ORIGINAL ARTICLE
Metastatic Prostate Adenocarcinoma to the Penis A Series of 29 Cases With Predilection for Ductal Adenocarcinoma Carla L. Ellis, MD, MS* and Jonathan I. Epstein, MDw
Abstract: Twenty-nine men with metastatic prostate adenocarcinoma to the penis were identified at our institution between 1993 and 2013. Of the 29 patients, 19 had a prior history of adenocarcinoma of the prostate, and 8 of those had ductal features in the primary lesion. Sixteen of 29 revealed ductal features in the metastasis. Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis. Seven penile metastases were proven to be of prostatic origin solely by immunohistochemistry. Three cases were originally misdiagnosed as urothelial carcinoma upon review of the penile lesion. Other variant morphologies in the metastases included sarcomatoid carcinoma, small cell carcinoma, and adenosquamous carcinoma. In summary, prostate carcinoma involving the penis displays ductal features considerably more often than prostate cancer in general. Features that can cause difficulty in recognizing metastatic prostate adenocarcinoma to the penis include the unusual anatomic site for prostate cancer, poor differentiation, an increased prevalence of variant morphology, a long interval from the primary lesion, and, in some cases, no documented history of a primary prostatic lesion. Immunohistochemical analysis should be performed to rule out prostate carcinoma in penile/penile urethral tumors with morphology that differs from typical squamous or urothelial carcinoma. Even in the setting of metastatic disease, there is a critical need for an accurate diagnosis so that the appropriate therapy can be initiated, symptomatic relief can be provided, and longterm survival achieved in some cases, while at the same time avoiding penectomy for a misdiagnosis of a primary penile cancer. Key Words: penis, prostate, metastasis, ductal adenocarcinoma (Am J Surg Pathol 2015;39:67–74)
P
rimary penile carcinoma is one of the rarest male genital tract tumors,1 particularly in countries or cultures in which circumcision is routinely practiced.
From the *Department of Pathology and Laboratory Medicine, Emory University Hospital and School of Medicine, Atlanta, GA; and wThe Johns Hopkins Hospital and School of Medicine, Baltimore, MD. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jonathan I. Epstein, MD, The Johns Hopkins Hospital, Weinberg Building, Rm. 2242, 401 N. Broadway Street, Baltimore, MD 21231 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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Approximately three quarters of penile secondary tumors originate in organs of the genitourinary tract, with prostate and urinary bladder being the 2 most common primary sites, and the remainder are of gastrointestinal origin.2 The first large series studied in 2006 contained 10 cases of penile metastases,1 and as of 2011, almost 400 total cases have been reported in the literature.2–7 There are no prior series devoted to penile metastases from prostate carcinoma, although there have been case reports on this topic.8–14 A study in 2001 summarized 9 cases of prostatic carcinoma metastatic to the penis and noted that features of the ductal variant of prostate adenocarcinoma predominated in metastatic penile lesion.15 Our aim was to review our experience with morphology and clinical outcomes in penile lesions metastatic from prostatic primaries.
MATERIALS AND METHODS A search of our pathology data system from 1993 to 2013 revealed 29 cases of metastatic carcinoma to the penis from the prostate. Cases involving the bulbar urethra were included. All cases were originally reviewed at the time of the diagnosis by the senior author (J.I.E.), and the morphologic features of the penile lesions were subsequently rereviewed by both authors with particular attention to: the presence of ductal or other variant features, the location of the lesion, and the type of procedure performed (needle biopsy, mass excision, penectomy). Metastases were diagnosed by morphology and immunohistochemical staining with 1 or more of the following markers: prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), prostein (p501s), prostate-specific membrane antigen (PSMA), or NKX3.1. We attempted to retrieve follow-up data on all patients including whether the patient was dead or alive, whether the history of primary prostate cancer was documented, and, if so, the type of procedure (transurethral resection of the prostate [TURP], radical prostatectomy, or needle biopsy), Gleason grade of the primary lesion, whether ductal features were present in the primary lesion, and the type and duration of treatment administered.
RESULTS Contributor’s Diagnosis Of the 29 cases, 27 were sent for consultation, and the remaining 2 cases were from patients treated at the www.ajsp.com |
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FIGURE 1. A, Poorly differentiated adenocarcinoma of the prostate involving the penis initially misdiagnosed as urothelial carcinoma (hematoxylin and eosin). B, Same case as (A) showing positivity for NKX3.1. C, Same case as (A) positive for PSA. D, Same case as (A) with focal perinuclear cytoplasmic granular staining for P501S. E, Subcutaneous metastasis of prostatic adenocarcinoma. This lesion was diagnosed as squamous cell carcinoma on intraoperative consultation, and a penectomy was performed (hematoxylin and eosin). F, Bland adenocarcinoma of the prostate undermining and growing onto the urethral surface (hematoxylin and eosin).
