CASE REPORT
Localized Crystal-Storing Histiocytosis Presenting as a Breast Nodule: An Unusual Presentation of a Rare Entity Shweta Chaudhary, MD,*,1 Maria Navarro, MD,* Jordan Laser, MD,* Evan Berman, MD,† and Tawfiqul Bhuiya, MD* *Department of Pathology and Lab Medicine, North Shore LIJ Health System, Lake Success, New York; †Department of Surgery, Forest Hills Hospital, Flushing, New York
n Abstract: Crystal-storing histiocytosis (CSH) is a rare disorder associated with crystalline immunoglobulin deposition in the cytoplasm of histiocytes and is usually associated with lymphoproliferative or plasma cell disorders (LP-PCD) that express monoclonal immunoglobulin. Localized CSH without underlying LP-PCD are extremely rare. We report a case of localized CSH in breast which was an unexpected difficult diagnosis. The awareness of this entity is of importance to delineate it morphologically from other common differential diagnosis and enable appropriate management. To date, this is the first case of localized CSH reported in breast in a patient with no known history of LP-PCD. n Key Words: breast, crystal-storing histiocytosis, hypoechoic nodule
CASE REPORT
A
30-year-old female with history of thalassemia trait, mild hepato-splenomegaly, and an episode of mild transient thrombocytopenia and hypogammaglobulinemia 3 years back presented with a nonpalpable breast mass. Her family history was notable for follicular lymphoma in her father. Ultrasonography (US) revealed a hypoechoic nodule with echogenic rim (1.2 9 0.9 9 0.7 cm) in right breast at 3 o’ clock location and 2 cm from the nipple. An US guided core biopsy was performed using a 14 gauge vacuum assisted biopsy needle. Six 14 g cores were obtained and a biopsy clip was placed in the lesion. Hematoxylin and eosin stained slides showed fibro-fatty breast tissue infiltrated with numerous spindled, ovoid, and polygonal cells with abundant cytoplasm containing granular to palisaded eosinophilic refractile material (Fig. 1a–c). Nuclei were bland with small inconspicuous nucleoli. Small
Address correspondence and reprint requests to: Shweta Chaudhary, MD, Department of Pathology and Lab Medicine, North Shore LIJ Health System, Lake Success, NY, USA, or e-mail: [email protected] 1 Present address: Department of Pathology, Icahn School of Medicine at Mount Sinai Medical Center, One Gustave L Levy Place, Annenberg Bldg. 15-44, Box-1194, New York, NY 10029, USA. DOI: 10.1111/tbj.12307 © 2014 Wiley Periodicals, Inc., 1075-122X/14 The Breast Journal, Volume 20 Number 5, 2014 539–542
amount of lymphoplasmacytic infiltrate with occasional Dutcher bodies was admixed. Immunostains for CD 68, myoglobin, smooth muscle actin, desmin, myogenin, inhibin, S-100, CD138 were performed. All immunostains performed were negative except CD68 which confirmed the lesional cells to be histiocytes (Fig. 1d). CD138 stain highlighted few plasma cells. Electron microscopy showed rectangular to rhomboid shaped crystalline structures measuring 291–333 nm in diameter, compatible with immunoglobulin crystals (Fig. 2). The diagnosis of crystal-storing histiocytosis (CSH) was made and excision was advised to rule out associated lymphoproliferative or plasma cell disorder (LP-PCD). A follow-up needle localized segmental excision was performed. Grossly, excision specimen (5.5 9 5.0 9 2.0 cm) demonstrated an ill-defined gray white firm area with central hemorrhage and surrounding fat necrosis (0.8 9 0.8 9 0.6 cm). Microscopy showed fatty mammary parenchyma with clusters of crystal-storing histiocytes similar to that seen in prior biopsy, reactive fibrosis, and rare small foci of atypical lymphoplasmacytic infiltrates (Fig. 3a). Immunohistochemistry panel showed lymphoplasmacytic infiltrates composed of a mixed B (CD20 positive) and T (CD3 and CD43 positive) cell population (Fig. 3b–d). In situ hybridization (ISH) studies performed for kappa and lambda expression showed a
540 • chaudhary et al.
(a)
(b)
(c)
(d)
Figure 1. Core biopsy showing infiltration by histiocytes with abundant eosinophilic granular to palisaded inclusions in the cytoplasm (a) H & E stain, 9100; (b and c) higher magnification of the same (H & E stain, 9400); (d) CD68 expression in the histiocytes (CD68 immunostain, 9200).
