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Skenes Glands Adenocarcinoma A Series of 4 Cases Aline C. Tregnago, MD* and Jonathan I. Epstein, MD*Abstract: Skenes (periurethral) gland adenocarcinoma is very rare, with only 7 cases reported in the literature. This is the rst series of cases on this entity. We describe the histologic, im- munohistochemical, and clinical ndings of 4 patients with Skenes gland adenocarcinoma retrieved from the Johns Hopkins Urologic Pathology Consult Service from 1984 to 2017. The average age at diagnosis of the 4 women was 74.5 years (range, 61 to 87 y). Tu- mors were treated by limited resections with negative margins. Tumor size ranged from 1.0 to 2.0 cm (mean, 1.5 cm). Average follow-up time was 40.7 months (range, 4 to 132 mo). Three of our cases were morphologically consistent with prostatic acinar ad- enocarcinoma with variable cribriform, fused, and poorly formed glands, analogous to Gleason score 4+4 = 8. Of these, one had mixed ductal features with neoplastic cells showing papillary car- cinoma with columnar cytology. These 3 lesions were positive for PSA, P501S, NKX3.1, and AMACR. Focal goblet cells positive for CK20 and negative for prostatic markers were seen in one of these cases, suggesting intestinal differentiation (although negative for CDX2 and SATB2). A fourth case had glandular and papillary formations with pseudostratied columnar epithelium and mucin secretion, showing positivity for CK7, ER, and P16, and negativity for prostatic markers, suggesting serous differentiation (although negative for PAX8 and WT1). PIN4 cocktail conrmed the origin in preexisting paraurethral glands in 3 of the cases. All patients were alive and free of recurrence or metastatic disease at the time of last follow-up. Because of the rarity of Skenes gland adenocarcinomas, there is no consensus regarding their treatment. Our ndings demonstrate that Skenes gland adenocarcinomas recapitulate morphologies and immunohistochemical markers seen in prostatic adenocarcinoma. However, it is unknown whether applying the same grading criteria for prostatic adenocarcinomas to Skenes gland adenocarcinoma is valid given the small number of cases with variable treatment and limited follow-up. Key Words: Skenes gland, adenocarcinoma, paraurethral gland adenocarcinoma (Am J Surg Pathol 2018;42:15131521) P rimary female urethral tumors are extremely rare, ac- counting for <0.003% of all urogenital tract malignancies in women. 1 Adenocarcinomas of the female urethra corre- sponds to 10% of the primary female urethral tumors. The most common histologic subtypes are clear cell ad- enocarcinoma and columnar cell/mucinous adenocarcinoma. 2 A rare subtype is adenocarcinoma arising from the paraurethral glands (Skenes glands), where only 7 cases have been reported in the literature. 1,38 This is the rst series on this entity, describing the histologic, immuno- histochemical, and clinical ndings on 4 cases of Skenes gland adenocarcinoma. MATERIALS AND METHODS A search using the Hopkins Pathology Database System for adenocarcinoma AND Skenes glands OR periurethral glandsor paraurethral glandswas per- formed covering 1984 through 2017. Four cases from the Johns Hopkins Urologic Pathology Consult Service were identied where the tumor was centered in the periurethral glands with no other primary site identied. Three of the 4 cases had morphologic features in some respects charac- teristic of periurethral gland adenocarcinoma and in 2 of these cases there was at least focal intraductal involvement of preexisting periurethral glands, as evidence that these tumors were primary at this site. The fourth case with unique morphologic features was conned to preexisting periurethral glands without an invasive component and no evidence of local spread from another site and hence was also considered primary to this site; the patient had 132 months follow-up after excision without identication of another source of the tumor. The original slides for all cases were reviewed. Immunohistochemical analysis was performed at our in- stitution using 4-μm-thick sections obtained from formalin- xed parafn-embedded tissue as noted in Table 1. Clinical history was obtained by contacting urologists and gynecologists. We requested vital status, medical history, and presence of recurrent disease for each patient. RNA in situ hybridization (ISH) for high-risk hu- man papillomavirus (HPV) E6/E7 mRNA was performed manually using the RNAscope HPV kit (Advanced Cell Diagnostics Inc., Hayward, CA) according to the manu- facturers instructions. Briey, 4-μm-thick formalin-xed and parafn-embedded tissue sections were pretreated with heat and protease before hybridization. Whole tissue sections were hybridized with a single cocktail of 18 From the Departments of *Pathology; and Urology, and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD. Conict of Intertest and Source of Funding: The authors have disclosed that they have no signicant relationships with, or nancial interest in, any commercial companies pertaining to this article. Correspondence: Jonathan I. Epstein, MD, Department of Pathology, Johns Hopkins Medical Institutions, 401 N. Broadway Street, Room 2242, Baltimore, MD 21231 (e-mail: [email protected]). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. ORIGINAL ARTICLE Am J Surg Pathol Volume 42, Number 11, November 2018 www.ajsp.com | 1513 Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Page 1: Skene s Glands Adenocarcinoma - uswr.ac.ir...Skene’s Glands Adenocarcinoma A Series of 4 Cases Aline C. Tregnago, MD* and Jonathan I. Epstein, MD*† Abstract: Skene’s (periurethral)

