Pregnancy Related Changes in Endometrium: A Morphological study, Emphasizing Diagnostic Pitfalls

    Alia Zubair, Shahid Jamal, Azhar Mubarik, Rabia Subuktageen and Fizza Batool

Histopathology Department, Army Medical College, Rawalpindi

Objective The goal of this study was to recognize and analyze the microscopic features of pregnancy related changes in endometrium and to differentiate them from benign and malignant pathologic conditions on routinely stained sections.

Study Design: Observational study

Place and Duration:  The study was carried out at the Departments of Histopathology, Army Medical College, Rawalpindi, from March 2007 to March 2008.

Materials and Methods: The sections (3-5 μ), stained with hematoxylin and eosin (H&E) stain were microscopically examined and histopathology reporting was done. A total of 165 cases were collected randomly.

Results: Out of 165 endometrial curettings, 25 cases contained purely glandular tissue showing Arias-Stella reaction, 55 cases exhibited both decidual tissue and gland changes, and 85 cases had decidual stromal changes only. Features of Arias-Stella reaction that could be mistaken as clear cell carcinoma were secretory and hypersecretory patterns (46.2 & 20.6% respectively). Ground glass nuclei with pseudoinclusions were observed in 15% of cases, which can look like nuclei of herpes virus-infected cells. Foci of monstrous cells mimicking intraepithelial carcinoma were identified in 3.7% cases. Necrotic and degenerated decidual stroma mimicking squamous cell carcinoma was found in 50 out of 140 cases. Decidual reaction with giant cells was found in 23.3% cases. In a few cases (4 out of 140), pale eosinophilic decidual cells were mixed with biphasic population of trophoblastic cells which could be difficult to distinguish from intermediate trophoblastic tumor or poorly differentiated carcinoma. Fifteen cases (10.7%) showed spindle cells pattern in decidual tissue.

ConclusionThe data suggests that the recognition of benign nature of pregnancy related changes in endometrial glands and stroma, is useful in the differentiation from malignant and infectious disorders. Awareness of these changes during pregnancy and postpartum may prevent interpretive errors and unnecessary surgical procedures.

Key words: Arias-Stella reaction, endometrium, pregnancy changes



Introduction

The Arias-Stella reaction is a benign, proliferative change which occurs in mullerian epithelium in response to increase in progesterone levels.1 It has been described in a variety of clinical settings, including uterine and extra-uterine pregnancy, gestational trophoblastic disease, and following the administration of progestational agents.2 Of these, the endometrial glandular changes referred to as the Arias-Stella reaction have classically been a diagnostic pitfall in histologic sections.3

The changes involving endometrial glandular epithelium are often alarming enough to cause diagnostic difficulties, especially when the history of pregnancy is not provided. The histologic diagnosis of Arias-Stella reaction can also be challenging when this phenomena occurs outside the setting of pregnancy or in older patients. The differential diagnosis also is problematic when serous or clear cell carcinoma focally arises within an endometrial polyp, as part of "endometrial intra-epithelial carcinoma", or in younger patients.4

The endometrial stroma displays a variable degree of decidual reaction which in the absence of placental villi can be mistakenly identified as malignant lesion. In the cases with marked change, there is frequently an intensive decidual reaction and the presence of decidual giant cells.5

Regenerative activity in decidual tissue can also mimic squamous cell carcinoma. Sometimes syncytiotrophoblastic cells mixed with decidual tissue can confuse with a poorly differentiated malignant tumor.
Cases of spindle cell deciduolosis have been reported.6

Multinodular growth of myofibroblastic cells without atypia have been observed. All these histologic manifestations of the Arias-Stella and decidual reaction continue to cause diagnostic confusion with benign lesions as well as adenocarcinoma. Careful scrutiny of hematoxylin-eosin-stained slides should allow recognition of the benign nature of these changes.

With this view in mind the histopathology of Arias-Stella reaction and stromal tissue was studied in the present study. The goal of this study was to recognize the microscopic features of above mentioned pregnancy related changes in endometrium and to differentiate them from benign and malignant pathologic conditions on routinely stained sections.

  Materials and Methods

A retrospective study was carried out at the Departments of Histopathology, Army Medical College, Rawalpindi. The Pathology Department receives endometrial curettings, from the Department of Gynecology, Militiary Hospital Rawalpindi and various civil hospitals as well. The specimens were fixed in 10% formalin. Curettings were described and morphology was recorded. Then they were placed in cassettes, kept in fixative for two hours and processed in the automatic tissue processor. Paraffin blocks were prepared. Sections (3-5μ) were cut and stained with hematoxylin and eosin (H&E) stain. Microscopic examination and histopathology reporting was done. A total of 165 cases were collected randomly over a period of about 1 year from March 2007 to March 2008.

