To Be (MDS) or Not To Be? The Conundrum of Cytoplasmic Vacuolation in Hematopoietic Precursors

Every hematopathologist and pathology trainee knows to be wary of the myriad of causes that could mimic the dysplastic changes seen in marrows involved by MDS. Many times morphology alone, without genetic or cytogenetic evidence of clonality can be tricky. The list of things that can recapitulate changes seen in MDS seems to grow longer every day – and with it the length of our ‘canned comments’ on ruling out reactive causes of dysplasia. Within the recent past, two bone marrow biopsies crossed my microscope, both sent to ‘rule out’ MDS. Both had almost identical morphologic findings, but very different diagnoses. Here are some representative images from the marrow aspirates and iron stains:

mds
Figure 1. Representative Wright-Giemsa stained cells from Case 1 (A and B) with accompanying iron stain (C) showing numerous ring sideroblasts.  Representative Wright-Giemsa stained cells from Case 2 (D) with accompanying iron stain (E) showing some ring sideroblasts. 

Discussion

Images A through C come from case 1, a 67-year-old woman with a past medical history of non-alcoholic steatohepatitis (NASH) complicated by hepatic encephalopathy and recurrent ascites who underwent bone marrow biopsy for new onset pancytopenia with transfusion-dependent anemia. The marrow was slightly hypercellular for age and showed progressive trilineage maturation. Granulocytic and erythroid progenitors did not reveal quantitatively significant dysplasia. The one dysplastic megakaryocyte identified is pictured here (panel A). Interestingly many erythroid and granulocytic precursors showed cytoplasmic vacuolation (panel B showing granulocytic vacuolation). An iron stain (panel C) revealed 44% ring sideroblasts. Case 2 is represented in images D and E and was from a 64-year-old man with no significant past medical history who presented with lethargy and anemia. This marrow was also slightly hypercellular for his age and showed borderline-significant dysplasia in megakaryocytic maturation. Granulopoiesis and erythropoiesis were unremarkable except for cytoplasmic vacuolations in many cells (panel D). An iron stain showed 8% ring sideroblasts (panel E).

Both cases were signed out descriptively, urging the clinician that we needed to rule out reactive causes of dysplasia before a definitive diagnosis of MDS could be rendered. In both cases we suggested waiting for the cytogenetics results for a more comprehensive analysis. Additionally, we recommended testing for serum copper since copper deficiency can be the cause of dysplastic morphology, cytoplasmic vacuolation, and ring sideroblasts.

Case 1 revealed markedly diminished copper and normal cytogenetics. Copper replenishment was curative. Case 2 revealed normal copper levels and a complex karyotype that contained numerous MDS-associated abnormalities confirming the clonal, and therefore malignant nature of these changes. Despite being almost identical morphologically, these case were diagnostically and prognostically poles apart.

Copper is an element that serves as a micronutrient required for hematopoiesis. It’s presence in many readily available foods including meat, fish, nuts, and seeds renders diet-related copper deficiency a rare phenomenon. Zinc-supplementation is one of the causes of copper deficiency in published reports. Copper deficiency has been well documented to mimic dysplastic changes seen in MDS; but these morphologic findings and cytopenia are reversible. Characteristically, cytoplasmic vacuolation is an important morphologic clue that there could be an underlying paucity of serum copper.  Another aspect of copper deficiency is the presence of ring sideroblasts which also can mean MDS. It is very important to consider this differential diagnosis when dealing with marrow specimens sent to rule out MDS. This Lablogatory post highlights the significant overlap between presentation and morphologic findings between MDS and copper deficiency supporting the notion that a high index of suspicion, good communication, stat copper levels, and cytogenetics or MDS FISH studies are very helpful in delineating benign from malignant.

References

  1. Dalal N. et al. Copper deficiency mimicking myelodysplastic syndrome. Clin Case Rep. 2015 May; 3(5): 325–327.
  2. Willis M.S. Zinc-Induced Copper Deficiency: A Report of Three Cases Initially Recognized on Bone Marrow Examination. AJCP. 2005 Jan; 123(1): 125–131
  3. D’Angelo G. Copper deficiency mimicking myelodysplastic syndrome. Blood Res. 2016 Dec; 51(4): 217–219.
  4. Karris S and Doshi V. Hematological Abnormalities in Copper Deficiency. Blood 2007 110:2677

 

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-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 Male with Mediastinal Mass

Case History

A 45 year old male underwent a chest MRA for aortic dilation due to his history of an aneurysmal aortic root. Upon imaging, an incidental anterior mediastinal mass was seen that measured 4.0 cm. In preparation for an upcoming cardiac surgery, the patient underwent a thymectomy with resection of the mass. The sample is a section from the mediastinal mass.

