| | Two splenic lesions in need of clarification: hamartoma and inflammatory pseudotumorAbstract This short review is dedicated to a precise pathologic characterization of 2 uncommon and poorly defined lesions of the spleen and to their distinction from histologically similar processes. Splenic hamartoma represents an abnormally formed red pulp and is characterized by the presence of sinus-like structures lined by CD8(+) endothelia. The great variety of its morphologic appearances may result from the preponderant growth of one or another of the several components of the red pulp, ie, CD34(+) capillaries, myoid cells and macrophages. Therefore, it is proposed that “cord capillary hemangioma,” myoid angio-endothelioma, and histiocyte-rich tumors are part of the spectrum of splenic hamartoma. Inflammatory pseudotumor (IPT) of the spleen is a reactive lesion, probably of multiple etiologies, chacterized by a mixture of inflammatory cells and a minor, disorganized component of spindle cells. The latter include fibroblasts, SMA(+) myofibroblasts, and CD68(+) spindled histiocytes, establishing a close similarity with the IPT of the lymph node. This benign process needs to be distinguished from 2 others that have a predominant spindle cell component arranged in parallel bundles: the IPT-like follicular dendritic cell tumor, which is consistently associated with Epstein-Barr Virus; and the inflammatory myofibroblastic tumor, also often Epstein-Barr Virus-related and similar to those of the soft tissues, lung and other organs. These 2 lesions are neoplastic and therefore have a potentially worse prognosis than IPT.
AMONG THE RARE lesions of the spleen, the hamartoma (H) and the inflammatory pseudotumor (IPT), 1 dating back to 18611 and the other described only recently,2 share a problem of poor definition. A close review of the literature shows that these terms have been often used loosely and may include pathologically diverse processes. Therefore, the same term might refer to different lesions in different studies, leading to misleading conclusions.
Although both processes are benign, lack of precise identification and terminology may result in serious clinical misperceptions and may obscure important biological differences. The equation of H with “splenoma,” with the consequent implication of an association of H with malignancies, and the confusion of IPT with inflammatory myofibroblastic tumor (IMT), a lesion with a more serious prognosis, are only two cases in point.
The discussion that follows, although it includes relevant clinical information on H and IPT, is mainly devoted to the pathological characterization of these lesions and to an attempt at clarifying their relationship with histologically similar, but nosologically different processes.
Splenic hamartoma  H, by definition, is an excessive and structurally disorganized growth of one or another component normally present in an organ. Hence, in the spleen, the term has been used traditionally to indicate a tumor-like excess of red pulp (“pulposal”), white pulp (“follicular” or “lymphoid”) or both (“mixed”).3, 4 However, in more recent studies, H refers exclusively to red pulp hamartomas.5, 6, 7, 8 There appears to be no more mention of those composed of white pulp, although these might correspond to cases reported as “localized reactive lymphoid hyperplasia.”9 To complicate the terminologic issue, H is often used synonymously with “splenoma.”3, 6, 10, 11 However, this term in other studies indicates a more or less defined mass, recognized with imaging techniques and grossly within the splenic parenchyma (“spleen in spleen”), and has included, not only Hs, but also hairy cell leukemia, myeloid metaplasia, and Hodgkin’s lymphoma.12 This confusion has lead to vastly overstating the association of splenic H with malignancies10, 12, 13 and to the conclusion that “splenic hamartomas might arise from acquired proliferative process.”13 As the term “splenoma” is too encompassing and has no significance of itself, it would be appropriate to discard it altogether. Finally, some studies of splenic “hamartomas” have also included vascular lesions such as hemangioma and hemangiomatosis14, 15 or others of difficult interpretation,16 complicating the evaluation of literature data. In particular, the relationship of H with small vessel hemangioma is contentious, some authors considering the two as distinct entities8 and others as one process.17, 18, 19 The discussion that follows is limited to the red pulp hamartoma. This is a rare lesion, of which only ≈140 cases have been reported.20 Its incidence in autopsy studies is as low as 0.06% (considering only the “pulposal” H3) or 0.024%13 and as high as 0.13%.7 H accounts for 0.17%13 to 0.2%21 of the lesions found in splenectomy specimens. Clinical findings H has no gender predilection and has been diagnosed at any age (11 months to 86 years).3, 6, 13 Approximately one sixth of the cases occurs in children (<16 years).20 The median age is higher (75 years) in an autopsy series3 than in one based on splenectomy specimens (40 years),6 and lowest (26 years) among patients presenting with hematologic manifestations.14 Most cases of H are an incidental finding at autopsy or at splenectomy. However, roughly 15% of them (and these are mostly large tumors7) present with symptoms: more commonly abdominal discomfort, malaise, fever, splenomegaly, cytopenias7, 14, 20, 22, 23 and, rarely, portal hypertension24, 25 or rupture.4, 26 The cytopenias may be caused by increased pooling and destruction of blood cells within the H14: although this mechanism has been doubted,7 it was supported in one case by studies with 51Cr-labeled red blood cells.27 Children with H are more often (≈50%) symptomatic than adults and, additionally, they may manifest growth retardation, night sweats and recurrent infections.20 H may be detected in association with malignancies, but this is a relatively uncommon7 and probably coincidental occurrence.28 The contention that this association is higher than in the general population12, 13 is due, as already mentioned, to the confusion between H and “splenoma,” as the latter includes all sort of malignancies forming a mass within the