Incidental granulomatous inflammation of the uterus.
Background. Granulomas of the uterine corpus have been reported in a variety of pathologic conditions but are relatively rare findings in routine histopathologic material.
Methods. This retrospective clinicopathologic study reviewed patients diagnosed with uterine granulomas between 1980 and 1999 in a tertiary referral center.
Results. The study group was comprised of 11 women, ranging in age from 37 to 90 years. All patients had histologically confirmed, non-necrotizing granulomas. The most common symptom prompting biopsy or hysterectomy was abnormal bleeding. Several concomittant histopathologies were noted. Eight of 11 patients had a known history of uterine instrumentation. None of the patients had clinical evidence of sarcoidosis or systemic infection, and stains for microorganisms were negative in all cases. Polarizable or foreign materials were not seen.
Conclusions. Well-formed, non-necrotizing granulomas are an infrequent finding in the uterus. A history of instrumentation may explain the presence of granulomas in a subset of patients.
GRANULOMATOUS INFLAMMATION of the uterus is a relatively uncommon finding that previously has been attributed to a variety of conditions, including infection, sarcoidosis, foreign-body reactions, and surgical procedures. Our institution's experience with incidentally-found uterine granulomatous inflammation is reviewed here. The clinicopathologic features of these cases are described, and an attempt is made to define their etiologies.
METHODS AND MATERIALS
We searched the surgical pathology files at the Cleveland Clinic and found 11 cases of granulomatous inflammation involving the uterus diagnosed between 1980 and 1999. Each case was identified and confirmed by review of all microscopic slides. Routine histologic sections were generated from paraffin-embedded and formalin-fixed tissue, cut 4 microns thick and stained with hematoxylin-eosin. All sections containing granulomas were polarized and examined for evidence of foreign material. In all cases, stains for fungal (Gomori methenamine silver stain) and mycobacterial organisms (Ziehl-Neelsen stain) were done. Concomitant uterine pathologies were noted.
The medical record was reviewed in each case to obtain information regarding patient age, menopausal status, history of uterine instrumentation, surgical procedures performed, and follow-up information. Particular attention was paid to whether the patient had a systemic disease to explain the presence of granulomas in the uterus and whether the diagnosis of granulomatous inflammation of the uterus had any documented clinical impact on treatment or further laboratory testing of the patient.
Eleven women with incidental findings of granulomas involving the uterus comprised the study group. At the time of diagnosis, the patients ranged in age from 37 to 90 years (mean 53 years, median 49 years); 6 patients were premenopausal and 5 were perimenopausal or postmenopausal. The most common clinical symptom prompting biopsy and/or surgery was uterine bleeding (n = 8); 1 of these 8 patients had a history of concomitant pelvic pain and another had a history of vaginal discharge. Of the remaining 3 patients, 1 presented with uterine prolapse, 1 with a pelvic mass, and the third with infertility. Eight of 11 patients had a known history of uterine instrumentation, which initially consisted of dilatation with curettage in 4 patients, endometrial biopsies in 2 patients, hysterosalpingogram in 1 patient, and hysteroscopy in 1 patient. Four of these patients had more than one episode of instrumentation. One patient had an intrauterine device (IUD) in place for 11 years before surgery.
None of the patients had a previous diagnosis of granulomas involving the uterus. There was no history of sarcoidosis or systemic infection with mycobacterial or fungal organisms.
Table 1 summarizes the clinicopathologic features of all 11 patients. They all had at least 1 identifiable granuloma of the uterus, involving the endometrium in 9 patients, the myometrium in 1 patient, and the cervix in 1 patient (Figure). Four patients had more than one granuloma identified. One patient, who had pelvic lymph node exploration done at the time of hysterectomy for endometrial adenocarcinoma, was found to have non-necrotizing granulomas in several pelvic lymph nodes. In all cases, the granulomatous inflammation was non-necrotizing. There was no polarizable material or evidence of foreign bodies noted in any of the cases. All granulomas were stained for mycobacteria using Ziehl-Neelsen stain, and for fungi using Gomori methenamine silver stain; no organisms were identified in any of the specimens.