Diagnosis

HVCD-HE-2x
H&E, 2x
HVCD-HE-4x
H&E, 4x
HVCD-HE-lollipop
H&E, 10x. Green Arrows: “lollipop” germinal centers
HVCD-HE-twinning
H&E, 10x. Red arrow: focal “twinning” of germinal centers

Sections show an enlarged lymph node with several follicles demonstrating atrophic-appearing germinal centers which are primarily composed of follicular dendritic cells. These areas are surrounded by expanded concentrically arranged mantle zones. Focal “twinning” of germinal centers is present. Additionally, prominent centrally placed hyalinized vessels are seen within the atrophic germinal centers giving rise to the “lollipop” appearance.

By immunohistochemistry, CD20 highlights B-cell rich follicles while CD3 and CD5 highlight abundant T-cells in the paracortical areas. CD10 is positive in the germinal centers while BCL2 is negative. CD21 highlights expanded follicular dendritic meshwork. CD138 is positive in a small population of plasma cells and are polytypic by kappa and lambda immunostaining. HHV8 is negative. MIB1 proliferation index is low while appropriately high in the reactive germinal centers.

Overall, taking the histologic and immunophenotypic findings together, the findings are in keeping with Castleman’s disease, hyaline vascular type. The reported clinical and radiographic reports suggest a unicentric variant.

Discussion

Castleman’s disease comes primarily in two varieties: localized or multicentric. The localized type is often classified as the hyaline vascular type (HVCD). Demographically, it’s a disease of young adults but can be found in many ages. The most common sites for involvement are the mediastinal and cervical lymph nodes.

The classic histologic findings of HVCD involve numerous regressed germinal centers with expanded mantle zones and a hypervascular interfollicular region. The germinal centers are predominantly follicular dendritic cells and endothelial cells. The mantle zone gives a concentric appearance, often being likened to an “onion skin” pattern. Blood vessels from the interfollicular area penetrate into the germinal center at right angles, giving rise to another food related identifier, “lollipop” follicles. A useful diagnostic tool is the presence of more than one germinal center within a single mantle zone.

The differential diagnosis of HVCD includes late stage HIV-associated lymphadenopathy, early stages AITL, follicular lymphoma, mantle cell lymphoma, and a nonspecific reactive lymphadenopathy. A history of HIV or diagnostic laboratory testing for HIV would exclude the first diagnosis. AITL usually presents histologically as a diffuse process but atypia in T-cells with clear cytoplasm that co-express CD10 and PD-1 outside of the germinal center are invariably present. EBER staining may reveal EBV positive B immunoblasts in early AITL, which would be absent in HVCD. The most challenging differential would include the mantle zone pattern of mantle cell lymphoma. Flow cytometry revealing a monotypic process with co-expression of cyclin D1 on IHC would further clarify the diagnosis.1

Overall, unicentric Castleman’s disease is usually of the hyaline vascular type. Surgical resection is usually curative in these cases with an excellent prognosis.2

 

References

  1. Jaffe, ES, Harris, NL, Vardiman, J, Campo, E, Arber, D. Hematopathology. Philadelphia: Elsevier Saunders, 2011. 1st ed.
  2. Ye, B, Gao, SG, Li, W et al. A retrospective study of unicentric and multicentric Castleman’s disease: a report of 52 patients. Med Oncol (2010) 27: 1171.

 

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 Man Presenting with Marked Thrombocytopenia One Year after Bone Marrow Transplantation

Case history

The patient is a 69-year-old man with a history of high-risk MDS (MDS-MLD-RS) diagnosed 1 year prior to his current visit. He was successfully treated with chemotherapy and bone marrow transplantation. For the next year, several marrow examinations were normal and chimerism analysis revealed >98% donor cells. Currently, he presents with vague symptoms and a CBC demonstrates marked thrombocytopenia of 4K/μL.  The low platelet count is initially thought to be related to GVHD; however, a bone marrow examination is performed to assess the status of his disease.