Figure 2. Electron microscopic images showing rectangular to rhomboid shaped crystalline structures measuring 291–333 nm in diameter, compatible with immunoglobulin crystals.
predominant lambda expression in plasma cells. B-cell gene rearrangement studies showed discrete bands in both IgH and IgK, typically indicating a monoclonal population, however definitive interpretation was limited by the small number of cells as it is difficult to exclude pseudoclonality with small sample. With the morphologic, immunophenotypic, and ancillary studies, a diagnosis of crystal-storing histiocytosis with atypical lymphoplasmacytic infiltrate was made and follow-up to rule out LP-PCD at any other body site was suggested.
The peripheral blood picture, red cell indices, hemoglobin electrophoresis, and iron studies were all in concordance with her history of thalassemia trait. All other lab results including serum immunoglobulin levels, serum, and urine protein electrophoresis and immunofixation studies, stool guaiac test, infectious mononucleosis screen, hepatitis screen, bilirubin, and lactate dehydrogenase levels were within normal limits. Whole body PET CT imaging was unremarkable. Twenty months follow-up was unremarkable for identification or development of any new disease process.
Localized Crystal-Storing Histiocytosis in Breast • 541
(a)
(b)
(c)
(d)
Figure 3. Excision biopsy with the histiocytic infiltration and focal lymphoplasmacytic infiltrates (a) H &E, 9100; (b–d) immunohistochemistry for CD20, CD3, and CD43 markers (9200).
DISCUSSION Crystal-storing histiocytosis occurs due to an intralysosomal accumulation of the paraproteins as crystalline inclusions in histiocytes associated with lymphoplasmacytic cells in hematopoietic, epithelial, or the stromal connective tissue of organs (1,2). It is postulated that conformational alteration in the protein structure is a crucial factor in pathogenesis of CSH, promoting crystallization, and adversely affecting its lysosomal degradation (2). The age at presentation varies widely, ranging from 17 to 81 years with an approximate equal incidence in males and females (3). The CSH can be localized (confined to a single site or organ) or generalized (involving two or more distant organ/sites). Most common sites of localized CSH are head, neck, and lung. About 90% of CSH cases are associated with an underlying LP-PCD (2,4). CSH may be associated with polyclonal features and has been reported in association with plasma cell granuloma, rheumatoid arthritis, and hypergammaglobulinemia (4). However, a few cases are reported where CSH preceded the diagnosis of LPD by a few months to 4 years (4). Our case was associated with lymphoplasmacytic infiltrate which showed predominant lambda expression on ISH and monoclonality on B-cell gene rearrangement studies. However, it was insufficient to make a diagnosis of LP-PCD in view of scant infiltrate showing mixed T- and B-cell population. Localized solitary extra medullary presentation is extremely rare and is exceptionally rare in breast. Till date, only one
case of multifocal breast involvement by CSH has been reported in a patient with past history of marginal zone lymphoma (5). Our case is unique for the localized presentation in breast with no past history of LP-PCD. This entity in breast can be easily missed or misinterpreted as fat necrosis and biopsy site changes in the absence of clinical suspicion. Careful evaluation of histiocytes for the presence of refractile crystals differentiates it from fat necrosis which is usually associated with clear vacuolated cytoplasm of histiocytes. Negativity for muscle markers (desmin, muscle specific actin, myoglobin) and presence of CD68 expression excluded diagnosis of rhabdomyoma. Presence of focal rod like inclusions in rhabdomyoma can closely mimic CSH but positivity for muscle markers will easily differentiate it from CSH. Absence of S100 immunostaining in our case excluded granular cell tumor as a differential. A granular cell tumor in addition to CD68 will be positive for S-100 protein. To conclude, it is essential to be aware of the existence of this entity in breast, allowing for accurate diagnoses and appropriate follow-up management especially in patients with no or previously unrecognized LP-PCD.
REFERENCES 1. Kapadia SB, Enzinger FM, Heffner DK, Hyams VJ, Frizzera G. Crystal-storing histiocytosis associated with lymphoplasmacytic neoplasms. Report of three cases mimicking adult rhabdomyoma. Am J Surg Pathol 1993;17:461–7.
542 • chaudhary et al.
2. Lebeau A, Zeindl-Eberhart E, Muller EC, et al. Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of literature. Blood 2002;100:1817–27. 3. Dogan S, Barnes L, Cruz-Vetrano WP. Crystal-storing histiocytosis: report of a case, review of the literature (80 cases) and a proposed classification. Head Neck Pathol 2012;6:111–20.
4. Jones D, Bhatia VK, Krausz T, Pinkus GS. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain. Hum Pathol 1999;30: 1441–8. 5. Gao FF, Khalbuss WE, Austin RM, Monaco SE. Cytomorphology of crystal storing histiocytosis in the breast associated with lymphoma: a case report. Acta Cytol 2011;55:302–6.