Surgical procedures included hysterectomy (either total abdominal or total vaginal) in 6 patients, endometrial biopsies in 4 patients, and endometrial curettage in 1 patient. Concomitant histopathologic findings included acute and chronic cervicitis in 4 patients, squamous meta plasia of the endometrium in 3 patients, leiomyomata of the uterus in 3 patients, complex hyperplasia with or without atypia of the endometrium in 2 patients, endometrial adenocarcinoma in 2 patients, endometritis in 2 patients, and atypical polypoid adenomyoma in 1 patient, benign endometrial polyps in 1 patient, and adenomyosis in 1 patient. One patient had no significant concomitant pathologic findings in the endometrial biopsy specimen. Postoperative follow-up ranged from 1 to 5 years. There was no evidence of treatment or further laboratory testing because of the finding of granulomatous inflammation. None of the patients were later diagnosed with sarcoid, tuberculosis, or other systemic diseases that might have caused granulomas. One patient had rebiopsy for endometrial hyperplasia, and 1 patient had a subsequent hysteroscopy done as a follow-up for squamous metaplasia of the endometrium.
Table 2 summarizes a list of etiologies reported in the literature to be associated with granulomatous inflammation in the uterus. Infectious etiologies are commonly-reported causes of granulomatous inflammation in any organ system. Uterine involvement by tuberculosis is well documented, (1-5); it involves the endometrium and/or the cervix rather than the myometrium in most cases. (1) Mycobacterial infections, particularly tuberculosis, classically result in the formation of necrotizing granulomas; however, non-necrotizing granulomas can certainly be encountered in patients infected with Mycobacterium tuberculosis. All of the granulomas in the current study were non-necrotizing. It has been hypothesized that tuberculous granulomas in the endometrium are sometimes not necrotic because of the turnover rate of these tissues as part of the normal menstrual cycle. (6,7) In nonendometrial tissue or in postmenopausal women, however, this would not be a factor and some evidence of caseous necrosis might be expected. Ziehl-Neelsen stains failed to show evidence of mycobacterial organisms in any of the cases in the current series. While this does not preclude the possibility of a mycobacterial infection, none of the patients showed systemic signs or symptoms of such an infection before examination of the uterine tissue or after surgery.
In addition to mycobacterial organisms, other infectious processes have been infrequently reported to be associated with the development of granulomatous inflammation in the uterus. (7-12) Some of these were parasitic diseases, such as schistosomiasis or Enterobius vermicularis (pinworm) infection. (10-12) Rare examples of fungal infection, such as coccidiomycosis, have also been reported to be associated with granulomatous endometritis. (9)
Evaluation of granulomatous inflammation should include staining for fungal organisms (eg, with Gomori methenamine silver stain), in addition to staining for mycobacterial organisms. Interestingly, rare cases of granulomatous uterine inflammation have also been attributed to viral infections. Frank et al (8) reported a case with multiple non-necrotizing granulomas in an endometrial curettage specimen, presumed to be viral in etiology No cytomegalovirus (CMV) inclusions were identified by light microscopic evaluation in that specimen; however, CMV inclusions were noted in an endocervical curettage specimen, and the organism was ultimately shown by polymerase chain reaction in DNA extracted from paraffin-embedded endometrial tissue. (8) Although not a pattern of tissue pathology typically associated with CMV, previous reports of granulomatous inflammation associated with CMV infection in other organ systems have been documented in the literature. (8) Christie and Krieger (7) reported a case of necrotizing granu lomatous inflammation of the uterine cervix, which they attributed to chlamydial infection. (7) There was no evidence of organisms, either by histologic examination or by additional ancillary staining, in any of the cases in the current series.
