Pregnancy Related Changes in Endometrium: A Morphological study, Emphasizing Diagnostic Pitfalls
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.
Conclusion: The 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
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
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
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.
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.
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).
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).
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-5: Degenerative decidual stromal
Figure-6: Florid decidual reaction with giant cell(H&E X100)
DiscussionThe 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;
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
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
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
of benign decidual tissue from trophoblastic disease
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
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,
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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HLA-G immunoreactivity is specific for intermediate trophoblast in