spleen. One case of splenic H presenting as multiple progressive nodules was described in a renal graft recipient.10 In recent times, the diagnosis of H has been made premortem and preoperatively,20 leading to elective splenectomy.22 Modern detection techniques include computed tomography (CT) scan, magnetic resonance imaging (MRI), ultrasound, technetium—99m scintigraphy.29 Differential criteria have been proposed to distinguish H from malignant lesions of the spleen by MRI and CT30 and H from hemangioma by MRI.31 Diagnosis of H by FNA32, 33 is said to be difficult and splenectomy was needed for a definitive diagnosis.33 In some cases diagnosed preoperatively, partial splenectomy was undertaken when the lesion was single and discrete20 and was as successful at relieving symptoms as total splenectomy. Gross findings The weights of spleen containing Hs vary widely: from 60 to 1790 g (median 380) in adults and from 120 to 400 g in children (<16 years), in the largest splenectomy series.6 The Hs vary in size from 0.3 to 20 cm,6, 7, 13 the median being around 5 cm.6 Large tumors (in excess of 2 cm) are rare in autopsy series, but represented the majority among the Hs detected at splenectomy of symptomatic patients.7 In fact, the median size of Hs in children with symptoms is 5.7cm20 and that in adults with symptoms is 12.5cm.14 Most Hs are single lesions. The reported proportion of H presenting as multiple lesions is very variable (largely based, I believe, on how strict the definition of H is): 0% in some pathology studies,3, 7 15% in the largest splenectomy series authored by 2 pathologists with special expertise in spleen disorders,6 and 50% in a surgical series in which red pulp Hs in many patients are said to be “numerous” or “extremely numerous,” deserving the term of “hamartomatosis.”4 The proportion of multiple Hs might be higher in children (30%20) and adults (33%14) presenting with symptoms. Hs are roundish, well-circumscribed, but not encapsulated nodules, often bulging over, and darker than, the surrounding compressed splenic tissue.6, 7 Focal areas of fibrosis and even diffuse fibrosis have been reported.6 Histologic and immunophenotypic findings In its classical form splenic H is characterized by tortuous vascular channels of different width similar to sinuses, absence of normal red pulp cords and absence of organized lymphoid tissue6 (Fig 1A). Its borders are ill-defined on H&E “because of its similarity to the surrounding red pulp.”5 The vascular spaces are lined by endothelial cells similar to those of the sinuses and between them is a disorganized stroma (Fig 1B). This may be loose and contain macrophages, other plump spindle cells, scattered lymphocytes, and entrapped red blood cells, but often shows fibrosis of variable degree.6, 7 Silver stains demonstrate disorderly arrangement of the reticulin fibers and frequent absence of annular fibers.6 Normal splenic trabeculae are decreased or absent and, although clusters of lymphocytes may occasionally be seen, well-formed lymphoid follicles of the white pulp are absent. Variations of these basic features have been described, including the presence of prominent plasmacytosis or extramedullary hematopoiesis, an abundance of macrophages (with erythrophagocytosis, siderosis and foam cells) or “large numbers of lipid-laden macrophages lining the sinuses.”6 The immunohistochemical key to the identification of the splenic H is the presence of vascular spaces lined by CD8(+) endothelia,5, 8, 20 as this feature is characteristic of the endothelia of normal splenic sinuses34, 35 (Fig 1C). So much so that, in a recent report, a tumor of the ovary was identified as a heterotopic splenic hamartoma based on this very feature.11 The endothelia of the vascular spaces in the H of the spleen also express vimentin and factor VIII, like other endothelia,5, 6, 8, 20, 36 but are negative20, 36 or only focally positive for CD34.5 Between these spaces there are abundant macrophages, which express lysozyme, Ki-M7, Ki-M8,6 and CD68, as well as B and T cells, scattered singly or in small aggregates. Small CD34(+) cord capillaries are numerous, but widely separated (Fig 1D). Organized lymphoid tissue as seen in the white pulp and, specifically, follicular dendritic cells are absent.6 The frequent fibrosis of the stroma is highlighted with antibodies to collagen type IV.6 Differential diagnosis The “considerable morphological variation” of splenic Hs “may cause problems in their differentiation from related lesions, such as splenic haemangiomas.”6 In fact, most hemangiomas of the spleen are of the cavernous type seen in other organs7, 8 and thus quite different from the H. However, there might be a small vessel (or capillary) hemangioma of the spleen and, if so, it is unclear what its relationship is to the H. While some believe the 2 lesions to be one and the same,17, 18, 19 at least a study, comparing 2 cases, suggests that they are distinct entities.8 They are distinguished by the phenotype of their endothelia, which is factor VIII(+), CD8(−), in the capillary hemangioma, and factor VIII(+) and CD8(+), in the H. In our experience, there are indeed 2 morphologically and immunohistochemically different lesions, the H and a “cord capillary hemangioma,” (CCH) whose relationship, however, is still open.36, 37 The H has a more uniform appearance throughout; its borders with the splenic parenchyma are ill-defined; and the tortuous, sinus-like vascular spaces are separated by an abundant, loose stroma containing macrophages and lymphocytes. In contrast, the CCH has a strikingly lobular pattern (Fig 2A); its borders with the compressed parenchyma are more definite; the lobules are separated and/or centered by bands of fibrosis, containing abundant plasma cells and iron deposits, and are composed of a loose tangle of ill-defined vascular channels, stromal cells, red blood cells (Figs 2B and C); fibrin deposits are often abundant, especially at the periphery of the lobules. In our immunohistochemical study of these lesions,36 we used the combination of factor VIII and CD34 (to which we have recently added CD8) to distinguish splenic sinuses [factorVIII(+), CD8(+) and CD34(−)] from the cord capillaries [factor