and David C. Wilbur1
(1)
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
Keywords
AdenocarcinomaOvaryStomachColonRectumAppendixLungBreastCell blockImmunohistochemistryIn situ hybridizationHuman papilloma virusExcept for the occasional adenocarcinoma of the endometrium, the appearance of extracervical adenocarcinoma in cervical cytology samples is rare. One large series reported 33 cases out of approximately 900,000 cervical cytology samples over a 22-year period for a rate of 0.004 % [1]. As was described in Chap. 6 for endometrial adenocarcinoma, extracervical adenocarcinoma may be directly sampled if the metastatic tumor has spread to the cervix or if the tumor cells have spontaneously detached from a location proximal to the cervix and shed down the fallopian tube and uterine corpus to be found as exfoliated cells in the cervical cytology sample. Adenocarcinoma is by far the most common variety of extracervical malignancy to present in cervical cytology [2]. A number of series detailing the surgical pathology findings of metastatic disease to the cervix have been published but rarely is adenocarcinoma in cervical cytology the trigger for clinical work-up [3–6]. This may be due to clinical practice variation as some institutions routinely obtain cervical cytology on all female cancer patients, even with known metastatic disease involving the cervix. Thus as reported in a recent Mexican series all 10 women with extracervical adenocarcinoma had cervical cytology with five smears positive for malignant cells [6]. Usually, patients having extracervical disease involving the cervix present with vaginal bleeding. Most often metastases to the cervix are identified at the time of the primary tumor diagnosis but cervical cytology can occasionally be the first manifestation of the primary cancer. In a few cases, the patients had no known malignancy making recognition of an extracervical primary important. The average age varies from 41 to 62 years, but a significant number of women in each series is younger than 40 years of age [3–6].
Primary tumors may arise from the genital tract or may be extragenital. The genital tumors most likely to be found in the cervix, in order of frequency are from the endometrium, ovary, fallopian tube, and primary peritoneal serous carcinoma. The extragenital organs most likely to give rise to metastatic adenocarcinoma to the cervix include tumors of the breast, stomach, and colon. Other less common sites include pancreas, gall bladder, appendix, and lung.
On cytology as well as surgical pathology, the morphology of metastatic adenocarcinoma in the cervix can be deceptively similar to a primary cervical adenocarcinoma due to predominant or exclusive mucosal involvement with morphologic resemblance to endocervical glandular epithelium [7–9]. However, most extracervical tumors exhibit features that suggest an origin from non-cervical sites, either by the tumor morphology or by the histologic pattern of involvement of the cervix.
Cytomorphology of Metastatic Tumors
Although certain types of adenocarcinomas may have cytologic characteristics which suggest the organ of origin, many of the more common metastatic adenocarcinomas found in cervical cytology have overlapping features which do not permit on morphology alone to distinguish one tumor from another. The more common metastatic sites include tumors arising from the ovary, colon, stomach, and breast [3, 4, 6]. Cytologic features common to adenocarcinomas include the smear background which may or may not contain evidence of necrosis [10]. The tumor cells are often present as a combination of single cells and three-dimensional groups with large hyperchromatic nuclei rimmed by irregular, thickened nuclear membranes. Nucleoli are usually strikingly prominent. The cytoplasm is usually delicate and variably vacuolated (Fig. 7.1). The number of tumor cells present may be few to many, depending on the site of gynecologic tract involvement. For tumors involving the lower tract, where direct sampling or many exfoliated cells occur, the numbers may be high. But in tumors originating in the upper gynecologic tract, where only a few cells may travel though the fallopian tubes and uterine corpus, the numbers of tumor cells seen in cervical specimens can be very low. A paucity of abnormal glandular cells is one reason that a definitive diagnosis of extragenital adenocarcinoma may not be made on a cervical cytology sample [1].
Fig. 7.1
Post-hysterectomy vaginal smear with a cluster of malignant glandular cells with prominent nucleoli and delicate cytoplasm consistent with recurrent endocervical adenocarcinoma (a); high power, SurePath, Papanicolaou stain; the subsequent biopsy showed the invasive recurrent adenocarcinoma (b); low power, hematoxylin and eosin
Certain morphologic clues may help determine the origin of the metastatic adenocarcinoma. The papillae of serous carcinoma of the endometrium, ovary, fallopian tube, and peritoneum most often present in cervical cytology as three-dimensional clusters of glandular cells due to exfoliation [11] (Fig. 7.2). The cells have abundant, clear (soap bubble-like) cytoplasm and hyperchromatic, eccentrically placed large nuclei with prominent nucleoli [1, 12] (Fig. 7.3). Less common are frond-like papillary tissue fragments often associated with psammoma bodies (Fig. 7.4). Most often no evidence of tumor diathesis (necrosis or lysed blood) is present but some cases can show evidence of background necrosis or granular debris [1]. Serous borderline tumors will resemble serous carcinoma in their three-dimensional cell arrangement but the nuclei are more often uniform with little of the pleomorphism of size and shape noted in fully malignant serous neoplasms [13] (Fig. 7.5).
Fig. 7.2
Serous carcinoma present as a frond-like cluster; high power, SurePath, Papanicolaou stain
Fig. 7.3
A soap bubble appearance of serous carcinoma caused by the voluminous intracytoplasmic vacuoles; high power, SurePath, Papanicolaou stain
Fig. 7.4
Serous carcinoma with focally vacuolated cytoplasm present as an elongate group of cells (a); a psammoma body is surrounded by compressed tumor cells (b); both images high power, SurePath, Papanicolaou stain
Fig. 7.5
Low grade serous borderline tumor cells with small nuclei tightly compressed into a compact three-dimensional cluster; high power, SurePath, Papanicolaou stain
Signet ring adenocarcinoma, usually from a gastric primary tumor, is morphologically identified in cytology samples by the presence of single malignant epithelial cells with a large intracytoplasmic vacuole that compresses the nucleus to edge of the cell [10] (Fig. 7.6).
