—  SHORT COURSE #25  —

Mesenchymal Tumors of the Corpus and Glandular Lesions of the Cervix

Case 1 - Glandular Lesions of the Cervix

Marisa R. Nucci and Esther Oliva


I) Introduction
Recognition of invasive and in situ glandular lesions of the cervix and their distinction from various benign mimics continues to be a challenge for the practicing surgical pathologist. As an additional stimulus to better understand these processes, there has been an apparent increase in both relative and absolute frequency of the incidence of invasive and in situ adenocarcinoma, particularly in women under 35 years of age [1, 2] . The challenge remains in recognizing histologically diverse malignant lesions as well as not misinterpreting the various benign glandular lesions of the cervix as premalignant or malignant. To address these issues, the following topics will be discussed with an emphasis on diagnostic problems and pitfalls:
  1. criteria for the diagnosis of in situ endocervical adenocarcinoma

  2. the concept of microinvasion in endocervical adenocarcinoma

  3. selected subtypes of endocervical adenocarcinoma

  4. pseudoneoplastic lesions and their distinction from invasive and in situ endocervical adenocarcinoma

  5. the distinction of endocervical from endometrial carcinoma, particularly in biopsy/curettage specimens


II) Endocervical Adenocarcinoma in Situ
About 50 years ago, the concept of a precursor lesion to invasive adenocarcinoma first appeared [3, 4] . Since that time, adenocarcinoma in situ (ACIS) has been widely accepted as representing the precursor lesion to invasive endocervical adenocarcinoma (ACA), which is based upon the following evidence:
  1. The mean age at diagnosis for ACIS (38 years) is approximately 10 years prior to the mean age at diagnosis for ACA [5, 6, 7, 8]

  2. ACIS is morphologically similar to ACA

  3. ACIS is frequently found in association with ACA

  4. Similar HPV types (types 16 and 18) are found in ACIS and ACA
General features of ACIS include the following:
  1. ACIS typically involves the surface epithelium and glands (crypts) at the squamocolumnar junction (tranformation zone) [6, 11, 12, 13]

  2. It can be present as a continuous lesion or it can also be multifocal (so-called "skip" lesions). [6, 12, 14, 15, 16]

  3. ACIS is associated with a squamous intraepithelial lesion in approximately 30-60% of cases [11, 17, 18]

  4. Most women are asymptomatic and lesion is identified by cytologic screening or incidentally in a cervical biopsy/leep/cone specimen; if symptomatic, most common complaint is abnormal vaginal bleeding [12, 13]
Diagnostic features of ACIS:
  1. Preservation of normal glandular architecture

  2. Crowded, enlarged, hyperchromatic, stratified nuclei

  3. Mitotic figures essential to diagnosis ("suspended" appearance)

  4. Apoptotic bodies are present in most cases

  5. Abrupt transition to normal endocervical epithelium is characteristic
Histologic subtypes of ACIS [15, 19, 20, 21, 22] :
  1. Endocervical (most common; can be admixed with other types)

  2. Endometrioid

  3. Intestinal (resembles intestinal goblet cells)

  4. Ciliated

  5. Squamomucinous intraepithelial lesions (SMILE)
Immunohistochemistry and ACIS [23]: [24, 25, 26]
  1. Often CEA positive (intracytoplasmic)

  2. High Ki-67 proliferative index

  3. P53 negative

  4. Altered (increased) cell cycle-related molecule expression (cyclin E, p16, p21, p27)

  5. Decreased ER/ PR expression

  6. p16 positive


III) Early Invasive Adenocarcinoma of the Endocervix
It is not unexpected that early invasive adenocarcinoma i.e. microinvasive carcinoma exists. The problem remains that there is no generally accepted consensus as to what the criteria are for the diagnosis of microinvasive carcinoma [14, 27, 28, 29, 30, 31] . Since there is no unifying concept of what the term "microinvasive" means when applied to glandular neoplasia, we commonly use the term superficial invasion and give a measurement for the depth of invasion. To further confound the issue, endocervical glands are, by their nature, somewhat complex and the point of invasion may occur anywhere along the profile of the gland, making measurement of the "depth" of invasion difficult. In these situations, the best assessment of the depth with a descriptive comment as to the location and possibly a phone call to the clinician is the best course of action.

The possibility invasion should be considered if you see the following:
  1. Atypical glands deeper than normal

  2. Small, irregularly shaped glands

  3. Individual glands

  4. Inflammatory or desmoplastic stroma

  5. Exuberant glandular budding

  6. Confluent foci of back-to-back glands

  7. Complex papillary pattern
Despite no consensus over the definition of microinvasion, how deep the neoplastic process extends – the depth of invasion – appears significant with regard to outcome, with an increasing probability of metastasis or recurrence with increasing depth of invasion. However, the exact depth at which metastatic potential is acquired is not known.