VIII(−), CD8(−) and CD34(+)]. While sinus-like vascular spaces lined by CD8(+) endothelia and CD34(+) cord capillaries can be seen in both lesions, the former are more prominent in the H and the latter are very numerous, crowded, and intricately interconnected in the CCH (Fig 2D). From a close reading of a classic paper on splenic Hs7 and evaluation of its illustrations, it is clear that at least 2 (and possibly three) of the five reported cases (Nos. 1, 2 and possibly No. 5) are, in fact, the lesion we refer to as CCH. This raises the issue of whether the striking histologic and immunohistochemical differences we outlined above8, 36 indicate 2 distinct entities or variations, albeit substantial, within the splenic H. This is an issue that neither our study or Zukerberg et al’s8 can resolve. However, the point can be made that sinuses and cord capillaries are both characteristic structures of the red pulp and either can predominate in a red pulp “hamartoma,” resulting in a classical H or a CCH, respectively. A similar point can be made about the relationship of classical H with the recently described “benign vascular neoplasms of the spleen with myoid and angioendotheliomatous features”38 (Figs 3A-C). These are solitary, well-circumscribed, but not encapsulated masses of the spleen, measuring between 1.9 and 6 cm. They feature an array of vascular spaces lined by attenuated CD8(−), CD34(+) endothelia, and separated by large stromal cells with indistinct borders which express vimentin, smooth muscle actin (SMA), and muscle specific actin (MSA), but not desmin. These lesions were not regarded as cellular Hs because “the vascular phenotype of the lining cells and the abundance of the SMA(+), MSA(+) polygonal cells diverge from previous reports of that entity.” However, in my experience, cord capillaries (although indeed they have not been evaluated in previous studies of splenic Hs) are present in H, where they appear widely separated and poorly ramified, and SMA(+) myoid cells are a normal constituent of the cords and wall of the sinuses.39, 40 Hence, these “benign vascular neoplasms,” although somewhat different from the classical H, might also be a variant of it. Finally, we have recently seen a splenic lesion with the characteristic gross appearances of a H, which features a solid growth of bland eosinophilic histiocytes alternating with vascular spaces (Fig 4A). Most of these are blood-filled spaces lined by CD68(+) histiocytes (hence, “pseudosinuses” of the type formed in hairy cell leukemia) (Figs 4B and C), but there are also numerous CD34(+) cord capillaries and scattered CD8(+) sinuses. Although the lesion might be an unusual histiocytic tumor, the participation in it of many red pulp structures is also consistent with a variant of H. A proposal The very real “considerable morphological variation” of splenic Hs and consequent “problems in their differentiation from related lesions”6 might, in conclusion, be a reflection of the complex composition of the red pulp. Hence, the excessive and structurally disorganized growth that we define as hamartoma may be represented by variable proportions of its various components (Fig 5). In this scenario, a classical H combines numerous CD8(+) sinuses with histiocytes and CD34(+) capillaries of the cords. The CCH displays a predominance of cord capillaries, with scattered residual sinuses. The “benign vascular neoplasms of the spleen with myoid and angioendotheliomatous features” contain both predominant myoid cells and capillaries of the cords with a few sinuses. And the histiocytic tumor we illustrate in Figure 4 might represent an excess of the histiocytes over other components of the red pulp or, as it were, a “histiocyte-rich” H. While this proposal, which needs verification in a large comparative study, might explain the similarities of these various lesions and the difficulties in separating them, it should not, however, obscure the pathologic differences among them. On the one hand, because these “variants” have not yet been separated, we do not know whether they differ in biological behavior from the classical H. On the other hand, care should be taken to distinguish these variants from morphologically similar lesions of neoplastic type. We have, for instance, seen 2 cases of fibrohistiocytic tumors of the spleen that had areas quite similar to H, but were elsewhere characterized by a spindle cell component with high mitotic activity. Etiology The origin of the splenic H is obscure. The possibility that it is the result of trauma to the spleen has been considered,41 but has received little support. As already discussed, it is believed by some that H is in fact a vascular neoplasm. These hypotheses are in contrast with the evidence presented above that the variable structure and cell composition of these lesions are those of an abnormally formed red pulp. Two case reports have described the association of splenic H with manifestations of tuberous sclerosis42, 43 and this has been accepted as supportive evidence of its hamartomatous origin.6, 24 In fact, this relationship is tenuous at best. Apart from its rarity (2 of 140 reported cases of H), it appears from the descriptions provided that those lesions were probably cavernous hemangiomas. In addition, the splenic changes reported in tuberous sclerosis by expert pediatric pathologists are quite different, consisting of collections of large eosinophilic cells, similar to those observed in the brain lesions.44 Inflammatory pseudotumor IPT of the spleen was first described by Cotelingam and Jaffe2 in 1984 as a well-defined mass composed of an admixture of inflammatory cells and a “spindle cell fibroblastic proliferation.” In a study of IPTs (of lymph nodes, spleen and liver), Arber et al45 were the first to prove that in some of these cases the spindle cells were SMA(+) myofibroblasts (MFs) or follicular dendritic cells (+) (FDCs) and that they could be infected by EBV.45 These findings were confirmed in later studies46 and established the heterogeneity of the lesions included under the term “IPT.” In a compilation of the literature on this topic,47 this “family of lesions of diverse nature and etiologies” appears to include: