Hematopathology Case Study: A 57 Year Old Male with History of Malignant Melanoma

Case History

A 57 year old male with a history of stage IA malignant melanoma presented with a new pink nodule on the right shoulder (see image provided) that has persisted for one month following a tetanus shot. Resultant specimen is a punch biopsy of the lesion.

calcl1.jpg

 

Diagnosis

calclhe10
H&E, 10x
calclhe20.jpg
H&E, 20x
calclhe50
H&E, 50x

 

calccd20
CD20
calccd3
CD3
calccd4
CD4
calccd8
CD8
calccd30low
CD30, low power
calccd30high
CD30, high power
calclgranzyme
Granzyme
calclperforin
Perforin

Sections show a punch biopsy of skin with a superficial as well as deep dermal infiltration of small and large lymphocytes. No epidermotropism is noted. An admixed background of inflammatory cells including eosinophils, neutrophils, and histiocytes is present.

By immunohistochemistry, CD2, CD4, and CD5 highlight the abundance of lymphocytes indicating a dominant T-cell population. CD30 highlights a major subset of larger lymphocytes that co-express perforin. Granzyme is positive only in a small subset of cells. CD3 is present in a subset of CD30 positive cells indicating downregulation of CD3 in neoplastic cells. By Ki-67, the proliferation index is focally high (70%). CD20 highlights rare B-cells. CD8 is positive in a small fraction of T-cells. EMA is negative.

Overall, the diagnosis is that of a primary cutaneous CD30 positive T-cell lymphoproliferative disorder. The differential diagnosis includes lymphomatoid papulosis, type C and primary cutaneous anaplastic large cell lymphoma.

Discussion 

Primary cutaneous CD30 positive T-cell lymphoproliferative disorders are the second most common cutaneous T-cell lymphoma (30% of cases). The primary groups within this entity include lymphomatoid papulosis (LyP) and cutaneous anaplastic large cell lymphoma.

Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is composed of larger cells that are anaplastic, pleomorphic, or immunoblastic morphology that express CD30 in over 75% of the tumor cells. C-ALCL most commonly affects the trunk, face, extremities, and buttocks and often present as a solitary or localized nodules or tumors with ulceration. Clinically, the lesions may show partial or complete remission similar to LyP but often relapse in the skin. Interestingly enough, approximately 10% of cases may disseminate to local lymph nodes.

The histologic pattern of C-ALCL demonstrates a non-epidermotropic pattern with cohesive sheets of large CD30 positive T-cells. Ulcerating lesions may show a morphologic pattern similar to LyP with abundant inflammatory cells such as histiocytes, eosinophils, neutrophils with few CD30 positive tumor cells. By immunophenotyping, the tumor cells are CD4 positive with variable loss of CD2, CD5 or CD3 and express cytotoxic markers such as granzyme B, TIA1, and perforin. Unlike systemic anaplastic large cell lymphoma, C-ALCL does not express EMA or ALK.

The 10 year disease related survival of C-ALCL is 90%. Lymph node status or multifocal lesions does not alter prognosis significantly.

The differential diagnosis also include LyP, type C. These lesions often present on the trunk and extremities and are characterized by popular, papulonecrotic and/or nodular skin lesions. After 3-12 weeks, the skin findings may disappear. Up to 20% of LyP may be preceded by, have concurrent, or followed by another type of lymphoma such as mycosis fungoides (MF), C-ALCL, or Hodgkin lymphoma.1

Briefly, there are up to 5 types of LyP (types A-E).2,3 The more recently described LyP type D and E are determined by either simulating an epidermotropic aggressive CD8 positive CTCL and angiocentric and angioinvasive CD8 positive CTCL, respectively.

LyP has an excellent prognosis but since these patients may have other lymphomas, long term follow up is advised.

Overall, C-ALCL and LyP type C show considerable overlap both morphologically and clinically so close clinical follow up is recommended, however both demonstrate an excellent prognosis.

References

  1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.
  2. Cardosa J, Duhra P, Thway Y, and Calonie E, “Lymphomatoid papulosis type D: a newly described variant easily confused with cutaneous aggressive CD8-positive cytotoxic T-cell lymphoma.” Am J Dermatopathol 2012 Oct; 34 (7): 762-765.
  3. Kempf W, Kazakov DV, Scharer L, et al. “Angioinvasive lymphomatoid papulosis: a new variant simulating aggressive lymphomas.” Am J Surg Pathol 2013 Jan; 37(1): 1-13.