Depth of Invasion and Risk of Recurrence/Metastasis [16, 32, 33, 34, 35, 36, 37, 38]

  #patients Depth # w/LND
Berek 1985 24 2-5mm 24 2 LN+
Teshima 1985 22 <5mm >1 1 R
Kaspar 1993 25 <5mm 25 2 R, 2 LN+
Ostor 1997 77 <5mm 48 1 R
Kaku 1997 30 <5mm 25 2 R
Schorge 1999 21 <3mm 16 0 R
Ostor 2000 436 <5mm 219 5 LN+
Webb 2001 301 <5mm 140 1 LN+
Katsamatsu 2002 79 <5mm 73 1 LN+
Smith 2002 (SEER) 560 < 5mm 197 3 LN+

R= recurrence
LN= lymph node
LND= lymph node dissection

IV) Endocervical Adenocarcinoma
An increase in the relative proportion of invasive adenocarcinoma to squamous cell carcinoma of the cervix has occurred in the past few decades [1, 39, 40] . Currently, approximately 25% of cervical cancer in the United States are classified as adenocarcinoma. Of factors evaluated, including number of sexual partners, age at first intercourse, history of genital infections, obesity, tobacco use, only HPV infection and oral contraceptive use appear to be risk factors (although the latter is controversial) [41, 42] . Exogenous hormonal use may also be a risk factor for cervical adenocarcinoma [43]. The following is a list of the types of endocervical adenocarcinoma; selected types will be discussed in this forum.

Types of Endocervical Adenocarcinoma
  1. Adenocarcinoma, NOS

  2. Adenoma Malignum

  3. Villoglandular Carcinoma

  4. Endometrioid Carcinoma

  5. Clear Cell Carcinoma

  6. Serous Carcinoma

  7. Adenosquamous Carcinoma

  8. Adenoid Cystic Carcinoma

  9. Adenoid Basal Carcinoma

  10. Mesonephric Carcinoma

  11. Microcystic Adenocarcinoma


A. Adenoma Malignum
Adenoma malignum - General
  1. Uncommon tumor

  2. Reproductive aged women

  3. May present with menometrorrhagia, vaginal discharge (mucoid), abnormal bleeding

  4. Cervix usually grossly abnormal

  5. Associated with Peutz-Jeghers syndrome

  6. Worse prognosis than endocervical adenocarcinoma, NOS

  7. Associated with mucinous ovarian carcinoma (primary and metastatic)
Adenoma malignum – Histology
  1. Deeply infiltrative glands

  2. Abnormally shaped glands

  3. Tall, mucin-rich epithelium

  4. At least focal malignant cytologic features

  5. At least focal areas of desmoplasia
Adenoma malignum – Special studies
  1. Almost exclusively produces neutral mucin

  2. Gastric (mucous cell) mucin phenotype (HIK 1083 +)

  3. CEA positive (cytoplasmic; may be focal)
Adenoma malignum was first described in the English language literature in 1963 by McKelvey and Goodlin who reported a series of five cases [44]. Since then, over 60 examples of adenoma malignum have been reported, including reports describing clear cell and endometrioid examples [45, 46, 47, 48, 49] . Adenoma malignum is an uncommon tumor that occurs in reproductive aged women (mean age 42 years). The most common symptoms at presentation are menometrorrhagia, vaginal (often mucoid) discharge and abnormal bleeding. 10-15% of patients have Peutz-Jeghers syndrome. Interestingly, the genetic locus of this syndrome was mapped to chromosome 19p and a study of sporadic adenoma malignum has shown loss of heterozygosity for eight microsatellite markers for the region 19p13.2-13.3 [50]. The cervix is usually grossly abnormal, being typically indurated or firm. Adenoma malignum is characterized histologically by the presence of deeply infiltrative, irregularly shaped glands (usually into the outer third of the cervical wall) that are typically associated with a desmoplastic response. Although bland appearing mucinous epithelial cells line many of the glands, malignant cytologic features are present at least focally. Patients with adenoma malignum tend to present at high stage and appear to fare worse than patients with conventional endocervical adenocarcinoma; in the largest series of cases 13/22 patients died and four experienced recurrence of their tumor [49]. Analysis of 57 cases of adenoma malignum reported in the literature with follow-up of two years reveals an overall survival rate of 28% for all stages and a survival rate of 50% for stage 1 tumors. Adenoma malignum may be associated with mucinous ovarian carcinomas, which in some cases appear to be metastases and in others independent primaries [51, 52, 53] . Immunohistochemically, adenoma malignum may be CEA positive [48, 54] ; however, the staining may be focal which limits its diagnostic use [49]. More recently it has become apparent that the glands of adenoma malignum differ from normal endocervical glands by mucin histochemistry, having cells that contain more neutral mucin rather than an equal amount of neutral and acidic mucin characteristic of non-neoplastic mucinous endocervical epithelium [55]. HIK-1083, an antibody that recognized gastric mucous cells, is positive in adenoma malignum [56, 57] ; however, it may also be positive in endocervical glandular hyperplasia [58].