Sarcoidosis is a systemic granulomatous disorder that has been previously reported to involve the uterus, (13-17) but involvement of the female genital tract by sarcoidosis is relatively rare. Exclusion of other causes for the inflammation, especially infectious etiologies, is warranted in patients with granlulomatous inflammation of the uterus and without a known history of sarcoidosis. Sarcoidal involvement of the uterus may include both endometrium and myometrium, in contrast to the relative rarity of myometrial involvement by tuberculosis. Menzin et al (17) even reported evidence of granulomas in a titerme leiomyoma of a patient with sarcoidosis. Clinical presentations of uterine sarcoidosis appear to be myriad and nonspecific, and include recurrent pelvic pain, uterine bleeding, infertility, and persistent vaginal discharge. (16) None of the patients in the current series were known to have sarcoidosis, either before surgery or during the follow-up period.
Rare examples of uterine granulomatous vasculitis have also been documented in the literature. Lhote et al (18) reported the case of a 61-year-old woman with a history of fever and weight loss over an 8-year period. Hysterectomy specimen showed evidence of giant-cell arteritis affecting the ovaries and myometrium. Interestingly, a temporal artery biopsy in the same patient showed evidence of temporal arteritis. Although granulomatous inflammation associated with infectious processes and sarcoidosis may also be vascular in nature, the presence of blood-vessel-associated granulomatous inflammation should at least raise the possibility of a true vasculitic process.
In patients with a history of surgery, foreign material from glove talc or suture may elicit a foreign-body giant-cell reaction. In many of these cases, histologic evidence of the foreign material may be evident by routine light microscopic evaluation, including polarization of the granuloma. An IUD may also elicit a focal foreign-body giant-cell reaction. Davis et al (19) reported foreign-body giant-cell reaction associated with iron-pigment residue from use of Monsel's solution in the uterine cervix at sites of previous biopsies. Independent of foreign material left behind during surgery, there has been association of surgery, particularly diathermy ablation procedures, with granulomatous inflammation. (20-27) In many of these cases, the granulomatous inflammation is associated with evidence of caseous necrosis related to the surgical procedure, as well as hemosiderin-type pigment. Evans et al (21) suggested that perhaps the basis for these lesions is an idiosyncratic reaction to focally-altered collagen ma terial. None of the current cases showed evidence of caseous necrosis associated with the granulomatous inflammation. Eight of the women, however, had a history of uterine instrumentation, which may have accounted for the etiology of their granulomas.
Other unusual causes of granulomatous inflammation in the endometrium have been reported. Radiation therapy has been described as an uncommon cause of granulomas. Rare examples of so-called ceroid granulomas have also been described in the uterus. (28-30) These lesions are marked by presence of granular pigment, which often accumulates within macrophages. In many cases, this type of granuloma is associated with previous hemorrhage and necrosis, such as is seen in either tumor necrosis or endometriosis. (30) Such granulomas were not identified in any of the cases in this study.
Despite staining for organisms, a search for foreign material, and a review of the medical record, the precise etiology of the granulomas was not known in a number of the patients in the current series. Presumably, in some cases, a history of surgery accounted for the presence of granulomas. Although the pathologic diagnosis of granulomas in these cases does not appear to prompt further evaluation of the patients for potential etiologies, consideration of such workup may be deemed appropriate in certain scenarios.