 

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: An 18-year-old Man with Acanthocytosis

Case History

We were asked to review the peripheral blood smear of an 18-year-old male who had presented to the emergency department with shortness of breath and abdominal distension. His past medical history was significant for numerous hospitalizations for recurrent fungal and bacterial pneumonia, pulmonary abscesses, osteomyelitis, necrotizing granulomas, and cervical lymphadenopathy requiring multiple lymphadenectomies. This history dates back to when he was 3 months old.

Blood Smear findings

The CBC demonstrated severe anemia and mild leukopenia. The peripheral blood smear showed numerous acanthocytes and poikilocytosis shown below.

McLeodAcantyocytes3

McLeodAcantyocytes4

Additional Clinical Findings

Abdominal ultrasonography demonstrated hepatosplenomegaly with enlarged porta-hepatis lymph nodes. Additionally, chest CT scanning demonstrated bilateral mass-like consolidations, prominent hilar lymphadenopathy, and osteolytic lesions of the vertebral bodies. A comprehensive investigation for opportunistic infections was negative. Lung and vertebral body biopsies (not pictured here) revealed poorly formed granulomas. A blood transfusion was considered; however, the patient had previously been demonstrated to express anti-Kx antibodies, which would require transfusion with exceedingly rare blood products.

Diagnosis

The preceding case history describes a patient with a contiguous gene deletion syndrome that includes chronic granulomatous disease (CGD) and the McLeod phenotype, demonstrating a fascinating disorder with important implications in hematopathology and several other disciplines of pathology.

Discussion

McLeod syndrome is a rare, X-linked disorder characterized by the deletion of the XK gene which encodes for the Xk protein. Overall, the lack of synthesis of the Xk protein leads to the lack of expression of the Kx antigen which in turn leads to a marked decrease in the quantities of Kell antigens. In this case, due to the presence of an anti-Kx antibody, the patient would require transfusion with either Kell-null or McLeod phenotype blood products. Unfortunately, only one unit of compatible blood was identified when the rare blood donor database was queried. The clinical team therefore elected for treatment with erythropoietin and iron supplementation which eventually lead to a modest increase in the patient’s hemoglobin concentration.

Acanthocytes, or spur cells, are spiculated red cells with a few projections of varying size and surface distribution that can be seen in a variety of clinical conditions including CGD with McLeod red cell phenotype. Other conditions include (but are not limited to) neuroacanthocytosis, malnutrition states, infantile pyknocytosis, (Lu) null Lutheran phenotype, hypothyroidism, myxedema, and Zieve syndrome. Acanthocytes should be distinguished from echinocytes, or burr cells, that also demonstrate multiple small projections but these are uniformly distributed on the red cell surface.

The prominent acanthocytosis seen in McLeod syndrome is thought to be due to an imbalance of the number of lipids in the inner layer relative to the outer layer. Related to this phenomenon is McLeod neuroacanthocytosis syndrome, a disorder with neurologic manifestations including movement disorders, cognitive alterations, and psychiatric symptoms. Although our patient did not exhibit these symptoms, McLeod neuroacanthocytosis syndrome is known to start in early to middle adulthood and the patient will need to be monitored for the onset of neurologic sequelae.

The McLeod phenotype is frequently associated with CGD due to the proximity of the XK gene to the CYBB gene on the X chromosome. The CYBB gene encodes for a subunit of the NADPH oxidase enzyme complex. A deficiency in NADPH oxidase activity leads to the characteristic increased susceptibility to severe bacterial and fungal infections seen in CGD. The nitroblue-tetrazolium test can be used to evaluate NADPH oxidase activity in the white blood cells and can help make a diagnosis of CGD. Histologically, CGD can show prominent necrotizing and non-necrotizing granulomas in various locations throughout the body.

Overall, treatment of CGD with McLeod red cell phenotype is supportive. There is no known cure or definitive treatment. The patient will likely continue to have infections with opportunistic organisms which will be treated on a case by case basis.