Skene’s Glands AdenocarcinomaA Series of 4 Cases

Aline C. Tregnago, MD* and Jonathan I. Epstein, MD*†

Abstract: Skene’s (periurethral) gland adenocarcinoma is veryrare, with only 7 cases reported in the literature. This is the firstseries of cases on this entity. We describe the histologic, im-munohistochemical, and clinical findings of 4 patients with Skene’sgland adenocarcinoma retrieved from the Johns Hopkins UrologicPathology Consult Service from 1984 to 2017. The average age atdiagnosis of the 4 women was 74.5 years (range, 61 to 87 y). Tu-mors were treated by limited resections with negative margins.Tumor size ranged from 1.0 to 2.0 cm (mean, 1.5 cm). Averagefollow-up time was 40.7 months (range, 4 to 132mo). Three of ourcases were morphologically consistent with prostatic acinar ad-enocarcinoma with variable cribriform, fused, and poorly formedglands, analogous to Gleason score 4+4= 8. Of these, one hadmixed ductal features with neoplastic cells showing papillary car-cinoma with columnar cytology. These 3 lesions were positive forPSA, P501S, NKX3.1, and AMACR. Focal goblet cells positivefor CK20 and negative for prostatic markers were seen in one ofthese cases, suggesting intestinal differentiation (although negativefor CDX2 and SATB2). A fourth case had glandular and papillaryformations with pseudostratified columnar epithelium and mucinsecretion, showing positivity for CK7, ER, and P16, and negativityfor prostatic markers, suggesting serous differentiation (althoughnegative for PAX8 and WT1). PIN4 cocktail confirmed the originin preexisting paraurethral glands in 3 of the cases. All patientswere alive and free of recurrence or metastatic disease at the timeof last follow-up. Because of the rarity of Skene’s glandadenocarcinomas, there is no consensus regarding their treatment.Our findings demonstrate that Skene’s gland adenocarcinomasrecapitulate morphologies and immunohistochemical markers seenin prostatic adenocarcinoma. However, it is unknown whetherapplying the same grading criteria for prostatic adenocarcinomasto Skene’s gland adenocarcinoma is valid given the small numberof cases with variable treatment and limited follow-up.

Key Words: Skene’s gland, adenocarcinoma, paraurethral glandadenocarcinoma

(Am J Surg Pathol 2018;42:1513–1521)

Primary female urethral tumors are extremely rare, ac-counting for <0.003% of all urogenital tract malignancies

in women.1 Adenocarcinomas of the female urethra corre-sponds to 10% of the primary female urethral tumors. Themost common histologic subtypes are clear cell ad-enocarcinoma and columnar cell/mucinous adenocarcinoma.2

A rare subtype is adenocarcinoma arising from theparaurethral glands (Skene’s glands), where only 7 caseshave been reported in the literature.1,3–8 This is the firstseries on this entity, describing the histologic, immuno-histochemical, and clinical findings on 4 cases of Skene’sgland adenocarcinoma.