Fig. 7.6
Single cells of gastric carcinoma with variable high nuclear to cytoplasmic ratios, plus a few cells with prominent single intracytoplasmic vacuoles; high power, SurePath, Papanicolaou stain
Lobular carcinoma of the breast will usually produce single and small groups of malignant epithelial cells often with an eccentrically positioned round hyperchromatic nucleus containing a distinct nucleolus, giving the cell a somewhat plasmacytoid appearance [14] (Fig. 7.7). The cells of lobular carcinoma tend to be small with a high nuclear to cytoplasmic ratio, a nucleus larger than the nucleus of an intermediate squamous cell and the cytoplasm may contain a solitary vacuole pushing the nucleus to the periphery of the cell [15, 16] (Fig. 7.8). If the majority of tumor cells are vacuolated a designation of signet ring carcinoma may be warranted [17].
Fig. 7.7
Lobular carcinoma of the breast appears as small uniform cells with round uniform nuclei which are sometimes eccentrically positioned giving the cell a plasmacytoid appearance; high power, SurePath, Papanicolaou stain
Fig. 7.8
Cells of lobular carcinoma may have solitary intracytoplasmic vacuoles as seen in this small cluster of malignant cells; high power, SurePath, Papanicolaou stain
Metastatic adenocarcinoma from the colon will usually produce strips of malignant glandular cells having cigar-shaped hyperchromatic nuclei in a staggered array (Fig. 7.9). Colonic tumors are notorious for being associated with abundant background necrosis. In the case of rectal adenocarcinomas, direct tumor extension via recto-vaginal fistulas result in fecal material (vegetable or meat cells) in the cervical cytology sample in addition to tumor cells (Fig. 7.10).
Fig. 7.9
The cells of metastatic colonic adenocarcinoma show glandular formation with round to cigar shaped nuclei; high power, SurePath, Papanicolaou stain
Fig. 7.10
If rectal carcinoma invades the cervix, a fistula may form. On cervical cytology abundant necrotic tissue may be identified (a) as well as vegetable material such as the rectangular shaped structure in this image (b); both images high power, SurePath, Papanicolaou stain
Work-up
If a glandular lesion identified on cervical cytology is suspected to have arisen outside of the endometrium, several steps should be taken.
History of malignancy: A history of malignancy will help to focus on the analysis. This history is often not provided to the pathologist the specimen requisition and should therefore be sought from the patient record. The abnormal cells in the cervical cytology sample can be compared to cytology or histology of any samples of the suspected primary tumor.
High risk HPV testing: Because most primary adenocarcinomas of the endocervix are positive for high risk HPV, testing of the residual material in the cytology sample is a practical step to help narrow the choices and is especially important in metastatic carcinomas that mimic primary cervical adenocarcinoma, such as endometrial or colonic tumors [7].
Cell block preparation: Liquid-based cytology samples afford the opportunity to utilize the residual sample for the preparation of a cell block (see Chap. 2) (Fig. 7.11) Cell blocks allow histologic evaluation of the abnormal cells, particularly architectural assessment of groups, and hence comparison to prior tumors are removed from the patient. Special stains, such as mucicarmine or immunohistochemical and in situ hybridization studies can be performed. For example, testing for high risk HPV can be done by in situ hybridization in order to see if any positive results obtained are actually from the tumor cells in question [7].
Fig. 7.11
A cell block was made from the SurePath cervical cytology vial (Fig. 7.2); hematoxylin-eosin, high power section showing small clusters of serous carcinoma; the multiple histologic sections which can be obtained from the cell block are useful for special stains
Immunohistochemical stains: If a cell block is prepared and the number of abnormal cells is sufficient, immunohistochemical stains may be very helpful. Because the majority of cervical adenocarcinomas are associated with high risk HPV, mainly HPV 16 and 18, immunohistochemical staining or in situ hybridization may be performed [18–20]. However, most of the less common types of endocervical adenocarcinoma, such as minimal deviation, gastric-type, intestinal-type, mesonephric and clear cell are not related to HPV infection [21]. p16 may be used as a surrogate marker for the presence of HPV but p16 is also overexpressed in certain extracervical tumors such as serous carcinoma of the uterine corpus [22]. Testing for estrogen and progesterone receptors are usually part of a panel to differentiate endocervical (negative) from endometrial (positive) adenocarcinoma [19]. Studies have supported the use of CEA and vimentin in addition to other markers [23, 24] to distinguish endocervical adenocarcinoma from adenocarcinoma originating from the endometrium. However, the use of CEA and vimentin has not been found to be helpful in all instances as the staining pattern is not uniform in all variants arising for a given site of origin [25, 26]. Examples of useful antibodies include TTF-1 and Napsin A for lung adenocarcinoma [27], cytokeratin (CK) 7, CK20, and CDX2 for lower gastrointestinal adenocarcinoma [28–30], CDX2, CK17, MUC1, and MUC2 for adenocarcinomas of the upper gastrointestinal tract [31, 32] and GATA3 and estrogen receptor for breast tumors [33]. The immunohistochemical panels are summarized in Table 7.1.
Table 7.1
Adenocarcinoma arising in different organs and corresponding immunohistochemical stains useful on cervical cytology cell blocks
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