Xanthogranulomatous salpingitis associated with fallopian tube mucosal endometriosis: a clue to the pathogenesis

Annals of Diagnostic Pathology 11 (2007) 117 – 121

Xanthogranulomatous salpingitis associated with fallopian tube mucosal endometriosis: a clue to the pathogenesis Muhammad Idrees, MDa, Konstantin Zakashansky, MDb, Tamara Kalir, MD, PhDa,4 a

The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Mount Sinai Medical Center, New York, NY 10029-6574, USA b Department of Gynecologic Oncology, Mount Sinai Medical Center, New York, NY 10029-6574, USA

Abstract

Xanthogranulomatous salpingitis is an unusual inflammatory lesion of the fallopian tube, characterized by accumulation of foamy macrophages in the wall of the fallopian tube along with other chronic inflammatory cells. Only a few cases of xanthogranulomatous salpingitis have been reported in the English medical literature, some under different nomenclature. An association, most commonly with pelvic inflammatory disease and endometriosis, has been suggested. A 41-year-old woman with prior history of breast carcinoma underwent bilateral salpingoophorectomy because of hematosalpinx. The histology revealed xanthogranulomatous salpingitis in the setting of extensive fallopian tube mucosal endometriosis, endometritis, and presence of an intrauterine contraceptive device. Multiple etiologies have been linked to the xanthogranulomatous process at this location in previously reported cases. A whole spectrum of changes may exist in this lesion and probably represent a specialized form of tissue reaction secondary to multiple etiologies. Although it has been associated with pelvic endometriosis, it has never been demonstrated through progressive changes, beginning with mucosal endometriosis to the full-blown xanthogranulomatous inflammation. To the best of our knowledge, this is the first reported case that demonstrates different stages in the pathogenesis of this lesion and provides an insight into the histiogenesis of this entity. D 2007 Elsevier Inc. All rights reserved.

Keywords:

Xanthogranulomatous salpingitis; Fallopian tube; Endometriosis; Lipofuscin

1. Introduction Xanthogranulomatous salpingitis (XGS) is a rare inflammatory lesion of the fallopian tube and is characterized by extensive infiltration of the fallopian tube by foamy histiocytes and a variable amount of inflammatory cells including plasma cells, lymphocytes, and occasional multinucleated giant cells. Only a few cases have been reported in the English medical literature. Multiple terms have been used to describe this entity. Pigmentosis tubae, xanthogranulomatous salpingiosis, pseudo–xanthomatous salpingitis, and inflammatory pseudotumor are alternate terms used for this entity [1- 4]. In a recently published article, the authors 4 Corresponding author. The Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Mount Sinai Medical Center, Box 1194, New York, NY 10029-6574, USA. Tel.: +1 212 241 8014; fax: +1 212 426 5129. E-mail address: [email protected] (T. Kalir). 1092-9134/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.12.004

reported the incidence of this entity (up to 5%) in surgically removed fallopian tubes [5]. In this report, the authors demonstrated hemosiderin-laden macrophages rather than lipofuscin, so it may not truly represent XGS, which sometimes has also been reported under the term pigmentosis tubae [5]. Xanthogranulomatous inflammation has been reported in multiple organs, most commonly in the kidney followed by the gall bladder [6,7]. The mechanism of this form of inflammatory response is not clear. Multiple etiologies have been attributed to the development of XGS. Pelvic endometriosis, pelvic inflammatory disease, intrauterine contraceptive device, inborn error in lipid metabolism by macrophages, unsuccessful antibiotic therapy and radiotherapy have been suggested [1,2,8,9]. We report a case of bilateral XGS in association with tubal mucosal endometriosis with atypical glandular hyperplasia, in a patient with an intrauterine contraceptive device in a setting of endometritis