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Johns Hopkins Hospital. Three cases were misdiagnosed at the referring institution as urothelial carcinoma (cases 20, 22, 27) (Figs. 1A–D), one as a urethral polyp and another as a villous adenoma. One case was misdiagnosed at the time of frozen section as a primary squamous cell carcinoma of the penis, and a penectomy was performed (Fig. 1E).
Location of Metastases and Demographics In 20 cases, the location of the biopsy of the metastasis was noted only as either “penile urethra or penis biopsy (Table 1) (Fig. 1F). Other more specific penile locations included: bulbar urethra (n = 4), penile corpora (n = 2), penile skin (n = 1), head of penis (n = 1), and “foreskin” (n = 1) (Fig. 2A). The mean age at the time of penile metastasis was 75 years (range, 58 to 90 y).
Metastatic Prostate Adenocarcinoma to the Penis
Prior History of Prostatic Adenocarcinoma Nineteen of 29 cases had a prior history of adenocarcinoma of the prostate, either by outside report or by slides reviewed at our institution. This includes a case in which a concurrent biopsy of the prostate and the penile metastases showed prostatic small cell carcinoma (case 5), a case in which prostate carcinoma was diagnosed 2 months after the penile metastasis (case 27), and a case that was referred from overseas in which the diagnosis of metastatic prostatic adenocarcinoma involving the penis was based on typical morphology of papillary prostatic ductal adenocarcinoma and further information on clinical history was not available (case 28). Seven cases were diagnosed by immunohistochemistry only (staining of the penile metastatic lesion by 1 or more of the following markers: PSA, PSAP, P501S,
TABLE 1. Demographic Data and Histologic Features Ductal Features? Primary
Ductal Features? Metastasis
NA Ductal
NA Yes
Yes Yes
Bulbar urethra Bulbar urethra
PSA, PSAP PSA, PSAP
NA Ductal Not graded
Yes Yes No
Yes Yes No
Penile urethra Penile urethra Penis
NA PSA, PSAP None
Age at Documented History of Grade of Case Dx. (y) Prostate Cancer: Procedure Primary
Penile Location IHC Marker of Metastasis Positive in Met.
1 2
81 83
3 4 5
85 71 70
Yes: Needle bx. Yes: Needle bx. Diagnosed after met. Yes: NA Yes: Needle bx. Yes: Needle bx. Concurrent
6 7 8
76 58 59
Yes: Needle bx. Yes: Needle bx. Yes: TURP
4+5 = 9 5+4 = 9 5+5 = 10
No No No
No No No
Penile urethra Penis Penis
PSAP NSE None
9 10 11 12
78 76 59 90
Yes, by IHC Yes, by IHC Yes: Needle bx. Yes, by IHC
NA NA 4+4 = 8 NA
NA NA Yes NA
Yes No Yes Yes
Penis Penile urethra Penis Penile urethra
13 14
84 68
Yes: Needle bx. Yes, by IHC
4+4 = 8 NA
NA NA
No No
Penile urethra Penile urethra
15 16 17 18 19
81 79 65 74 74
Yes: Needle bx. Yes, by IHC Yes: Needle bx. Yes: Needle bx. Yes: Needle bx.
