Case 6 -

Atypical Stromal Cells From Leiomyoma Barbara A. Crothers Walter Reed Army Medical Center Washington, DC

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Smooth muscle cells from cervical leiomyoma. Cervical Thin Prep® Pap test, Papanicolaou stain Clinical History A 50 year old woman presented to the GYN clinic with a history of recent vaginal spotting over four months. Her cervical Pap test requisition stated that she was not postmenopausal, had not had a hysterectomy, was on birth control pills and had a normal Pap test one year ago. The physician also noted that she had a cervical polyp on examination and recent abnormal endometrial bleeding. Case 6 - Figure 1 - The slide contains scattered normal squamous cells and a sheet of endocervical repair but also a single smooth muscle cell with irregular, wispy cytoplasm. Thin Prep® Pap test, Papanicolaou stain, 40X. Case 6 - Figure 2 - The two smooth muscle cells at the top of the image have nuclei at least 4X the area of the normal metaplastic cells in the image. Thin Prep® Pap test, Papanicolaou stain, 60X. Case 6 - Figure 3 - The nuclei of the smooth muscle cells have smooth nuclear membranes, fine to moderately granular chromatin, multiple nucleoli and chromocenters. The cytoplasm is characteristically granular, ill-defined and fades into the background. Thin Prep® Pap test, Papanicolaou stain, 60X. Case 6 - Figure 4 - Two normal squamous cells abut a collection of leiomyoma cells with inconspicuous cytoplasmic borders. The leiomyoma nuclei are variable in size with folds and areas of chromatin condensation. Thin Prep® Pap test, Papanicolaou stain, 60X. Case 6 - Figure 5 - Reactive endocervical cells from the polyp. The nuclei are round, uniform in size and have inconspicuous nucleoli. The cytoplasm of the cell at the top of the image contains neutrophils, a common finding in cervical/endocervical polyps. Thin Prep® Pap test, Papanicolaou stain, 60X. Cytology On low power, the slide is hypocellular, with large cohesive groups of reparative metaplastic /endocervical cells and scattered single cells with variable nuclear sizes and nuclear to cytoplasmic ratios. These single cells have eccentrically located nuclei with a moderate amount of finely granular, delicate, indiscrete cytoplasm. The nuclei vary in size from 2-3 times that of a normal intermediate cell nucleus. The chromatin is finely granular, often hyperchromatic, and a small, round nucleolus is present in most cells. The nuclear membranes are delicate, slightly irregular and some have nuclear folds. The background of the Pap test also shows amorphous debris. There are normal endocervical cells and squamous cells present. Differential Diagnosis Repair Atypical polypoid adenomyoma Mullerian adenosarcoma Carcinosarcoma Endometrial stromal sarcoma Leiomyosarcoma Endometrioid adenocarcinoma Cytological Diagnosis - Initial: Atypical glandular cells, favor neoplastic. Comment: It is difficult to determine whether the atypical cells are endocervical or endometrial in origin. The differential diagnosis would include endometrioid adenocarcinoma or possibly a tumor with squamous and glandular components. Additional clinical evaluation would be prudent. - Final: Atypical stromal cells from leiomyoma. Histological Diagnosis Cervix, biopsy: Cellular leiomyoma. Discussion Cervical polypoid leiomyomas are not common lesions and there is no description of these cells in liquid-based Pap tests in the literature. This lesion was a 2.4 cm polyp with a distinct stalk. Histologically, the polyp was moderately cellular with a pattern of interweaving fascicular growth and thick-walled, hyalinized blood vessels. The surface of the polyp was denuded and inflamed. Smooth muscle cells were loosely cohesive but evenly spaced, with variably-sized nuclei and occasional multinucleation. The stroma was focally edematous. No mitoses were found. Immunohistochemical stains on the polyp were strongly positive for desmin and weakly positive for smooth muscle actin and estrogen receptor. The tumor cells were negative for CD 10, CD 34, myoD1, myogenin, MYF-4, and S100. Leiomyomas in the cervix present as cervical masses that are covered with normal epithelium and stroma and typically do not shed cells unless ulcerated. However, cervical and endocervical polyps may become traumatized, thereby losing their epithelial lining and exposing stromal cells to direct collection, as in this case. Most reports of the cellular features of leiomyomas in the literature involve descriptions of cells acquired from direct fine needle aspiration and not from exfoliation. With aspiration, cells from leiomyomas tend to exhibit more cohesion than those from leiomyosarcomas. Leiomyoma cells are rare inhabitants of Pap slides. In this case, the cells tend to exfoliate singly and in small poorly-cohesive groups. The cytoplasm is distinctive by virtue of its granular texture, variable shape and ill-defined, amorphous quality. Unlike the chromatin of high-grade sarcomas, their chromatin is evenly distributed with chromocenters and indiscrete nucleoli; there is no chromatin clumping or clearing. Cellular leiomyomas have nuclei that vary from round to slightly spindle-shaped and have scanty cytoplasm. They