Malacoplakia of the Uterine Cervix: A Case Report

Malacoplakia is an uncommon chronic granulomatous inflammation that rarely affects the female genital tract. A case of a 78-year-old woman with malacoplakia involving the uterine cervix and the vagina is described. The patient complained of vaginal bleeding. Clinically, a 13-mm mass was detected in the cervix, which was confirmed by ultrasound scan and magnetic resonance imaging. Histological examination showed a dense histiocytic infiltrate with abundant Michaelis–Gutmann bodies involving the uterine cervix and the upper vagina. The presence of Escherichia coli was confirmed in the lesion by immunohistochemistry and polymerase chain reaction. Only 12 cases of cervical malacoplakia have been reported to date. This condition should be included in the differential diagnosis of cervical tumors.


Introduction
Malacoplakia is an uncommon chronic granulomatous condition that usually affects the urinary tract. It was first described by Michaelis et al. in 1902 [1]. The disease results from the inability of macrophages to destroy phagocytized bacteria and is usually associated with coliform infections, and particularly with Escherichia coli. Although malacoplakia is usually subsequent to infections, it has been described in association with malignant tumors [2].
Histologically, the lesion is characterized by the presence of large histiocytes, some of which contain pathognomonic Michaelis-Gutmann (MG) bodies. These structures are nucleus sized, basophilic bodies containing calcium, sometimes with a laminated structure and a bull's-eye appearance. The histiocytic infiltrate is usually accompanied by a mixed inflammatory infiltrate composed of plasma cells and leukocytes.

