Hematopathology Case Study: What’s in Those Histiocytes?

Case history

A 50 year old female with a past medical history significant for Sjogren’s syndrome and ventricular tachycardia s/p ICD placement presented for a routine chest X-ray in which a 1.8 cm spiculated left upper lobe lung mass was identified. A subsequent PET scan revealed FDG avidity. Other Imaging revealed no lymphadenopathy. The patient is a non-smoker and has no other comorbidities. A core needle biopsy with fiducial placement was performed.

Diagnosis

histio1
H&E 10x
histio2
H&E, 20x
histio3
H&E, 50x
histio4
CD3
histio5
CD20
histio6
CD79a
histio7
IgG
histio8
CD68
histio9
CD138
histio10
Kappa ISH
histio11
Lambda ISH

Sections of lung core biopsy material show numerous histiocytes containing eosinophilic intracytoplasmic globular inclusions. An admixed population of plasma cells are seen which are present in aggregates along with mature appearing lymphocytes. The plasma cells also demonstrate globular inclusions within their cytoplasm.

By immunohistochemistry, CD3 highlights scattered mature T-cells while CD20 highlights B-cells present in focal aggregates. Numerous plasma cells are present and are positive for CD138, CD79a, BCL2, and MUM1. By in situ hybridization, plasma cells are greatly kappa predominant. IgG is positive in the majority of the plasma cells with only rare cells staining for IgA and IgM. CD68 is positive in the numerous histiocytes.

IGH gene rearrangement studies by PCR demonstrated was positive, indicating a clonal population.

Overall, the findings are consistent with a crystal-storing histiocytosis with an associated plasma cell neoplasm or low-grade B-cell lymphoproliferative disorder.

Following the diagnosis, the patient received stereotactic body radiation therapy given the localized findings.

Discussion

In this case, the findings are morphologically consistent with crystal-storing histiocytosis (CSH), which is a rare lesion that is the result of intralysosomal accumulation of immunoglobulin. The immunoglobulin is stored as crystalline structures within histiocytes that occupy the vast majority of a mass forming lesion. Multiple sites can be involved, which include bone marrow, lymph nodes, liver, spleen, gastrointestinal tract, and kidney. Most often, the lesion is confined to a single site but occasional generalized forms with multiple organ involvement have been described. CSH is also often associated with B-cell lymphoproliferative disorders or plasma cell dyscrasias, but rarely are the result of chronic inflammatory conditions.

The assessment of CSH requires excellent staining to identify the quality of the histiocytes. As mentioned, CSH will show intracytoplasmic inclusions that are eosinophilic in nature. Mimickers of CSH include mycobacterial and fungal infections, mycobacterial spindle cell pseudotumor, malakoplakia, HLH, storage disorders such as Gaucher’s, as well as histiocytic lesions such as xanthogranuloma, Langerhans cell histiocytiosis, fibrous histiocytoma, Rosai Dorfman disease and rarely other eosinophilic tumors such as rhabdomyoma, granular cell tumor, and oncocytic neoplasms.1

A thorough review of the literature as well as a clinicopathologic study by Kanagal-Shamanna R et al revealed that the localized type of CSH was the dominant presentation in which over 90% of cases showed isolated masses. Per previous reviews, localized lesions were often found in the head and neck as well as lung.2 A study group in which 13 cases that showed CSH, 12 demonstrated an underlying lymphoma or plasmacytic neoplasm. Interestingly, in 5 of the cases, the histiocytic infiltrate was so prominent and dense that it obscured the underlying neoplasm. In these particular cases, immunohistochemistry and PCR were of great importance.

Although the majority of cases of CSH are the result of an underlying lymphoproliferative disorder or plasma cell neoplasm, rare cases of report inflammatory processes have been described, particularly in the setting of an immune mediated process such as rheumatoid arthritis or Crohn disease.