infective IPTs, such as the mycobacterial spindle cell pseudotumor; inflammatory myofibroblastic tumors (IMT); inflammatory FDC tumors (later renamed “IPT-like FDC tumors48); and the IPT of the lymph node49 (Whether this last lesion deserves49, 50 or not47 this term is clearly a matter of opinion). This complexity, however, has not yet been widely recognized, even in very recent studies of splenic IPT. In 1 study,52 many of the cases collected from the literature are clearly IPTs as described originally,2 but are said to fit the criteria set by Coffin, et al51 which apply instead to IMTs. In another, it is stated that recent evidence that the spindle cells in IPT are MFs has prompted “the currently preferred designation of IMT,”53 implying that the 2 processes are one and the same. In actual fact, it has become apparent that, under the term of IPT of the spleen, there are at least 3 different lesions that need to be separated because of important differences in cell composition, etiology and, possibly, prognosis (Table 1). Their relative frequency is difficult to assess with certainty, but, as it can be gleaned from the few series that include examples of all 3,45, 46, 54 is roughly equivalent (33%). The best defined is the IPT-like FDC tumor, also reported in the liver and peripancreatic region.48 It is characterized by a striking female predominance; frequent systemic symptoms; indolent behavior as compared to conventional intra-abdominal FDC tumors; histology of dispersed FDCs in a prominent inflammatory background; and consistent evidence of EBV infection of the spindle cells.48, 54 These tumors are all ALK-1(−).48, 55 The second type is the IMT of the spleen, similar to the IMTs observed in the lung, soft tissues, and other locations.51 A good proportion of them (60% in one study53) are EBV(+), although the evidence indicating infection of the spindle cells, rather than lymphocytes, is sporadic.45, 46 These cases are ALK-1(−).53, 55 Although in splenic IMTs the follow-up after splenectomy has been uneventful,53 around 50% of IMT in other locations have been shown to be monoclonal processes and, particularly those located in the abdomen, have shown a malignant potential, with recurrences or metastases.50 There remains a third group of lesions, which have the features originally described by Cotelingam and Jaffe2 and in which the predominant spindle cells are not SMA(+) MFs.45, 54, 56, 57 This is the group which best deserves the term of IPT of the spleen and is probably the splenic counterpart of the IPT of the lymph node.50 This is, therefore, the one to which the rest of this discussion is largely devoted. Detailed reviews of such cases reported in the literature (23 and 32 patients, respectively) can be found in 2 studies.57, 58 Clinical findings IPTs of the spleen have been detected almost exclusively in adults (19–87 years, median 53), and the vast majority above 30 years of age.58 Only 2 cases have been reported in children (16 and below).59, 60 There is no gender predilection. A substantial proportion (33%57; 48%58) of IPTs are discovered incidentally in spleens resected therapeutically or during staging laparotomy, or in autopsy spleens. The presence of symptoms is roughly correlated with the size of the lesion: small ones are usually incidental, larger ones are associated with symptoms.58 Symptomatic patients most often manifest left upper quadrant pain, fever of unknown origin, and splenomegaly. This last sign is noted at physical examination in 22% of patients, but is recorded much more frequently (59%) after preoperative imaging or at surgery.57 A variety of imaging techniques have been used for detection.61, 62, 63 The mass is most often described as low density on CT scan, as hypoechoic on ultrasound and as hypervascular on angiography.57 Laboratory findings are nonspecific and include leukocytosis, anemia, thrombocytopenia and, rarely, hypergammaglobulinemia, elevated ESR [erythrocyte sedimentation rate],57 hypercalcemia64 or elevated serum levels of soluble IL-2 receptor.65 Surgery is curative and follow-up negative. Pathologic findings The reported spleen weight and appearance in patients with splenic IPT vary widely depending on the associated disease, but the descriptions of the lesion are quite consistent.57, 58 IPT is a well-circumscribed, not encapsuled, usually solitary nodule. It is centered often by a cystic or soft area, and uncommonly by fibrosis66 or hemorrhage.67 In 13% to 16% of cases, 2 or more discrete nodules have been reported. The size is between 0.3 and 12.7 cm in largest dimension (median 6.2 cm), the lesions in symptomatic patients being larger (median 8.7 cm58). As in IPT localized to other organs, occasionally thrombosis of hilar vessels68, 69 or fibrin thrombi in the veins adjacent to the lesion58 may be found. Infiltration of the greater curvature of the stomach and the pancreas68, 69 and association with splenic hemangioma70, 71 and with an antecedent IPT in the liver72 have also been reported occasionally. Little has been added to the classical original description of splenic IPT.2 The lesion has well-defined borders (Fig 6A) and is located in the red pulp, with islands of white pulp entrapped at the periphery. IPT is represented by a mixture of inflammatory cells and a “spindle cell fibroblastic proliferation” (Figs 6B and C). The former include lymphocytes, plasma cells, foamy histiocytes, more or less well-formed granulomas with giant cells and, in association with necrosis, also granulocytes. Fibrosis is common50, 57 and in many cases the cellular infiltrate has a zonal distribution around a central area of necrosis.58, 73 The lymphocytes are mostly T cells50, 56, 58 and, in 2 cases evaluated by flow cytometry, CD4(+) cells were predominant.58 B cells are scattered or contained in residual follicles50 and the plasma cell population is polytypic. The spindle cell component appears to be an essential part of the definition, but it was not further identified.2, 58 It is also mentioned in most later descriptions of IPT, where it is clearly neither the predominant component nor is it atypical or arranged in a storiform pattern.57 Most of these cells are vimentin(+) fibroblasts. As