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and a previous history of breast carcinoma with subsequent chemotherapy. The utility of immunohistochemical and histochemical stains is discussed, and relevant literature review is performed (Table 1). 2. Case report A 41-year-old woman originally presented to her gynecologist with diffuse lower abdominal discomfort which slightly increased in intensity with the onset of menstruation. The patient had an otherwise unremarkable gynecological history and, at the time of presentation, had regular menstrual cycles. Her obstetrical history was significant for 3 normal vaginal deliveries. The patient’s medical history was remarkable for an infiltrating poorly differentiated duct carcinoma of the breast a year ago for which she underwent a lumpectomy followed by chemotherapy comprising adriamycin, cytoxan, and 5FU. At the completion of her chemotherapy, the patient underwent prophylactic bilateral mastectomy and axillary lymph node dissection, which was negative for presence of any residual tumor. At the time of the initial presentation, the bimanual pelvic examination revealed bilateral tender and slightly enlarged adnexa. Transvaginal and transabdominal ulltrasonograms revealed bilateral cystic tubular structures, measuring 7.5  2 cm on the right and 8.5  2.2 cm on the left. These findings were radiologically consistent with large bilateral hematosalpinx. Uterine findings were remarkable for the presence of an intrauterine device (IUD) and adenomyosis. The patient was offered diagnostic laparoscopy vs ultrasonographic follow-up in 6 weeks. At the time of consultation, the patient’s symptoms resolved and she opted for conservative management. Follow-up ultrasonography, performed after 5 weeks, demonstrated a slight decrease in size of the cystic structures. Repeat transvaginal ultrasonogram was scheduled in 4 months to assess an interval change. The pelvic ultrasound performed 4 months later revealed stabilized bilateral tubal structures consistent with hematosalpinx, embedded IUD, adenomyosis, and 1.4 -cm left ovarian cyst. Laparoscopic bilateral salpingoophorectomy and IUD removal were performed. During the surgery, diffuse pelvic endometriosis with extensive adhe-

Fig. 1. Cross section of fallopian tube showing thickened golden yellow plicae filling and distending the entire lumen.

sions and bilateral 6  3-cm hematosalpinx was noted. In addition, adhesiolysis and pelvic endometriosis ablation were performed. 3. Gross pathology The tubes were bilaterally enlarged. The right fallopian tube was 5 cm in length and the left was 4 cm, with a diameter of 2 and 1 cm, respectively. The fimbriated ends were marked by golden yellow, rope-like, thick processes. Sectioning revealed markedly dilated lumens, into which bulged markedly thickened and elongated plicae (Fig. 1). The wall of the fallopian tube was markedly thickened with moderate edema and ranged 0.3 to 0.5 cm in thickness. The serosal surfaces were remarkable for focal bilateral adhesions. No gross lesions or endometriosis was identified on the serosal surfaces. The ovaries were moderately enlarged containing multiple small hemorrhagic cysts as

Table 1 Immunohistochemical and histochemical stains Stains

Reactions and staining pattern

CD68

Strong diffuse membranous staining in histiocytes. Negative epithelium and inflammatory cells Strong diffuse membranous staining of inflammatory cells and histiocytes Strong epithelial staining. Negative histiocytes and inflammatory cells Diffuse strong cytoplasmic staining in the histiocytes Focal strong perivascular histiocytes and endothelial cells Diffuse strong histiocytic cytoplasmic staining

LCA AE1/AE3 Fontana Masson Iron AFB

AFB indicates acid fast bacillus.

Fig. 2. Photomicrograph of cross section of fallopian tube showing markedly distended plicae with foamy histiocytes and chronic inflammatory cells. Note granular brownish material inside the foamy histiocytes (H&E, original magnification 50).

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well as multiple corpora albicantia and multiple minute cortical cysts. 4. Histology Both the ovaries were entirely submitted along with representative fallopian tubes. The sections were paraffin embedded, and hematoxylin-eosin (H&E)–stained slides were examined. The right fallopian tube sections revealed marked expansion of the plicae by foamy macrophages with light brown pigment in most of the macrophages (Fig. 2). No stromal tissue was identified in the plicae. The foamy macrophages were directly abutting the muscle wall of the fallopian tube without intervening stroma. The overlying tubal epithelium showed hyperplastic changes with focal crowding of the cells. Ciliated mature tubal epithelial cells were identified. The histiocytic proliferation was so exuberant that all of the plicae were tightly packed without any luminal space. A large number of inflammatory cells were also present admixed with the foamy macrophages. The most common cell types were lymphocytes followed by plasma cells and mast cells. Rare multinucleated giant cells were also identified. Numerous small thin-walled vessels, surrounded by macrophages, were noticed in the distended plicae. Prominent perivascular chronic inflammatory infiltrates were identified. The macrophages were filled with yellowish brown granular material, and the amount of this material varied in different fields. Red cell extravasation was identified throughout the lesion. No inflammatory cells or foamy macrophages were noted in the muscle layer, which was mildly edematous. Bilateral ovaries revealed multiple cystic follicles, epithelial inclusion cysts, and cortical endometriosis. A small leiomyoma was also identified in relation to the right ovary. Left fallopian tube revealed extensive mucosal endometriosis (Fig. 3A). Foci of endometriosis were also identified in myosalpinx (Fig. 3B). The endometriosis showed simple