References

  1. Heyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Current opinion in immunology. 2003 Oct 31;15(5):578-84.
  1. Jung HH, Danek A, Walker RH, Frey BM, Gassner C. McLeod neuroacanthocytosis syndrome.
  1. Khodadad JK, Weinstein RS, Marsh LW, Steck TL. Shape determinants of McLeod acanthocytes. Journal of Membrane Biology. 1989 Mar 1;107(3):213-8.
  1. Watkins CE, Litchfield J, Song E, Jaishankar GB, Misra N, Holla N, Duffourc M, Krishnaswamy G. Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review. Clinical and Molecular Allergy. 2011 Nov 23;9(1):13.

 

MM

-Michael Moravek, MD is a 2nd year anatomic and clinical pathology resident at Loyola University Medical Center. Follow Dr. Moravek on twitter @MoravekMD

Mirza-small

-Kamran M. Mirza, MD PhD is an Assistant Professor of Pathology and Medical Director of Molecular Pathology at Loyola University Medical Center. He was a top 5 honoree in ASCP’s Forty Under 40 2017. Follow Dr. Mirza on twitter @kmirza.

Hematopathology Case Study: A 45 Year Old Man with Cytopenias and High Ferritin

Case history

A 45 year-old man presented with vomiting and diarrhea for 5 days. Laboratory studies demonstrated anemia and thrombocytopenia, an elevated ferritin level (23,772 ug/L) and methemoglobinemia. Chest roentgenography revealed cardiomegaly. A follow-up ECHO showed a desreased ejection fraction of 15%. Work-up confirmed viral myocarditis and G6PD deficiency as the cause of the cardiac findings and methemoglobinemia respectively. His clinical condition deteriorated despite therapy: he developed acute kidney and liver failure and had worsening cytopenias. A bone marrow biopsy was performed.

Histomorphological findings

image-121
Bone marrow aspirate smear (100x)
BM17-228 HLH 100x-2
Bone marrow aspirate smear (100x)
CPC Core biopsy 20x
Bone marrow core biopsy (H&E, 20x)
CPC Core biopsy 40x
Bone marrow core biopsy (H&E, 40x)
CPC Core biopsy 100x
Bone marrow core biopsy (H&E, 100x)

Evaluation of the peripheral blood (not pictured) confirmed a macrocytic anemia with marked anisopoikilocytosis including schistocytes, polychromasia, nucleated red blood cells, absolute neutrophilia, monocytosis and thrombocytopenia. The marrow aspirate smear demonstrated appropriate maturation in all cell lines. Scattered hemophagocytic histiocytes (pictured above) were noted. The bone core biopsy was high-normocellular for age with progressive trilineage hematopoeisis. Scattered histiocytes with internalized erythroid cells and debris were visualized. There was no increase in blasts. Flow cytometry analysis performed on the bone marrow aspirate did not show a significant increase in blast population. Gating on the lymphocytes did not show a B-cell monoclonal population or T-cell abnormality by markers assayed.

Diagnosis

High-normocellular marrow with progressive trilineage hematopoeisis and prominent hemophagocytic histiocytes.

Overall the patient met the clinical criteria (see below) for Hemophagocytic Lymphohistiocytosis (HLH); with fever (≥38.5 C), splenomegaly, bicytopenia, presence of hemophagocytic histiocytes in bone marrow and high ferritin level (>500ng/mL).

A clinical diagnosis of HLH was rendered.

Discussion

HLH is an uncommon hematologic disorder that is often fatal.  The underlying pathogenesis involves an exaggerated but ineffective inflammatory response of excessive macrophage and T-cell activation, and impairment of natural killer (NK) and cytotoxic T-cell function. HLH has familial and acquired forms. Secondary, or acquired HLH can be associated with infections (especially viral etiologies), underlying malignancy (particularly lymphomas and leukemias), and medications used for systemic lupus erythematosus. Clinically, autoimmune disease-associated HLH overlaps significantly with macrophage activation syndrome (MAS).

HLH is a clinical diagnosis that can be established with molecular testing or by meeting five of eight clinical and laboratory diagnostic criteria according to the HLH-2004 guidelines.