B. Adenoid Basal Carcinoma
Adenoid Basal Carcinoma – General
  1. Uncommon cervical tumor

  2. Propensity to occur in postmenopausal women

  3. Patients usually asymptomatic

  4. Usually no appreciable mass

  5. May be found in association with other tumor types
Adenoid Basal Carcinoma – Histology
  1. Lobulated nests and buds of bland basaloid cells

  2. Central atypical squamous differentiation

  3. Nests may undergo cystification

  4. Usually associated with a squamous intraepithelial lesion

  5. Absence of stromal response
Adenoid Basal Carcinoma – Special studies
  1. Associated with integrated high risk HPV types

  2. No k-ras mutations identified

  3. P53 overexpression may occur
Adenoid Basal Carcinoma – Features that distinguish it from Adenoid Cystic Carcinoma
  1. Does not usually form a mass

  2. Lack of cribriform pattern with intervening hyaline material

  3. Lesser degree of nuclear atypia

  4. Lack of expansile growth pattern

  5. Lack of stromal response
Adenoid basal carcinoma (ABC) is an uncommon tumor of the cervix that was first described by Baggish and Woodruff in 1966 [59]. Since its original description, over 40 cases of this unusual neoplasm have been described [60, 61, 62, 63, 64, 65, 66] . The tumor is usually an incidental finding in cone biopsy or hysterectomy specimens in postmenopausal women. ABC is characterized histologically by nests and islands of basaloid cells with central squamous or glandular differentiation and peripheral nuclear palisading. The squamous nests usually appear dysplastic but may also have a metaplastic appearance. Typically, there is no stromal reaction around the nests of tumor. The prognosis of patients with features typical of ABC is excellent. ABC may occur in association with/as a component of other tumor types including squamous cell carcinoma, adenosquamous carcinoma, and adenoid cystic carcinoma [65, 67, 68] .

Adenoid basal cell carcinoma appears to be biologically and histologically distinct from adenoid cystic carcinoma [65]in that it tends to be an incidental finding and patients have an excellent prognosis. Because of its excellent prognosis, the term adenoid basal epithelioma has been suggested [62]. However, the possibility that there may be a histogenetic relationship between adenoid basal carcinoma and adenoid cystic carcinoma has been raised [69]. Both tumors occur in postmenopausal women, have the capacity for divergent differentiation and are associated with high-risk HPV types; rare tumors with features of both adenoid cystic and adenoid basal cell carcinoma have also been described [69].

V) Pseudoneoplastic Glandular Lesions of the Uterine Cervix
The distinction between benign proliferative glandular lesions of the endocervix and well-differentiated invasive cervical adenocarcinoma continues to be problematic, as highlighted by the number of reports in the literature considering this diagnostic issue. Interestingly, the relatively recent recognition of a number of potential mimics of invasive adenocarcinoma of the endocervix underscores the likelihood that in the past many of these benign yet floridly proliferative lesions have been mistaken for invasive adenocarcinoma. For instance, in one institutional review five cases diagnosed as invasive adenocarcinoma over a 14-year period were reclassified as benign mimics [48]. Although a variety of immunoperoxidase stains have been tried, ultimately the recognition of benign pseudoneoplastic glandular lesions of the cervix rests upon their distinctive histologic features.

A number of benign processes may mimic either adenocarcinoma in situ, invasive adenocarcinoma or both.

Benign Mimics of Endocervical Adenocarcinoma:
  1. Tunnel Clusters

  2. Microglandular Hyperplasia

  3. Mesonephric Hyperplasia

  4. Endocervical Glandular Hyperplasia

  5. Arias-Stella Reaction

  6. Endocervicosis

  7. Endocervical Adenomyoma

  8. Florid Cystic Endosalpingiosis

  9. Deep Glands and Cysts

  10. "Ectopic" Prostatic Tissue
Benign Mimics of Endocervical Adenocarcinoma in Situ
  1. Tuboendometrioid Metaplasia

  2. Endometriosis

  3. Endocervicitis

  4. Radiation Therapy

  5. Arias-Stella Reaction


A. Tunnel Clusters
Tunnel Clusters – General Features:
  1. Reproductive aged women

  2. Possible association with pregnancy and parity

  3. May cause a gross abnormality
Type A Tunnel Clusters – Histology:
  1. Lobular architecture

  2. Multiple small, closely-packed glands

  3. Columnar mucinous epithelium

  4. Little cytologic atypia

  5. Few mitoses
Type B Tunnel Clusters- Histology:
  1. Lobular architecture

  2. Multiple small, closely packed, cystically dilated glands

  3. Cuboidal or flattened epithelium

  4. Inspissated, mucinous secretions

  5. Little cytologic atypia

  6. Few mitoses
Fluhmann first introduced the term "tunnel cluster" in his description of the histology of the endocervix [70, 71] . While tunnel clusters are usually an incidental histologic finding, they may sometimes be florid and cause a gross abnormality that is striking to both the clinician and the pathologist. Fluhmann identified tunnel clusters in approximately 40% of women in the first trimester of pregnancy and attributed them to involution of endocervical glands (crypts) that had become hyperplastic as a response to the altered hormonal milieu of pregnancy. Although there is an association with pregnancy and parity, tunnel clusters can also occur in nulligravida women. Fluhmann has separated tunnel clusters into two subcategories: Type A and Type B. Separation into subcategories is not clinically relevant, and indeed type A and B tunnel clusters are often intermixed with merging between the two types; however, their distinction is important as they pose their own relatively unique problems in the distinction from invasive adenocarcinoma.

Type A tunnel clusters
Type A tunnel clusters are characterized by a lobulated proliferation of small, closely packed glands that are lined by columnar mucinous epithelium. Type A tunnel clusters may be diagnostically challenging, particularly when they exhibit an irregular, pseudoinfiltrative border and/or when they exhibit degenerative nuclear atypia. The latter may be particularly alarming if one is not aware that this type of change can occur [72]. The main differential diagnosis is with extremely well-differentiated endocervical adenocarcinoma (adenoma malignum). The common admixture of type A and B tunnel clusters, in combination with the predominantly lobulated architecture, absence of desmoplasia and lack of deep, widely infiltrative glands helps distinguish it from adenoma malignum.