Overall, although a rare entity, it is important to be aware of CSH and its mimickers as this can be an elusive diagnosis to make, especially when the histiocytic infiltrate is dense.

References

  1. Kanagal-Shamanna R, et al. “Crystal-Storing Histiocytosis: A Clinicopathologic Study of 13 Cases,” Histopathology. 2016 March; 68(4): 482-491.
  2. Dogan S, Barnes L, Cruz-Vetrano WP “Crystal-storing histiocytosis: a report of a case, review of the literature (80 cases) and a proposed classification,” Head Neck Pathol. 2012; 6:11-120.

 

PhillipBlogPic-small

-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Molecular Perspectives of Diffuse Large B-cell Lymphoma

Case

A 100 year old female was seen for follow-up for her hypertension, mild renal impairment, and fatigue. The patient also stated a three week duration of pain in the area of the right upper quadrant that radiates to her back. No other symptoms or concerns were expressed.

An abdominal CT was performed which showed a 6.6 x 2.1 cm soft tissue mass in the right posterior chest wall that also encases the 11th rib. Given the concern for a malignant process, a core needle biopsy was obtained for histology only.

b-cell1
H&E, 20x
b-cell2
H&E, 50x
b-cell3
CD20
b-cell4
CD10
b-cell5
BCL6
b-cell6
MUM1
b-cell7
Ki-67

The H&E stained sections show a diffuse infiltration of atypical lymphoid cells that are large in size with irregular nuclear contours, vesicular chromatin, and some with prominent nucleoli. Frequent apoptotic bodies and mitotic figures were seen. By immunohistochemistry, CD20 highlights the infiltrating cells, which are positive for BCL2, BCL6, and MUM1 (major subset). CD10 is negative within the atypical lymphoid population. CD3 highlights background T-cells. Ki-67 proliferation index is approximately 70%. EBER ISH is negative.

Overall, the findings are consistent with diffuse large B-cell lymphoma, NOS with a non-GCB phenotype by the Hans algorithm.

Discussion

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell lymphoma in adults comprising 30%-40% of new adult lymphomas. Approximately 50% of patients will be cured, even in advanced cases; however, those that fail conventional therapy ultimately succumb to their illness.1 Up to 30% of patients have refractoriness or relapse after initial therapy with rituximab based regimens, particulary R-CHOP (ritixumab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

In the era of new molecular techniques and in the context of the heterogeneous nature of DLBCL, it has become important to accurately assess cell of origin (COO) as this has prognostic implications. With the seminal paper from Alizadeh and colleagues, gene expression profiling (GEP) by a microarray platform produced the concept of germinal center (GCB) versus activated B-cell (ABC) types of DLBCL.2 In the context of prognosis and R-CHOP therapy, the GCB type has a 3 year PFS of 75% as opposed to the ABC type that has a 3 year PFS of 40% (P<.001).3 Although GEP analysis is considered the ideal modality for determining COO, however, given the constraints of most modern hematopathology practices, surrogate immunohistochemical algorithms were developed to aid in COO determination. Of the multiple algorithms, the Hans algorithm is the most widely used and accepted for IHC determination of COO.

b-cell8
Adapted from Hans et al., Blood, 2004

The COO determination has revealed multiple genetic alterations that are shared between the GCB and ABC phenotype while distinct changes have been identified in each type. Molecular mechanisms at play include, but are not limited to, histone modification, blocks to terminal differentiation, cell cycle activation, PI3K/AKT signaling activation, mTOR pathway activation, as well as a multitude of other signaling cascades. A common shared dysregulated pathway between GCB and ABC types include mutations in CREBBP and EP300, which is in approximately 30% of DLBCL cases and slightly enriched in the GCB group. Mutations/deletions in these genes result in inactivation and alter histone modification subsequently thought to contribute to acetylation of BCL6, which is a key regulatory protein in lymphomagenesis. Up to 33% of DLBCL have mutations in MLL2, which has a broad effect on chromatin regulation and epigenomic alteration. Approximately 35% of DLBCL cases with up to two- to three-fold increase in ABC type cases have genetic alterations in BCL6, particularly chromosomal rearrangements and mutations in the 5’ sequence. Pasqualucci et al also described other factors that lead to BCL6 inactivation, including mutations in MEF2B and FBXO11.4