HLH-2004: Revised diagnostic guidelines for HLH10

The diagnosis HLH can be established if one of the two criteria below is met:

  1. A molecular diagnosis consistent with HLH (i.e., reported mutations found in either PRF1 or MUNC13-4); or
  2. Diagnostic criteria for HLH are fulfilled (i.e., at least five of the eight criteria listed below are present:
    • Persistent fever
    • Splenomegaly
    • Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood):
      • Hemoglobin <90g/L (in infants <4 weeks: <100g/L)
      • Platelets <100 x 109/L
      • Neutrophils <1.0 x 109/L
    • Hypertriglyceremia and/or hypofibrinogenemia:
      • Fasting triglycerides ≥3.0 mmol/L (i.e., ≥ 265mg/dl)
      • Fibrinogen ≤1.5 g/L
    • Hemophagocytosis in bone marrow* or spleen or lymph nodes, no evidence of malignancy
    • Serum ferritin ≥ 500µg/L (i.e., 500 ng/ml)
    • Low or absent NK cell activity (according to local laboratory reference)
    • Increased serum sIL2Rα (according to local laboratory reference)

*In hematopathology, the finding of relevance is the presence of hemophagocytic histiocytes in the marrow or other biopsies organs. While debris-laden histiocytes are commonly noted in marrow aspirates, the findings of engulfed erythroid cells is warranted to call a ‘hemophagocytic’ histiocyte.

Often a bone marrow biopsy will be performed in cases where there is clinical suspicion for HLH. This serves to try and visualize the hemophagocytic activity, and to rule out other diseases with similar clinical presentations as HLH. The pathologic evaluation of HLH is tricky, since there is no established criteria for quantitation of hemophagocytic histiocytes in a bone marrow aspirate. Furthermore, hemophagocytosis is not specific to HLH and can be seen in other conditions such as: post-blood transfusion, chemotherapy, sepsis and major operations. Published data shows that the presence of hemophagocytosis has a sensitivity of 83% and a specificity of only 60% in diagnosing HLH.

What about immunohistochemical staining for the histiocytes? While IHC can help outline histicoytic cells, unfortunately, quantitation of hemophagocytic histiocytes in the core biopsy or clot sections with the aid of CD68 immunostains does not correlate well with disease probability either.

Overall, the nonspecificity of hemophagocytosis in the marrow, even when present in high amounts, should remind both pathologists and clinicians that an isolated finding of hemophagocytosis lacks specificity and does not necessarily suggest HLH when the clinical presentation and laboratory findings are not compatible with the diagnosis. However, there still remains value in bone marrow biopsy examination in cases where clinical suspicion for HLH is high; in order to exclude other marrow processes; and in the rare case where there may not have been clinical suspicion of HLH but the presence of hemophagocytic histiocytes can raise that differential.

For additional images of hemophagocytic histiocytes check out these amazing picture tweets by Dr. Kate Dannheim (@KDannheimMD) https://twitter.com/KDannheimMD/status/933128799818002432) and Dr. Bharat Ramlal (@BeRaad87): https://twitter.com/HHPathology/status/926087105381531648

 

References

  1. Ho C, Yao X, Tian L, et al. Marrow Assessment for Hemophagocytic Lymphohistiocytosis Demonstrates Poor Correlation with Disease Probability. Am J Clin Pathol. 2014 Jan;141(1):62-71
  2. Hunter JI et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31.

 

AIK

-Ayse Irem Kilic is a 1st year anatomic and clinical pathology resident at Loyola University Medical Center. Follow Dr. Kilic on twitter @iremessa.

Mirza-small

-Kamran M. Mirza, MD PhD is an Assistant Professor of Pathology and Medical Director of Molecular Pathology at Loyola University Medical Center. He was a top 5 honoree in ASCP’s Forty Under 40 2017. Follow Dr. Mirza on twitter @kmirza.

Hematopathology Case Study: A 72 Year Old Female with History of Lung Adenocarcinoma

Case history 

A 72 year-old female with a history of stage IA lung adenocarcinoma diagnosed in 2009 s/p resection underwent a surveillance CT scan of the chest which revealed an enlarged right upper lobe paramediastinal lung nodule. A subsequent MRI of the abdomen and PET scan revealed mediastinal lymphadenopathy with numerous boney lesions. Due to the prior history of lung cancer, a right iliac bone biopsy was performed.

Diagnosis

myesar-he-10
H&E, 10x
myesar-he-20
H&E, 20x
myesar-he-50
H&E, 50x
myesar-cd-45
CD45
myesar-cd-117
CD117
myesar-cd-34
CD34
myesar-cd-68
CD68
myesar-cd-56
CD56
myesar-mpo
MPO
myesar-cd-43
CD43

Sections of bone show an extensive intramedullary infiltration by large cells with moderate amounts of cytoplasm, irregular nuclear contours, moderately condensed chromatin and some cells with inconspicuous nucleoli.