Localized Crystal-Storing Histiocytosis Presenting as a Breast Nodule: An Unusual Presentation of a Rare Entity Shweta Chaudhary, MD,*,1 Maria Navarro, MD,* Jordan Laser, MD,* Evan Berman, MD,† and Tawfiqul Bhuiya, MD* *Department of Pathology and Lab Medicine, North Shore LIJ Health System, Lake Success, New York; †Department of Surgery, Forest Hills Hospital, Flushing, New York
n Abstract: Crystal-storing histiocytosis (CSH) is a rare disorder associated with crystalline immunoglobulin deposition in the cytoplasm of histiocytes and is usually associated with lymphoproliferative or plasma cell disorders (LP-PCD) that express monoclonal immunoglobulin. Localized CSH without underlying LP-PCD are extremely rare. We report a case of localized CSH in breast which was an unexpected difficult diagnosis. The awareness of this entity is of importance to delineate it morphologically from other common differential diagnosis and enable appropriate management. To date, this is the first case of localized CSH reported in breast in a patient with no known history of LP-PCD. n Key Words: breast, crystal-storing histiocytosis, hypoechoic nodule
CASE REPORT
A
30-year-old female with history of thalassemia trait, mild hepato-splenomegaly, and an episode of mild transient thrombocytopenia and hypogammaglobulinemia 3 years back presented with a nonpalpable breast mass. Her family history was notable for follicular lymphoma in her father. Ultrasonography (US) revealed a hypoechoic nodule with echogenic rim (1.2 9 0.9 9 0.7 cm) in right breast at 3 o’ clock location and 2 cm from the nipple. An US guided core biopsy was performed using a 14 gauge vacuum assisted biopsy needle. Six 14 g cores were obtained and a biopsy clip was placed in the lesion. Hematoxylin and eosin stained slides showed fibro-fatty breast tissue infiltrated with numerous spindled, ovoid, and polygonal cells with abundant cytoplasm containing granular to palisaded eosinophilic refractile material (Fig. 1a–c). Nuclei were bland with small inconspicuous nucleoli. Small
Address correspondence and reprint requests to: Shweta Chaudhary, MD, Department of Pathology and Lab Medicine, North Shore LIJ Health System, Lake Success, NY, USA, or e-mail: [email protected] 1 Present address: Department of Pathology, Icahn School of Medicine at Mount Sinai Medical Center, One Gustave L Levy Place, Annenberg Bldg. 15-44, Box-1194, New York, NY 10029, USA. DOI: 10.1111/tbj.12307 © 2014 Wiley Periodicals, Inc., 1075-122X/14 The Breast Journal, Volume 20 Number 5, 2014 539–542
amount of lymphoplasmacytic infiltrate with occasional Dutcher bodies was admixed. Immunostains for CD 68, myoglobin, smooth muscle actin, desmin, myogenin, inhibin, S-100, CD138 were performed. All immunostains performed were negative except CD68 which confirmed the lesional cells to be histiocytes (Fig. 1d). CD138 stain highlighted few plasma cells. Electron microscopy showed rectangular to rhomboid shaped crystalline structures measuring 291–333 nm in diameter, compatible with immunoglobulin crystals (Fig. 2). The diagnosis of crystal-storing histiocytosis (CSH) was made and excision was advised to rule out associated lymphoproliferative or plasma cell disorder (LP-PCD). A follow-up needle localized segmental excision was performed. Grossly, excision specimen (5.5 9 5.0 9 2.0 cm) demonstrated an ill-defined gray white firm area with central hemorrhage and surrounding fat necrosis (0.8 9 0.8 9 0.6 cm). Microscopy showed fatty mammary parenchyma with clusters of crystal-storing histiocytes similar to that seen in prior biopsy, reactive fibrosis, and rare small foci of atypical lymphoplasmacytic infiltrates (Fig. 3a). Immunohistochemistry panel showed lymphoplasmacytic infiltrates composed of a mixed B (CD20 positive) and T (CD3 and CD43 positive) cell population (Fig. 3b–d). In situ hybridization (ISH) studies performed for kappa and lambda expression showed a
540 • chaudhary et al.
(a)
(b)
(c)
(d)
Figure 1. Core biopsy showing infiltration by histiocytes with abundant eosinophilic granular to palisaded inclusions in the cytoplasm (a) H & E stain, 9100; (b and c) higher magnification of the same (H & E stain, 9400); (d) CD68 expression in the histiocytes (CD68 immunostain, 9200).