Type B tunnel clusters
Type B tunnel clusters also have a lobular architecture, but are composed of dilated glands lined by cuboidal or flattened epithelium and filled with inspissated, mucinous secretions. Type B tunnel clusters are usually less of a diagnostic problem; however, they can extend deeply into the cervical wall mimicking malignancy. In a series reported by Segal and Hart [73], cysts corresponding to type B tunnel clusters were grossly identified in 40% of cases and of these, one third exhibited significant distortion of the cervical wall. A confounding factor in the interpretation of these lesions is cystic invasive cervical adenocarcinoma [74]. Distinction between type B tunnel clusters and endocervical adenocarcinoma, either of the cystic or adenoma malignum type is chiefly made by close inspection of the epithelium. Cytologic features of malignancy are present at least focally in cases of carcinoma but are absent in type B tunnel clusters.

B. Microglandular Hyperplasia
Microglandular Hyperplasia- General:
  1. Usually young adults

  2. Apparent association with OCP and pregnancy

  3. Usually incidental finding
Microglandular Hyperplasia – Histology:
  1. Small, closely packed glands

  2. Cuboidal or columnar lining cells

  3. Prominent subnuclear vacuoles

  4. Acute inflammatory exudate in lumen

  5. Squamous metaplasia/Subcolumnar reserve cell hyperplasia

  6. Little mitotic activity
Microglandular Hyperplasia – Unusual Histologic Features:
  1. Solid foci

  2. Signet-ring cells

  3. Hyalinized stroma

  4. Reticular growth pattern

  5. Hobnail-like appearance

  6. Nuclear pleomorphism
Microglandular Hyperplasia – Features that it distinguish from Clear Cell Carcinoma:
  1. Only focal nuclear atypia

  2. Presence of subnuclear vacuoles and intracytoplasmic mucin

  3. Lack of glycogen

  4. Lack of infiltrative pattern

  5. Presence of reserve cell hyperplasia/squamous metaplasia
Microglandular Hyperplasia – Features that distinguish it from Endometrial Adenocarcinoma:
  1. Spectrum of cytologic atypia

  2. Reserve cell hyperplasia

  3. Subnuclear vacuoles

  4. Continuity with cervical stroma

  5. Age of patient/clinical presentation
First described in 1967 by Taylor et al [75] and shortly thereafter christened "microglandular hyperplasia" (MGH) by Kyriakos et al [76], this pseudoneoplastic lesion continues to be as diagnostically challenging today as it was over thirty years ago. The potential for misinterpretation as carcinoma is underscored in the initial series of reports describing this lesion, in which a number of the cases were initially considered by the referring pathologist as cervical adenocarcinoma [75, 77] . There is an apparent association of MGH with oral contraceptive use and pregnancy [75, 76, 77, 78, 79, 80, 81, 82] although a recent report has challenged this association [83].

MGH usually occurs in reproductive aged women; however, approximately 6% of reported cases have occurred in postmenopausal women [75, 78] . Although usually an incidental finding, microglandular hyperplasia may cause a visible gross abnormality – most commonly erosion or a polyp –and sometimes it can be raised and friable, clinically mimicking malignancy. Histologically, MGH may be unifocal or multifocal, polypoid or non-polypoid; it may involve the surface of the endocervix or extend into the deeper portions of the endocervical glands/clefts. Despite these varied aspects, MGH characteristically consists of closely packed irregularly shaped glands of varying size, often with cystic dilatation, with little intervening stroma, the latter usually infiltrated by acute and chronic inflammatory cells. The glands are lined by columnar or cuboidal mucin-containing cells, which commonly exhibit sub- and supranuclear vacuoles. Squamous metaplasia and subcolumnar reserve cell hyperplasia is often present. The intraglandular mucinous secretions contain inflammatory cells, particularly polymorphonuclear leukocytes. The nuclei of the endocervical cells are generally uniform. However, occasionally pleomorphism may be present, often as a spectrum from banal to focally atypical. Generally, there is little mitotic activity (< 1 mitosis/ 10 high power fields). Unusual histologic features of MGH, which may cause confusion with carcinoma, include areas of solid growth, a reticular pattern, signet ring cells, hobnail cells, pseudoinfiltrative pattern, and stromal hyalinization [78, 84] .

The differential diagnosis of MGH includes cervical carcinoma, particularly clear cell carcinoma and endometrial adenocarcinoma, particularly the "microglandular hyperplasia-like"carcinomas. Both cervical clear cell carcinoma and MGH may exhibit solid, cystic and tubular growth patterns and both can have a hyalinized stroma; however, unlike clear cell carcinoma, MGH usually contains intracytoplasmic mucin and lacks intracellular glycogen, which is a characteristic finding in clear cell carcinoma. In addition, even though focal moderate nuclear atypia may be seen in MGH, cervical clear cell carcinoma always exhibits a greater degree of nuclear atypia. Other helpful features characteristic of MGH include the lack of a truly infiltrative pattern, lack of a papillary growth pattern (seen in some clear cell carcinomas) and the presence of sub- and supranuclear vacuoles and reserve cell hyperplasia. In cases of MGH with unusual features (solid, signet ring cell etc), more typical areas of MGH are present which helps in their recognition. Rarely an endocervical adenocarcinoma of the usual type may have areas that mimic microglandular hyperplasia; however, the degree of cytologic atypia and the mitotic activity typically exceeds that seen in microglandular hyperplasia [85].