ABC type DLBCL often displays canonical pathway activation of NF-ƙB signaling, which ultimately promotes survival, proliferation, and inhibition of apoptosis. This potentially is a result of alterations in the CBM signalosome (CARD11, BCL10, and MALT1) with up to 10% of ABC-DLBCL cases having a mutation in CARD11. Another modality of ABC activation is through the B-cell receptor signaling pathway in which 20% of cases harbor a CD79A or CD79B mutation.  Interestingly enough, recurring mutations in MYD88 occur in ~30% of ABC-DLBCLs, which results in upregulation of NF-kB and Janus kinase-signal transducers. Other important genetic alterations include involvement by signaling pathways of spleen tyrosine kinase (SYK), PI3K, Bruton tyrosine kinase (BTK), and protein kinase C-β (PKC-β).

GCB type DLBCL often expresses CD10, LMO2, and BCL6 and has a less understood and distinct pathway when compared to ABC-DLBCL. The most common alterations include t(14;18) IGH-BCL2 (30-40%), C-REL amplification (30%), EZH2 (20%) and PTEN mutations (10%). These changes are almost never seen in ABC-DLBCL.

b-cell9.png
Adapted from Pasqualucci et al., Semin Hematol, April 2015

Although the findings in GCB and ABC type DLBCL are described, they are not absolute and multiple studies done by whole exome sequencing (WES) and whole genome sequencing (WGS) have elucidate further complexities and genetic changes. In 2015, data from Novak and colleagues revealed CNAs and mutations that were associated EFS, which also underscored the important 24 month milestone for survival.5 Morin et al in 2013 described 41 novel genes in DLBCL which demonstrated just how complex and heterogeneous DLBCL truly is (see figure below).6

b-cell10.png
Adapted from Morin et al., Blood, 2013.

As common as DLBCL is, there is much to be understood not only for lymphomagenesis, but for correct classification and risk stratification. Many targeted therapies have been designed and are in trials at the moment, but given the nature of DLBCL and its heterogeneity, more work on the molecular front is needed. Modalities for assessing COO are currently on the market but are not widely used. Perhaps COO determination by IHC may be an antiquated method, but it is currently the standard by which most pathologists practice. Overall, DLBCL in all its forms is not a uniform entity that can easily be defeated, but requires thought and diligence in achieving a cure.

 

  1. Lohr, JG et al. “Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing,” Proc Natl Acad Sci USA. 2012; 109(10): 3879-3884
  2. Alizadeh AA, et al. “Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling,” Nature 2000, 403:503-11
  3. Sehn, L and Gascoyne, R “Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity,” Blood. 2015;125(1):22-32
  4. Pasqualucci, L and Dalla-Favera, Riccardo, “The Genetic Landscape of Diffuse Large B Cell Lymphoma,” Semin Hematol. 2015 April; 52(2): 67-76
  5. Novak, AJ et al. “Whole-exome analysis reveals novel somatic genomic alterations associated with outcome in immunochemotherapy-treated diffuse large B-cell lymphoma,” Blood Cancer Journal (2015) 5
  6. Morin, R et al. “Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing,” 2013;122(7):1256-1265

 

PhillipBlogPic-small

-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Hematopathology Case Study: A 69 Year Old Female with Persistent Monocytosis

Case History

A 69 year old female with a past medical history significant for endometrial adenocarcinoma, traumatic brain injury, atrial fibrillation, hypertension, hyperlipidemia, and persistent monocytosis (absolute monocyte count ranging from 1.6-3.7 K/uL) who had an indeterminate lesion identified in the T5 vertebra, read as “hemangioma, although surrounding edema is worrisome for malignancy” upon staging imaging for history of endometrial carcinoma.

