Correspondence Pinki Pandey, MD, E-15, Maharishi Markandeshwar Institute of Medical Science and Research, Maharishi Markandeshwar University, Mullana, Ambala 133203, Haryana, India. Email: email@example.com
Secretory carcinomas of the endometrium are uncommon tumors representing only 1–2% of endometrial carcinomas and have received very little attention in the literature. These are usually grade 1 tumors architecturally and cytologically. We report a case of secretory carcinoma endometrium in a 42-year-old woman presenting with irregular vaginal bleeding and underwent a hysterectomy revealing secretory carcinoma endometrium. The histological features of secretory carcinoma are reminiscent of normal early secretory endometrium (17–22 days), displaying a well differentiated glandular pattern having columnar cells with subnuclear or supranuclear vacuolization containing clear glycogenated cytoplasm. It is extremely important to distinguish secretory carcinoma from clear cell carcinoma in view of the excellent prognosis of the former and the unfavorable prognosis of the latter.
Secretory carcinoma is a variant of typical endometrial carcinoma distinct from clear cell carcinomas. It is a rare pattern, representing only 1–2% of endometrial carcinomas.1 Their histological features are reminiscent of normal early secretory endometrium (17–22 days). They are always well differentiated and associated with good prognosis. These tumors are rare in pure form but may be seen frequently as foci within other endometrioid carcinomas. It is very important to distinguish it from clear cell carcinoma in view of the excellent prognosis of the former and the unfavorable prognosis of the latter.
The case is being reported because of its extreme rarity as per the literature published worldwide. Relevant resources were identified by a Pubmed/Medline search for databases from January 1950 to January 2010 using the keywords secretory carcinoma, endometrioid carcinoma, secretory endometrium. A total of seven papers were identified including four case reports,2-5 two case series6,7 and one population based registry of all uterine tumors,8 the present case being the first one from the Indian subcontinent. An attempt is made to document the histological features of secretory carcinoma endometrium in a 42-year-old female, who presented with irregular vaginal bleeding, with discussion of the differential diagnoses.
A 42-year-old woman (para 2, live 2) presented with complaints of irregular bleeding per vaginum for one year. She attained menarche at 12 years of age. Her menstrual cycles had been normal until one year previously when she developed intermenstrual and postmenstrual bleeding per vaginum. But for one month she was having bleeding per vaginum on and off, which was not controlled even after treatment. She was not using any contraception. There was neither history of exogenous hormone use nor history of drug intake like tamoxifen. There was no history of dilation and evacuation in the past. There was no past or family history of diabetes mellitus and hypertension. Physical examination showed the patient to be obese with mild pallor. The rest of the general and systemic examination was normal.
Per speculum examination showed mild cervicitis and normal vagina. Per vaginum examination revealed a firm, mobile, irregular, 14 weeks size anteverted uterus with clear bilateral fornices. Hematological and other lab parameters were within the normal range. Ultrasonography revealed endometrial hyperplasia, thickness measuring 19 mm.
Pap smear was negative for intraepithelial lesion or malignancy. Subsequently she underwent total abdominal hysterectomy and bilateral salpingooophorectomy.
The specimen consisted of globoid uterus with cervix and bilateral adnexae. Uterus along with cervix measured 12 × 10 × 4 cm. Cut section revealed thickened and irregular endometrium and an obliterated endometrial cavity by friable polypoidal growth. Left ovary measured 3.5 × 3.0 × 1.0 cm and cut section showed a corpus luteal cyst (Fig. 1). Both fallopian tubes and right ovary were unremarkable. Paraffin-embedded sections prepared from different parts of the tumor were studied by hematoxylin and eosin stain, periodic acid-Schiff (PAS) stain with and without diastase treatment and alcian blue stain.
Microscopically, the entire endometrium was replaced by tumor and there was no uninvolved endometrium. Tumor consisted of variable sized tubular glands lined by a very regular single-layered to pseudostratified, tall-columnar epithelium. The cells lining these glands showed mild pleomorphism, small, vesicular and uniform nuclei, fine nuclear chromatin and clear cytoplasm in the supra- and subnuclear positions (Figs 2,3). Tumor cells were seen invading the superficial myometrium in the form of solid nests (Fig. 4).