DiGug1.png
Wright-Geimsa, 2X
DiGug2.png
Wright-Geimsa, 100X
DiGug3
E-Cadherin IHC, 4X

Microscopic Description

Examination of the bone marrow reveals a markedly hypercellular marrow for age with a proliferation of abnormal erythroid cells comprised of sheets of immature and maturing red cell precursors with basophilic cytoplasm. There is a marked increase in larger cells with deeply basophilic cytoplasm, prominent nucleoli, dispersed chromatin, perinuclear hoffs, and a high nuclear to cytoplasmic ratio consistent with pronormoblasts. These pronormoblasts comprised 31% of a 500-cell cell count. Additionally, the background marrow revealed a total of 81% erythroid precursors with marked morphologic atypia and dyspoiesis. Significant dysmegakaryopoiesis is noted. There is no significant increase in myeloid blasts.

Immunophenotyping

Immunohistochemical staining for E-cadherin, CD61 and CD34 is performed. These stains confirm no increase in CD34 positive blasts. CD61 highlights numerous dyspoietic megakaryocytes with widely separated nuclear lobes. E-cadherin staining is impressive, with over 80% of marrow cellularity shown to be comprised of E-cadherin positive erythroid cells.

Diagnosis

The patient’s history of MDS with current dyspoiesis, presence of >80% immature erythroid precursors with >30% proerythroblasts is diagnostic of Acute Myeloid Leukemia, NOS (Pure Erythroid Leukemia) per 2017 revision of the World Health Organization classification of myeloid neoplasms.

While successive chimerism reports thus far had shown >98% donor cells, the chimerism associated with this marrow biopsy reveals a decrease in the percentage of donor cells to 44% confirming the relapsed nature of his myeloid malignancy.

Discussion

Di Guglielmo syndrome, known as M6 leukemia in the FAB classification, was named after Giovanni Di Guglielmo, an Italian hematologist who first characterized the disease in 1917. After a few iterations in different classification schemes, the 2008 WHO Classification characterized two types of ‘erythroleukemia’ the erythroid/myeloid type and the pure erythroid leukemia. The former category of erythroid/myeloid type was removed in the 2017 update of the WHO classification with cases meeting criteria for that diagnosis now falling under the category of MDS. ‘Pure Erythroid Leukemia’ remains, and comes under the AML, NOS category, requiring >80% erythroid progenitors with > 30% proerythroblasts.

An extremely rare leukemia, PEL usually occurs as a progression of previous MDS and very uncommonly as de novo disease. Morphologically, PEL reveals proerythroblasts with deeply basophilic, agranular cytoplasm which is usually vacuolated. Occasionally, smaller ‘blasts’ with scant cytoplasm may resemble lymphoblasts. PEL is an exception to the rule of needing 20% ‘myeloid blasts’ to make an acute leukemia, since often the true myeloblast count is low.

In trephine core biopsies erythroid progenitors may take up an intra sinusoidal growth pattern with a sheet-like arrangement and typically reveal some element of background dysmegakaryocytopoiesis. When PEL lacks specific erythroid differentiation, it may be difficult to differentiate from other types of AML such as Acute Megakaryoblastic Leukemia. Park and colleagues recently categorized some under reported morphologic features of PEL and recurrent cytogenetic abnormalities associated with this disease. These findings included (but were not limited to) a broad morphologic spectrum of erythroblast morphology from undifferentiated blasts to proerythroblasts. They reported bone marrow tumour necrosis in trephine biopsies in over 70%  of their cases. Of the cases wherein karyotyping was available, there was a highly complex and monosomal karyotype noted involving the TP53 gene locus.

PEL is associated with an aggressive course with a median survival of 3 months.

References

  1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016 Jan 1:blood-2016.
  2. Wang W, Wang SA, Jeffrey Medeiros L, Khoury JD. Pure erythroid leukemia. American journal of hematology. 2017 Mar 1;92(3):292-6.
  3. Park DC, Ozkaya N, Lovitch SB. Acute leukaemia with a pure erythroid phenotype: under-recognized morphological and cytogenetic signatures associated universally with primary refractory disease and a dismal clinical outcome. Histopathology. 2017 Aug;71(2):316-321. doi: 10.1111/his.13207. Epub 2017 May 5.