A more common diagnostic problem, and one that causes significant difficulty, is the distinction of MGH from endometrial carcinomas that can closely simulate it [85]. This problem is particularly difficult when small fragments of an endometrial tumor are present in endocervical curettage specimens or conversely, when fragments of MGH are present in an endometrial sampling. Since MGH may be seen in postmenopausal women, the age of the patient is not always helpful; however, prior to diagnosing microglandular hyperplasia in a postmenopausal patient, one should always consider the possibility that the fragments in question may have originated in the endometrium. Helpful clues that favor MGH include the presence of reserve cell hyperplasia, continuity with endocervical stroma, and sub- and supranuclear vacuoles. Features that favor endometrial carcinoma include continuity of the focus in question with endometrial stroma, stromal foam cells, other fragments of endometrium with mucinous change, or characteristic features of atypical endometrial hyperplasia. [86] It is important to realize that one cannot always be certain whether the fragment in question has originated in the cervix or the endometrium; therefore, requesting a fractional curettage to exclude the possibility of an endometrial malignancy is a reasonable course of action.

Immunoperoxidase stains for CEA should be used with caution, if at all, in the distinction between microglandular hyperplasia and adenocarcinoma. While microglandular hyperplasia is CEA negative and adenocarcinomas are usually strongly CEA positive (cytoplasmic), a significant subset of carcinomas, including adenoma malignum, can be negative or only focally positive for CEA [49, 54, 87, 88] . Therefore, whereas a positive CEA stain would suggest carcinoma, a negative stain is not helpful. As a note of caution, the patterns of CEA staining in other pseudoneoplastic endocervical lesions have not been exhaustively studied.

C. Mesonephric Hyperplasia
Mesonephric Remnants
  1. Vestigial elements of mesonephric ducts

  2. Present in up to 22% of cervices

  3. Cuboidal epithelial lining with uniform nuclei

  4. Intraglandular eosinophilic material

  5. Rare mitotic figures
Mesonephric Hyperplasia – General
  1. Reproductive aged women

  2. Most often incidental finding

  3. Distinction between remnants and hyperplasia arbitrary (> 6mm focus)

  4. Three histologic subtypes (Lobular, Diffuse, Pure Ductal)
Mesonephric Hyperplasia – Features that distinguish it from Clear Cell Carcinoma
  1. Benign cytology

  2. Intraglandular secretions

  3. Lack of glycogen

  4. Orderly architectural pattern

  5. Lack of stromal response, distinctive solid growth and hobnail appearance
Mesonephric Hyperplasia – Features that distinguish it from Mesonephric Carcinoma
  1. Lack of irregular, disorderly invasion

  2. Lack of back-to-back glandular crowding

  3. Lack of significant mitotic activity

  4. Lack of nuclear atypia

  5. Lack of lymphatic/vascular/perineural invasion
Mesonephric Hyperplasia – Features that distinguish it from Endocervical Adenocarcinoma
  1. Lack of irregularly shaped glands

  2. Lack of tall columnar mucinous epithelium

  3. Lack of desmoplastic stromal response

  4. Lack of nuclear atypia

  5. Lack of significant cytologic atypia
Mesonephric (wolffian) remnants are the vestigial elements of the mesonephric ducts. In men, the mesonephric ducts develop into the efferent ducts of the testis, epididymis, vasa deferentia, seminal vesicles, and ejaculatory ducts; however, in women, the ducts usually regress but can persist as small foci in the broad ligament, cervix and vagina [89]. Mesonephric remnants are present in up to 22% of cervices, usually in the lateral wall, a feature that may be responsible for an underestimation of the frequency of this finding, since most routine histologic sections are from the anterior and posterior cervix [89]. Mesonephric remnants consist of small cysts and/or tubules lined by bland cuboidal or low columnar non-ciliated epithelium. The cytoplasm may appear clear or eosinophilic but does not contain mucin or glycogen. The former feature helps distinguish mesonephric from endocervical epithelium. Characteristically, a densely eosinophilic luminal secretory product, which can be PAS positive, is present.