4+4 = 8 NA 5+5 = 10 4+4 = 8 4+4 = 8
No NA Yes No No
No No No Yes Yes
Penile corpora Penis Penile corpora Penile urethra Penile urethra
20 21
82 76
Yes, by IHC Yes, by IHC
NA NA
NA NA
Yes No
Penis Penile skin
22
73
Yes, by IHC
NA
NA
No
Penile urethra
23
85
Yes: Radical prostatectomy
5+4 = 9
Yes
Yes
Foreskin
PSA, PSAP PSAP PSA, P501S PSA, P501S, PSMA PSA PSA, P501S, PSMA None PSA PSA None PSA, P501s, PSMA P501s, NKX3.1 PSA, P501S, PSMA, NK3.1 PSA, P501S, PSMA, NKX3.1 PSA, NKX3.1
24 25 26 27
69 63 83 81
NA 3+4 = 7 NA 4+4 = 8
NA Yes NA Yes
Yes Yes Yes Yes
Penile urethra Bulbar urethra Penile urethra Penis
PSA, PSAP PSA, PSAP PSA PSAP
28 29
66 88
Yes, per report: NA Yes: Radical prostatectomy Yes, by IHC Yes: TURP diagnosed after met. NA Yes: TURP
NA 3+5 = 8
NA No
Yes No
Bulbar urethra Head of penis
None PSA, P501s, NKX3.1
Other Histologic Findings
Small cell carcinoma—primary & mets. Extensive LVI Sarcomatoid carcinoma in met. Extensive LVI
LVI
Adenosquamous features
Extensive LVI Extensive LVI
bx. indicates biopsy; Dx., diagnosis; IHC, immunohistochemistry; LVI, lymphovascular invasion; met., metastasis; NA, not available; NSE, nonspecific enolase; P501s, prostein; PSA, prostate-specific antigen; PSAP, prostate-specific acid phosphatase; PSMA, prostate-specific membrane antigen.
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FIGURE 2. A, Gleason pattern 5 adenocarcinoma with comedonecrosis undermining penile skin. B, Papillary prostatic ductal adenocarcinoma. C, Cribriform prostatic adenocarcinoma with ductal and acinar features. D, Papillary prostatic ductal adenocarcinoma with foamy gland features undermining penile urothelium (upper right). E, Needle core biopsy of the penis with cribriform acinar prostate adenocarcinoma. F, Sheets of Gleason pattern 5 adenocarcinoma with relatively uniform cytology, prominent nucleoli, and delicate eosinophilic cytoplasm (all images stained with hematoxylin and eosin).
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Metastatic Prostate Adenocarcinoma to the Penis
FIGURE 3. A, Penile metastasis with prostatic adenosquamous carcinoma (hematoxylin and eosin). B, Extensive vascular invasion of prostate adenocarcinoma beneath penile skin (hematoxylin and eosin). C, Crushed high-grade adenocarcinoma (left) verified as being of prostatic origin with PSA immunoreactivity (right). D, Poorly preserved, scant, and crushed carcinoma involving the penis in a man with a history of prostatic adenocarcinoma, Gleason score 4+4 = 8 (left). PSA positivity confirms the diagnosis of metastatic prostate adenocarcinoma (right).
PSMA, and NKX3.1) and had no known history of prostatic adenocarcinoma by any report. In the remaining 3 cases, the history of prostate cancer was not known at the time of the penile metastasis and was determined after a clinical history search (case 6) or after prostate biopsy performed following the penile diagnosis (cases 2 and 27) revealed the history of prostatic adenocarcinoma. The median interval between the diagnosis of the primary lesion and the penile metastasis was 3.2 years (range, 6 mo to 23 y). Three cases were misdiagnosed as invasive poorly differentiated urothelial carcinoma (cases 20, 22, and 27). In 1, there were concurrent biopsies of the prostatic urethra and penis diagnosed at the outside institution as urothelial carcinoma, which after workup at a second outside institution were PSAP positive, and a subsequent TURP confirmed the diagnosis of prostatic adenocarcinoma (case 27). The second penile metastasis r
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misdiagnosed as urothelial carcinoma on review at our institution was positive for PSA and NKX3.1 and was diagnosed as Gleason score 5+5 = 10 (case 22) (Figs. 1A–D). The third case had a history of urothelial carcinoma, and the penile lesion was diagnosed as urothelial carcinoma. We reviewed and diagnosed this lesion as metastatic prostate adenocarcinoma with focal ductal features, as it was NKX3.1 and P501S positive (case 20).
Histology Histopathologic information about the prostatic primary was obtained in 17/29 (58.6%) cases. Overall, the primary lesion was diagnosed by needle biopsy in 12 cases. Three cases were diagnosed by TURP, 2 by radical prostatectomy, and in 2 cases information on the resection method was not available. The Gleason grades of the primary lesions were as follows: 5+5 = 10 (n = 2), www.ajsp.com |
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5+4 = 9 or 4+5 = 9 (n = 3), 4+4 = 8 (n = 6), 3+5 = 8 (n = 1), 3+4 = 7 (n = 1), and unknown (n = 4). Ductal features were noted in the primary lesion in 8/16 (50%) cases with available information; 1 case was pure ductal adenocarcinoma of the prostate. Of the 29 cases, 16 (55.2%) revealed ductal features in the metastasis (Figs. 2B–D). Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis (Table 1). The remaining penile metastases with the following exceptions were usual acinar adenocarcinoma (Figs. 2E, F). Other variant morphologies in metastases included sarcomatoid carcinoma (n = 1), small cell carcinoma (n = 1), and adenosquamous carcinoma (n = 1) (Fig. 3A). Angiolymphatic invasion was present in 5 metastases (Fig. 3B). Immunohistochemical markers to confirm prostatic origin in difficult cases (PSA, PSAP, PSMA, and NKX3.1) were variably used in 22 cases (Figs. 3C, D).