MATERIALS AND METHODSA search using the Hopkins Pathology Database

System for “adenocarcinoma AND Skene’s glands ORperiurethral glands” or “paraurethral glands” was per-formed covering 1984 through 2017. Four cases from theJohns Hopkins Urologic Pathology Consult Service wereidentified where the tumor was centered in the periurethralglands with no other primary site identified. Three of the 4cases had morphologic features in some respects charac-teristic of periurethral gland adenocarcinoma and in 2 ofthese cases there was at least focal intraductal involvementof preexisting periurethral glands, as evidence that thesetumors were primary at this site. The fourth case withunique morphologic features was confined to preexistingperiurethral glands without an invasive component and noevidence of local spread from another site and hence wasalso considered primary to this site; the patient had132 months follow-up after excision without identificationof another source of the tumor.

The original slides for all cases were reviewed.Immunohistochemical analysis was performed at our in-stitution using 4-μm-thick sections obtained from formalin-fixed paraffin-embedded tissue as noted in Table 1. Clinicalhistory was obtained by contacting urologists andgynecologists. We requested vital status, medical history,and presence of recurrent disease for each patient.

RNA in situ hybridization (ISH) for high-risk hu-man papillomavirus (HPV) E6/E7 mRNA was performedmanually using the RNAscope HPV kit (Advanced CellDiagnostics Inc., Hayward, CA) according to the manu-facturer’s instructions. Briefly, 4-μm-thick formalin-fixedand paraffin-embedded tissue sections were pretreatedwith heat and protease before hybridization. Wholetissue sections were hybridized with a single cocktail of 18

From the Departments of *Pathology; and †Urology, and Oncology,Johns Hopkins Medical Institutions, Baltimore, MD.

Conflict of Intertest and Source of Funding: The authors have disclosedthat they have no significant relationships with, or financial interestin, any commercial companies pertaining to this article.

Correspondence: Jonathan I. Epstein, MD, Department of Pathology,Johns Hopkins Medical Institutions, 401 N. Broadway Street, Room2242, Baltimore, MD 21231 (e-mail: [email protected]).

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

ORIGINAL ARTICLE

Am J Surg Pathol � Volume 42, Number 11, November 2018 www.ajsp.com | 1513

Copyright r 2018 Wolters Kluwer Health, Inc. All rights reserved.

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high-risk HPV genotypes (16, 18, 26, 31, 33, 35, 39, 45, 51,52, 53, 56, 58, 59, 66, 68, 73, and 82). The preamplifier,amplifier, and horse radish peroxidase–labeled probeswere then hybridized sequentially, followed by color de-velopment with diaminobenzidine. Probes to the bacterialgene dapB and the endogenous UBC mRNA were used asnegative and positive controls, respectively, for each case.The HPV status was scored qualitatively as either positiveor negative, using the dapB-stained slides as reference.HPV-positive cases had definitive punctate brown stainingpresent in at least a subset of tumor cells.

RESULTSThe average age at diagnosis of the 4 women was

74.5 years (range, 61 to 87 y). Diagnostic specimens in-cluded 1 biopsy and 3 limited resections. Tumor size wastaken from clinical reports and ranged from 1.0 to 2.0 cm(mean, 1.5 cm). Follow-up data were obtained for allcases, with an average follow-up time of 40.7 months(range, 4 to 132mo). All patients were alive and free ofrecurrence or metastatic disease at the time of last follow-up (Table 2).

Case #1A 63-year-old female underwent a local resection of a

periurethral nodule measuring 1.5 cm. Microscopically, awell-circumscribed lesion grew within the lumen of Skene’sglands without any recognizable invasion (Fig. 1). Thespecimen was not inked at the outside institution, and thetumor extended close to but did not contact the specimenedges in the plane of sections on the slides. The tumor wascomposed of glandular and papillary formations lined bypseudostratified columnar epithelium with intraluminalmucin secretion. Nuclei were enlarged with coarsechromatin and loss of polarity. Atypical mitotic figureswere frequently seen and basal apoptotic bodies were noted.Immunohistochemistry demonstrated a basal cell layersurrounding the tumor with either patchy or continuousstaining for high–molecular-weight cytokeratin (HMWCK)