Mesonephric hyperplasia, which is presumed to arise from mesonephric remnants, is an uncommon lesion that occurs predominantly in reproductive aged women and is most often an incidental finding; however, occasionally it may cause symptoms and/or a visible gross abnormality [89, 90, 91] . In fact, we have seen a case that caused concentric enlargement of the cervix ("barrel shaped cervix") which clinically mimicked carcinoma. Criteria for the distinction between mesonephric remnants and mesonephric hyperplasia are arbitrary. Nonetheless, Ferry and Scully have suggested foci over 6 mm as a cutoff for separating mesonephric remnants from mesonephric hyperplasia [89]. Mesonephric hyperplasia has been divided into three categories: lobular mesonephric hyperplasia, diffuse mesonephric hyperplasia and pure mesonephric ductal hyperplasia. Separation into these three different categories is not clinically significant; however, it is important to recognize that mesonephric hyperplasia may have a varied appearance. Lobular mesonephric hyperplasia is characterized by a proliferation of loosely organized, variably sized, mesonephric tubules predominantly arranged in lobules, whereas in the diffuse form, no lobular pattern is apparent. The diffuse form of mesonephric hyperplasia may be the most diagnostically challenging because it appears infiltrative and may extend deeply into the cervical wall, mimicking a well-differentiated adenocarcinoma. This latter feature may cause significant difficulty in interpretation of cone biopsy specimens involved by mesonephric hyperplasia, since extension to the deep margin of resection may suggest involvement by adenocarcinoma. Pure ductal hyperplasia, the least common subtype of the mesonephric hyperplasias, is characterized by a prominent duct lined by hyperplastic-appearing epithelium with papillary tufting with usually minimal associated proliferation of tubules. Unusual histologic patterns of mesonephric hyperplasia include a retiform type with slit-like anastamosing tubules, an endometrioid appearance suggestive of epididymal differentiation, and pigment deposition reminiscent of the type seen in seminal vesicle epithelium [90]. Given that the mesonephric ducts normally develop into epididymis and seminal vesicle in men, it is not surprising that proliferation of mesonephric remnants in women may try to recapitulate these structures. Mitotic activity is characteristically low (less than 1/10 hpf) and only mild cytologic atypia is seen in mesonephric hyperplasia [89, 90] .

The differential diagnosis of mesonephric hyperplasia includes mesonephric carcinoma, endocervical adenocarcinoma and clear cell carcinoma. Mesonephric carcinoma is exceedingly rare, therefore florid mesonephric hyperplasia should be excluded before making this diagnosis. Confounding the difficulty, however, is the co-existence of mesonephric carcinoma with mesonephric hyperplasia [89], suggesting mesonephric hyperplasia is a precursor lesion. Mesonephric carcinoma more often causes a visible gross abnormality than mesonephric hyperplasia; however, as mentioned, mesonephric hyperplasia can also produce a grossly visible lesion. Histologically, mesonephric carcinoma exhibits a greater degree of glandular crowding ("back-to-back" glandular growth), an irregular, disorderly growth pattern, greater nuclear atypia, prominent mitotic activity and often an associated stromal reaction. Although the tubules of mesonephric hyperplasia can be cystic and impart a resemblance to the tubulocystic variant of cervical clear cell carcinoma, the cells lining the tubules of clear cell carcinoma usually have more abundant glycogen-rich clear cytoplasm and more prominent nuclear atypia. In addition, areas of solid growth and protrusion of lining epithelial cells imparting a hobnail appearance, features typical of clear cell carcinoma, are not seen in mesonephric hyperplasia.

D. Lobular and Diffuse Laminar Endocervical Glandular Hyperplasia
Lobular and Diffuse Laminar Endocervical Glandular Hyperplasia - General
  1. Reproductive aged women

  2. Unclear association with OCP/HRT

  3. Usually incidental finding
Lobular Endocervical Glandular Hyperplasia, NOS – Histology
  1. Lobular proliferation

  2. Small to moderately sized glands often centered around a larger gland

  3. Usually confined to inner half of cervical wall

  4. Single layer of tall, mucin-rich columnar cells with bland, basally located nuclei

  5. Occasional reactive atypia
Diffuse Laminar Endocervical Glandular Hyperplasia – Histology
  1. Diffuse, band-like proliferation

  2. Closely packed, evenly spaced, benign-appearing endocervical glands

  3. Usually confined to inner third of cervix

  4. Sharply demarcated deep border

  5. Marked inflammatory response
Lobular and Diffuse Endocervical Glandular Hyperplasia – Features that distinguish them from Adenoma Malignum
  1. Orderly arrangement of glands

  2. Lack of infiltrative pattern

  3. Lack of deep invasion

  4. Lack of significant cytologic atypia
It is not surprising that endocervical glands, like other glandular structures, can be hyperplastic. The etiology, however, of lobular and diffuse laminar endocervical glandular hyperplasia is not clear. An association with oral contraceptive use, hormone replacement therapy or history of prior pregnancy has not been established.

Lobular Endocervical Glandular Hyperplasia
The term "lobular endocervical glandular hyperplasia, not otherwise specified" was introduced recently to describe a striking proliferation of endocervical glands that can cause diagnostic difficulty in the distinction from adenoma malignum [92]. Similar patterns of endocervical hyperplasia, illustrated as part of other reports, likely represents this entity [58, 93, 94] . This lesion usually occurs in reproductive aged women as an incidental finding; however, unlike other pseudoneoplastic endocervical lesions presented herein, a greater percentage of cases present with a visible gross abnormality or clinical symptoms, as seen in six of sixteen cases (37%) from two published series [58, 92] . Microscopically, this type of endocervical glandular hyperplasia is characterized by a distinctly lobular proliferation of small to medium-sized rounded glands, which are often centered on a larger gland. The proliferation of glands is typically well demarcated from the surrounding stroma and is usually confined to the inner half of the cervical wall. The glands are lined by tall columnar mucinous epithelium, similar to normal endocervical glands, and are separated by unremarkable cervical stroma. No significant cytologic atypia or mitotic activity is present.

