Polypoid nodular histiocytic hyperplasia associated with endometrioid adenocarcinoma of the endometrium: report of a case

A 45 year old woman underwent Laparoscopy-assisted total hysterectomy with staging procedure following a diagnosis of endometrial endometrioid adenocarcinoma on her endometrial biopsy. The hysterectomy specimen showed a FIGO I stage 1a, endometrioid carcinoma. A separate polypoid lesion in the endometrium, distinct from the carcinoma, was also identified. Microscopically the polypoid lesion was “nodular histiocytic hyperplasia ”. The H&E, immunohistochemical staining findings and the differential diagnoses are discussed in this report. Although description of similar lesions is available in the literature, the current lesion is unique as it is identified in a hysterectomy specimen in its entirety and its association with an endometrial endometrioid carcinoma. Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/ vs/1060511915121922

Endometrium, Nodular histiocytic hyperplasia, Endometrioid carcinoma

Nodular histiocytic hyperplasia, initially thought to be of mesothelial origin because of their sites of occurrences, was reported in hernia sac [1]. Subsequently similar le- sions have been reported from various other body sites, e.g., the pericardial sacs and cardiac valves [2], periton- eum [3] and pleura [4]. Their presence in endometrial biopsy may mimic neoplasia. A recent series published seven cases of nodular histiocytic hyperplasia [5]. The cases, so far reported in the literature, are associated with benign lesions only. Since the previously reported cases were encountered in endometrial biopsies the le- sions were fragmented. We report here a case of a nodu- lar histiocytic hyperplasia associated with FIGO I/III endometrial endometrioid adenocarcinoma. We also de- scribe the lesion in its entirety; as noted above, all previ- ous descriptions of this entity were based on their presence in biopsy specimens . Case presentation A 45 year-old woman with a history of uterine fibroids presented with vaginal bleeding. She was Gravida 1 and Para 0, with a history of termination of pregnancy. A pelvic ultrasound showed a 9.1 x 8.0 x 4.0 cm partially distorted uterus with multiple hypoechoeic nodular areas, the largest being 4 x 3 cm and a thickened, 1.8 cm, endometrial stripe. Pathologic findings An endometrial biopsy revealed a FIGO I endometrial endometrioid type adenocarcinoma. After weighing-in all the options presented to her, the patient opted for a Laparoscopy-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy and staging procedure. Gross examination of the specimen revealed a 172 gms, 9.6 x 6.5 x 5.6 cm distorted uterus with multiple subserosal and intramural fibroids. Upon opening the uterus, a 4.5 x 4.2 cm shaggy polypoid lesion was identi- fied in the endometrial cavity involving both uterine walls. In addition a 0.7 x 0.5 cm polypoid lesion (Figure 1a) was found on the anterior wall of the endo- myometrium with smooth surface. The fibroids were noted in the intramural and subserosal locations. * Correspondence: [email protected] Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Alpert Medical School of Brown University, 101 Dudley Street, Providence, Rhode Island 02905, USA © 2014 Akhter et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Akhter et al. Diagnostic Pathology 2014, 9:93 http://www.diagnosticpathology.org/content/9/1/93 Figure 1 Photomicrographs of Nodular Histiocytic Hyperplasia. 1a (H&E): Low power magnification of polypoid nodular histiocytic hyperplasia; 1b (H&E): Closely packed histiocytes near the base of the polyp; 1 c (H&E): pink hyalinized fibrous bands separating aggregates of histiocytes; 1d (H&E): thick-walled blood vessel mimicking “onion-skinning”;1 e (H&E): more sclerosis towards the surface of the polyp; 1 f (IHC): histiocytic immunohistochemistry marker (CD68) showing diffuse positivity; 1 g (IHC): Pancytokeratin marker (AE1/AE3) is completely negative (surface epithelium is reactive serving as positive internal control); 1 h (IHC): HMB45 is negative. Figure 2 Photomicrographs of Endometrioid adenocarcinomaarising in a background of secretory Endometrium.2a (H&E): Low power view of FIGO I endometrioid carcinoma; 2 b (H&E): high power view of the same tumor; 2 c (H&E): Carcinoma is arising in a background of secretory endometrium. Akhter et al. Diagnostic Pathology 2014, 9:93 Page 2 of 4 http://www.diagnosticpathology.org/content/9/1/93 Microscopically, a smooth surfaced polypoid lesion was found to consist mostly of aggregates of histiocytes that were more closely packed near the endomyometrial junction, i.e., the base of the lesion (Figure 1b). Pink hya- linized fibrous bands are noted throughout the polypoid lesion (Figure 1c). Many blood vessels with thickened hyalinized walls are present throughout the lesion, more commonly towards the surface (Figure 1d). Towards the surface, the histiocytes were relatively sparse and sepa- rated by sclerosis (Figure 1e). The polyp was lined by a thin, attenuated, layer of endometrial epithelium (Figure 1e). The histiocytes resembled perivascular epi- thelioid cells. And presence of thick walled blood vessels within the lesion raised the question of a perivascular epithelioid cell tumor (PEComa). Immunohistochemical stains reveal that the lesional cells are strongly and dif- fusely reactive to a histiocytic marker, CD68, (Figure 1f ) and non-reactive to HMB45 (Figure 1h), pancytokeratin (AE1/AE3), (1 g) Epithelial membrane antigen (EMA), Desmin, Smooth Muscle Actin (SMA), CD10, Vimentin. FIGO grade I stage 1a endometrioid adenocarcinoma was noted in the endometrium as well (Figure 2a and Figure 2b). The tumor involves areas of adenomyosis; however, true myometrial invasion was not present. The carcinoma was arising in background of functional endo- metrium (Figure 2c). The lower uterine segment and cervix were free of tumor. No lymph-vascular space in- vasion was identified. The bilateral ovaries and fallopian tubes were unremarkable. The regional lymph node dis- section was all negative for metastatic carcinoma.

