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Papillary syncytial metaplasia of fallopian tube endometriosis: a potential pitfall in the diagnosis of serous tubal intraepithelial carcinoma.

Risk-reducing salpingo-oophorectomy (RRSO) is strongly recommended for women carrying BRCA1 and BRCA2 mutations, since it results in marked reduction in the risk of subsequent ovarian, fallopian tube, and primary peritoneal cancer. Risk-reducing salpingo-oophorectomy performed in premenopausal women also leads to marked reduction in the risk of subsequent breast cancer. (1) The prevalence of occult invasive and in situ carcinomas of the fallopian tube in these specimens is about 10% if both ovaries and tubes are submitted in their entirety for surgical pathologic examination. Although most of these occult carcinomas involve the tubal fimbriae, and are tubal intraepithelial carcinomas (TICs), (2-4) other sites, such as the midportion of the isthmus, are also involved. (5) Indeed, a recent study (6) found 15 cases of tubal carcinoma in 212 bilateral fallopian tube specimens from salpingectomies performed for a variety of benign and malignant conditions. Of these 15 cases, 3 occurred exclusively in the mucosa of tubal ampulla/isthmus. Since the subsequent course of resected TIC is unclear, the care management of these women is uncertain. Nevertheless, it is important to recognize TIC and distinguish it from other similar morphologic entities, if only to better understand the subsequent course of disease for these patients. The purpose of this case report is to describe a potential pitfall in the histopathologic diagnosis of TIC.


A 52-year-old white woman, gravida 2, para 2, with a personal history of ductal carcinoma in situ and a family history of breast cancer (mother) and ovarian cancer (aunt) was counseled at a familial ovarian cancer clinic. Testing revealed a BRCA2 germline mutation; the patient elected to undergo an RRSO, and hysterectomy was performed. The gross examination of the hysterectomy and bilateral salpingo-oophorectomy specimen was unremarkable. Both fallopian tubes and ovaries were submitted in toto for histologic examination by using the recommended procedure for this specimen. (7) Microscopic examination of the medial end of the right fallopian tube demonstrated a worrisome florid pseudopapillary epithelial proliferation characterized by marked stratification and loss of cellular polarity (Figure 1, A). The epithelium within this pseudopapillary lesion showed an increased nucleocytoplasmic ratio, round large nuclei, and prominent nucleoli (Figure 1, B). Mitoses were not identified. Focally, some cilia could be recognized (Figure 1, C). Examination of the uterus revealed an unremarkable cervix, late menstrual endometrium, and adenomyosis. The ovaries were unremarkable. The medial left fallopian tube was also lined by endometrium for a short distance, and this endometrium resembled the eutopic endometrium, being menstrual in type (Figure 2). Deeper sections of the pseudopapillary lesion of the right fallopian tube were undertaken, and these showed a focus of endometrium adjacent to the pseudopapillary proliferation undergoing stromal collapse and breakdown, with associated neutrophilic infiltration. The pseudopapillary lesion was no longer evident. However, the combination of these findings led to a diagnosis of papillary syncytial metaplasia of the right fallopian tube, despite the associated unusual nuclear atypia, rather than TIC.


The normal fallopian tubal epithelium is composed of 3 basic epithelial cell types: ciliated cells, secretory cells, and intercalated peg cells, overlying a loose connective tissue submucosa and an outer myosalpinx, composed of inner circular and outer longitudinal layers. This normal epithelium is characterized by simple columnar nonstratified epithelium with a mixture of the above 3 basic cell types, which tend to vary in number and distribution, depending on the anatomic region of fallopian tube and the phase of menstrual cycle. The intercalated peg cell is now considered to be either a phenotypic alteration of a secretory cell or some form of a reserve cell. (8)

Multiple studies in the past have shown that fallopian tube may be the primary source of pelvic serous carcinoma involving ovary and fallopian tube, irrespective of BRCA status. (3-5) Detailed histologic examination of prophylactic salpingo-oophorectomy specimens from high-risk patients has led to recognition of early carcinomas still confined to the fallopian tube epithelium, known as serous TIC. Recognition of serous TIC is important as it is likely a precursor lesion of serous cancer and is a possible target for early serous cancer detection and prevention. The tubal epithelium of serous TIC is characterized by (1) increased nuclear to cytoplasmic ratio with more rounded nuclei, (2) loss of cell polarity, (3) prominent nucleoli, (4) absence of ciliated cells, and (5) mitotic activity. In addition to these cytologic features, architectural findings can be observed, including marked epithelial stratification, small fracture lines in the epithelium, and exfoliation of small epithelial cell clusters from the tubal surface with or without degenerative changes. (7) Rarely, TIC may have an endometrioid appearance ("endometrioid TIC") characterized by stratified columnar epithelium with a lower nuclear to cytoplasmic ratio.