Case Report
A 78-year-old woman complained of vaginal bleeding that had persisted for one month that had not resulted in anemia (hemoglobin 122 g/L). The patient had a history of Sjögren's syndrome treated with corticoids, a pulmonary thromboembolism 3 months before, and had cognitive deficit secondary to an episode of cerebral ischemia. The vaginal bleeding was confirmed by the caretakers.
The gynecological examination was limited due to pain. The ultrasound examination showed a 14 × 7-mm mass located in the posterior lip of the uterine cervix, with no other pathologic findings. A Pap-smear test and biopsy samples from the cervix and vagina were taken. The Pap-smear showed abundant large histiocytes and glandular cells with mild, non-specific atypia ( Figure 1). The cervical and vaginal biopsies showed granulation tissue with a mixed inflammatory infiltrate and several histiocytes with granulated cytoplasm. No epithelial dysplasia was seen in any sample. Magnetic resonance imaging confirmed a 14-mm mass located in the cervix, showing stromal infiltration of the cervical stroma and focally involving the upper vagina ( Figure 2). The patient did not receive any additional treatment. In spite of the absence of histological confirmation and due to the impossibility of conducting a proper clinical evaluation due to the pain, the lesion was clinically diagnosed as suspicious of cervical cancer, based on the imaging exams (ultrasound scan, magnetic resonance), the vaginal bleeding and the non-specific cytologic atypia. An informed consent was signed by the patient.
A total hysterectomy was performed due to clinical suspicion of cervical cancer. Macroscopically, the cervix showed a yellowish and indurated lesion with poorly delimited margins, involving the whole uterine cervix and extending focally to the upper vagina ( Figure 3).
The specimen was fixed in 10% neutral buffered formalin and embedded in paraffin following routine procedures. Paraffin sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), and von Kossa. E. coli was detected using a mouse monoclonal antibody (Anti-E. coli LPS antibody 2D7/1 [ab35654], 1:100; Abcam, Cambridge, UK) following the manufacturer's protocol. Immunohistochemistry was performed with the Autostainer Link 48 automated system (Dako Co., Carpinteria, CA, USA) using the EnVision system (Dako) and magenta as chromogen. Sjögren's syndrome treated with corticoids, a pulmonary thromboembolism 3 months before, and had cognitive deficit secondary to an episode of cerebral ischemia. The vaginal bleeding was confirmed by the caretakers. The gynecological examination was limited due to pain. The ultrasound examination showed a 14 × 7-mm mass located in the posterior lip of the uterine cervix, with no other pathologic findings. A Pap-smear test and biopsy samples from the cervix and vagina were taken. The Pap-smear showed abundant large histiocytes and glandular cells with mild, non-specific atypia ( Figure 1). The cervical and vaginal biopsies showed granulation tissue with a mixed inflammatory infiltrate and several histiocytes with granulated cytoplasm. No epithelial dysplasia was seen in any sample. Magnetic resonance imaging confirmed a 14-mm mass located in the cervix, showing stromal infiltration of the cervical stroma and focally involving the upper vagina ( Figure 2). The patient did not receive any additional treatment. In spite of the absence of histological confirmation and due to the impossibility of conducting a proper clinical evaluation due to the pain, the lesion was clinically diagnosed as suspicious of cervical cancer, based on the imaging exams (ultrasound scan, magnetic resonance), the vaginal bleeding and the non-specific cytologic atypia. An informed consent was signed by the patient.   A total hysterectomy was performed due to clinical suspicion of cervical cancer. Macroscopically, the cervix showed a yellowish and indurated lesion with poorly delimited margins, involving the whole uterine cervix and extending focally to the upper vagina ( Figure 3).  A total hysterectomy was performed due to clinical suspicion of cervical cancer. Macroscopically, the cervix showed a yellowish and indurated lesion with poorly delimited margins, involving the whole uterine cervix and extending focally to the upper vagina ( Figure 3).  A polymerase chain reaction (PCR) for E. coli was performed in paraffin-embedded tissue. For DNA extraction, 10 µm thick sections of formalin-fixed, paraffin-embedded tissue were incubated overnight in 20 µL of proteinase K solution (1 mg/mL) at 56 • C. Subsequently, proteinase K was heat inactivated by incubation of the sections at 95 • C for 10 min, and samples were spun and cooled down at −20 • C for 1-2 min. DNA was isolated using a commercially available kit (QIAamp Tissue Kit; Qiagen, Hilden, Germany). DNA yields were quantified spectrophotometrically using the NanoDrop ND-1000 (Thermo Scientific NanoDrop, Wilmington, DE, USA). Detection of E. coli was performed using specific primers and probes (LightMix ® Modular E. coli uidA, TIB MOLBIOL Syntheselabor GmbH, Berlin, Germany). The LightMix ® modular assay was run in a LightCycler ® 480 II instrument (Roche Diagnostics, Indianapolis, IN, USA). PCR cycle threshold values > 37 were considered negative.
Microscopically, a dense inflammatory was identified in the cervix and upper vagina. The infiltrate involved the lamina propria and extensive ulceration of the superficial epithelium was observed and was composed mostly by CD68 positive macrophages with a large foamy or granular cytoplasm showing abundant basophilic inclusions in the cytoplasm. The surgical margins were free of infiltrate. These inclusions were laminated and positive with PAS and von Kossa stains (MG bodies). Immunohistochemically, abundant intracytoplasmic E. coli bacilli were identified ( Figure 4). Additionally, the PCR detected E. coli DNA, confirming the diagnosis.
The patient was asymptomatic 13 months after surgery.
The diagnosis is based on microscopic findings of macrophages with MG bodies, which can occasionally be identified in Pap smears [5,6,16,17]. However, MG bodies can be abundant or scant and may be completely absent in the cytological samples, as in the present case. These structures can be identified inside or outside the cytoplasm of macrophages and typically show positive staining with PAS and von Kossa stains [5,16,17]. In the present case, E. coli, the microorganism most commonly identified as causing malacoplakia, was detected immunohistochemically and by PCR in the lesion, confirming the diagnosis. This is the first malacoplakia of the uterine cervix in which the responsible microorganism was identified by immunohistochemistry. In the previously reported cases, E. coli infection was confirmed in two patients by tissue and urine culture [14,18]. In two other patients, a concomitant granuloma inguinale was present, and other agents, such as Klebsiella, have also been associated with malacoplakia [9]. Due to the few cases reported, the clinical management remains unclear. In the present case, the decision of performing a hysterectomy in the absence of a histological diagnosis was based on the evidence of a cervical mass in the imaging exams (US scan, MRI), together with the serious limitations to the clinical evaluation and her advanced age. It was thus considered that the advantages of solving the clinical symptoms and excluding/confirming a malignant tumor exceeded the risks of possible overtreatment. In this respect, it is interesting to note that, as clearly shown in Table 1, hysterectomy [6,7,14,18] is the most frequent treatment reported. Antibiotic therapy has also been reported in some patients [15][16][17]. All cases have shown a benign behavior. However, due to the limited experience, conclusions on the effectiveness of the different treatments cannot be drawn.

Conclusions
In summary, malacoplakia is an inflammatory alteration that can mimic or can be associated with a malignant tumor; in light of this, it is important remember that malacoplakia of female genital tract exists.

Funding:
The authors did not receive support from any organization for the submitted work.
Institutional Review Board Statement: Ethical review and approval were waived for this study, due to that our institution does not require Ethics Committee approval for individual case reports.

Informed Consent Statement:
Our institution does not require Ethics Committee approval for individual case reports. The patient had signed an informed consent, allowing performing research analyses.