and conclusions Nodular histiocytic hyperplasia is a rare lesion often inci- dentally encountered in endometrial biopsies. Majority of these lesions are reported in the literature as single case report. The largest series, so far has been reported in the literature, is based on 7 cases [5]. The lesion, when en- countered in endometrial biopsies and present in small fragments, may mimic a neoplasm. So far all the re- ported cases are, however, associated with benign dis- eases. The current report is based on a case of nodular histiocytic hyperplasia associated with a FIGO I/III endometrial endometrioid adenocarcinoma. The lesion itself is identified grossly in its entirety as a distinct en- tity presenting as an endometrial polyp . The differential diagnoses of this entity include Lang- erhans cell histiocytosis, xanthogranulomatous endomet- ritis, malakoplakia, signet-ring cell changes of the endometrial stromal cells, etc. Available reports in the literature have elaborated how to distinguish nodular histiocytic hyperplasia from their mimics. The current case showed some resemblance with perivascular epithe- lioid cell tumor (PEComa) or an epithelioid smooth muscle tumor with many small hyalinized blood vessels. Microscopic and multifocal PEComa of the female geni- tal tract have been reported [6,7]. One interesting find- ing noted in the current case is the presence of hyalinized fibrous strands throughout the lesion; af e a - ture often seen in endometrial stromal tumors. The cyto- logic appearance of the tumor cells seen in endometrial stromal tumor is, however, completely different from what was seen in nodular histiocytic hyperplasia. The cells in endometrial stromal tumor are small, mostly round and darkly stained, especially in low grade stro- mal sarcoma . Special stains that were performed to rule out the mimics show the lesional cells of nodular histiocytic hyperplasia are strongly and diffusely reactive to histio- cytic marker, CD68. All other markers including, epithe- lial markers (AE1/AE3), smooth muscle markers, and endometrial stromal cell marker (CD10) were non- reactive. HMB45, a marker for PEComa, was also negative. The site of nodular histiocytic hyperplasia was clearly located on the surface of endometrium with smooth lin- ing and protruding into the endometrial cavity . It is speculated that the nodular histiocytic aggregates may result from previous endometrial biopsy. The current case did have a recent history of endometrial bi- opsy one month prior to her hysterectomy. The previous biopsy in this case revealed endometrial carcinoma with squamous differentiation and no evidence of histiocytic aggregate. It is also of note that the appearance of the foamy histiocytes often seen in endometrial biopsies is also different from the histiocytes present in nodular hyperplasia as they lack the foamy cytoplasm. Mazur and Kurman [8] proposed that these histiocytes apparently reside in the endometrial cavity and reported their presence in association with hydrometra and be- nign bleeding patterns. The authors postulated that it may represent a response to what they have proposed as “intracavitary debris. ” The current case was associated with an endometrioid adenocarcinoma so presence of some “intracavitary debris ” is not unlikely. As noted be- fore the polypoid lesion was seen projecting into the endometrial cavity. A possibly related, but morphologically dissimilar, his- tiocytic endometrial lesion has been reported by Iezzoni and Mills in their study of non-neoplastic endometrial signet-ring cells [9]. No signet-ring cells are identified in this case. Kim et al. proposed that the endometrial stromal cells showing progestational changes with atrophic endomet- rial glands trapped in the middle may produce histologic similarities that may vaguely resemble histiocytic aggre- gate [10]. Unlike nodular histiocytic aggregate, decidua- lized stromal cells do not form a discrete nodule. Kim et al. also speculated that the nodules may not originate Akhter et al. Diagnostic Pathology 2014, 9:93 Page 3 of 4 http://www.diagnosticpathology.org/content/9/1/93 in the endometrium because no vasculature was seen in their cases [10]. The current case documents many blood vessels in the nodule and thus contradicts that specula- tion of Kim et al. In conclusion, nodular histiocytic hyperplasia may not always be associated with benign/inflammatory lesions as previously reported in the literature. The current case documents its association with endometrioid carcinoma of the endometrium. The patient is currently followed routinely and is dis- ease free 80 months after surgery. Consent The patient has given consent for the use of the images and case presentation for educational and scientific pur- poses provided the unique patient identification is not revealed. Competing interest The authors declare no competing financial interest. All the authors have actively participated in the diagnosis and manuscript writing. Authors’ contributions SA is the Stuart Lauchlan International Visiting Fellow in Gynecologic and Breast Pathology and participated in writing up the case report and MRQ is the attending Pathologist on the case. WDL offered his expert opinion in finalizing the case. All authors read and approved the manuscript. Received: 19 February 2014 Accepted: 9 April 2014 Published: 12 May 2014