already mentioned, recent reports indicated that a portion of these cells were SMA(+) MFs,45, 54, 56, 57 not an unexpected finding in a focally fibrosing lesion. As a matter of fact, at least one of the original cases (No. 12) was later shown to contain SMA(+) cells.45 In addition, CD68(+) spindled histiocytes are also found, which are the characteristic component of the IPT of the lymph node.49, 74 There are instead no spindle cells expressing desmin or FDC markers (CD21 or CD35), or S-100(+) interdigitating cells.50 Whether the spindle cells of the splenic IPTs contain EBV is difficult to assess retrospectively. In the study by Arber et al,45 3 cases containing SMA(+) EBV(+) spindle cells might be IMTs. Of the other 3, in which no SMA(+) cells were noted (IPTs?), only one was EBV(+). The EBV(+) splenic lesions briefly mentioned in other studies46, 54 were either SMA(+) IMTs or IPT-like FDC tumors. While EBV was detected in a case of splenic IPT,65 all 4 cases of IPT of the spleen in a recent study50 were EBV(−), a feature shared with the cases of IPT of the lymph node. In the same study the spindle cells of splenic IPT were all ALK(−) and HHV-8(−).50 Differential diagnosis It has been stressed that, although splenic IPT may mimick a lymphoma (large cell type or Hodgkin’s lymphoma) grossly and radiologically, the histologic distinction is usually not difficult, in the absence of any cellular atypicality in the former lesion.2, 57, 58 For the same reason and the lack of prominent spindle cells or storiform pattern, IPT is easily distinguished from inflammatory malignant fibrous histiocytoma.66, 69 The absence of sinuses and the abundant inflammatory component and necrosis differentiate IPT from H.58 And the absence of a predominant lymphoid component, and especially of hyperplastic germinal centers, distinguishes it from the rare cases of “localized reactive lymphoid hyperplasia.”9 More difficult is the differential diagnosis with other “IPTs.” IPT is identifiable by a disorderly mixture of cells in a collagenous stroma and lacks a prominent spindle cell component, parallel bundling of cells or a storiform pattern,57 features characteristic of IMT53 (Figs 7A and B). Both lesions contain SMA(+) spindle cells, but one would opt for IPT when they are not numerous nor arranged in fascicles, and for IMT when they are predominant and organized (Fig 7C). Evidence of EBV in the spindle cells definitely favors an IMT (Fig 7D). IPT is histologically very similar to IPT-like FDC tumors48 and the distinction, in the absence of the “fascicular arrangement of syncytial plump to spindle cells” noted in some of these tumors,75 might be impossible without the help of immunohistochemistry.50 Pathogenesis Although the IPT of the spleen is clearly a reactive lesion, its etiology is obscure. There appears to be a general consensus that it might represent the non-specific result of a variety of mechanisms.45, 57, 58, 67 The association with a vascular thrombosis is only rarely proven68 and is thought to be unlikely.58 However, an intraparenchymal hemorrhage, related in some patients to idiopathic thrombocytopenic purpura, might occasionally be the initial event.58 An infectious origin has been supported by some authors,72, 76 although, in most reports, it appears to have been ruled out using the appropriate special stains for microorganisms. However, polymerase chain reaction had to be used in 1 case of IPT of the intestine to prove a bacterial etiology, leading the authors to stress the importance of actively searching for an infective agent in all cases of IPT.77 An autoimmune mechanism has also been hypothesized on two grounds: the concurrence of idiopathic thrombocytopenic purpura in a few patients with splenic IPT and the histologic similarities of this lesion to processes such as Riedel’s thyroiditis and idiopathic retroperitoneal fibrosis.58 It is relevant, in this regard, to mention that IPT of the spleen looks to us and to others50 as the counterpart of the IPT of the node and that the latter has been compared to inflammatory fibrosclerosing lesions, based on histogical similarities and the association of both with phlebitis.47 In the same vein, the IPT of the lymph node and that of the spleen share an abundance of spindle histiocytes,49, 50, 74 and idiopathic retroperitoneal fibrosis has been described as a “macrophage-rich process.”78 Conclusions The IPT of the spleen, as originally reported, is a benign lesion with distinctive histologic and immunophenotypic features and probably diverse etiologies. It is part of a family of lesions which until recently have been confused together. In fact, a possible histogenetic relationship between the splenic IPT, IMT and IPT-like FDC tumor of the spleen is purely speculative. One theory proposes that IMT and FDC tumors share a common MF lineage and that “occasional cases with features of IMT may represent a less aggressive subset of FDC, with graded myofibroblastic differentiation.”53 Another suggests the possibility that splenic IPT in which FDCs become infected with EBV, via their EBV-receptor CD21,45 may evolve into IPT-like FDC tumors.79 In contrast, there is strong evidence that the IPT of the spleen is distinct in cell composition and probable etiology from both the IMT and the IPT-like FDC tumor and that it is related to the IPT of the lymph node, both representing CD68(+) histiocyte-rich lesions. References 1.
1
Rokitansky K.
Über splenome.
Lehrbuch der Pathologischen Anatomie. Vol. III. Wien. 1861;. 2.
2
Cotelingam JD, Jaffe ES.
Inflammatory pseudotumor of the spleen.
Am J Surg Pathol. 1984;8:
. 3.
3
Berge T.
Splenoma.
Acta Pathol Microbiol Scand. 1965;63:333–339. MEDLINE 4.
4
Morgenstern L, McCafferty L, Rosenberg J, et al.
Hamartomas of the spleen.
Arch Surg. 1984;119:1291–1293. MEDLINE 5.
5
Arber DA, Strickler JG, Chen YY, et al.
Splenic vascular tumors (A histologic, immunophenotypic, and virologic study).
Am J Surg Pathol. 1997;21:827–835. MEDLINE |
CrossRef
6.
6
Falk S, Stutte HJ.
Hamartomas of the spleen (A study of 20 biopsy cases).
Histopathology. 1989;14:603–612. MEDLINE |
CrossRef
7.
7
Silverman ML, LiVolsi VA.
Splenic hamartoma.
Am J Clin Pathol. 1978;70:224–229. MEDLINE 8.