 

Mike

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

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-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 42 Year Old Female with Right Breast Mass

Case History

A 42-year-old female presented with a right breast mass at an outside hospital that was concerning for carcinoma. A core needle biopsy was performed of right breast mass and the case was sent for expert consultation.

Diagnosis

SHML5x
H&E, 5x
SHML10x
H&E, 10x
SHML20x
H&E, 20x
SHML50x
H&E, 50x

Sections of core needle biopsy material are composed primarily of adipose tissue shows a dense lymphohistiocytic infiltrate with histiocytes being the dominant cell type. Admixed plasma cells are present within the infiltrate. The histiocytes have abundant granular cytoplasm with irregular nuclear contours and some nuclei containing inconspicuous nucleoli. Frequent lymphocytic emperipolesis is identified. Immunohistochemistry performed at the outside facility show positivity for S100 and CD163 within the histiocytes, further highlighting the lymphocytic emperipolesis. Cytokeratin immunostains are negative.

Overall, the morphologic and immunophenotypic findings are consistent with a diagnosis of extranodal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

Discussion

Sinus histiocytosis with massive lymphadenopathy (SHML) was first described by Rosai and Dorfman in 1969, however, similar findings may be present in extranodal sites thus earning the designation of Rosai-Dorfman disease (RDD). Although primarily present in lymph nodes, RDD may involve extranodal sites with sinuses and skin being the most frequently affected tissue types. Clinically, RDD often maintains a benign and self-limited course but may undergo exacerbations and recur, requiring surgical management. On histologic examination, RDD involves a rich inflammatory infiltrate with histiocytes, plasma cells, and lymphocytes. The histiocytes usually display a unique phenotype in which lymphocytes are phagocytosed, a process termed emperipolesis. By immunohistochemistry, these histiocytes are positive for S-100 and histiocytic markers (CD68 and CD163) and are negative for CD1a1.

The largest cohort studied involved 423 cases with 182 having extranodal manifestations2. Chest involvement was first reported by Govender et al. in 1997 in a 34-year-old female3. Overall, RDD is considered rare with a slight male predilection and young African-Americans being the most commonly affected. Sites involved ranging from most common to least common include lymph nodes, skin, upper respiratory tract, and bone4.

Extranodal sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease, is a rare pathologic entity that histologically shows a dense lymphohistiocytic infiltrate and emperipolesis, a hallmark of the disease. Although lymph nodes are the most common site of involvement, extranodal sites may be affected and RDD should remain in the differential for lesions that contain abundant histiocytes, plasma cells, and lymphocytes as well as the classic feature of emperipolesis.

References

  1. Komaragiri et al.: Extranodal Rosai–Dorfman disease: a rare soft tissue neoplasm masquerading as a sarcoma. World Journal of Surgical Oncology 2013 11:63.
  2. Penna Costa AL, Oliveira e Silva N, Motta MP, Athanazio RA, Athanazio DA, Athanazio PRF: Soft tissue Rosai–Dorfman disease of the posterior J Bras Pneumol 2009, 35:717–720.
  3. Govender D, Chetty R: Inflammatory pseudotumour and Rosai–Dorfman disease of soft tissue: a histological continuum? J Clin Pathol 1997, 50:79–
  4. Montgomery EA, Meis JM: Rosai–Dorfman disease of soft tissue. Am J Surg Pathol 1992, 16:122–129.

 

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 64 Year Old Man with Widespread Lymphadenopathy

Case history

A 64-year-old, previously healthy man presented with a history of cervical and axillary lymphadenopathy of unknown duration. He did not endorse night sweats, weight loss, or fever. Radiologic examination (CT chest and MRI abdomen) revealed numerous enlarged mediastinal, peritracheal, periaortic, periportal and retroperitoneal lymph nodes. He underwent excisional biopsy of a 3.5 cm axillary lymph node.

foll-lymph

Microscopic Description

Histologic examination of the node revealed distortion of nodal architecture by a proliferation of neoplastic-appearing follicles. Follicles were distinct from one another, and closely packed. In areas the follicles were present back-to-back. Follicular centers were comprised of mostly small, cleaved centrocytes and showed no obvious zonation. There was loss of tingible body macrophages.