1. Rosai J, Dehner LP: Nodular mesothelial hyperplasia in hernia sacs. A benign reactive condition simulating a neoplastic process. Cancer 1975, 35:165–175. 2. Luthringer DJ, Virmani R, Weiss SW, Rosai J: A distinctive cardiovascular lesion resembling histiocytoid (epithelioid) hemangioma. Evidence suggesting mesothelial participation. Am J Surg Pathol 1990, 14:993–1000. 3. Clement PB: Reactive tumor-like lesions of the peritoneum. Am J Clin Pathol 1995, 103:673–76. 4. Ordonez NG, Ro JY, Ayala AG: Lesions described as nodular mesothelial hyperplasia are primarily composed of histiocytes. Am J Sung Pathol 1998, 22:285–92. 5. Prakash V, Domfeh AB, Fadare O: Nodular histiocytic aggregates in the endometrium: a report of 7 cases. Int J Gynecol Pathol 2013, 33:52–57. 6. Chia-Lang F, Yun-Ho C, Wei-Yu C: Microscopic endometrial perivascular epithelioid cell nodules: a case report with the earliest presentation of a uterine perivascular epithelioid cell tumor. Diagn Pathol 2012, 7:117. 7. Wang Y, Gao L, Zheng W-Q: Multifocal PEComa (PEComatosis) of the female genital tract and pelvis: a case report and review of the literature. Diagn Pathol 2012, 7:23. 8. Mazur MT, Kurman RJ: Artifacts and contaminants .I n Diagnosis of Endometrial Biopsies and Curettings: A Practical Approach. Edited by Mazur MT, Kurman RJ. New York: Springer; 1995:22. 9. Iezzoni JC, Mills SE: Nonneoplastic endometrial signet-ring cells. Vacuolated decidual cells and stromal histiocytes mimicking adenocarcinoma. Am J Clin Pathol 2001, 15:249–55. 10. Kim K-R, Lee YH, Ro JY: Nodular histiocytic hyperplasia of the endometrium. Int J of Gynecol Pathol 2002, 21:141–146. doi:10.1186/1746-1596-9-93 Cite this article as: Akhter et al. : Polypoid nodular histiocytic hyperplasia associated with endometrioid adenocarcinoma of the endometrium: report of a case. Diagnostic Pathology 2014 9:93. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Akhter et al. Diagnostic Pathology 2014, 9:93 Page 4 of 4 http://www.diagnosticpathology.org/content/9/1/93