8
Zukerberg LR, Kaynor BL, Silverman ML, et al.
Splenic hamartoma and capillary hemangioma are distinct entities (Immunohistochemical analysis of CD8 expression by endothelial cells).
Hum Pathol. 1991;22:1258–1261. MEDLINE |
CrossRef
9.
9
Burke JS, Osborne BM.
Localized reactive lymphoid hyperplasia of the spleen simulating malignant lymphoma (A report of seven cases).
Am J Surg Pathol. 1983;7:373–380. MEDLINE 10.
10
Buchler Mal-Najjar A, Guerraoui A, et al.
Appearance of multiple progressive nodules in the spleen of a renal graft recipient.
Nephrol Dial Transplant. 1997;12:1739–1741. MEDLINE |
CrossRef
11.
11
Cualing H, Wang G, Noffsinger A, et al.
Heterotopic ovarian splenoma (Report of a first case).
Arch Pathol Lab Med. 2001;125:1483–1485. MEDLINE 12.
12
Steinberg JJ, Suhrland M, Valensi Q.
The spleen in the spleen syndrome (The association of splenoma with hematopoietic and neoplastic disease—compendium of cases since 1864).
J Surg Oncol. 1991;47:193–202. MEDLINE |
CrossRef
13.
13
Lam KY, Yip KH, Peh WC.
Splenic vascular lesions (Unusual features and a review of the literature).
Aust N Z J Surg. 1999;69:422–425. MEDLINE 14.
14
Beham A, Hermann W, Vennigerholz F, et al.
Hamartoma of the spleen with haematological symptoms.
Virchows Arch A Pathol Anat Histopathol. 1989;414:535–539. MEDLINE 15.
15
Saguem MH, Laarif M, Remadi S, et al.
Diffuse bilateral glomerulocystic disease of the kidneys and multiple cardiac rhabdomyomas in a newborn (Relationship with tuberous sclerosis and review of the literature).
Pathol Res Pract. 1992;188:367–373. MEDLINE 16.
16
Pardo-Mindan FJ, Vazquez JJ, Joly M, et al.
Splenic hamartoma, vascular type, with endothelial proliferation.
Pathol Res Pract. 1983;177:32–40. MEDLINE 17.
17
Benjamin BI, Nohler DN, Sandusky WR.
Hemangioma of the spleen.
Arch Intern Med. 1965;115:280–284. MEDLINE 18.
18
Coe JI, Von Drashek SC.
Hamartoma of the spleen (A report of four cases).
Am J Pathol. 1952;28:663–671. MEDLINE 19.
19
Grahamy JC, Weidner WA, Vinik M.
The angiographic features of organizing splenic hematoma (?hamartoma).
Am J Roentgenol Radium Ther Nucl Med. 1969;107:430–433. MEDLINE 20.
20
Hayes TC, Britton HA, Mewborne EB, et al.
Symptomatic splenic hamartoma (Case report and literature review).
Pediatrics. 1998;101:E10. 21.
21
Kraus MD, Fleming MD, Vonderheide RH.
The spleen as a diagnostic specimen (A review of 10 years’ experience at two tertiary care institutions).
Cancer. 2001;91:2001–2009. 22.
22
Wirbel RJ, Uhlig U, Futterer KM.
Case report (Splenic hamartoma with hematologic disorders).
Am J Med Sci. 1996;311:243–246. MEDLINE |
CrossRef
23.
23
Zissin R, Lishner M, Rathaus V.
Case report (Unusual presentation of splenic hamartoma; computed tomography and ultrasonic findings).
Clin Radiol. 1992;45:410–411. Abstract |
Full-Text PDF (1200 KB)
|
CrossRef
24.
24
Iakovidou J, Panayiotides J, Papacharalambous X, et al.
Splenic hamartoma (A case report).
Eur J Surg Oncol. 1995;21:688–690. Abstract |
Full-Text PDF (2228 KB)
|
CrossRef
25.
25
Singh K, Subbramaiah A, Choudhary SR, et al.
Splenic hamartoma with portal hypertension (A case report).
Trop Gastroenterol. 1992;13:155–159. 26.
26
Ferguson ER, Sardi A, Beckman EN.
Spontaneous rupture of splenic hamartoma.
J La State Med Soc. 1993;145:48–52. MEDLINE 27.
27
Teates CD, Seale DI, Allen MS.
Hamartoma of the spleen.
Am J Roentgenol Radium Ther Nucl Med. 1972;116:419–422. MEDLINE 28.
28
Ninet J, Naouri A, Colon S, et al.
[Triple association: extramembranous glomerulonephritis, renal adenocarcinoma and splenic hamartoma: Apropos of a case].
Rev Med Interne. 1994;15:546–554. MEDLINE |
CrossRef
29.
29
Paterson A, Frush DP, Donnelly LF, et al.
A pattern-oriented approach to splenic imaging in infants and children.
Radiographics. 1999;19:1465–1485. MEDLINE 30.
30
Ohtomo K, Fukuda H, Mori K, et al.
CT and MR appearances of splenic hamartoma.
J Comput Assist Tomogr. 1992;16:425–428. MEDLINE 31.
31
Ramani M, Reinhold C, Semelka RC, et al.
Splenic hemangiomas and hamartomas (MR imaging characteristics of 28 lesions).
Radiology. 1997;202:166–172. MEDLINE 32.
32
Keogan MT, Freed KS, Paulson EK, et al.
Imaging-guided percutaneous biopsy of focal splenic lesions (update on safety and effectiveness).
Am J Roentgenol. 1999;172:933–937. 33.
33
Kumar PV.
Splenic hamartoma (A diagnostic problem on fine needle aspiration cytology).