CBC at the time was: WBC 9.8; HGB 12.9; HCT 37.6; PLT 154; MCV 92 fL; MCH 31.7.

Automated differential showed: 43.0 Neutrophils; 34.8 Lymphocytes; 20.0 Monocytes; 1.4 Eosinophils; 0.2 Basophils; 0.6 Immature granulocytes.

Absolute monocyte count was 1.95 K/uL.

This lesion was biopsied and given the findings, a subsequent bone marrow biopsy was performed on 5/4/2017. The bone marrow core biopsy contained multiple compact aggregates of spindle shaped cells with hypogranular cytoplasm, morphologically compatible with atypical mast cells. Within these aggregates, numerous eosinophils are present. By immunohistochemistry, the mast cells are brightly positive for CD117 and mast cell tryptase. Concurrent bone marrow aspirate flow cytometry demonstrated a small population of mast cells that co-expressed CD2 and CD25.

Of note, the patient was found to have a persistent absolute monocytosis. Flow cytometry revealed an abnormal population of monocytes that displayed aberrant phenotypic expression of CD2 and CD56 (subset).

Next-generation sequencing revealed two truncation mutations in the TET2 gene (K988* in 34.6% of the reads and Q1138* in 36.4% of the reads). Cytogenetic analysis revealed a normal female karyotype (46,XX).

myelomono1

myelomono2

myelomono3

Overall, an immunophenotypically abnormal population of mast cells and monocytes are present in the context of a long-standing absolute monocytosis and the presence of two TET2 truncating mutations, supporting a diagnosis of systemic mastocytosis with an associated hematologic non-mast cell lineage disorder (best classified as chronic myelomonocytic leukemia).

Discussion

A diagnosis of systemic mastocytosis is a combination of clinical, morphologic, immunophenotypic, and molecular analyses, as required by the World Health Organization (WHO 2008). By current consensus guidelines, SM variants are partly distinguished by clinicopathologic criteria referred collectively as B and C findings. B findings include: >30% of bone marrow mast cells (MC) on biopsy and/or serum tryptase levels >200 ng/mL; increased marrow cellularity/dysplasia without meeting diagnostic criteria for another myeloid neoplasm; or enlargement of liver, spleen, or lymph nodes without evidence of organ damage. C findings include: evidence of organ damage caused by a local MC infiltrate, such as abnormal liver function and/or ascites, hypersplenism, cytopenias, large osteolytic lesions/fractures, and malabsorption with weight loss caused by MC infiltrate in the gastrointestinal tract.

Systemic mastocytosis commonly occurs in two types with different clinical courses based upon the aforementioned findings. Indolent SM (ISM) is defined by the absence of C findings. Smoldering SM is a subtype of ISM that displays 2 or more B findings. ISM may become more aggressive and a descriptive term of advanced SM refers to a category including aggressive SM (ASM), mast cell leukemia (MCL), and “SM with an associated myeloid neoplasm.” The latter entity comprises more than 90% of cases that have previously been referred to as SM with an associated hematologic non-mast cell lineage disorder (SH-AHNMD).

ASM and MCL are characterized by organ damage and histologic characteristics. ASM often exhibits multifocal bone marrow infiltration of atypical mast cells that are often spindled in shape with hypogranular or immature morphology. Marked fibrosis often accompanies the infiltrate as well as a KIT D816V mutation. MCL is codified by more than 20% of the marrow aspirate nucleated cells represent by mast cells and on core biopsy, a compact infiltrate is often identified with usually low level fibrosis. In MCL, circulating mast cells are greater than 10% of nucleated cells but according to Gotlib et al., the aleukemic MCL (less than 10% circulating mast cells) is more common.

In the context of our patient, myeloid neoplasms associated with SM are often represented by MDS, MPN, or MDS/MPN overlap disorders, and occasionally AML.