Immunohistochemical staining can be used as an adjunctive technique in the diagnosis of TIC. Usually, serous TIC demonstrates diffuse strong nuclear staining patterns for p53 and MIB-1. On occasion, p53 immunohistochemical staining may be absent, secondary to a deletion mutation of the gene that precludes recognition of the protein by the antibody. These immunohistochemical stains have been recommended when there is diagnostic uncertainty. (7)

Precision in the morphologic diagnosis of TIC is challenging, and several benign morphologic entities need to be considered to avoid overdiagnosis of TIC (Table). Perhaps the most common differential diagnosis is tubal hyperplasia, which can virtually mimic carcinoma in some cases of salpingitis. (9) Histologically, the normal epithelium can undergo prominent epithelial proliferation and be transformed into closely packed glands with cribriform and sievelike patterns. The constituent epithelium can show loss of nuclear polarity, mild to moderate degrees of atypia, conspicuous nucleoli, and rare mitoses. The adjacent stroma of the tubal plicae is usually edematous. In striking cases, pseudoinvasion of muscularis by gland-like structures, lymphatic penetration by epithelial cells, and prominent mesothelial hyperplasia may occur and can further suggest a malignant diagnosis. A number of features can be used to distinguish tubal hyperplasia from TIC. Tubal hyperplasia is characterized by the presence of abundant inflammation, and the absence of a mass lesion, severe atypia, and abnormal mitotic figures. Since both malignancy and infections can coexist, it should be noted that these 2 diagnoses are not necessarily mutually exclusive. (10)

Both surgical and histologic artifacts may be misconstrued as TIC but are usually easily identified. Thermal damage to the tubal fimbrial epithelium can lead to the appearance of a stratified, cellular epithelium. This effect is usually easily identified by the characteristic streaming pattern of thermal injury. Tangential histologic sectioning of normal tubal epithelium can also produce the appearance of epithelial proliferation but is distinguished by its bland, regular pattern ("honeycomb").

Arias Stella reaction in the fallopian tube is exceedingly rare but can potentially mimic malignancy. History of pregnancy, hormonal intake--especially by premenopausal or postmenopausal women--its focal nature, and lack of brisk mitotic activity may be helpful features. (11)

Therapeutic radiation treatment can also lead to the development of epithelial atypia of columnar and glandular epithelium throughout the endocervix, endometrium, and fallopian tube. These changes, however, are quite characteristic and unlikely to be mistaken for TIC, or present in an RRSO specimen.

Metaplastic papillary tumor of the fallopian tube also needs to be considered in the differential diagnosis of TIC. Usually, it is an incidental finding in tubal segments removed after pregnancy. It is characterized by intraluminal papillary growth with cellular buds and mucinous metaplasia without significant atypia or brisk mitotic activity. All reported cases have had indolent clinical behavior. (12)

Transitional metaplasia of the tubal epithelium has also been described, (13) but its orderly transitional maturation, characteristic nuclear grooves, and bland cytologic appearance make it unlikely to be confused with TIC. Although eosinophilic, secretory, and mucinous metaplastic changes of the tubal epithelium may occur, these changes are less likely to be confused with TIC.

In some cases, examination of proliferative foci of the tubal epithelium may reveal some, but not all, of the features of TIC, such as epithelial pseudostratification, nuclear enlargement, and nuclear molding, but overall polarity and interdigitating ciliated epithelium is retained. These cases have been varyingly designated as "atypical hyperplasia," "tubal dysplasia," or "tubal atypia," and perhaps represent the greatest challenge in the accurate diagnosis of TIC. When such atypical foci exhibit p53 positivity, the term proliferative p53 signature has been proposed. (14) In addition, secretory cell hyperplasia or outgrowth is characterized by greater pseudostratification of secretory-type epithelium, which lacks significant atypia, and may, or may not, show alterations in p53 staining. Although there is interest in both of these morphologic lesions with respect to their potential role in tubal carcinogenesis, they are not of clinical value and accordingly, should not be used as a clinical diagnostic term.

This case report adds papillary syncytial metaplasia of tubal endometriosis to the list of possible differential diagnoses of TIC and has not been described previously in this diagnostic context. Papillary syncytial metaplasia is usually encountered in a menstrual or collapsing endometrium after ovulatory and anovulatory cycles and is believed to be a regenerative phenomenon. Histologically, the surface epithelium forms an eosinophilic syncytiumlike mass with indistinct cell borders and shrunken and pyknotic nuclei, overlying rounded balls of collapsing stroma. The syncytium is typically infiltrated by neutrophils, and true nuclear atypia is not seen. (15) Our case demonstrated all the abovementioned histologic features, although the stromal collapse and neutrophilic infiltration were only appreciated on deeper histologic sections. Both the tubal location and nuclear atypia were exceptional features in this case. Immunohistochemical staining for p53 was not informative in this case, since the papillary lesion was not apparent on deeper sections.

In summary, this case illustrates that several of the key criteria used for a diagnosis of TIC can be seen in papillary syncytial metaplasia of tubal mucosal endometriosis, including marked epithelial stratification with loss of polarity, increased nucleocytoplasmic ratio, and rounded nuclei with chromatin clearing and prominent nucleoli. Nevertheless, papillary syncytial metaplasia is distinguished from TIC by the presence of ciliated cells and acute inflammation, in conjunction with the absence of marked cytologic atypia and any mitotic activity. Papillary syncytial metaplasia of tubal mucosal endometriosis should now be added to the list of differential diagnoses for an atypical tubal papillary proliferation.