The main, and most important, diagnosis to exclude is well-differentiated adenocarcinoma (adenoma malignum). The histologic features most helpful in this distinction are the orderly lobulated proliferation of glands in lobular endocervical glandular hyperplasia and its lack of irregular stromal infiltration, absence of a desmoplastic stromal response, and lack of malignant cytologic features. The distinction of lobular endocervical glandular hyperplasia from other pseudoneoplastic endocervical glandular lesions is only of academic interest and is not important for patient management.

Diffuse Laminar Endocervical Glandular Hyperplasia
This type of endocervical glandular hyperplasia, first reported by Jones et al [95], is characterized by a diffuse proliferation of closely-packed endocervical glands that appears as a discrete layer that is sharply demarcated from the underlying cervical stroma. All cases have been incidental findings in hysterectomy specimens from reproductive aged women and the process is usually confined to the inner one third of the cervical wall. A marked inflammatory response may be present, and reactive epithelial atypia may be seen; however, a desmoplastic stromal response is absent.

As with most of these pseudoneoplastic endocervical glandular processes, the main differential diagnosis is with adenoma malignum. Features helpful in distinguishing diffuse laminar endocervical hyperplasia from adenoma malignum include lack of a desmoplastic stromal response, lack of deeply and irregularly infiltrative glands, and absence of significant nuclear atypia in the former.

E. Arias-Stella Reaction
Arias-Stella Reaction:
  1. Present in up to 10% of gravid hysterectomies

  2. Usually focal

  3. Usually involves superficial glands

  4. Markedly enlarged cells with abundant eosinophilic/vacuolated cytoplasm

  5. Spectrum of nuclear atypia

  6. Hobnail appearance

  7. Mitoses uncommon
Arias-Stella Reaction – Features that Distinguish it from Clear Cell Carcinoma:
  1. No mass lesion

  2. Usually focal change

  3. Nuclei exhibit spectrum of cytologic atypia

  4. Abundant eosinophilic/vacuolated cytoplasm
The Arias-Stella reaction can sometimes be diagnostically challenging, particularly if one is not aware it can involve endocervical in addition to endometrial glands. Arias-Stella type changes were detected, at least focally, in endocervical glands in up to 10% of gravid hysterectomy specimens [96, 97] . The lesion is usually focal and tends to involve superficial glands rather than deep ones [97, 98] . Involvement of endocervical polyps can also occur [99]. The histologic features of Arias-Stella reaction of the endocervix are similar to the changes in the endometrium. Namely, the affected cells are markedly enlarged, have abundant vacuolated and/or eosinophilic cytoplasm, and enlarged hyperchromatic nuclei. The cells lining the glands characteristically protrude into the lumen resulting in a hobnail appearance. Mitotic figures are very uncommon. Although many of the affected cells can appear strikingly pleomorphic, a spectrum of atypia is characteristic of Arias-Stella reaction with bland, normal appearing, relatively unaffected cells present immediately adjacent to cells that are quite atypical.

Arias-Stella reaction of the endocervix may mimic cervical clear cell carcinoma, particularly in biopsy specimens. However, clear cell carcinoma is more commonly associated with a mass lesion, exhibits an infiltrative growth pattern, and commonly also has solid or papillary areas of growth. In addition, the spectrum of atypia, from normal appearing to pleomorphic, characteristic of Arias-Stella reaction, is not seen in clear cell carcinoma. Arias-Stella reaction may also mimic endocervical adenocarcinoma in situ; however, adenocarcinoma in situ is more mitotically active and usually lacks the cytoplasmic vacuolization and hobnail appearance so characteristic of the Arias-Stella reaction. Prior to diagnosing clear cell carcinoma or adenocarcinoma in situ in a pregnant patient, Arias-Stella reaction should be excluded.

F. Endocervicosis
  1. Cytologically benign mucinous epithelium

  2. Centered in outer cervical wall/paracervical soft tissue

  3. No stromal response
Endocervicosis may also be potentially misinterpreted as well-differentiated adenocarcinoma. However, the mucinous lining epithelium of endocervicosis is bland, there is no stromal response (although occasionally response to extravasated mucin can be seen) and the process, unlike endocervical adenocarcinoma, is typically centered in the outer cervical wall and often involves paracervical soft tissue [100].

G. Endocervical Adenomyoma
  1. Biphasic tumor (glands/cysts and myomatous stroma)

  2. Grossly circumscribed/polypoid

  3. Lobulated proliferation of glands with single layer of bland mucinous epithelium
Endocervical adenomyoma is a biphasic tumor composed of glands and cysts lined by a single layer of endocervical-type mucinous epithelium admixed with benign appearing smooth muscle that may be confused with adenocarcinoma [101]. It can be distinguished from well-differentiated endocervical adenocarcinoma by its gross circumscription, polypoid appearance, frequent lobulation of glands, lack of infiltrative pattern, lack of desmoplasia, and lack of cytologic atypia.

H. Florid Cystic Endosalpingiosis
  1. May present as a mass with transmural involvement of cervix

  2. Variably sized cysts lined by benign tubal-type epithelium

  3. Focal intraglandular papillae may be present
Florid cystic endosalpingiosis may be confused with well-differentiated endocervical adenocarcinoma of the endometrioid subtype, particularly since it may present as a grossly evident mass and also because it may exhibit architectural complexity [102]. Florid cystic endosalpingiosis, however, is centered in the outer part of the cervical wall, lacks desmoplasia, and lacks significant cytologic atypia.