TABLE 1 Clinicopathologic Features of Patients With Granulomatous Inflammation of the Uterus Age Presenting Previous Uterine Patient (yrs) Symptom Instrumentation Procedure 1 49 Menorrhagia Yes x 2 Endometrial bx 2 37 Menorrhagia Yes x 6 TAH/BSO 3 38 Menometorrhagia Yes x 3 Endometrial curettage 4 78 Postmenopausal Yes x 1 TAH/BSO bleeding 5 45 Menorrhagia Yes x 1 TAH/BSO 6 39 Infertility Yes x 3 Endometrial bx History of IUD 7 90 Uterine prolapse Yes x 1 TVH 8 43 Pelvic mass No TAH/BSO 9 51 Menometorrhagia No Endometrial bx 10 64 Postmenopausal Yes x 1 Endometrial bx bleeding 11 50 Menorrhagia No TAH/BSO Foreign/ Type of Polarizable No. of AFB & GMS Patient Granuloma Material Granulomas Stains 1 Non-necrotizing None 1 Negative 2 Non-necrotizing None 1 Negative 3 Non-necrotizing None Multiple Negative 4 Non-necrotizing None 1 Negative 5 Non-necrotizing None 1 Negative 6 Non-necrotizing None 2 Negative 7 Non-necrotizing None 1 Negative 8 Non-necrotizing None Multiple Negative 9 Non-necrotizing None 1 Negative 10 Non-necrotizing None 1 Negative 11 Non-necrotizing None 3 Negative Concomitant Patient Pathology 1 Exaggerated proliferative-phase endometrium, complex hyperplasia, squamous metaplasia 2 Acute and chronic inflammation, complex hyperplasia with atypia 3 Atypical polypoid adenomyoma 4 Endometrial adenocarcinoma 5 Endometritis, adenomyosis, leiomyoma 6 None 7 Endometrial polyp, leiomyomata, accute and chronic cervicitis 8 Endometrial adenocarcinoma, acute and chronic cervicitis 9 Exaggerated proliferative-phase endometrium, squamous metaplasia 10 Endometritis 11 Squamous metaplasia, lciomyomata, chronic cervicitis AFB = Acid-fast bacillus GMS = Gomori methenamine silver IUD = intrauterine device, bx = biopsy, TAH/BSO = transabdominal hysterectomy with bilateral salpingo-oophorectomy, TVH = transvaginal hysterectomy TABLE 2 Summary of Possible Etiologies of Uterine Granulomatous Inflammation Infection (mycobacterial, fungal, viral, parasitic) Sarcoid Vasculitis Foreign-body giant-cell reaction (intrauterine device, parasite, foreign material) Ceroid accumulation Radiotherapy Previous instrumentation/surgery (eg, diathermy ablation) Unknown
(1.) Nogales-Ortiz F, Taracon I, Nogales FF Jr: The pathology of female genital tuberculosis: a 31-year study of 1436 cases. Obstet Gynecol 1979; 53:422-428
(2.) Coleman DV: A case of tuberculosis of the cervix. Acta Cytol 1969; 13:104-106
(3.) Schaeffer G: Tuberculosis of the female genital tract. Clin Obstet Gyneco1 1970; 13:965-998
(4.) Kherdekar M, Kher A, Sharma KD: Tuberculosis of the endometrium. a histopathologic study of 355 cases. Indian J Pathol Microbiol 1977; 20:39-52
(5.) Freedman LJ, Coleman B, Blasco L: Tuberculous peritonitis and endometritis mimicking a "frozen pelvis." Am J Obstet Gynecol 1979; 134:719-721
(6.) Shireman PK: Endometrial tuberculosis acquired by a health care worker in a clinical laboratory. Arch Pathol Lab Med 1992; 116:521-523
(7.) Christie AJ, Krieger HA: Indolent necrotizing granulomas of the uterine cervix, possibly related to chlamydial infection. Am] Obstet Gynecol 1980; 136:958-960
(8.) Frank TS, Himebaugh KS, Wilson MD: Granulomatous endometritis associated with histologically occult cytomegalovirus in a healthy patient. Am J Surg Pathol 1992; 16:716-720
(9.) Bylund DJ, Nanfro JJ, Marsh WL Jr: Coccidioidomycosis of the female genital tract. Arch Pat hot Lab Med 1986; 110:232-235
