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Postchemotherapy Histiocyte-Rich Pseudotumor Involving the Spleen

Pranil Chandra DO, Yong Hannah Wen MD, PhD, Sandeep Tuli DO, Bruce G. Raphael MD, Edward L. Amorosi MD, L. Jeffrey Medeiros MD, Sherif Ibrahim MD, PhD
DOI: http://dx.doi.org/10.1309/AJCPC67QOGJXCEZB 342-348 First published online: 1 September 2009

Abstract

We report 2 cases of splenic postchemotherapy histiocyte-rich pseudotumor. Each patient had a history of diffuse large B-cell lymphoma, treated with multiagent chemotherapy. Computed tomography scans performed on both patients showed splenic masses. A positron emission tomography scan performed on 1 patient showed increased metabolic activity. The preoperative diagnosis in both patients was recurrent lymphoma, prompting splenectomy. The splenectomy specimens showed multiple, tan-white, firm nodules, up to 3.5 cm in diameter, that were histologically composed of central necrotic B cells (CD20+/CD3−), consistent with necrotic lymphoma, surrounded by numerous lipid-laden (xanthomatous) histiocytes. Clinical staging studies at the time of splenectomy showed no other sites of disease. We conclude that these histologic and immunophenotypic findings represent chemotherapy-induced tumor necrosis with a florid histiocytic reaction mimicking residual viable lymphoma. Others have used descriptive terminology or the term xanthomatous pseudotumor for these lesions that have been only rarely reported in the spleen previously.

Key Words:
  • Spleen
  • Pseudotumor
  • Postchemotherapy
  • Xanthomatous histiocytes
  • Necrosis

Cytotoxic chemotherapy is known to induce tumor necrosis via a variety of mechanisms. For patients with lymphoma in whom chemotherapy is effective, tumor masses usually resolve, and there is no clinical or radiologic evidence of disease. However, in a subset of patients, particularly patients with very large and bulky tumor masses, necrotic tumor may persist as a residual mass for a variable time after therapy.1,2 In general, residual masses are more common in patients with Hodgkin lymphoma, possibly related to the use of radiation therapy in management.

One of the challenges of radiologic examination in patients with residual masses after therapy is the distinction of residual viable lymphoma from tumor necrosis. Unlike computed tomography (CT) or magnetic resonance imaging, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) offers the advantage that one can assess the metabolic activity of the cells in the mass.2 Necrotic tumor is not metabolically active, and, therefore, PET scan is very helpful in determining the need for additional therapy in this clinical setting. Nevertheless, in some patients, biopsy may be required to resolve this question. When the residual mass is necrotic tumor, histologic examination reveals eosinophilic ghosts of necrotic lymphoma cells associated with inflammation. Rarely, the inflammatory response can be pronounced.

The term xanthomatous pseudotumor has been proposed for mass-forming lesions composed of numerous lipid-laden histiocytes and tumor necrosis following chemotherapy.3,4 Two such cases designated by this term have been reported in the literature: a small-intestine mass associated with obstruction in a 9-year-old boy after chemotherapy for Burkitt lymphoma and a breast mass in a 46-year-old woman after adjuvant therapy for high-grade invasive ductal carcinoma. In both cases, numerous lipid-laden histiocytes without viable neoplastic cells were identified.

In this report, we describe 2 cases involving the spleen that are part of the spectrum of xanthomatous pseudotumor. Both patients had diffuse large B-cell lymphoma (DLBCL) and were treated with multiagent chemotherapy, and radiologic examination after completion of therapy revealed splenic lesions. In 1 patient, the splenic lesions were positive by FDG-PET scan. Splenectomy was performed to exclude the possibility of persistent or recurrent lymphoma. We suggest the term postchemotherapy histiocyte-rich pseudotumor for these lesions because we believe it more specifically captures the clinical setting and histologic findings.

Report of Cases

Case 1

A 74-year-old man with a history of prostatic adenocarcinoma, treated by prostatectomy, developed DLBCL involving the liver and other sites that were initially diagnosed pathologically by examination of a liver needle biopsy specimen. A PET/CT scan for staging demonstrated multiple metabolically active masses in the liver, spleen, retroperitoneum, and pelvis. In the spleen, there was a large area of intense uptake associated with a 10 × 8-cm mass. The patient was treated with 5 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for a period of 2 months. A PET/CT scan, performed 1 month after chemotherapy, showed complete response of all sites of disease except the spleen, in which a 3 × 2-cm mass was metabolically active. A subsequent PET/CT scan performed 1 month later, 4 months after initial diagnosis, revealed a mild increase in size and more extensive uptake in the splenic lesion and was, therefore, interpreted as progression of residual lymphoma Image 1. Splenectomy was then performed, and no evidence of lymphoma was identified by pathologic examination. Four months after splenectomy, the patient developed recurrent, generalized DLBCL and was treated with 2 cycles of rituximab, ifosfamide, carboplatin, and etoposide chemotherapy with stem cell transplantation. At last follow-up, the patient had no evidence of disease, 28 months after last therapy.