I. Deep Glands and Cysts
Endocervical glands may sometimes be located deep in the cervical stroma. When these glands are abundant, they may mimic well-differentiated adenocarcinoma [103]. Features that help distinguish deep glands from carcinoma include lack of cytologic atypia, lack of desmoplasia and lack of architectural complexity (abnormal size and shape of glands).

Nabothian cysts may also lie deep in the cervical stroma and cause concern [104], raising the possibility of a cystic endocervical adenocarcinoma [74]; however, the latter has glands that are more irregularly distributed and cytologically malignant, whereas the former has benign appearing epithelium with little to no mitotic activity.

J. "Ectopic" Prostatic Tissue
"Ectopic" prostatic tissue, in the form of ducts and acini, some of which may have a papillary or cribriform pattern and central squamous metaplasia, can involve the cervical stroma [105]. They are usually as an incidental finding; however, they may form a grossly appreciable mass. This lesion may occasionally be mistaken for adenoid basal carcinoma since both have central squamous differentiation; however, the latter characteristically has a basaloid proliferation of small nests. "Ectopic" prostatic tissue is also PSA and PRAP positive; whereas, four cases of adenoid basal carcinoma that have been stained at the Brigham and Women's Hospital have been negative for these markers.

K. Tuboendometrioid Metaplasia
  1. Present in up to 30-60% of examined cervices

  2. Usually seen in upper portion of canal

  3. Can involve superficial or deep glands

  4. Usually not associated with gland irregularity or intraglandular proliferation

  5. Can see nuclear enlargement and crowding, but little to no mitotic activity

  6. Can be surrounded by reactive appearing stroma
Tuboendometrioid metaplasia may be mistaken for adenocarcinoma in situ (ACIS) in either histologic or cytologic preparations [106, 107, 108] . It is a common finding; in a recent series, tubal metaplasia was found in 31% of 108 cone biopsy and hysterectomy specimens examined [109]. In another series, tubal metaplasia was even more prevalent [110]. Tuboendometrioid metaplasia may be seen in the transformation zone, upper endocervix and may involve either superficial or deep glands. It may also partially involve a gland, a feature in common with ACIS. This process may be related to recent cone biopsy, having been found in cone biopsy sites in 26% of hysterectomy specimens [111]. ACIS with tubal differentiation may rarely occur [19]. The atypia in these cases is usually severe and mitotic figures and apoptotic bodies easily found.

L. Endometriosis
  1. Can be superficial or deep

  2. Reproductive aged women

  3. Mitotically active

  4. Stromal component may be obscured by edema/ulceration or be a minor component
Prior to diagnosing ACIS, consideration of the possibility of endometriosis should be considered. Superficial endometriosis most closely mimics ACIS [112]; however, the presence of endometrial stroma, bland epithelial cytologic features and usual lack of apoptotic bodies is helpful in this distinction. Occasionally, the glands involved by tuboendometrioid metaplasia may exhibit architectural irregularity and the stroma surrounding the glands may be hypercellular raising the possibility of adenocarcinoma [113]; however, the cytology of the epithelium is bland.

M. Endocervicitis
  1. Be cautious of diagnosing ACIS in a background of intense inflammation

  2. Nuclei usually have finely stippled chromatin and nucleoli

  3. Mitotic figures can be present

  4. Beware of poorly preserved nuclei
N. Radiation Therapy
  1. Enlarged, pleomorphic, occasionally smudged nuclei; nucleoli can be present

  2. Fine or degenerated appearing chromatin

  3. Abundant, occasionally vacuolated cytoplasm

  4. Reactive stroma

  5. History is essential
O. Final Comments
In general, histologic features that favor a benign glandular process vs. adenocarcinoma of the cervix include bland cytology, sharp demarcation, orderly growth pattern, lack of deep extension, and lack of stromal reaction. Conversely, histologic features that favor a malignant process include glands located deeper than normal endocervical glands, irregularly shaped glands, small individual glands, significant cytologic atypia and desmoplasia.

VI) Endocervical vs. Endometrial Adenocarcinoma
Primary mucinous carcinoma of the endometrium may be difficult to distinguish from endocervical adenocarcinoma, particularly in biopsy/curettage material. Part of this problem stems from the fact that mucinous carcinoma can exhibit mucinous differentiation reminiscent of endocervical glandular epithelium and endocervical adenocarcinoma may show endometrioid differentiation.

Features that favor an endometrial primary:
  1. Bulk of tumor is present in the endometrial vs. endocervical sampling

  2. Other fragments of endometrium showing atypical hyperplasia (EIN)

  3. Other fragments of endometrium showing mucinous metaplasia

  4. Foamy stromal cells

  5. Carcinoma is vimentin positive - lateral membrane staining [114]

  6. Age of patient

  7. Tumor is ER positive [115, 116]

  8. Tumor is HPV negative
Features that favor an endocervical primary:
  1. Bulk of tumor is present in the endocervical vs. endometrial sampling

  2. Presence of endocervical adenocarcinoma in situ

  3. Separation of neoplastic glands by desmoplastic stroma

  4. Carcinoma is vimentin negative

  5. Carcinoma is HPV positive

  6. Age of patient
In some cases, supplementation of the clinical impression of the primary site by radiologic methods may be helpful [117, 118, 119] .

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