TABLE 1. Details of Antibodies Used in ImmunohistochemistryAntibody Clone Dilution Vendor

CDX2 EPR2764Y Predilute DakoCK7 M7018 1:500 DakoCK20 Ks20.8 Predilute DakoEstrogen receptor SP-1 Predilute VentanaNKX3.1 Polyclonal Prediluted BiocareP501s PCK-26 Prediluted VentanaPAX8 Polyclonal 1:800 PharmingenPIN4* cocktail 13H4 Prediluted ZetaPSA Polyclonal Prediluted VentanaSATB2 EP281 Prediluted CellmarqueP16 ultra INK4a Prediluted Ventana

*HMWCK, p63, AMACR.

TABLE 2. Clinicopathologic Data of Patients With Skene’s Gland Adenocarcinoma Reported to Date.

ReferencesAge(y)

FirstSymptoms

Size(cm) Site

SerumPSA IHC Mets. Treatment Other Malignancies

Svanholmet al3

72 Polypoidtumor

1.0 Urethra NA PSA+, PSAP+ No Local excision History of ovariancarcinoma treated withsurgery and radiation

Zaviacicet al1

70 Flat tumor 1.5 Anteriorvaginal wall

NA PSA+, PSAP+ No None Metastatic RCC

Dodsonet al5

70 Flat tumor 2.0 Adjacent tothe urethra

5.9 PSA+, PSAP+ No Wide excision andbilateral inguinofemoral

lymphadenectomy

None

Slobodaet al4

46 Stressincontinenceand urethritis

3.5 Paraurethral NA PSA+, PSAP+ Leftinguinallymphnodes

Local excision None

Murphyet al6

NA NA NA NA NA PSA+ NA NA NA

Pongtippanet al8

88 Grosshematuria

3.0 Periurethral 1.3 PSA+ No External beamradiotherapy

None

Korytkoet al7

71 Painlesshematuria,

urgeincontinence

3.0 Bladderneck

54.5 PSA+, PSAP+ No Intensity modulatedradiation therapy

None

Presentreport

63 NA 1.5 Periurethral NA PSA+, PSAP+,NKX3.1+, PIN4

No Local excision None

Presentreport

87 Periurethralnodule

2.0 Periurethral 0.8 PSA+, PSAP+,NKX3.1+, PIN4

No Local excision None

Presentreport

87 Bleedingurethral polyp

1.0 Periurethral NA PSA+, PSAP+,NKX3.1+, PIN4

No Local excision History of cervical cancertreated with surgeryand radiation

Presentreport

61 Urethral polyp 1.5 Periurethral 4.9 PSA+, PSAP+,NKX3.1+, PIN4

No Local excision None

IHC indicates immunohistochemistry; Mets., metastases; NA, not available; RCC, renal cell carcinoma.

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and p63, consistent with in situ carcinoma. The tumor wasdiffusely positive for cytokeratin 7 (CK7) and estrogen re-ceptor (ER), focally positive for CDX2 and HMWCK, and

negative for NKX3.1, prostate-specific antigen (PSA),P501S, alpha-methylacyl-Coa racemase (AMACR), p63,WT1, PAX8, SATB2, and CK20 (Fig. 1). To address

FIGURE 1. Case 1. A, Low magnification of tumor growing within Skene’s glands lumens. B, Cribriform glands lined by pseu-dostratified columnar epithelium. C, Papillary structures lined by cells with similar cytology with intraluminal mucin secretion.D, PIN4 shows focal positivity for HMWCK in the tumor (bottom) with a patchy basal cell layer around negative glands (top) andnegative for AMACR. E, CK7 positive staining. F, Diffuse immunoreactivity for ER.

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whether the tumor could be a high-risk HPV-relatedadenocarcinoma, either originating in the endocervix andextending/metastatic to the periurethral region or primary inthis site, immunohistochemical analysis of p16 expressionand ISH for high-risk HPV RNA were performed. Thetumor had diffuse expression of p16 but there was nodetectable HPV by ISH. Following simple excision, thepatient was alive 132 months later with no further detailsavailable.