Image 1

A, Initial positron emission tomography (PET) scan demonstrating widespread disease. B, The 2-month follow-up study after initiation of therapy reveals almost complete resolution of disease, except for a small area of residual activity in the spleen. C, The 4-month follow-up study reveals increased size and activity in the splenic lesions suggestive of residual lymphoma. D, Axial PET, computed tomography, and fusion image from the 4-month follow-up study in C that reveals the metabolic area in the spleen to correspond to the low-attenuation mass in the spleen.

Case 2

A 67-year-old man developed DLBCL manifested by abdominal pain, low-grade fever, weight loss, and splenomegaly. An abdominal CT scan showed extensive retroperitoneal lymphadenopathy and 2 large hypodense lesions in an enlarged spleen, each 8 cm in greatest dimension. DLBCL was diagnosed by percutaneous needle biopsy of a retroperitoneal lymph node. The patient was treated with 6 cycles of CHOP. A follow-up abdominal CT scan 3 months after chemotherapy was completed (9 months after initial diagnosis) revealed no retroperitoneal lymphadenopathy. However, there were 2 low-attenuation lesions within the spleen, each 2 cm in diameter, that were stable as shown by a subsequent abdominal CT scan performed 1 month later. Splenectomy was performed to exclude residual lymphoma. At last clinical follow-up, 14 years after diagnosis, the patient was well with no evidence of lymphoma.

Materials and Methods

The spleen specimens were weighed, serially sectioned at 1-cm intervals, and fixed in buffered formalin. Tissue samples were then embedded in paraffin, routinely processed, and stained with H&E and the periodic acid–Schiff (PAS) reaction.

Immunohistochemical studies were performed using fixed, paraffin-embedded tissue sections and a variable panel of antibodies. Both cases were assessed for CD3, CD10, CD20, CD68, cytokeratin (AE1/AE3), and prostate-specific antigen (PSA). Additional antibodies assessed in only 1 case included CD1a, CD21, CD35, S100 protein, anaplastic lymphoma kinase (ALK), lysozyme, and Ki-67.

Results

Case 1

The spleen was 165 g and 12.5 × 8.5 × 4 cm. The capsule was intact and smooth. Cut sections revealed 7 tan-gray, firm nodules throughout the spleen, ranging in size from 0.5 to 3.5 cm. The uninvolved splenic parenchyma was tan-red and unremarkable. Microscopically, the nodules were well-circumscribed, consisting of sheets of histiocytes surrounding central necrotic foci composed of eosinophilic ghosts of intermediate to large cells Image 2A and Image 2B. No viable lymphoma cells were identified. The histiocytes were mostly round to polygonal, clear or more eosinophilic, and had abundant pale to foamy cytoplasm Image 2C and Image 2D. In general, the histiocytes closest to the necrosis had the clear cytoplasm. Some histiocytes had a spindled shape Image 2E. The nuclei were ovoid to spindled, relatively uniform, and small. No cytologic atypia or mitotic activity was noted.

Immunohistochemical analysis showed that the necrotic foci were highlighted by CD20 and were negative for CD3 and CD68, supporting necrotic B-cell lymphoma cells Image 3B. Histiocytes were positive for CD68 Image 3A and negative for CD3 and CD20. The necrotic cells and histiocytes were negative for all other markers tested, including CD1a, CD3, CD10, CD20, CD21, CD35, cytokeratin, S-100 protein, and PSA. The Ki-67 index was low, with fewer than 5% of cell nuclei being positive.

Case 2

The spleen was 227 g. The surface was smooth. The cut surface had 2 yellow nodules, 2 × 1.8 × 0.8 cm and 1.2 × 1.0 × 0.4 cm. Microscopically, the centers of the nodules were composed of medium to large, eosinophilic ghosts of cells surrounded by numerous foamy histiocytes associated with granulomas and cholesterol clefts Image 4A and Image 4B. Immunohistochemical analysis showed that the necrotic cells were reactive with CD20 and negative for CD3 and CD68, supporting necrotic B-cell lymphoma cells. The histiocytes were positive for CD68 and lysozyme and were negative for CD3 and CD20. The necrotic cells and histiocytes were negative for CD10, ALK, cytokeratin, and PSA.