Results

Out of 165 endometrial curettings, 25 cases contained purely glandular tissue showing Arias-Stella reaction, 55 cases exhibited both, decidual tissue and glands; and 85 cases had decidual stroma only. Overall 80 slides were studied for Arias-Stella reaction and 140 cases for decidual changes (Table 1).

 

Table 1: Pregnancy induced morphological changes found in endometrial curetting

(n = 165)

Changes observed

No of cases (%)

Only Glandular changes

(Arias-Stella reaction)

25 (15.2%)

Only decidual tissue change

85 (51.5%)

Mixed decidual tissue & glandular change

55 (33.3%)

Features of Arias-Stella reaction that could be mistaken as malignancy i.e. secretory and hypersecretory patterns were seen in 46.2 & 20.6% cases (Figure-1). This secretory pattern appeared as marked nuclear enlargement and the endometrial cells contained subnuclear and supranuclear vacuoles. The glands demonstrated luminal papillary projections (Figure-2). Foci of monstrous cells, described so as these are having enlarged hyperchromatic nuclei, of ovoid or round shape with granular or vesicular viable chromatin, an irregular outline. Some cells may have giant nuclei and are bizarre looking. Such cells were observed in 3.7% cases. Arias-Stella reaction is frequently associated with ground glass, eosinophilic nuclear "inclusions", which in some cases may be very striking, look like nuclei of herpes virus-infected cells and can cause diagnostic problem. In this study 15% of the cases exhibited this appearance (Figure-3). Other less significant patterns of Arias-Stella reaction were showing minimal atypia and proliferative patterns (8 & 5 cases respectively).

Different types of decidual tissue changes were found in 140 cases (table and figure-4). The necrotic and degenerated decidual stroma seen with increasing duration of pregnancy, having vacuolar degeneration and fragmentation of the decidua cells, attain darkly eosinophilic cytoplasm and can mimic squamous cell carcinoma. Such change was observed in 50 out of 140 cases (Figure 5). When there is florid decidual reaction then giant cells may be seen. When such cells are outside the endometrium, are called ectopic. Such cells were found in 23% cases (Figure-6). Thirty six cases were of benign decidual tissue, which were to be differentiated from trophoblastic disease. In a few cases (4 out of 140), pale eosinophilic decidual cells were mixed with biphasic population of trophoblastic cells which could be difficult to distinguish from intermediate trophoblastic tumor or poorly differentiated carcinoma was also identified. Fifteen cases (10.7%) showed spindle cells in decidual tissue.

 

Figure 1: Pregnancy induced morphological features of endometrial glands (n = 80)

Figure-2: Hypersecretery pattern, having hyperchromatic nuclei and papillary projections. (H&EX400)

Figure-3: Glands having ground glass nuclei (H&E X 100)


  Figure 4: Pregnancy induced morphological features of endometrial stroma (n = 140)

Figure-5: Degenerative decidual stromal change(H&EX400)

 

Figure-6: Florid decidual reaction with giant cell(H&E X100)

Discussion

The Arias-Stella reaction was first described in 1954 by Javier Arias-Stella.5 In this type of reaction there is focal, unusual, decidual changes in endometrial epithelium that consist of intraluminal budding, nuclear enlargement, and hyperchromatism with cytoplasmic swelling and vacuoles. The main characteristic of the reaction is cellular enlargement, mainly of the nucleus, to double or many times normal size.

The varied morphological features of these changes which can result in diverse problems in differential diagnosis are; 

Diagnostic issues related to endometrial glands Secretory / hypersecretory patterns that can mimic clear cell carcinoma Javier Arias-Stella7 has documented the features of secretory and hypersecretory pattern of Arias-Stella phenomena, which can mimic carcinoma. Maximum number of cases (46.2% and 20.6%) in the present study demonstrated this change and same was observed previously.7,8

The principal consideration in the differential diagnosis of above mentioned patterns was clear cell carcinoma. The features most helpful in this distinction as described by Nucci and Young8, were the usual lack of a suspicious mass for cancer, absence of a desmoplastic response, lack of an infiltrative pattern, spectrum of cytological atypia, low nuclear-cytoplasmic ratio, and usual lack of mitotic activity.
Awareness of these changes during pregnancy and postpartum may prevent interpretive errors and unnecessary surgical procedures.