Fig. 3. Endometriosis of fallopian tube. (A) Mucosa and lamina propria of fallopian tube totally replaced by endometrial-type gland and stroma (H&E, original magnification 50). (B) Endometriosis in myosalpinx (H&E, original magnification 50).

Fig. 4. Endometriosis with hyperplastic glands and foamy histiocytes.

hyperplasia without atypia (Fig. 4). The stromal cells appeared plump and loosely arranged in the plical matrix. Extravasated blood and small amount of fibrin were identified in the stroma with dispersed foamy macrophages (Fig. 4). Other areas revealed XGS with small amount of endometriosis. Different sections revealed a whole spectrum from only endometriosis to mixed endometriosis and xanthomatous inflammation, to only XGS. A T-shaped intrauterine contraceptive device was also removed at the time of surgery with subsequent endometrial curettings. Small amount of endometrial tissue attached to the IUD revealed proliferative endometrium with pseudo– sulfur granules (hematoidin). The endometrial curetting revealed multiple plasma cells in the endometrial stroma, suggesting the diagnosis of endometritis. 5. Histochemistry and immunohistochemistry The Fontana-Masson stain revealed diffuse granular staining in the macrophages (Fig. 5A). The iron stain

Fig. 5. Histochemical stains. (A) Diffuse Fontana-Masso staining in histiocytes. (B) Iron staining is prominent in perivascular histiocytes and endothelial cells. (C) Diffuse acid-fast staining in histiocytes, suggesting the ceroid pigment.

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Fig. 6. Immunohistochemical stains. (A) CD68, strong immunoreactivity of foamy histiocytes. (B) LCA, highlighting the inflammatory leukocytes. (C) AEI/AE3 (low- and high-molecular-weight cytokeratin) showing strong immunoreactivity for epithelial cells.

showed weak staining in the perivascular histiocytes and endothelial cells (Fig. 5B). The acid-fast stain revealed extensive ceroid pigment in the macrophages (Fig. 5C). Immunohistochemical stains performed on paraffin-embedded sections demonstrated strong CD68 staining in foamy histiocytes (Fig. 6A). Leukocyte common antigen (LCA) staining revealed multiple inflammatory cells dispersed among the xanthomatous foam cells in a prominent perivascular pattern (Fig. 6B). The tubal epithelium was strongly reactive to AEI/AE3 (high- and low-molecular-weight cytokeratin) (Fig. 6C). 6. Discussion Xanthomatous inflammatory response has been reported in many organs using different terminologies. Multiple etiologies have been linked to this kind of inflammatory response. It is not clear why this particular type of inflammation occurs in response to stimuli that under usual circumstances would present in a totally different manner both clinically and histologically. This entity has been most commonly reported in kidney and gallbladder and rarely in other organs [6,7]. In the fallopian tube, it has been noticed, most often, with endometriosis and pelvic inflammatory disease. The association of this entity with endometriosis is interesting in a manner that it is extremely rare yet does not develop in large number of pelvic endometriosis cases that are commonly seen in young females of reproductive age. What is the link? It is difficult to establish, as multiple other factors may contribute to the final histological appearance of this entity. In the present case, we demonstrated extensive mucosal endometriosis to the extent of glandular hyperplasia and transition to XGS to the extent of complete replacement of lamina propria by foamy histiocytes and inflammatory cells in one fallopian