Case #2An 87-year-old female presented with a 2 cm ure-

thral mass at the 5 o’clock position. A limited resectionwas performed with negative margins. The urethral andbladder mucosa was normal. Serum PSA was 0.8 μg/L atthe time of the biopsy and 0.1 μg/L 6 months later. Thepatient is asymptomatic with undetectable serum PSAlevels at 19 months following surgery.

Microscopically, the lesion consisted of multiplewell-defined large nests of cribriform or poorly formedglands undermining the epithelial surface (Fig. 2). Theneoplastic cells showed pale cytoplasm, relativelymonotonous nuclei and prominent nucleoli. The tumorwas morphologically indistinguishable from Gleason score4+4= 8 adenocarcinoma of the prostate. Tumor cells werepositive for PSA, P501S, NKX3.1, and AMACR. Over95% of the tumor lacked a basal cell layer with HMWCKand p63 with a small focus of carcinoma surrounded by abasal cell layer (Fig. 2).

Case #3An 87-year-old female with advanced Alzheimer

dementia requiring permanent bladder catheter presentedwith a bleeding urethral polyp measuring 1.0 cm. She hada history of radiation treatment for uterine cervical cancerwhen she was 30 years old, and a bladder tumor of un-certain type transurethrally resected 2 years earlier. A lo-cal resection of the urethral lesion was performed withnegative margins. No further treatment was recommendedand there was no recurrence after 8 months of follow-up.

Microscopically, there was a 0.4 cm nodular lesionlocated in the stroma below benign urothelium (Fig. 3).The periphery of the lesion demonstrated well to poorlyformed and fused glands with acinar differentiationcomposed of cuboidal cells with eosinophilic cytoplasmand prominent nucleoli. The center of the lesion wascomposed primarily of papillary fronds lined by variablycuboidal and columnar epithelium with abundantamphophilic cytoplasm and prominent nucleoli. Focallyin the center of the lesion was a cribriform componentwith cuboidal epithelium and similar cytology. Overall,the analogous grade if the tumor was arising in theprostate would have been Gleason score 4+4= 8.HMWCK and p63 showed a continuous basal cell layeraround the papillary and cribriform component which waslacking around the peripheral acinar component. Bothcomponents were positive for PSA, P501S, NKX3.1,and AMACR.

Case #4A 61-year-old female presented with a urethral le-

sion that she claimed was present for ∼5 years, initiallythought to be a urethral caruncle. Cystoscopy was per-formed and showed a polypoid mass on a stalk extendingposteriorly from the urethral wall, measuring 1.5 cm. Re-section of the polypoid lesion with negative margins wereperformed. There was also a trigonal mass that the patientrefused to biopsy. A serum PSA was 4.96 μg/L at the timeof the biopsy. The patient is asymptomatic after 4 monthsof follow-up.

The surface of the polypoid lesion was lined by re-active squamous metaplasia with extension into under-lying glands giving rise to an analogous pattern seen innecrotizing sialometaplasia. Microscopically, over 95% ofthe tumor was composed of invasive poorly formed, fused,and small cribriform glands with pale eosinophilic cyto-plasm, relatively monotonous nuclei and prominent nu-cleoli, comparable to a Gleason score 4+4= 8 prostaticadenocarcinoma (Fig. 4). Very focally there was a gradualtransition from fused glands that looked indisting-uishable from prostate adenocarcinoma to glands withslightly more atypical nuclei and prominent goblet celldifferentiation (Fig. 5). The areas of the tumor thatresembled adenocarcinoma of the prostate were positivefor PSA, P501S, NKX3.1, and racemase, along with focalpatchy positivity for CK20. P63 failed to show basal cellsand there was nonspecific staining for HMWCK in theperipheral area of the tumor. The area of the tumor withgoblet cells was diffusely positive for CK20, failed to labelwith prostatic markers, and was also negative for CDX2and SATB2.