A PAS stain showed variable positivity with the presence of eosinophilic fine granular material in the vacuolated cells but the stains for mucin were negative. Left ovary showed the presence of corpus luteal cyst. No vascular or lymphatic invasion was seen. Cervix, bilateral fallopian tubes and ovaries were free of tumor cells. The diagnosis rendered was secretory adenocarcinoma endometrium (architecture grade I and nuclear grade I).
The postoperative period was uneventful and she has had no complication or local recurrence after one year of follow up.
Endometrial adenocarcinomas are usually type I cancers associated with manifestations of endogenous or, exogenous hyperestrogenic stimulation and a favorable prognosis. Subtypes include adenocarcinomas with squamous differentiation and secretory, ciliated cell and villoglandular variants.
Secretory adenocarcinomas of the endometrium are uncommon tumors, most frequent in postmenopausal women without exogenous or, abnormal levels of progesterone, often present with abnormal vaginal bleeding. The age range is from 35 to 79 years, with a mean age of 55–58.6,8 They tend to occur in nulliparous, obese, hypertensive, and/or diabetic women, frequently with ovarian hormone producing lesions, or in women who have received exogenous estrogens and are generally low grade and low stage, slowly progressive and associated with a favorable prognosis.
In 1973, Silverberg and De Giorgi7 reported 12 cases of clear cell carcinoma of endometrium including two that had previously been reported. Among these 12 cases, they had demonstrated one or more of four basic patterns – tubular, solid, papillary and secretory. There were four cases that showed a pattern of secretory carcinoma, seen predominantly in postmenopausal women. This pattern resembled benign endometrium in the secretory phase, while the other three usually contained foci reminiscent of arias-stella phenomenon. In their study, they demonstrated that the difference between secretory carcinoma and clear cell carcinoma is cytologic. Clear cell carcinoma has cells with nuclei with high-grade cytologic characteristics, often protruding hobnail like glandular lumina. The nuclear changes are also distinct, with irregular nuclear outlines and chromatin clumping, especially along the nuclear envelope. Nucleoli often are large and may be multiple. Conversely, in secretory carcinoma the tumor consisted of tubular glands lined by a very regular, single layered to pseudostratified, tall columnar epithelium in which clear cytoplasm was present in both supra and subnuclear positions. The nuclei were small, vesicular and uniform.7 In 1980, Dickersin et al.9 described the ultrastructural pathology of 16 cases of clear cell carcinoma and compared them with the light microscopic findings. They observed that cytoplasmic glycogen and short, blunt microvilli were the outstanding features of clear cell carcinoma in both solid and tubulocystic tumor pattern, whereas golgi apparatus and numerous mitochondria were the less consistent findings. The fine structural characteristics were similar to those reported for clear cell adenocarcinoma of the endometrium and ovary in older women.9
Grossly, secretory carcinoma is almost uniformly exophytic even when deeply invasive. At times the tumor may appear to be composed of polypoidal masses. Myometrial invasion by carcinoma may result in enlargement of the uterus and it appears as well-demarcated, firm, gray-white tissue with linear extensions beneath an exophytic mass or as multiple, white nodules with yellow areas of necrosis within the uterine wall.
Microscopically, secretory carcinoma displays a well-differentiated glandular pattern and is composed of columnar cells, often unstratified, with subnuclear or supranuclear vacuolization containing clear glycogenated cytoplasm, closely resembling day 17–22 secretory endometrium.6,10 Secretions are present in the gland lumina, even in women past menopause. It is usually grade I architecturally and by nuclear features. There is minimal cellular atypia, stratification and pleomorphism.