Follow-up Of 26 patients with follow-up information, 13 are dead.16 The median interval between the penile metastasis and death (known in 11/13 cases) was 1.7 years (range, 1 to 12 y). Twelve patients are alive at a median of 1.4 years after the penile metastases (range, 9 mo to5.3 y) (Table 2). Most patients had received radiation therapy for their
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primary lesions and androgen deprivation therapy following the penile metastases.
DISCUSSION Penile metastases are exceedingly rare but when present are most commonly from the prostate and bladder.3,15,17 The diagnosis should be considered, particularly in elderly men, or in the setting of a penile lesion or priapism in patients with a known history of bladder or prostate malignancies.4,18 The first case of a metastasis to the penis was reported in 1870 by Eberth,19 and as of 2011, approximately 400 cases have been reported in the literature. Herein we describe the largest series (29 cases) of prostate adenocarcinoma metastatic to the penis. The most prominent histologic finding in our study is the propensity of metastatic prostate adenocarcinoma of the penis to have features of ductal adenocarcinoma. Prostatic duct adenocarcinomas show a variety of architectural patterns, including papillary, cribriform, PIN-like, and individual glands mimicking colonic adenocarcinoma. The defining feature of ductal adenocarcinoma is the presence of tall pseudostratified epithelial cells, in contrast to the cuboidal to columnar single cell layer of epithelium seen with acinar prostatic
TABLE 2. Treatment and Follow-up Interval Primary and Met.
Treatment of Primary/Metastasis
Follow-up
1 2 3 4 5
23 y Primary 2 mo after penis met. NA 4y Concurrent
Radiation/ADT NA NA NA NA
6 7 8 9 10 11
NA 1 y 2 mo 1 y 1 mo NA NA 3 y 2 mo
12 13 14 15 16 17 18 19 20 21
5y 7y 8y 1y 3y 2 y 1 mo 3 y 3 mo 4y NA NA
NA NA NA NA NA Radical prostatectomy, radiation/chemotherapy then ADT Radiation Radiation and ADT NA Unknown, eventually ADT Radical prostatectomy and ADT/radiation NA Radiation and ADT Radiation and ADT NA Radiation and ADT
Dead with lymph node mets. 1 y 8 mo after penis met. NA Dead with 4 y 4 mo after penis met. NA Dead at least 12 y after penis mets. with residual prostate small cell carcinoma Dead date unknown Dead 3 y 6 mo after penis met. Dead lung and bone mets. 9 y after penis met. Dead 1 y 4 mo after penis met. Dead, interval unknown Alive 1 y 5 mo after penis met. and lymph node mets.
22 23 24 25 26 27 28 29
NA 11 mo NA 7 y 8 mo NA Primary 2 mo after penile met. NA 6 mo
NA NA Radiation Radical prostatectomy, radiation, ADT NA Radiation and ADT NA ADT
Case
Dead 1 y 3 mo after penis met. Dead with other mets. 2 y 6 mo after penis met. Alive 4 y 2 mo after penis met. Alive 4 y 1 mo after penis met. Alive 3 y 4 mo after penis met. Also with bladder mets. Dead with bone mets. 2 y 7 mo after penis met. Dead with extensive mets. 1 y 1 mo after penis met. Alive 5 y 4 mo after penis met. Alive 1 y 5 mo after penis met. Dead 1 y after penis met. with liver and multiple lymph node mets. Alive 1 y 3 mo after penis met. Alive 2 y after penis met. Alive 1 y 4 mo after penis met. Alive 11 mo after penis met. Alive 11 mo after penis met. Alive, interval unknown NA Alive 9 mo after penis met.
ADT indicates androgen deprivation therapy; met., metastasis; NA, not available.