DISCUSSIONNormal female paraurethral glands were first described

by De Graaf9 in 1672, and due to their embryological andmorphologic similarity with the prostatic glands, he calledthem “the female prostate.” In 1948, Huffman10 studied indetail the anatomy of these glands in women and stated theirlocation in the anterior wall of the vagina and their ducts toempty into the distal third of the urethra. Their resemblanceto prostatic glands was further defined by Virchow in 185311

and Skene in 1880.12

In 1984, Pollen and Dreilinger13 and Tepper et al14

reported that normal Skene’s glands showedimmunohistochemical staining for PSA and prostate-spe-cific acid phosphatase (PSAP). These glands are the mainsource of PSA secretion in women, who have baselineserum PSA values around 0.2 μg/L. This is also the rec-ognized upper limit for serum PSA values for men whohave undergone radical prostatectomy without evidence ofbiochemical recurrence.15 Elevated serum PSA levels havebeen reported in women with pathologic conditionsaffecting the paraurethral glands.16

Skene’s gland adenocarcinoma are extremely rare.There are only 7 prior reported cases.1,3–8 The cases re-ported to date occurred in older women and usually pre-sented as polypoid or flat periurethral tumors, similarly to

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ours. Some of them were symptomatic and presented withgross hematuria or urinary urgency. Only one reported casehad metastatic disease to the inguinofemoral lymph nodes.4

The pathologic findings were consistent with prostatic aci-nar adenocarcinoma and immunohistochemical stains werepositive for PSA and PSAP in all cases.

FIGURE 2. Case 2. A, Well-defined large nests beneath the epithelial surface with spread to the deep margin. B, Cribriform andpoorly formed glands. C, Cells with pale cytoplasm, monotonous nuclei and prominent nucleoli. D, Positive staining for PSA. E, Thetumor was positive for AMACR with most areas devoid of a basal cell layer, yet focally present with positivity for p63 and HMWCK(lower right). F, Diffusely positive for NKX3.1.

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Three of our cases were morphologically consistentwith prostatic acinar adenocarcinoma. If one graded thetumor in an analogous manner to prostatic adenocarcinoma

they would have all be Gleason score 4+4= 8 with variablycribriform, fused, and poorly formed glands. One of thetumors had mixed ductal features with neoplastic cells

FIGURE 3. Case 3. A, Nodular lesion in the stroma. B, Variable architecture with papillary (top), individual acini (center) andcribriform glands (bottom). C, Cuboidal cells with eosinophilic cytoplasm and prominent nucleoli. D, Papillary fronds lined bycolumnar cells. E, Positivity for NKX3.1. F, PIN4 shows positivity for AMACR, with basal cells surrounding the papillary component.

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FIGURE 4. Case 4. A, Low magnification showing an infiltrative lesion with overlying reactive squamous metaplasia. B, Fused andcribriform glands within inflamed stroma. C, Higher magnification of invasive cribriform glands. D, Fused glands were also noted.E, PIN4 stains show lack of p63 staining with nonspecific staining in a nonbasal cell distribution for HMWCK and positivity forAMACR. F, Cribriform, fused, and poorly formed glands resembling adenocarcinoma of the prostate were diffusely positive forNKX3.1.

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showing papillary carcinoma with columnar cytology.These cases demonstrate that Skene’s gland ad-enocarcinomas strikingly recapitulate some of the differentmorphologies seen in prostatic adenocarcinoma. Of the 7cases reported in the prior literature, all tumors had a cri-briform component. In addition, individual glands weredescribed and illustrated by Svanholm et al3 and Slobodaet al4 and only described by Pongtippan et al.8 Solid com-ponents were described but not illustrated in the cases bySloboda et al,4 Dodson et al,5 and Pongtippan et al.8 Single

file formation was described but not convincingly depictedby Svanholm et al.3 Combining the prior literature and ourcases, Skene’s gland adenocarcinoma typically resembleshigh-grade prostatic adenocarcinoma with a cribriformpredominant pattern, although other morphologies analo-gous to Gleason pattern 3, solid pattern 5 and for the firsttime shown in our cases fused and poorly formed glands ofpattern 4. Our series was also the first to demonstrate usingPIN4 cocktail that these analogous tumors to prostate ad-enocarcinoma arise within a duct in preexisting paraurethral

FIGURE 5. Case 4. A, Adenocarcinoma resembling prostatic adenocarcinoma (upper right) merging with area showing goblet cellfeatures (lower left). B, Higher magnification showing glands with amphophilic cytoplasm and focal goblet cells. C, Area withgoblet cell differentiation showing diffuse CK20 positivity. D, PIN4 cocktail showing absence of p63 and HMWCK with positiveAMACR (upper left) with focal nonspecific labeling of HMWCK (right) in areas of goblet cell differentiation.