(10.) McMahon JN, Connolly CE, Long SV, et al: Enterobius granulomas of the uterus, ovary and pelvic peritoneum. two case reports. Br J Obstet Gynaecol 1984; 91:289-290
(11.) Campbell JS, Mandavia S, Threlfall W, et al: Pinworm granuloma of cervix uteri--incidental observation following IUD use and cone biopsy.] Trop Med Hyg 1981; 84:215-217
(12.) Knuth KR, Fraiz J, Fisch JA, et al: Pinworm infestation of the genital tract. Am Fam Physician 1988; 38:127-130
(13.) Pearce KF, Nolan TE: Endometrial sarcoidosis as a cause of postmenopausal bleeding a case report. J Reprod Med 1996; 41:878-880
(14.) DiCarlo FJ Jr, Dicarlo JP, Robboy SJ, et al: Sarcoidosis of the uterus. Arch Pat hot Lab Med 1989; 113:941-943
(15.) Chalvardjian A: Sarcoidosis of the female genital tract. Am J Obstet Gynecol 1978; 132:78-80
(16.) HO K-L. Sarcoidosis of the uterus. Hum Pathol 1979; 10:219-222
(17.) Menzin AW, You TT, Deger RB, et al: Sarcoidosis in a uterine leiomyoma. Int J Gynaecol Obstet 1995; 48:79-84
(18.) Lhote F, Mainguene C, Griselle-Wiseler V, et al: Giant cell arteritis of the female genital tract with temporal arteritis. Ann Rheum Dis 1992; 51:900-903
(19.) Davis JR, Steinbronn KK, Graham AR, et al: Effects of Monsel's solution in uterine cervix. Am J Clin Pathol 1984; 82:332-335
(20.) McCulloch TA, Wagner B, Duffy S, et al: The pathology of hysterectomy specimens following trans-cervical resection of the endometrium. Histopathology 1995; 27:541-47
(21.) Evans CS, Goldman RL, Klein HZ, et al: Necrobiotic granulomas of the uterine cervix. a probable postoperative reaction. Am J Surg Pathol 1984; 8:841-844
(22.) Akosa AB, Boret F: Necrotising granulomas of the uterine corpus. J Clin Pathol 1993; 46:953-955
(23.) Clark IW: Necrotizing granulomatous inflammation of the uterine body following diathermy ablation of the endome-trium. Pathology 1992; 24:32-33
(24.) Ferryman SR, Stephens M, Gough D: Necrotising granulomatous endometritis following endometrial ablation therapy. Br J Obstet Gynaecol 1992; 99:928-930
(25.) Silvemagel SW, Harshbarger KE, Shevlin DW: Postoperative granulomas of the endometrium: histological features after endometrial ablation. Ann Diagn Pathol 1997; 1:82-90
(26.) Ashworth MT, Moss CI, Kenyon WE: Granulomatous endometritis following hysteroscopic resection of the endometrium. Histopathology 1991; 18:185-187
(27.) Smart PJ, Hetherington JF: Postoperative uterine granulomata following endometrial resection. Pathology 1995; 27:209-211
(28.) Shintaku M, Sasaki M, Babi Y: Ceroid-containing histiocytic granuloma of the endometrium. Histopathology 1991; 18:169-172
(29.) Al Nafussi AI, Hughes D, Rebello G: Ceroid granuloma of the uterine cervix. Histopathology 1992; 21:282-284
(30.) Ooi K, Riley C, Billson V, et al: Ceroid granulomas in the female genital system. J Clin Pathol 1995; 48:1057-1059
RELATED ARTICLE: KEY POINTS
* Infectious etiologies are commonly reported causes of granulomatous inflammation of the uterus.
* Involvement of the female genital tract by sarcoidosis is a relatively rare occurrence.
* Foreign material from suture or glove talc may elicit a foreign-body giant-cell reaction in patients with a history of surgery.
* Previous surgery may account for the presence of granulomas in some cases.
From the Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.
Reprint requests to Richard A. Prayson, MD, Cleveland Clinic Foundation, Department of Anatomic Pathology (L25), 9500 Euclid Ave, Cleveland OH 44195.