Figure 2. Electron microscopic images showing rectangular to rhomboid shaped crystalline structures measuring 291–333 nm in diameter, compatible with immunoglobulin crystals.
predominant lambda expression in plasma cells. B-cell gene rearrangement studies showed discrete bands in both IgH and IgK, typically indicating a monoclonal population, however definitive interpretation was limited by the small number of cells as it is difficult to exclude pseudoclonality with small sample. With the morphologic, immunophenotypic, and ancillary studies, a diagnosis of crystal-storing histiocytosis with atypical lymphoplasmacytic infiltrate was made and follow-up to rule out LP-PCD at any other body site was suggested.
The peripheral blood picture, red cell indices, hemoglobin electrophoresis, and iron studies were all in concordance with her history of thalassemia trait. All other lab results including serum immunoglobulin levels, serum, and urine protein electrophoresis and immunofixation studies, stool guaiac test, infectious mononucleosis screen, hepatitis screen, bilirubin, and lactate dehydrogenase levels were within normal limits. Whole body PET CT imaging was unremarkable. Twenty months follow-up was unremarkable for identification or development of any new disease process.
Localized Crystal-Storing Histiocytosis in Breast • 541
(a)
(b)
(c)
(d)
Figure 3. Excision biopsy with the histiocytic infiltration and focal lymphoplasmacytic infiltrates (a) H &E, 9100; (b–d) immunohistochemistry for CD20, CD3, and CD43 markers (9200).
DISCUSSION Crystal-storing histiocytosis occurs due to an intralysosomal accumulation of the paraproteins as crystalline inclusions in histiocytes associated with lymphoplasmacytic cells in hematopoietic, epithelial, or the stromal connective tissue of organs (1,2). It is postulated that conformational alteration in the protein structure is a crucial factor in pathogenesis of CSH, promoting crystallization, and adversely affecting its lysosomal degradation (2). The age at presentation varies widely, ranging from 17 to 81 years with an approximate equal incidence in males and females (3). The CSH can be localized (confined to a single site or organ) or generalized (involving two or more distant organ/sites). Most common sites of localized CSH are head, neck, and lung. About 90% of CSH cases are associated with an underlying LP-PCD (2,4). CSH may be associated with polyclonal features and has been reported in association with plasma cell granuloma, rheumatoid arthritis, and hypergammaglobulinemia (4). However, a few cases are reported where CSH preceded the diagnosis of LPD by a few months to 4 years (4). Our case was associated with lymphoplasmacytic infiltrate which showed predominant lambda expression on ISH and monoclonality on B-cell gene rearrangement studies. However, it was insufficient to make a diagnosis of LP-PCD in view of scant infiltrate showing mixed T- and B-cell population. Localized solitary extra medullary presentation is extremely rare and is exceptionally rare in breast. Till date, only one
case of multifocal breast involvement by CSH has been reported in a patient with past history of marginal zone lymphoma (5). Our case is unique for the localized presentation in breast with no past history of LP-PCD. This entity in breast can be easily missed or misinterpreted as fat necrosis and biopsy site changes in the absence of clinical suspicion. Careful evaluation of histiocytes for the presence of refractile crystals differentiates it from fat necrosis which is usually associated with clear vacuolated cytoplasm of histiocytes. Negativity for muscle markers (desmin, muscle specific actin, myoglobin) and presence of CD68 expression excluded diagnosis of rhabdomyoma. Presence of focal rod like inclusions in rhabdomyoma can closely mimic CSH but positivity for muscle markers will easily differentiate it from CSH. Absence of S100 immunostaining in our case excluded granular cell tumor as a differential. A granular cell tumor in addition to CD68 will be positive for S-100 protein. To conclude, it is essential to be aware of the existence of this entity in breast, allowing for accurate diagnoses and appropriate follow-up management especially in patients with no or previously unrecognized LP-PCD.
REFERENCES 1. Kapadia SB, Enzinger FM, Heffner DK, Hyams VJ, Frizzera G. Crystal-storing histiocytosis associated with lymphoplasmacytic neoplasms. Report of three cases mimicking adult rhabdomyoma. Am J Surg Pathol 1993;17:461–7.
542 • chaudhary et al.
2. Lebeau A, Zeindl-Eberhart E, Muller EC, et al. Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of literature. Blood 2002;100:1817–27. 3. Dogan S, Barnes L, Cruz-Vetrano WP. Crystal-storing histiocytosis: report of a case, review of the literature (80 cases) and a proposed classification. Head Neck Pathol 2012;6:111–20.
4. Jones D, Bhatia VK, Krausz T, Pinkus GS. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain. Hum Pathol 1999;30: 1441–8. 5. Gao FF, Khalbuss WE, Austin RM, Monaco SE. Cytomorphology of crystal storing histiocytosis in the breast associated with lymphoma: a case report. Acta Cytol 2011;55:302–6.