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carcinomas. In its pure form, ductal adenocarcinoma accounts for
Metastatic Prostate Adenocarcinoma to the Penis A Series of 29 Cases With Predilection for Ductal Adenocarcinoma Carla L. Ellis, MD, MS* and Jonathan I. Epstein, MDw
Abstract: Twenty-nine men with metastatic prostate adenocarcinoma to the penis were identified at our institution between 1993 and 2013. Of the 29 patients, 19 had a prior history of adenocarcinoma of the prostate, and 8 of those had ductal features in the primary lesion. Sixteen of 29 revealed ductal features in the metastasis. Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis. Seven penile metastases were proven to be of prostatic origin solely by immunohistochemistry. Three cases were originally misdiagnosed as urothelial carcinoma upon review of the penile lesion. Other variant morphologies in the metastases included sarcomatoid carcinoma, small cell carcinoma, and adenosquamous carcinoma. In summary, prostate carcinoma involving the penis displays ductal features considerably more often than prostate cancer in general. Features that can cause difficulty in recognizing metastatic prostate adenocarcinoma to the penis include the unusual anatomic site for prostate cancer, poor differentiation, an increased prevalence of variant morphology, a long interval from the primary lesion, and, in some cases, no documented history of a primary prostatic lesion. Immunohistochemical analysis should be performed to rule out prostate carcinoma in penile/penile urethral tumors with morphology that differs from typical squamous or urothelial carcinoma. Even in the setting of metastatic disease, there is a critical need for an accurate diagnosis so that the appropriate therapy can be initiated, symptomatic relief can be provided, and longterm survival achieved in some cases, while at the same time avoiding penectomy for a misdiagnosis of a primary penile cancer. Key Words: penis, prostate, metastasis, ductal adenocarcinoma (Am J Surg Pathol 2015;39:67–74)
P
rimary penile carcinoma is one of the rarest male genital tract tumors,1 particularly in countries or cultures in which circumcision is routinely practiced.
From the *Department of Pathology and Laboratory Medicine, Emory University Hospital and School of Medicine, Atlanta, GA; and wThe Johns Hopkins Hospital and School of Medicine, Baltimore, MD. Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Jonathan I. Epstein, MD, The Johns Hopkins Hospital, Weinberg Building, Rm. 2242, 401 N. Broadway Street, Baltimore, MD 21231 (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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Approximately three quarters of penile secondary tumors originate in organs of the genitourinary tract, with prostate and urinary bladder being the 2 most common primary sites, and the remainder are of gastrointestinal origin.2 The first large series studied in 2006 contained 10 cases of penile metastases,1 and as of 2011, almost 400 total cases have been reported in the literature.2–7 There are no prior series devoted to penile metastases from prostate carcinoma, although there have been case reports on this topic.8–14 A study in 2001 summarized 9 cases of prostatic carcinoma metastatic to the penis and noted that features of the ductal variant of prostate adenocarcinoma predominated in metastatic penile lesion.15 Our aim was to review our experience with morphology and clinical outcomes in penile lesions metastatic from prostatic primaries.
MATERIALS AND METHODS A search of our pathology data system from 1993 to 2013 revealed 29 cases of metastatic carcinoma to the penis from the prostate. Cases involving the bulbar urethra were included. All cases were originally reviewed at the time of the diagnosis by the senior author (J.I.E.), and the morphologic features of the penile lesions were subsequently rereviewed by both authors with particular attention to: the presence of ductal or other variant features, the location of the lesion, and the type of procedure performed (needle biopsy, mass excision, penectomy). Metastases were diagnosed by morphology and immunohistochemical staining with 1 or more of the following markers: prostate-specific antigen (PSA), prostate-specific acid phosphatase (PSAP), prostein (p501s), prostate-specific membrane antigen (PSMA), or NKX3.1. We attempted to retrieve follow-up data on all patients including whether the patient was dead or alive, whether the history of primary prostate cancer was documented, and, if so, the type of procedure (transurethral resection of the prostate [TURP], radical prostatectomy, or needle biopsy), Gleason grade of the primary lesion, whether ductal features were present in the primary lesion, and the type and duration of treatment administered.
RESULTS Contributor’s Diagnosis Of the 29 cases, 27 were sent for consultation, and the remaining 2 cases were from patients treated at the www.ajsp.com |
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FIGURE 1. A, Poorly differentiated adenocarcinoma of the prostate involving the penis initially misdiagnosed as urothelial carcinoma (hematoxylin and eosin). B, Same case as (A) showing positivity for NKX3.1. C, Same case as (A) positive for PSA. D, Same case as (A) with focal perinuclear cytoplasmic granular staining for P501S. E, Subcutaneous metastasis of prostatic adenocarcinoma. This lesion was diagnosed as squamous cell carcinoma on intraoperative consultation, and a penectomy was performed (hematoxylin and eosin). F, Bland adenocarcinoma of the prostate undermining and growing onto the urethral surface (hematoxylin and eosin).