Discussion

Chemotherapeutic induction of tumor necrosis is a well-known phenomenon. As a response to tumor necrosis and presumed release of chemotactic substances, circulating monocytes are recruited to the site and differentiate into histiocytes (macrophages). Histiocytes then become activated and increase in size, with increased levels of lysosomal enzymes and phagocytic capability. Chemokines produced by activated histiocytes stimulate the recruitment of additional monocytes from the circulation, and, consequently, histiocyte accumulation in response to tumor necrosis can be abundant. It seems reasonable to hypothesize that this process can be pronounced in the spleen because it is a major repository of phagocytic cells and it has a rich vascular supply. The spatial distribution and lipid-laden (foamy) cytoplasm of the histiocytes observed in both cases we report illustrate this process of recruitment of monocytes from the circulation and their differentiation into histiocytes with phagocytic activity.

It is not uncommon for patients with Hodgkin lymphoma and non-Hodgkin lymphoma, after multiagent chemotherapy, to have residual masses for which the clinical differential diagnosis includes persistent lymphoma vs necrotic tumor.1,2 Residual masses are more common in patients with large, bulky masses and in patients with Hodgkin lymphoma.2 After completion of therapy, CT or PET scan is commonly used to evaluate for residual lymphoma.1,57 CT scans are very sensitive for detecting residual masses but are less helpful in distinguishing viable from necrotic lymphoma. In contrast, a PET scan theoretically is more helpful because nonviable tissue is not metabolically active.2 However, the PET scan was misleading in case 1 in this report. Presumably, the numerous histiocytes in this lesion accounted for the uptake of FDG in this case. Others have shown that abundant posttherapy inflammatory changes can yield false-positive PET scan results after therapy, particularly in the first few months after completion of therapy.2,8,9

Image 2

(Case 1) A, Low-power view of necrotic foci composed of ghosts of cells (H&E, ×100). B, Foamy histiocytes surrounding the necrotic foci (H&E, ×200). C, Higher magnification of foamy histiocytes showing bland morphology and lack of mitotic figures (H&E, ×400). D, Histiocytes with eosinophilic cytoplasm (H&E, ×400). E, Histiocytes with spindled morphology (H&E, ×400).

Although residual masses after therapy are not uncommon in patients with lymphoma and can also occur in patients with solid tumors, residual masses are most often found at lymph node sites or within the mediastinum.2,7,10 Extranodal sites, including the spleen, are less commonly involved, and splenectomy is rarely performed in this clinical setting. As a result, postchemotherapy histiocyte-rich pseudotumor has been only rarely reported in the spleen. We found 1 report in the literature that is relevant to the 2 cases we report. Ford and colleagues11 described 2 patients with splenic involvement by non-Hodgkin lymphoma, one patient with Burkitt lymphoma and the other DLBCL, in whom PET scans after chemotherapy showed uptake. Splenectomy was performed in these cases in which distinct lesions composed of necrosis and chronic inflammation were identified. Granulomatous inflammation was described in 1 case, but numerous lipid-laden histiocytes, as seen in the 2 cases we report, were not specifically mentioned. Others have reported tumor-like lesions involving other extranodal sites, including the intestine, breast, and mediastinum in patients being treated for Burkitt lymphoma, breast carcinoma, and Hodgkin lymphoma, respectively.3,4,12 In these prior reports, the terms xanthomatous pseudotumor and benign histiocytic proliferation with xanthomatous changes were used for these lesions because they were composed of numerous histiocytes with foamy cytoplasm. The 2 cases we report are very similar to these lesions. We have chosen to use the term postchemotherapy histiocyte-rich pseudotumor because we believe it more closely captures the clinical setting and pathologic findings of these lesions.

Image 3

(Case 1) Immunohistochemical stains showed CD68+ histiocytes (A; ×400) and CD20+ necrotic cells (B, ×40; inset, ×400).

Image 4

(Case 2) Microscopic images. A, Low-power view of the lesion (H&E, ×12.5). B, Foamy histiocytes (H&E, ×400).