(1.) Society of Gynecologic Oncologists Clinical Practice Committee Statement on Prophylactic Salpingo-oophorectomy [SGO Committee statement]. Gynecol Oncol. 2005; 98(2):179-181.

(2.) Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006; 30(2):230-236.

(3.) Cass I, Holschneider C, Datta N, Barbuto D, Walts AE, Karlan BY. BRCA-mutation associated fallopian tube carcinoma: a distinct clinical phenotype? Obstet Gynecol. 2005; 106(6):1327-1334.

(4.) Colgan TJ, Murphy J, Cole DE, Narod S, Rosen B. Occult carcinoma in prophylactic oophorectomy specimens: prevalence and association with BRCA germline mutation status. Am J Surg Pathol. 2001; 25(10):1283-1289.

(5.) Shaw PA, Rouzbahman M, Pizer ES, Pintile M, Begley H. Candidate serous precursors in fallopian tube epithelium of BRCA1/2 mutation carriers. Mod Pathol. 2009; 22(9):1133-1138.

(6.) Calkin SM, Rabban JT. Non-fimbrial localization of early fallopian tube carcinoma: implications for prophylactic surgery technique in women with hereditary risk for pelvic serous carcinoma [poster]. USCAP 2011 Annual Meeting (Poster 1012), San Antonio, Texas.

(7.) Clarke BA, Crum CP, Nucci MR, et al. Protocol for the examination of specimens from patients with carcinoma of the fallopian tube. Available at: http:// be_11protocol.pdf. Accessed January 10, 2011.

(8.) Mills SE. Histology for Pathologists. 3rd ed. New York, NY: Lippincott Williams & Wilkins; 2006:1048-1054. Michael R. Hendrickson, Kristen A. Atkins, Richard L. Kempson. Uterus and Fallopian Tubes (Chapter 41).

(9.) Cheung AN, Young RH, Scully RE. Pseudocarcinomatous hyperplasia of the fallopian tube associated with salpingitis. Am J Surg Pathol. 1994; 18(11):1125 1130.

(10.) Gungor T, Keskin HL, Zergeroglu S, et al. Tuberculous salpingitis in two of five primary fallopian tubecarcinomas. J ObstetGynaecol. 2003; 23(2):193-195.

(11.) Milchgrub S, Sandstad J. Arias-Stella reaction in fallopian tube epithelium: a light and electron microscopic study with a review of the literature. Am J Clin Pathol. 1991; 95(6):892-895.

(12.) Bartnik J, Powell WS, Moriber-Katz S, Amenta PS. Metaplastic papillary tumor of the fallopian tube: case report, immunohistochemical features, and review of the literature. Arch Pathol Lab Med. 1989; 1 13(5):545-547.

(13.) Rabban JT, Crawford B, Chen LM, Powell CB, Zaloudek CJ. Transitional cell metaplasia of fallopian tube fimbriae: a potential mimic of early tubal carcinoma in risk reduction salpingo-oophorectomies from women with BRCA mutations. Am J SurgPathol. 2009; 33(1):111-119.

(14.) Mehrad M, Ning G, Chen EY, et al. A pathologist's road map to benign, precancerous, and malignant intraepithelial proliferations in the fallopian tube. Adv Anat Pathol. 2010; 17(5):293-302.

(15.) Hendrickson MR, Kempson RL. Endometrial epithelial metaplasias: proliferations frequently misdiagnosed as adenocarcinoma: report of 89 cases and proposed classification. Am J Surg Pathol. 1980; 4(6):525-542.

Harkiran Kaur, MD, MSc; Elyse Levinsky, MD; Terence J. Colgan, MD

Accepted for publication January 11, 2012.

From the Departments of Pathology and Laboratory Medicine (Drs Harkiran and Colgan) and Obstetrics and Gynaecology (Dr Levinsky), Mount Sinai Hospital, Toronto, Canada.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Terence J. Colgan, MD, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Joseph & Wolf Lebovic Health Complex, Room 6-502-3, 600 University Ave, Toronto, ON M5G 1X5, Canada (e-mail:

Entities to Be Considered in the Diagnosis of Tubal Intraepithelial

Reactive hyperplasia and atypia of the tubal epithelium
Surgical (thermal) and histologic artifacts
Arias-Stella phenomenon of tubal epithelium
Radiation effects on tubal epithelium
Tubal metaplasias--papillary metaplastic tumor and transitional
Atypical hyperplasia/tubal atypia
Secretory hyperplasia of tubal epithelium
Papillary syncytial metaplasia of tubal mucosal endometrium


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Title Annotation:Case Reports
Author:Kaur, Harkiran; Levinsky, Elyse; Colgan, Terence J.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Case study
Date:Jan 1, 2013
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