Immunophenotyping

Immunohistochemical analysis revealed CD20-positive B cells in a follicular pattern. The germinal centers revealed an underlying follicular dendritic meshwork highlighted by staining for CD21. Interestingly, while the germinal centers demonstrated immunopositivity for BCL-6, there was minimal to absent CD10 staining on follicular B cells. Analysis of BCL-2 staining revealed only few cells to be positive within the follicular centers, consistent with resident follicular helper T cells (Th cells). Equivalent numbers of CD3 and CD5 positive T cells were noted in the interfollicular zones. The Ki-67 proliferation index was estimated at 15-20% within follicular centers. Flow cytometric phenotyping demonstrated a lambda light chain restricted clonal B-cell population expressing CD20, CD19 and, FMC7. These neoplastic B-cells were negative for CD5 and CD10 expression.

Diagnosis

The morphologic features were consistent with Follicular Lymphoma; however the phenotype (BCL-2 negativity in follicular centers) was unusual for this diagnosis. Fluorescence in situ hybridization (FISH) was negative for an IgH/BCL-2 fusion; however, a BCL-6 rearrangement at the 3q27 locus was detected in 70% of the cells.  Taken together, a diagnosis of Follicular Lymphoma with a BCL-6 rearrangement was given.

Discussion

Follicular lymphoma (FL) is a germinal center derived B-cell neoplasm. The majority of cases exhibit the pathognomonic translocation t(1418)(q32; q21). This translocation leads to overexpression of the anti-apoptotic BCL-2 protein, which can be detected by immunohistochemistry on germinal center B cells. Lymphoma cells are usually positive for germinal center origin markers BCL-6 and CD10 and do not co-express CD5. As exhibited in this case, FL can exhibit biologic heterogeneity and may not express these typical markers. The follicular proliferation with absence of germinal center zonation and tingible body macrophages as seen in this case represents classic morphology of follicular lymphoma but aberrant phenotypic markers [and absence of t(14;18)] may be a pitfall in this diagnosis.

FL with lacking of CD10 expression, BCL-2 expression, and t(14;18) translocation and harboring only BCL-6 positivity with 3q27 rearrangement is rare. Only few such cases have been reported in the literature. Published data reveals that the hallmark t(14;18) translocation is absent in about 10-15% of FL. The majority of these cases are negative for BCL-2 expression, and 9-14% of them demonstrate BCL-6 rearrangement (3q27 locus). While BCL-6 rearrangement can be present in both the usual t(14;18) harboring FL, and also in cases without t(14;18), the latter is rare. Interestingly, studies have shown BCL-6 rearrangements to be more frequent in in BCL-2 rearrangement negative FL – which is evidence of the anti-apoptotic role of non-rearranged BCL-6 in certain microenvironments.

One third of t(14;18) negative FL are also reported to have rare or negative expression of CD10. Morphologically, this subtype has been shown to have significantly larger follicles than  their t(14;18)-positive counterparts, but the distinction may not be obvious in all cases. Some of these cases are shown to have a component of monocytoid B cells. This findings can be problematic in differentiating these FL cases from marginal zone lymphoma (MZL) that can also harbor BCL-6 rearrangements and lack t(14;18), CD10 and BCL-2 positivity. Absence of prominent marginal zone proliferation, BCL-6 protein expression and characteristic genetic alterations present in MZL, such as trisomies 3, 7, and 18 can help differentiating MZL from t(14;18)-negative FL.

This case highlights the importance of morphologic evaluation of a excisional biopsy tissue, and FISH studies to help identify the rare t(14;18) negative FL. While the reported cases are few, there is no published difference in prognosis or survival when compared to t(14;18)-positive FL. As such, it is not clear whether the follicular lymphoma grading scheme applies to t(14;18)-negative FL; however, no significant grading difficulties or differences have been reported.

References

  1. Jardin F, Gaulard P, Buchonnet G, et al. Follicular lymphoma without t(14;18) and with BCL-6 rearrangement: a lymphoma subtype with distinct pathological, molecular and clinical characteristics. Leukemia. 2002;16:2309–2317
    2. Leich E, Salaverria I, Bea S, et al. Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations. Blood. 2009;114(4):826-834.

 

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Aadil Ahmed, MD is a 3rd-year anatomic and clinical pathology resident at Loyola University Medical Center. Follow Dr. Ahmed on Twitter @prion87.

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 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.
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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.