with smooth to coarse chromatin and occasional prominent nucleoli
Immunoreactive for MOC31, Napsin, TTF-1, Ber-EP4, and CK7.
Reactive mesothelial cells with wide cytomorphological spectrum
Background of mixed inflammatory cells
Microorganisms may be seen.
CMML is a rare aggressive entity. The incidence is fewer than 1100 newly diagnosed cases each year in the United States and is characterized by cytopenia, dysplasia, and monocytosis within the bone marrow and peripheral blood. It comes under a category called myelodysplastic syndrome/ myeloproliferative neoplasm. This disease is typically found in older men with a mean age of 70 years and is notoriously difficult to treat. Although there are multiple prognostic models discussed, there has not yet been a definite CMML-specific prognostic system involving molecular alterations. Despite the advent of new drug treatments such as hypomethylating agents, currently, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) still is the only curative treatment available. Even with allo-HSCT, the overall 5-year survival rates after therapy are 18–47%. The transformation rate to AML is 17–19%.
There are only 10 reported cases of pleural effusions associated with CMML reflecting the incidence of this poorly understood phenomenon. These cases are summarized in Table 1. Five of these cases resulted from leukemic infiltration; two of these patients expired soon after transformation into AML and further systemic complications, but three of them resolved with steroids and chemotherapeutic drugs.
|Year of publication, country||Author||No. of reported cases||Type of CMML||Cytogenetic and morphological features||Reactive effusion versus malignant effusion||Pleural effusion as an initial presentation (IP) or during the course of the disease (DC)||The outcome of the patient|
|1998, Greece||Bourantas et al.||4||Not specified (NS)||NS||A single case of effusion secondary to leukemic infiltration and other cases with reactive effusion||2-IP
|Expired due to acute leukemia|
|1998, Turkey||Hiçsönmez et al.||Two children||NS||NS||Effusion secondary to leukemic infiltration||DC||Successfully treated with short-course high-dose methylprednisolone|
|2004, Japan||Watanabe et al.||1||NS||NS||Effusion secondary to leukemic infiltration||DC||Effusion resolved after iv/oral etoposide. However, the patient expired in 4 months due to transformation into AML and colonic involvement leading to colonic perforation, panperitonitis, and multiple bleeding gastric ulcers|
|1||CMML-2||Normal karyotype||Effusion secondary to leukemic infiltration||IP||Successfully treated with hydroxycarbamide.|
|1||CMML-1||Trisomy (46, XX, +1, der (1;15) (q10; q10) in 11 of 20 interphase cells.||Reactive effusion (polyserositis)||IP||Successfully treated with corticosteroids|
|1||NS||NS||Indeterminate||DC||Sudden massive effusion during cytoreductive therapy|
The case, we presented, is 1.6 years into post-unrelated donor peripheral blood stem cell transplant and is doing well without relapse or leukemic infiltration.
COMPETING INTEREST STATEMENT BY ALL AUTHORS
Vinod B. Shidham is the the editor of this journal. He does not have any competing interest.
AUTHORSHIP STATEMENT BY ALL AUTHORS
Each author has participated sufficiently in the work and take public responsibility for appropriate portions of the content of this article. All authors read and approved the final manuscript. Each author acknowledges that this final version was read and approved.
ETHICS STATEMENT BY ALL AUTHORS
As this is case without identifiers, our institution does not require approval from institutional review board (IRB) (or its equivalent).
LIST OF ABBREVIATIONS (In alphabetic order)
AML - Acute myeloid leukemia
CMML - Chronic myelomonocytic leukemia
DC - During course of disease
FNA - Fine needle aspiration
IP - Initial presentation
NS - Not specified
SCIP - Subtractive coordinate immunoreactivity pattern.
EDITORIAL/PEER- REVIEW STATEMENT
To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double-blind model (the authors are blinded for reviewers and vice versa) through automatic online system.
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