Monstrous Cell Pattern versus endometrial intraepithelial carcinoma In present observation monstrous cells were seen in 3.7% cases and this pattern has been described by others.7 It can be misinterpreted as intraepithelial carcinoma. This may be a very difficult issue especially if this change is associated with a stromal response without any reliable clinical history or if the microscopic picture is unusually extensive. However, a constellation of features including lack of an infiltrative pattern, a predominant superficial location, an orderly, arrangement of the glands, the usual lack of a desmoplastic stromal reaction, and bland nuclei in adjacent glands may indicate that a problematic glandular lesion is non neoplastic Optically clear nuclei that can mimic herpetic infection of endometrium Ground glass, eosinophilic nuclear "inclusions", which in some cases may be very striking, resembling herpesvirus-infected cells has been described previously by Dardi et al.9

On analysis of such cells no viral particles were found. Immunoelectron microscopy has been used to differentiate them from herpetic infection. On H&E, this differentiation is not possible but recognition of these inclusions in endometrium with history of pregnancy can prevent over diagnosis of viral infection. In present observation, 15% of cases displayed such type of ground glass nuclei.
A few less significant changes of Arias- Stella reaction like minimal atypia with focal nuclear enlargement and proliferative or nonsecretory pattern can also be a feature,7 and was observed in a few cases of present series.

Diagnostic issues related to decidual stroma

The endometrial stroma usually exhibits striking progestational changes during pregnancy.6 Microscopically, the cells in florid decidual reactions contain ample, ‘glassy’ eosinophilic cytoplasm with well-defined cell borders and typically exhibit a solid, somewhat cohesive architecture. Nuclei are centrally placed and round to ovoid, lacking atypia.10

Necrotic and degenerated decidual stroma mimicking squamous cell carcinoma Such pattern has been reported previously.6 and was observed in 50 cases of present series also. Although mild nuclear atypia may be seen within decidual cells, the characteristic findings within tumor deposits of intercellular bridges, dyskeratotic cells, “keratin pearls,” mitoses, and a desmoplastic reaction are not seen in the decidual tissue.11

Florid decidual reaction with giant cells: mimicking metastatic carcinoma In such pregnancy related change, there is frequently an intensive decidual reaction with presence of decidual giant cells,5 such type of cells can mimic with a poorly differentiated carcinoma. This reaction was observed in 35 cases of present study. Deposits of such decidual tissue outside the endometrium, known as ectopic decidua can even raise more diagnostic challenge. The major diagnostic implication would be misdiagnosis as metastatic carcinoma. Such a case of a pregnant lady was reported, in which the intraoperative frozen section of a pelvic lymph node with ectopic decidual change was mistakenly identified as metastatic carcinoma.12

Differentiation of benign decidual tissue from trophoblastic disease In this study 36 cases showed benign looking decidual tissue with pale eosinophilic cytoplasm and small rounded nuclei. Without any history of pregnancy and if the material does not contain placental villi, such type of cells are likely to be mistaken for intermediate trophoblasts seen in placental site nodule, which is a benign lesion found most often in the endometrium1, following an antecedent pregnancy within the previous 3–5 years. It is caused by benign proliferation of intermediate trophoblasts.13

However, given a history of previous pregnancy, if the possibility of placental site nodule or placental site tumour is suspected, then referral for colposcopy should be considered.14

Sometimes pale eosinophilic decidual cells mixed with biphasic population of cytotrophoblasts and multinucleated syncytiotrophoblasts can be difficult to distinguish from intermediate trophoblastic tumor or poorly differentiated carcinoma. Intermediate trophoblastic tumor is a rare tumor which may contain large atypical cells having large nuclei and even multinucleated cells but a biphasic cell population is not seen.  Diagnosis from poorly differentiated carcinoma can be difficult but immunostains can be helpful if clinical history does not sort out the issue.15

Spindle cell change in decidual cells the evidence for spindle cell change comes from the data provided by studies of ectopic decidual tissue.6, 12

In cases of spindle cell deciduolosis, oval to spindled decidual cells are found. One should know the possibility of spindle cell metaplasia in decidual tissue so that misdiagnosis of metastatic carcinoma and spindle cell lesions can be avoided. Such metaplastic spindle cells have bland nuclei and no atypia or mitoses.  

Conclusion

The data suggests that the knowledge and recognition of benign nature of pregnancy related changes in endometrial glands and stroma, are useful in the differentiation from malignant and infectious disorders. Awareness of these changes during pregnancy and postpartum may prevent interpretive errors and unnecessary surgical procedures.

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