By immunohistochemistry, the neoplastic cells are immunoreactive for CD45, MPO, CD68, CD56, and CD43. The cells are negative for cytokeratins, TTF-1, CD20, CD10, PAX5, BCL6, MUM1 and CD79a. CD3 and CD5 highlight rare scattered T-cells.

Overall, in the context of multiple osseous lesions, these findings are representative for a myeloid sarcoma.

Discussion 

Myeloid sarcoma is a tumor mass consisting of myeloid blasts with or without maturation occurring at any site other than the bone marrow. Infiltration of blasts at any site are not classified as a myeloid sarcoma unless there is effacement of tissue architecture. Frequent sites for involvement by a myeloid sarcoma include skin, lymph node, gastrointestinal tract, bone, soft tissue, and testis.

Detection of a myeloid sarcoma is considered as an equivalent diagnosis of acute myeloid leukemia. It may precede or coincide with AML as well as be a presenting finding in those that relapse from AML.

Morphologically, the blasts may or may not show features of maturation and efface the architecture of the involved site. Immunophenotypically, CD68 is considered the most commonly expressed marker followed by MPO, CD117, lysozyme, CD34, TdT, CD56, CD30, glycophorin and CD4. Interestingly enough, CD123 may be expressed in those cases that also have inv(16). It must be emphasized that those cases that meet criteria for a mixed phenotypic acute leukemia (MPAL) cannot be classified as a myeloid sarcoma.

By cytogenetics, 55% of myeloid sarcomas have aberrant cytogenetic findings including monosomy 7, MLL rearrangements, inv(16), and other chromosomal changes. In the pediatric population, t(8;21) may be observed and is less frequent in adults. NPM1 is mutated in 16% of cases.

Lastly, the differential diagnosis should be kept broad in cases that appear lymphoid in nature yet do not mark appropriately. It is often expressed that the primary morphologic differential is a lymphoma, including lymphoblastic lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, blastic plasmacytoid dendritic cell neoplasm, and other small round blue cell tumors of childhood.

Reference

  1. Swerdlow SH, Campo E, Harris NL, et al.  WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008

 

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 56 Year Old Male with an Enlarged Lymph Node

Case History

A 56-year-old male with a past medical history significant for HIV currently on HAART presented to his primary care physician with an isolated enlarged left inguinal lymph node. In the context of his immunocompromised state, the patient was sent for a core needle biopsy of the lymph node to further elucidate the etiology of the isolated lymphadenopathy.

Diagnosis

luetiche20x
H&E, 20x
luetiche50x
H&E, 50x
leutiche100x
H&E, 100x
luetictrep
Treponema immunoperoxidase

The core needle biopsy demonstrated multiple suppurative granulomata with a mixed inflammatory background including abundant plasma cells. The plasma cells are also found to surround small blood vessels. A Treponema immunostain was performed which highlighted the spirochetes. Overall, the diagnosis is that of luetic lymphadenitis.

Discussion

Syphilitic infections can cause isolated lymphadenopathy, especially in the inguinal lymph nodes. The morphologic features of luetic lymphadenitis include interfollicular plasmacytosis, capsular fibrosis, endarteritis, and occasionally sarcoid-like granulomata with rare cases demonstrating suppurative features. The differential diagnosis includes rheumatoid arthritis associated lymphadenopathy but a key histologic difference is that the capsular fibrosis of luetic lymphadenitis will have an infiltrate of lymphocytes and plasma cells while RA associated lymphadenopathy traditionally does not. Immunohistochemistry for Treponema organisms also serves to confirm the diagnosis. It is important to keep in mind the patient’s clinical history when interpreting the biopsy was as well as the differential for interfollicular plasmacytosis with capsular fibrosis.

 

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 68 Year Old Man with Dyspnea on Exertion

Case History

A 68 year old male with no significant past medical history who enjoys long distance cycling presented to an outside emergency department with dyspnea on exertion. Laboratory values at the outside facility showed profound anemia (Hb 10 g/dL) and physical exam revealed lymph adenopathy. The patient was discharged but presented again to his primary care physician with profound dyspnea on exertion, especially after climbing one flight of stairs. Of note, his anemia had worsened with a new Hb of 7 g/dL. For evaluation of the anemia, the patient had a Coomb’s test and it was positive, overall consistent with cold agglutinin disease. For evaluation of the lymphadenopathy, a CT abdomen and chest revealed celiac, portocaval, mesenteric and retroperitoneal lymphadenopathy as well as mild splenomegaly. Due to these findings, the patient presented to Beth Israel Deaconess Medical Center for further evaluation and biopsy of a retroperitoneal lymph node.