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glands. In case 3 most of the tumor was surrounded by abasal cell layer, and in case 2 a basal cell layer was focallypresent. Another unique finding in one of our cases wasthat, although the vast majority of the tumor was identicalto prostate adenocarcinoma, focally there were glands withgoblet cells that were strongly CK20 positive and negativefor prostate markers. This focus was suggestive of showingintestinal differentiation, although immunohistochemistryfor CDX2 and SATB2 was negative.

This series also presents the novel finding that in addi-tion to tumors analogous to prostatic adenocarcinoma,tumors may also arise in the paraurethral glands showingsome serous differentiation. Case 1 definitively arose in theparaurethral gland with the entire tumor confined to thegland. The lesion was diffusely positive for CK7, ER, andp16, and negative for markers of prostatic origin. However, itwas difficult to classify the lesion definitively as Mullerianbecause it was negative for PAX8 and WT1 and high-riskHPV by RNA ISH.

Our study is the first to demonstrate immunoreactivityfor other prostatic markers (ie, NKX3.1 and P501S) in additionto PSA and PSAP. NKX3.1 is a nuclear protein found to bepositive in the vast majority of prostatic adenocarcinomas.17,18

P501S or prostein is a cytoplasmic marker expressed in bothbenign and neoplastic prostate tissues.19 We also performed thePIN4 cocktail, which showed positivity for racemase anddemonstrated lack of basal cells. In case 4, there was focalnonspecific staining of the carcinoma for HMWCK withnegative staining for p63, which has also seen in a minority ofprostatic adenocarcinomas.

Because of the rarity of Skene’s gland ad-enocarcinomas, there is no consensus regarding their treat-ment. Local extent can be vary from polypoid noninvasiveto deeply invasive tumors. Of the 7 prior cases in the liter-ature, 3 were treated by local/extended surgical resection, 2by radiotherapy, 1 seen at autopsy for an unrelated death,and 1 with no information about therapy. In addition toroutine follow-up with physical and imaging examinations,serum PSA should be performed both at the time of diag-nosis and after treatment, as some reports show a decreasein serum levels following successful therapy.5,7,8 Combiningour cases with those in the literature, all have tumor anal-ogous to Gleason pattern 4 with a few having solid areasthat would be graded as Gleason pattern 5 in the prostate.The one lesion with ductal morphology that we had in ourseries was predominantly in situ with apparently negativemargins such that its prognosis may be favorable. It is un-known whether applying the same grading criteria for pro-static adenocarcinoma to Skene’s gland adenocarcinoma forprognostic purposes is valid given the limited number ofcases with variable treatment and in many cases limitedfollow-up. Although our remaining 3 cases which resembledinfiltrating Gleason score 4+4= 8 acinar adenocarcinomawere treated by local excision with no evidence of recurrence,

the lesions were relatively small, margins of resection werenegative for tumor, and the follow-up was limited. Whetherlimited resection, as opposed to en bloc resection of theurethra, is optimal therapy for these rare tumors is stillnot known.

REFERENCES1. Zaviacic M, Sidlo J, Borovsky M. Prostate specific antigen and

prostate specific acid phosphatase in adenocarcinoma of Skene’sparaurethral glands and ducts. Virchows Archiv A Pathol AnatHistopathol. 1993;423:503–505.

2. Moch H, Humphrey PA, Ulbright TM, et al. WHO Classification ofTumours of the Urinary System and Male Genital Organs, 4th ed.International Agency for Research on Cancer; Lyon, France: 2016.

3. Svanholm H, Andersen OP, Rohl H. Tumour of female paraurethralduct. Immunohistochemical similarity with prostatic carcinoma.Virchows Archiv A Pathol Anat Histopathol. 1987;411:395–398.

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Am J Surg Pathol � Volume 42, Number 11, November 2018 Skene’s Glands Adenocarcinoma

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