The secretory pattern may be focal or diffuse. These tumors are rare in pure form but may be seen frequently as foci within other endometrioid adenocarcinomas. The adjacent non-malignant endometrium typically shows change consistent with prolonged or unopposed estrogen effect (e.g., hyperplasia, stromal breakdown and thrombosis of vessels). In young women the endometrium adjacent to secretory carcinoma typically shows a secretory pattern that is more advanced than 17 days. In most of the premenopausal patients when a hysterectomy and bilateral salpingooophorectomy are performed a corpus luteum is found, as in our case. Nonetheless, a relationship to progesterone stimulation is not always demonstrable and most of the women are postmenopausal. The secretory activity in the tumor may be transient because it has been observed in curettings but not in the later hysterectomy specimen.8
Tobon and Watkins6 suggest that there are two types of secretory carcinoma; in young women the tumor cells are capable of responding to their environmental hormonal influences, possibly in a cyclical fashion, whereas in older women past the menopause the neoplasm has become deregulated so that it exhibits a cell function that is no longer under environmental control.
The presence of clear cells in the genital tract neoplasms often reflexly prompts the diagnosis of a clear cell tumor but clear cells may be seen in many other neoplasms. Histologic differential diagnoses of secretory carcinoma endometrium include clear cell carcinoma, atypical hyperplasia with secretory change, endometrioid adenocarcinoma with squamous differentiation and low grade mucinous carcinoma.
It is extremely important to distinguish secretory carcinoma from clear cell carcinoma in view of the excellent prognosis of the former. The latter is considered to be type 2 non-endometrioid carcinoma with a poor prognosis; often selected for adjuvant chemotherapy and/or radiotherapy even in the absence of myoinvasion at hysterectomy. Although both types have cells with clear, glycogen-rich cytoplasm, secretory carcinoma does not demonstrate papillary or cystic architecture, and it does not show grade 3 nuclear atypia or the hobnail pattern commonly seen in clear cell carcinoma. In our case, the tumor did not exhibit any of the abovementioned features of a clear cell carcinoma.
A rare case of apparent secretory carcinoma may show foci with high grade nuclei, suggesting that clear cell carcinoma may be present, so it is important to thoroughly sample any low grade tumor with clear cytoplasm to determine if grade 3 nuclei and a more aggressive neoplasm may be present.
The most important diagnostic problem is excluding atypical hyperplasia with secretory effect and is based on the presence of stromal invasion and back-to-back glands found in carcinoma. This may be achieved by extensive tissue sampling and a careful study of histopathological findings. Atypical hyperplasia and endometrioid carcinoma may retain responsiveness to progestins and develop a secretory appearance. A good clinical history should be provided for the pathologist to avoid this confusion.
Cells with clear cytoplasm may also be seen in the squamous component of an endometrioid adenocarcinoma with squamous differentiation. Although both types have intracytoplasmic glycogen, clear squamous cells tend to be polygonal and usually merge with more typical squamous cells with abundant eosinophilic cytoplasm.
The morphologic features of low grade mucinous carcinoma overlaps with the patterns of so-called secretory carcinoma, both types of tumors have abundant pale cytoplasm and basal nuclei with minimal stratification. In mucinous carcinoma the cells contain cytoplasmic mucin, in contrast to secretory carcinoma, which contains glycogenated cytoplasmic vacuoles. The distinction is largely academic, however, because the tumor grade rather than cytoplasmic differentiation determines prognosis, these neoplasms show no difference in behavior from endometrioid tumors of similar grade.
In 1982 Christopherson et al.,8 noted that the presence of myometrial invasion, the death of a patient from recurrent disease at 30 months, and the presence of metastases in the patients who survived for 5 years indicate that the secretory activity does not signify that these well-differentiated tumors are benign.
Secretory endometrial adenocarcinomas have also been related to tamoxifen therapy, which is a primary hormonal therapy for breast cancers as well as its chemoprevention and is the known drug to cause endometrial hyperplasia and endometrial carcinoma.3,5
The treatment protocol is hysterectomy and bilateral salpingooophorectomy; the same as that for endometrioid carcinoma of the same stage and grade.
In essence, secretory adenocarcinoma endometrium is a well-differentiated tumor with excellent prognosis. An attempt is made to document the histologic features of secretory carcinoma endometrium with discussion of the differential diagnoses. This unusual pattern of low grade adenocarcinoma endometrium is being reported because of its extreme rarity and to contribute in the spectrum of uterine neoplasia.