The differential diagnoses for these splenic lesions included metastatic carcinoma, histiocytic sarcoma, Langerhans cell histiocytosis, storage diseases such as Gaucher disease, inflammatory myofibroblastic tumor, and follicular dendritic cell sarcoma. In case 1, the patient had a history of prostate carcinoma, and, therefore, metastatic prostate carcinoma needed to be excluded. Although most prostate carcinomas do not resemble postchemotherapy histiocyte-rich pseudotumor, there is an unusual variant of prostate carcinoma known as foamy gland carcinoma. This neoplasm is characterized by cells with abundant xanthomatous cytoplasm and the absence of nuclear enlargement and prominent nucleoli.13 The pale and focally clear cytoplasm of the histiocytes in the lesions we report also resembled, in part, metastatic renal cell carcinoma. Splenic metastases of various types of carcinoma, including renal cell carcinoma, although rare, are reported in the literature.14 The anticytokeratin and anti-PSA antibodies were very helpful; no keratin- or PSA-positive cells were identified in the 2 splenic lesions we report, effectively excluding carcinoma.

Numerous histiocytes forming a mass and associated with necrosis raised the possibility of histiocytic sarcoma, which is a rare malignant neoplasm composed of cells with morphologic and immunophenotypic features similar to mature tissue histiocytes.15 Histiocytic sarcomas most commonly occur in skin, lymph nodes, and extranodal sites, but splenic involvement has been reported. These neoplasms can also manifest as a solitary mass, with or without systemic symptoms.16 Usually the neoplastic cells of histiocytic sarcoma show some degree of nuclear atypia and mitotic activity that were not present in either of the cases we report.15 Furthermore, histiocytic sarcomas tend to behave in an aggressive manner, with most patients dying of progressive disease. In the 2 cases in this report, the bland cytologic appearance of the histiocytes and resolution of disease following splenectomy exclude the diagnosis of histiocytic sarcoma.

Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells histologically characterized by cells with twisted and grooved nuclei and frequently associated with necrosis and eosinophils. Langerhans cells typically express CD1a, S-100 protein, and langerin, and electron microscopy shows Birbeck granules.17,18 In the 2 cases we report, neither the cytologic features nor the immunophenotype (negative for CD1A and S-100 protein) supported the diagnosis of Langerhans cell histiocytosis. In storage diseases, often there is relevant clinical history before a patient undergoes splenectomy. In Gaucher disease in particular, affected patients often have hepatosplenomegaly and other manifestations. In the spleen, glycolipid-laden macrophages are diffusely distributed in the red pulp of the spleen and stain positively in the PAS reaction.19 In the 2 cases we report, the patients had no history to support the possibility of a storage disease, the splenic lesions were focal masses, and the histiocytes were negative for PAS.

The focal spindled morphology of the histiocytes in our cases also raised the possible diagnoses of inflammatory myofibroblastic tumor (IMT) and follicular dendritic cell (FDC) tumor/sarcoma. IMT is a neoplastic proliferation of bland-appearing spindle cells of myofibroblastic derivation, often with associated inflammatory cells, including histiocytes, lymphocytes, neutrophils, and plasma cells, that has been reported in the spleen.20 The spindle cells of IMT can be positive for ALK. Histologically, the cells in the 2 cases we report were not as spindled as typically seen in IMT, and the immunophenotype (CD68+/ALK–) supported a histiocytic origin. FDC tumor/sarcoma is a neoplastic proliferation of bland to more atypical, spindled or epithelioid cells, with immunophenotypic features of FDCs, such as expression of CD21, CD23, CD35, clusterin, and epidermal growth factor receptor.21 Lesions designated as sarcoma typically have cytologic atypia and mitotic activity or a history of recurrence. The histiocyte-rich cytologic appearance without prominent spindling, the absence of atypia, and the negative results for CD21 and CD35 (performed in case 1) excluded the possibility of FDC tumor/sarcoma.

In summary, we present 2 cases of postchemotherapy histiocyte-rich pseudotumor involving the spleen in patients treated for DLBCL. Both lesions were detected after completion of chemotherapy by PET/CT scan (case 1) or CT scan (case 2) and led to splenectomy for suspected persistent lymphoma. Postchemotherapy histiocyte-rich pseudotumor is a florid response to chemotherapy-induced tumor necrosis that only rarely has been reported in the spleen.

Notes

Upon completion of this activity you will be able to:

  • recognize the clinical, morphologic, and immunohistochemical features of postchemotherapy histiocyte-rich pseudotumor.

  • differentiate postchemotherapy histiocyte-rich pseudotumor from other entities in the differential diagnosis.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™ per article. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.

The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Questions appear on p 472. Exam is located at www.ascp.org/ajcpcme.

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