Associated lymphoid or plasma cell neoplasms have been described, but in a much lower frequency.

In accordance with the diagnostic implications, KIT D816V mutational analysis is important therapeutically. Most patients with SM harbor the KIT D816V mutation (>80% in one clinical series; 90-100% in research studies using purified MCs), which is a considered imatinib-resistant mutation. Midostaurin (a second generation TKI) may provide some disease response while nilotinib or dasatinib are usually less likely to lead to a durable response. The rare patients who have a juxtamembrane domain KIT mutation are much more likely to respond to imatinib or masitinib.

For disease response, criteria were first published in 2003 by Valent, et al. In a reiterated version published in 2007, the evaluation of clinical evidence of organ damage (C findings), was the foundation for determining appropriate response. Another facet to determining response was in relation to BM MC burden, serum tryptase level, and organomegaly, which further subcategorized the levels of major response (MR). MR was defined as normalization of 1 or more C findings. In turn, MR was divided into 3 categories:

  1. Complete remission (resolution of MC infiltrates in organs, serum tryptase less than 20 ng/mL, and disappearance of SM-associated organomegaly)
  2. Incomplete remission (decrease in MC infiltrates in organs and/or serum tryptase levels and/or visible regression of organomegaly by >50%)
  3. Pure clinical response (without decrease in MC infiltrates, serum tryptase levels, or organomegaly)

Partial response (PR) is defined as incomplete regression of 1 or more C findings and include good partial response (GPR; >50% regression of 1 or more C findings) and minor response (<50% regression).

Lastly, the Mayo Clinic published revised response criteria in 2010 which established minimal baseline laboratory abnormalities for organ damage to be evaluated in order to allow for more accurate assessment of response to therapy that is clinically more relevant.

Overall, systemic mastocytosis is a rare entity that displays a range of presentations that can be described as indolent up to an aggressive (advanced) phenotype. The hallmarks for diagnosis include histologic, immunophenotypic, molecular, and clinical findings.

 

References

  1. Gotlib, J et al. “International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis,” Blood, 2012.
  2. Horny HP et al. “Mastocytosis,” In: Swerdlow S et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008:53-63
  3. Valent P et al. “Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria.” Leuk Res. 2003;27(7):635-641.
  4. Pardanani A, et al. “A critical reappraisal of treatment response criteria in systemic mastocytosis and a proposal for revisions. Eur J Haematol. 2010;84(5):371-378.

 

PhillipBlogPic-small

-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Hematopathology Case Study: A 7 Year Old Transplant Patient with Neck Swelling

A 7 year old male with a history of restrictive cardiomyopathy status-post orthotopic heart transplant in June, 2010 that was on maintenance doses of tacrolimus and mycophenolate mofetil presented to his primary pediatrician left neck swelling. Starting in January 2017, the patient began with neck pain and swelling in the context of a recent gastrointestinal illness. Per CT report of the neck, a rim enhancing well-defined suppurative level III lymph node measuring 1.4 x 1.2 x 2.1 cm with adjacent soft tissue inflammatory changes extending into the left parapharyngeal space was identified. The patient was subsequently started on antibiotics and was discharged home with some improvement of swelling and pain.

The patient then presented again with continued neck swelling, although painless this time, and the patient’s cardiologist was contacted, who recommended a decrease in tacrolimus dosing. An otolaryngology evaluation was requested and given the concerning findings, the patient was admitted for further work-up, including a biopsy with a lymphoma protocol.

burlym1

burlym2

burlym3
BCL6
burlym4
BCL2
burlym6
EBER

 

burlym5
Flow Cytometry

 

Results

Flow cytometry revealed a kappa restricted CD10 positive mature B-cell population.

On biopsy examination, a population of monotonous lymphoid cells that are large in size with round to mildly irregular nuclear contours, open chromatin, and multiple inconspicuous nucleoli are present in a diffuse pattern. Abundant apoptotic bodies and mitotic figures are noted and occasional “starry sky” features are present. By immunohistochemistry, BCL6 highlights the neoplastic lymphocytes while BCL2 highlights background T-cells. EBER is negative.