A core needle biopsy of a retroperitoneal lymph node was obtained per the recommendation of hematology/oncology.

Diagnosis

AITL-1
H&E, 10X
AITL-2
H&E, 20X
AITL-3
H&E, 50X
AITL-4
CD3
AITL-5
CD20
AITL-6
CD10
AITL-7
CD4
AITL-8
CD7
AITL-9
CD21
AITL-10
Ki-67
AITL-11
EBER ISH
AITL-12
PD1
AITL-13
CXCL13

The core needle biopsy material demonstrated a lymphoid population that was polymorphic in appearance with medium to large sized lymphocytes with moderate amounts of pale cytoplasm, irregular nuclei, vesicular chromatin, and some cells with prominent nucleoli. The background cellular population is composed of a mixed inflammatory component including small lymphocytes, scattered neutrophils, eosinophils, and histiocytes.

By immunohistochemistry, the medium to large sized cells with pale cytoplasm are positive for CD3, CD2, CD4, and CD5 with complete loss of CD7. CD20 highlights scattered background B-cells. CD21 is positive in disrupted follicular dendritic meshworks. CD10 and BCL6 are negative in neoplastic cells. PD1 is positive in neoplastic cells with a subset co-expressing CXCL13. By Ki-67 immunostaining, the proliferation index is 50-70%. By in situ hybridization for Epstein-Barr virus encoded RNA, a subset of cells are positive.

Overall, with the morphologic and immunophenotypic features present, the diagnosis is that of angioimmunoblastic T-cell lymphoma.

Discussion

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of peripheral T-cell lymphoma and accounts for 15-20% of T-cell lymphoproliferative disorders and 1-2% of all non-Hodgkin lymphomas. Clinical features include presentation with late stage disease with associated generalized lymphadenopathy, hepatosplenomegaly, systemic symptoms, and polyclonal hypergammaglobulinemia. Of note, this patient did have an SPEP that was within normal limits. Other findings, although less common, include effusions and arthritis. Laboratory findings often include cold agglutinins with hemolytic anemias, a positive rheumatoid factor (RF), and anti-smooth muscle antibodies. A hallmark of AITL is the expansion B-cells positive for EBV is seen, which may be an indicator of underlying immune dysfunction. The clinical course is often aggressive with a median survival of less than three years and often succumb to infectious etiologies because of an immune dysregulation.1

The pathogenesis and relation to other TFH neoplasms of PTCL, NOS is poorly understood. Recent literature indicates dysregulation in key pathways, including the CD28 and TCR-proximal signaling genes, NF-kappaB/NFAT pathway, PI3K pathway, MAPK pathway, and GTPases pathway.2 The complexity of these pathways has long been an issue for TFH lymphoproliferative disorders and has provided insight to potential molecular signatures (see figure 1 adapted from Vallois 2016).

AITL-14
Figure 1 from Vallois 2016

Another recent publication provided additional information regarding molecular insights. Confirmed mutational analyses reveals a high proportion of cases carry a TET2 mutation with less frequent changes in DNMT3A, IDH2, RHOA, and PLCG1. Specifically, RHOA, PLCG1, and TNFRSF21 encode proteins critical for T-cell biology and most likely promote differentiation and transformation into an aggressive clinical course (see figure 2 adapted from Wang 2017).3

AITL-15
Figure 2 adapted from Wang 2017

Overall, AITL is an uncommon TFH cell derived lymphoproliferative disorder characterized by a TFH immunophenotype, expanded and arborizing high endothelial venules, expansion of the follicular dendritic cell meshworks, and EBV positive B-cells in a background of a polymorphic infiltrate. Although it is hypothesized that the underlying mechanism of neoplasia is related to immune dysfunction, new molecular insights have demonstrated that multiple events occur ranging from early molecular changes to later acquired mutations that allow for malignant transformation.

References

  1. Swerdlow, S., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th. ed., IARC press: 2008
  2. Vallois, D., et al. “Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas,” 2016; 128(11): 1490-1502.
  3. Wang, M., et al., “Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling,” 2017; 8(11): 17763-17770.

 

 

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: 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.

 

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-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.