Acta Cytol. 1995;39:391–395. MEDLINE 34.
34
Buckley PJ, Dickson SA.
Monoclonal antibodies to T-helper/inducer and T-suppressor/cytotoxic lymphocyte subsets recognize antigens on splenic sinusoidal lining cells.
Am J Clin Pathol. 1984;82:167–172. MEDLINE 35.
35
Hsu SM, Cossman J, Jaffe ES.
Lymphocyte subsets in normal human lymphoid tissues.
Am J Clin Pathol. 1983;80:21–30. MEDLINE 36.
36
Krishnan J, Danon AD, Frizzera G.
Use of anti-Factor VIII-related antigen (F8) and Qbend10 (CD34) antibodies helps classify the benign vascular lesions of the spleen.
Mod Pathol. 1993;6:94A. 37.
37
Rosati S, Frizzera G.
Pseudoneoplastic lesions of the hematolymphoid system.
In:
Wick MR, Humphrey PA, Ritter JH editor. Pathology of Pseudoneoplastic Lesions. Philadelphia, PA: Lippincott-Raven; 1997;p. 449–543. 38.
38
Kraus MD, Dehner LP.
Benign vascular neoplasms of the spleen with myoid and angioendotheliomatous features.
Histopathology. 1999;35:328–336. MEDLINE |
CrossRef
39.
39
Pinkus GS, Warhol MJ, O’Connor EM, et al.
Immunohistochemical localization of smooth muscle myosin in human spleen, lymph node, and other lymphoid tissues (Unique staining patterns in splenic white pulp and sinuses, lymphoid follicles, and certain vasculature, with ultrastructural correlations).
Am J Pathol. 1986;123:440–453. MEDLINE 40.
40
Toccanier-Pelte MF, Skalli O, Kapanci Y, et al.
Characterization of stromal cells with myoid features in lymph nodes and spleen in normal and pathologic conditions.
Am J Pathol. 1987;129:109–118. MEDLINE 41.
41
Wolf BC, Neiman RS.
In: Disorders of the spleen. Philadelphia, PA: Saunders; 1989;p. 192–193. 42.
42
Darden JW, Teeslink R, Parrish A.
Hamartoma of the spleen (A manifestation of tuberous sclerosis).
Am Surg. 1975;41:564–566. MEDLINE 43.
43
Van Heerden JA, Longo MF, Cardoza F, et al.
The abdominal mass in the patient with tuberous sclerosis.
Arch Surg. 1967;95:317–319. MEDLINE 44.
44
Bender BL, Yunis EJ.
Splenic involvement in tuberous sclerosis. Report of three cases.
Virchows Arch A Pathol Anat Histol. 1981;391:363–369. MEDLINE |
CrossRef
45.
45
Arber DA, Kamel OW, van de Rijn M, et al.
Frequent presence of the Epstein-Barr virus in inflammatory pseudotumor.
Hum Pathol. 1995;26:1093–1098. Abstract |
Full-Text PDF (15970 KB)
|
CrossRef
46.
46
Prevot S, Sevestre M, Vercelli-Retta G, et al.
Inflammatory pseudotumor of the spleen: A disease frequently associated with EBV latent infection: A study of 10 cases. 1996;
. 47.
47
Chan JK.
Inflammatory pseudotumor (A family of lesions of diverse nature and etiologies).
Adv Anat Path. 1996;3:156–171. 48.
48
Cheuk W, Chan JK, Shek TW, et al.
Inflammatory pseudotumor-like follicular dendritic cell tumor (A distinctive low-grade malignant intra-abdominal neoplasm with consistent Epstein-Barr virus association).
Am J Surg Pathol. 2001;25:721–731. MEDLINE |
CrossRef
49.
49
Perrone T, DeWolf-Peeters C, Frizzera G.
Inflammatory pseudotumor of lymph nodes. A distinctive pattern of nodal reaction.
Am J Surg Pathol. 1988;12:351–361. MEDLINE 50.
50
Kutok JL, Pinkus GS, Dorfman DM, et al.
Inflammatory pseudotumor of lymph node and spleen (an entity biologically distinct from inflammatory myofibroblastic tumor).
Hum Pathol. 2001;32:1382–1387. Abstract | Full Text |
Full-Text PDF (324 KB)
|
CrossRef
51.
51
Coffin CM, Humphrey PA, Dehner LP.
Extrapulmonary inflammatory myofibroblastic tumor (A Clinical and pathological pathological survey).
Semin Diagn Pathol. 1998;15:85–101. MEDLINE 52.
52
Variami E, Terpos E, Vgenopoulou S, et al.
Inflammatory pseudotumor of the spleen (a case report and review of the literature).
Ann Hematol. 1999;78:560–563. MEDLINE |
CrossRef
53.
53
Neuhauser TS, Derringer GA, Thompson LD, et al.
Splenic inflammatory myofibroblastic tumor (inflammatory pseudotumor) (A clinicopathologic and immunophenotypic study of 12 cases).
Arch Pathol Lab Med. 2001;125:379–385. MEDLINE 54.
54
Delsol G, Stutte HJ.
Inflammatory pseudotumours of the spleen.
Histopathology. 1998;32:172–179. MEDLINE |
CrossRef
55.
55
Chan JK, Cheuk W, Shimizu M.
Anaplastic lymphoma kinase expression in inflammatory pseudotumors.
Am J Surg Pathol. 2001;25:761–768. MEDLINE |
CrossRef
56.
56
Madrigal B, Perezdel Rio MJ, Vara A, et al.
Inflammatory pseudotumor of the spleen (An old concept with many questions).