Overall, despite a negative t(8;14) IGH/MYC translocation, the findings are best considered to be of an EBV-negative post-transplant lymphoproliferative disorder with morphologic features consistent with Burkitt lymphoma.

Discussion

Post-transplant lymphoproliferative disorders (PTLD) are a relatively rare complication in a variety of transplants that occurs in 2-10% of post-transplant patients. Overall, following a solid organ transplant (SOT), PTLD development is 1-5% of recipients with the highest incidence in intestinal and multivisceral transplantations (5-20%). Another factor is EBV status of the recipient, for which those that are EBV-naïve and lack cellular immunity to EBV are susceptible to graft-mediated EBV infection and ultimately developing an increased incidence in early PTLD. This population is overrepresented by pediatric transplant recipients1.

The presentation is highly variable and ranges from benign proliferations to overt lymphoproliferative disorders. Classifications for PTLD include early lesions, which are oligo- or polyclonal proliferations of EBV positive B cells have either a predominant infectious mononucleosis-like proliferation or a plasmacytic hyperplasia form. Polymorphic PTLD is a similar concept to the early proliferative lesions but the host architecture of the native structure is disrupted. Lastly, monomorphic PTLD is an entity that fulfills criteria for a non-Hodgkin lymphoma and is diagnosed according to the criteria of non-transplant associated lymphomas. Within pediatric registry studies, monomorphic PTLD accounts for 35-83% of all PTLD cases. B-cell lymphomas, particularly DLBCL, comprise the vast majority of monomorphic PTLD with plasmacytoma and T-cell lymphoproliferative disorders much less common2.

In this particular case, with the patient having been 7 years post-transplant and negative studies for EBV present, it is not surprising that germinal center phenotypic markers are highly expressed, such as CD10 and BCL6, which has been well elucidated by Jagadeesh, et al. Although not many genetic studies have been performed on post-transplant B-cell lymphomas, regardless of EBV status, there is some data demonstrating trisomies of 9 and/or 11 with translocations 8q24.1 (C-MYC), 3q24 (BCL6), and 14q32 (IGH). Rinaldi et al. noticed a lack of genetic lesions characteristic of postgerminal center derivation, such as gain of chromosome 3 (FOXP1, BCL6, and NFKBIZ) and 18q (BCL2 and NFATC1) together with losses of 6q (PRDM1 and TNFAIP3) in post-transplant DLBCL.  A number of DNA mutations have also been described including genes associated with somatic hypermutation (SHM) such as PIM-1, PAX5, C-MYC, and RhoH/TTF. These particular mutations are also found to be independent of EBV status1.

Overall, post-transplant lymphoproliferative disorders occur in a variety of transplant settings across many age groups and can be dependent on EBV and CMV status as well as the type and degree of immunosuppression. Although many variations take place in PTLD, patients with the monomorphic type are diagnosed according to their non-transplant counterparts. Current perspective includes further analysis of molecular and cellular mechanisms incorporated into research projects, which could better aid in prognostic implications and future therapeutics.

  1. Morscio, et al. “Molecular pathogenesis of B-cell posttransplant lymphoproliferative disorder: What do we know so far?” Clinical and Developmental Immunology 2013.
  2. Mynarek, et al. “Posttransplant lymphoproliferative disease after pediatric solid organ transplantation,” Clinical and Developmental Immunology 2013.

 

PhillipBlogPic-small

-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.