tube. The other fallopian tube revealed complete obliteration of the lamina propria by foamy histiocytes without any evidence of endometriosis. One could speculate that this microscopic appearance may represent the final, burntout phase of the endometriosis as a complete transition from endometriosis to complete replacement of all structures by foamy histiocytes. Another major association is with pelvic inflammatory disease. Escherichia coli, Bacteroides fragilis, Staphylococcus aureus, and Salmonella typhi infections have been reported to cause XGS [8-11]. It has been proposed that inflammation secondary to endometriosis, infection, or other cause such as radiation may contribute to the development of this kind of reactive process. The bleeding secondary to any abovementioned causes may be a prerequisite to the xanthomatous process and probably leads to the accumulation of excessive foamy macrophages. The material present in the macrophages is mostly ceroid (lipofuscin-like) as shown by the strong staining by acid-fast stain. On the other hand, the amount of hemosiderin in the cells was minimal as shown by focal iron staining. The origin of iron is not clear, but erythrophagocytosis and an abnormal tubal environment could play a role [12]. The presence of iron only in perivascular and endothelial cells may indicate an active clearing mechanism that promptly removes the excess iron and, hence, hemosiderin. In our case, Fontana-Masson staining was diffusely distributed in the foamy histiocytes. The source of lipofuscin is probably lipid peroxidation of lysosomes and cellular constituents. There are 2 theories regarding the lipofuscin production, the peroxidase theory and the proteolytic decline theory in normal aging. The peroxidase theory is based on the fact that generation of free oxygen radicals generated during the normal metabolism oxidizes the fatty acids that are taken up by the lysosomes, which do not have any antioxidative mechanism to get rid of these oxidized lipids. Furthermore, the excess amount of iron, zinc, and copper in the lysosomes may act as catalyst for further lipid peroxidation after lysosomal engulfment [13]. Iron-promoted lipid peroxidation may alter the lysosomal membranes and contribute to the excessive accumulation of lipofuscin-like pigment in the xanthomatous cells of XGS [12]. The proteolytic decline theory comes hand in hand with the normal aging phenomena and suggests that, with advancing age, lysosomes may handle lipofuscin precursors less efficiently, leading to the accumulation of pigment in aging cells [13]. The lipofuscin and ceroid are both stained with Fontana-Masson; however, these pigments may be differentiated by virtue of acid-fast staining of ceroids [14]. Our case was stained with Fontana-Masson stain as well as with acid-fast stain, suggesting the presence of ceroid rather than the lipofuscin, a byproduct of normal aging phenomenon. Furuya et al [3] proposed that the xanthogranulomatous inflammation secondary to endometriosis should be considered as a separate entity and termed it pseudo-XGS. On the

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other hand, they suggested that pelvic inflammatory disease associated xanthogranulomatous changes should be termed as pure XGS; however, they acknowledge that overlaps between these entities exist. Other authors believe that all these entities belong to a wide spectrum of changes caused by multiple etiologies and prefer to group them together as XGS [15]. The stimulus for inflammatory cells including histiocyte has yet to be elucidated, and the association with different etiological factors still has to be demonstrated. The presence of inflammatory cells can be made prominent by performing LCA immunostain. This may be important in differentiating a newly reported entity, xanthelasma of the fallopian tube, from xanthograulomatous salpingitis. In the present case, the numbers of inflammatory cells varied in different fields ranging from minimal to abundant. The inflammatory cells were present in the vicinity of blood vessels, suggesting active recruitment from the blood. It has been suggested that these lesions may be associated with malakoplakia because of the presence of abundant histiocytes and potential infectious etiology, which may represent a part of the spectrum; however, no Michealis-Guttman bodies have ever been identified. In some of the previous reports, XGS has been linked to intrauterine contraceptive device [8]. In the present case, the patient did have an IUD for 5 years and the endometrial curettings revealed chronic endometritis. It cannot be ascertained how this can effect the final histopathologic appearance of the lesion. Finally, the effect of chemotherapy to the development of this lesion cannot be independently evaluated as has been reported with the radiotherapy. This case report demonstrated the strong association of endometriosis to the process of xanthogranulomatous inflammation and displays a whole spectrum of changes, demonstrating a likely histogenesis of the lesion. The role of IUD, endometriosis, and chemotherapy, if any, may be supplemental. Xanthogranulomatous salpingitis represents

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