may contain occasional mitotic figures and blend into the adjacent myometrium [10]. On fine needle aspiration, leiomyomas shed small, highly cohesive fragments of spindle cells, often arranged in parallel, with uniform cigar-shaped nuclei. Their chromatin is finely granular with distinct nucleoli. The cytoplasm is typically delicate with elongated, tapering ends. Single cells are rare [1]. One reason for the predominance of single cells in this case may be due to high cellularity and stromal edema. Individual cells from repair may resemble those of leiomyoma but the cytoplasm in repair is typically dense and glassy with distinct borders, similar to squamous metaplasia. Pseudopodia may be present. Because repair is typically cohesive and exfoliates in sheets, individual reparative cells are unusual on Pap slides. Nuclear membranes in repair are usually smooth or only mildly irregular. The differential diagnosis includes atypical polypoid adenomyoma (APA), a polypoid lesion that occurs in the endometrium, lower uterine segment or endocervix. These lesions combine irregular, angulated endometrioid-type glands in a myofibromatous stroma. The glandular component appears on Pap tests as hyperchromatic crowded sheets of cells with nuclear pseudostratification, mimicking adenocarcinoma in situ. The glandular component can show feathered edges and rosette formation, but does not show mitotic activity. The nuclei are oval to elongate with fine- to moderately- granular, even chromatin and small nucleoli. Presence of the stromal component has not been reported on Pap slides and there is no tumor diathesis [2]. Mullerian adenosarcoma usually presents as a bulky endometrial or endocervical polyp filling the uterine cavity. The tip of the polyp may be ulcerated and hemorrhagic. Malignant stromal cells usually resemble high grade endometrial stromal sarcoma with coarse chromatin, scant cytoplasm, and poor cohesion, appearing as single cells or in small groups. The nuclei are oval or slightly elongated with conspicuous nucleoli and nuclear clefts. The glandular component shows cytological features of normal glandular cells with mild atypia and may not be recognized as part of the lesion [11]. The cytology of carcinosarcoma may consist of stromal cells identical to those of Mullerian adenosarcoma, but the malignant population is biphasic with a corresponding malignant epithelial component. The cytomorphology of malignant cells can vary greatly dependent upon the presence of heterologous or homologous elements [7] and the differentiation of the stromal and glandular components. Stromal cells may form tight, cohesive disordered groups or appear as single bizarre-shaped cells with ill-defined cytoplasm. These cases are typically recognized as malignant by virtue of their high cellularity, pleomorphism, classic malignant features, and tumor diathesis, although there may be few sarcomatous cells in the Pap slide [4]. Endometrial stromal sarcoma is high on the cytological differential diagnosis, as these cells contain round to oval nuclei that vary little in size and tend to exfoliate as single cells and small loosely cohesive groups. The chromatin can be variably fine or slightly coarse, but nucleoli are conspicuous. Basophilic, foamy cytoplasm closely rims the cells, is ill-defined [7], and less abundant than in leiomyoma. Leiomyosarcoma cells have large, hyperchromatic, club-like nuclei with elongated, bipolar cytoplasm. The chromatin is coarse, irregular and varies from cell to cell. Nuclear membranes are often irregular with divots. Very few cells tend to exfoliate and appear on Pap slides [7]. The groups are generally cohesive but single malignant cells are more common than in leiomyomas [1]. In some cases, multinucleation, cellular pleomorphism and tumor necrosis alert the observer to their malignant nature. Endometrial adenocarcinoma, when well-differentiated, exfoliates in three-dimensional, cohesive groups of cells with a high N:C ratio, scant cytoplasm and coarse chromatin. Well-differentiated endometrial adenocarcinoma would not be high in this differential since in most cases, the tumor cells resemble normal exfoliated endometrial cells. Poorly differentiated tumors are recognized by nuclear and cytoplasmic enlargement, prominent nucleoli, and frequent cytoplasmic vacuolation, often with neutrophils within the vacuoles. The background in these cases has been described as 'granular' or 'watery' on conventional Pap smears but may appear clean in liquid-based preparations. The Bethesda System (TBS) terminology does not always easily accommodate unusual findings on Pap tests, as in this case. In TBS, the best category for this lesion would be "other (malignant) neoplasm". Of themselves, these cells are not diagnostic for leiomyoma but a stromal tumor can be suspected based upon the cytological features described. References Barbazza R, Chiarelli S, Quintarelli GF, Manconi R. Role of fine-needle aspiration cytology in the preoperative evaluation of smooth muscle tumors. Diagn Cytopathol. 1997;16(4):326-30. Baschinksky D, Keyhani-Rofagha S, Hameed A. Exfoliative cytology of atypical polypoid adenomyoma. A case report. 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