Hematopathology Case Study: A 54 Year Old Male with Acute Onset of Progressive Neck Swelling

Case History

A 54 year old male with a diagnosis of HIV (last CD4 count was 301 on 11/2016) currently on HAART presented to the Beth Israel Deaconess Medical Center (BIDMC) ED on 2/28/2017 with an acute onset of progressive neck swelling over the course of 4-5 days. Laboratory values on presentation was significant for a LDH of 1061 IU/L. Other laboratory values were stable. Upon CT imaging with contrast of the neck, an extensively necrotic right cervical lymphadenopathy was present and was extending into the supra- and infraclavicular chain. No mediastinal or hilar lymphadenopathy was noted.

On 3/1/2017, the patient underwent an ultrasound guided core needle biopsy of the right cervical mass (see images). By immunohistochemistry, the neoplastic cells are positive for CD138 and MUM1. PAX5 shows dim and heterogeneous staining in a subset of cells while CD79a highlights a minor component of the lymphoid population. CD3 and CD5 are positive in T-cells occupying a small subset of the lymph node. CD20, BCL2, BCL6, BCL1, CD30, CD56 and HHV8 are negative. By Ki-67 immunostaining, the proliferation index approaches 100%. In-situ hybridization for Epstein-Barr virus encoded RNA (EBER ISH) is positive in a major subset of cells.

3-23-fig1

3-23-fig2
CD20 (left) and CD3
3-23-fig3
MUM1 (left) and CD138
3-23-fig4
EBER ISH (left) and Ki-67

By cytogenetic analysis, only two cells were available for metaphase interpretation and it showed a translocation between the long arms of chromosomes 8 and 14 and by FISH, a t(8;14)(q24.1;q32) was noted, indicating an IGH/MYC rearrangement.

3-23-fig5

Overall, the morphologic, immunophenotypic, and cytogenetic findings in conjunction with the clinical features of a HIV positive male and EBV association, the diagnosis is in keeping with a plasmablastic lymphoma.

3-23-fig6

Discussion

Plasmablastic lymphoma is a diffuse proliferation in which the cells resemble immunoblasts but share an immunophenotype similar to that of plasma cells. First described in the oral cavity, especially among HIV infected patients, it can present in a variety of extranodal sites, such as skin, soft tissue, and gastrointestinal tract. Although uncommon, plasmablastic lymphoma has its highest incidence among HIV infected individuals. Most patients are at stage III or IV at presentation with an intermediate to high risk IPI score. The tumor cells of plasmablastic lymphoma are invariably infected by Epstein-Barr virus (EBV) and are consistently negative for HHV8. According to Balague et al.2, up to 39% of plasmablastic lymphomas demonstrate a MYC translocation, all of which involved the IGH gene. Generally, plasmablastic lymphoma displays a complex karyotype, although some cases display an isolated MYC rearrangement without a complex karyotype. Taddesse-Heath et al.3 has shown a small cohort that is positive for gains in odd-numbered chromosomes 3, 5, 7, 9, 11, and/or 15, similar to that seen in plasma cell myeloma. The clinical course of plasmablastic lymphoma is quite aggressive with most patients dying within one year after diagnosis. Current first line treatment for plasmablastic lymphoma is dose-adjusted EPOCH with or without bortezomib, intrathecal prophylaxis, and possible autologous stem cell transplantation in first remission candidates. Future directions of therapy include chimeric antigen receptor (CAR) T-cells and small molecular inhibitors against the MYC bromodomain4.

References

  1. Swerdlow, S., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th. ed., IARC press: 2008
  2. Balague, O., et al., “Plasmablastic lymphomas are genetically characterized by frequent MYC translocations [abstract],” Mod Pathol 2009; 22:255A.
  3. Taddesse-Heath, L., et al., “Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features,” Mod Pathol 2010; 23:991-999.
  4. Castillo, J., et al., “The biology and treatment of plasmablastic lymphoma,” Blood 2015; 125:2323-2330.

 

PhillipBlogPic-small

-Phillip Michaels, MD is a board certified anatomic and clinical pathologist who is a current hematopathology fellow at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. His research interests include molecular profiling of diffuse large B-cell lymphoma as well as pathology resident education, especially in hematopathology and molecular genetic pathology.