Sangre (Barc). 1998;43:227–230. MEDLINE 57.
57
Seijo L, Unger PD, Strauchen JA.
Inflammatory pseudotumor of the spleen.
Int J Surg Pathol. 1996;3:289–298. 58.
58
Thomas RM, Jaffe ES, Zarate-Osorno A, et al.
Inflammatory pseudotumor of the spleen (A clinicopathologic and immunophenotypic study of eight cases).
Arch Pathol Lab Med. 1993;117:921–926. MEDLINE 59.
59
Aru GM, Abramowsky CR, Ricketts RR.
Inflammatory pseudotumor of the spleen in a young child.
Pediatr Surg Int. 1997;12:299–301. MEDLINE |
CrossRef
60.
60
Soares-Oliveira M, Carvalho JL, Estevao-Costa J, et al.
Inflammatory pseudotumor of the spleen in a child.
Med Pediatr Oncol. 2001;37:77–78. MEDLINE |
CrossRef
61.
61
Hayasaka K, Soeda S, Hirayama M, et al.
Inflammatory pseudotumor of the spleen (US and MRI findings).
Radiat Med. 1998;16:47–50. MEDLINE 62.
62
Irie H, Honda H, Kaneko K, et al.
Inflammatory pseudotumors of the spleen (CT and MRI findings).
J Comput Assist Tomogr. 1996;20:244–248. MEDLINE |
CrossRef
63.
63
Suga K, Miura K, Kume N, et al.
Tc-99m colloid and Ga-67 imaging of splenic inflammatory pseudotumor correlation with ultrasound, CT, and MRI.
Clin Nucl Med. 1999;24:334–337. MEDLINE |
CrossRef
64.
64
Shepherd JJ, Fassett RG, Challis D.
Hypercalcaemia associated with inflammatory pseudotumour of the spleen.
Br J Surg. 1992;79:50. MEDLINE |
CrossRef
65.
65
Yamaguchi M, Yamamoto T, Tate G, et al.
Specific detection of Epstein-Barr virus in inflammatory pseudotumor of the spleen in a patient with a high serum level of soluble IL-2 receptor.
J Gastroenterol. 2000;35:563–566. MEDLINE |
CrossRef
66.
66
McHenry CR, Perzy-Gall HB, Mardini G, et al.
Inflammatory pseudotumor of the spleen (a rare entity that may mimic hematopoietic malignancy).
Am Surg. 1995;61:1067–1071. MEDLINE 67.
67
Monforte-Munoz H, Ro JY, et al.
Inflammatory pseudotumor of the spleen (Report of two cases with a review of the literature).
Am J Clin Pathol. 1991;96:491–495. MEDLINE 68.
68
Fu KH, Liu HW, Leung CY.
Inflammatory pseudotumours of the spleen.
Histopathology. 1990;16:302–304. MEDLINE |
CrossRef
69.
69
Sheahan K, Wolf BC, Neiman RS.
Inflammatory pseudotumor of the spleen (A clinicopathology study of three cases).
Hum Pathol. 1988;19:1024–1029. MEDLINE |
CrossRef
70.
70
Matsubayashi H, Mizoue T, Mizuguchi Y, et al.
A case of hemangioma accompanied by inflammatory pseudotumor of the spleen.
J Clin Gastroenterol. 2000;31:258–261. MEDLINE |
CrossRef
71.
71
Nasir A, Budhrani SS, Hafner GH, et al.
Inflammatory pseudotumor of the spleen associated with a cavernous hemangioma diagnosed at intra-operative cytology (Report of a case and review of literature).
In Vivo. 1999;13:87–92. 72.
72
DiVita G, Soresi M, Patti R, et al.
Concomitant inflammatory pseudotumor of the liver and spleen.
Liver. 2001;21:217–222. MEDLINE |
CrossRef
73.
73
Dalal BI, Greenberg H, Quinonez GE, et al.
Inflammatory pseudotumor of the spleen (Morphological, radiological, immunophenotypic, and ultrastructural features).
Arch Pathol Lab Med. 1991;115:1062–1064. MEDLINE 74.
74
Facchetti F, De Wolf Peeters C, De Wever I, et al.
Inflammatory pseudotumor of lymph nodes (Immunohistochemical evidence for its fibrohistiocytic nature).
Am J Pathol. 1990;137:281–289. MEDLINE 75.
75
Shek TW, Liu CL, Peh WC, et al.
Intra-abdominal follicular dendritic cell tumour (A rare tumour in need of recognition).
Histopathology. 1998;33:465–470. MEDLINE |
CrossRef
76.
76
Wiernik PH, Rader M, Becker NH, et al.
Inflammatory pseudotumor of spleen.
Cancer. 1990;66:597–600. 77.
77
Cheuk W, Woo PCY, Yuen KY, et al.
Intestinal inflammatory pseudotumour with regional lymph node involvement (Identification of a new bacterium as the aetiological agent).
J Pathol. 2000;192:289–292. MEDLINE |
CrossRef
78.
78
Hughes D, Buckley PJ.
Idiopathic retroperitoneal fibrosis is a macrophage-rich process (Implications for its pathogenesis and treatment).
Am J Surg Pathol. 1993;17:482–490. MEDLINE 79.
79
Arber DA, Weiss LM.
EBV in follicular dendritic cells.
Am J Surg Pathol. 1996;20:1426–1427. MEDLINE |
CrossRef
a Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA b Department of Pathology, Washington Hospital Center, Washington, DC, USA  Address reprint requests to Glauco Frizzera, MD, Department of Pathology and Laboratory Medicine, New York Presbyterian Hospital, 525 East 68th St, (Starr 715), New York, NY 10021, USA
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