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Johns Hopkins Hospital. Three cases were misdiagnosed at the referring institution as urothelial carcinoma (cases 20, 22, 27) (Figs. 1A–D), one as a urethral polyp and another as a villous adenoma. One case was misdiagnosed at the time of frozen section as a primary squamous cell carcinoma of the penis, and a penectomy was performed (Fig. 1E).
Location of Metastases and Demographics In 20 cases, the location of the biopsy of the metastasis was noted only as either “penile urethra or penis biopsy (Table 1) (Fig. 1F). Other more specific penile locations included: bulbar urethra (n = 4), penile corpora (n = 2), penile skin (n = 1), head of penis (n = 1), and “foreskin” (n = 1) (Fig. 2A). The mean age at the time of penile metastasis was 75 years (range, 58 to 90 y).
Metastatic Prostate Adenocarcinoma to the Penis
Prior History of Prostatic Adenocarcinoma Nineteen of 29 cases had a prior history of adenocarcinoma of the prostate, either by outside report or by slides reviewed at our institution. This includes a case in which a concurrent biopsy of the prostate and the penile metastases showed prostatic small cell carcinoma (case 5), a case in which prostate carcinoma was diagnosed 2 months after the penile metastasis (case 27), and a case that was referred from overseas in which the diagnosis of metastatic prostatic adenocarcinoma involving the penis was based on typical morphology of papillary prostatic ductal adenocarcinoma and further information on clinical history was not available (case 28). Seven cases were diagnosed by immunohistochemistry only (staining of the penile metastatic lesion by 1 or more of the following markers: PSA, PSAP, P501S,
TABLE 1. Demographic Data and Histologic Features Ductal Features? Primary
Ductal Features? Metastasis
NA Ductal
NA Yes
Yes Yes
Bulbar urethra Bulbar urethra
PSA, PSAP PSA, PSAP
NA Ductal Not graded
Yes Yes No
Yes Yes No
Penile urethra Penile urethra Penis
NA PSA, PSAP None
Age at Documented History of Grade of Case Dx. (y) Prostate Cancer: Procedure Primary
Penile Location IHC Marker of Metastasis Positive in Met.
1 2
81 83
3 4 5
85 71 70
Yes: Needle bx. Yes: Needle bx. Diagnosed after met. Yes: NA Yes: Needle bx. Yes: Needle bx. Concurrent
6 7 8
76 58 59
Yes: Needle bx. Yes: Needle bx. Yes: TURP
4+5 = 9 5+4 = 9 5+5 = 10
No No No
No No No
Penile urethra Penis Penis
PSAP NSE None
9 10 11 12
78 76 59 90
Yes, by IHC Yes, by IHC Yes: Needle bx. Yes, by IHC
NA NA 4+4 = 8 NA
NA NA Yes NA
Yes No Yes Yes
Penis Penile urethra Penis Penile urethra
13 14
84 68
Yes: Needle bx. Yes, by IHC
4+4 = 8 NA
NA NA
No No
Penile urethra Penile urethra
15 16 17 18 19
81 79 65 74 74
Yes: Needle bx. Yes, by IHC Yes: Needle bx. Yes: Needle bx. Yes: Needle bx.
4+4 = 8 NA 5+5 = 10 4+4 = 8 4+4 = 8
No NA Yes No No
No No No Yes Yes
Penile corpora Penis Penile corpora Penile urethra Penile urethra
20 21
82 76
Yes, by IHC Yes, by IHC
NA NA
NA NA
Yes No
Penis Penile skin
22
73
Yes, by IHC
NA
NA
No
Penile urethra
23
85
Yes: Radical prostatectomy
5+4 = 9
Yes
Yes
Foreskin
PSA, PSAP PSAP PSA, P501S PSA, P501S, PSMA PSA PSA, P501S, PSMA None PSA PSA None PSA, P501s, PSMA P501s, NKX3.1 PSA, P501S, PSMA, NK3.1 PSA, P501S, PSMA, NKX3.1 PSA, NKX3.1
24 25 26 27
69 63 83 81
NA 3+4 = 7 NA 4+4 = 8
NA Yes NA Yes
Yes Yes Yes Yes
Penile urethra Bulbar urethra Penile urethra Penis
PSA, PSAP PSA, PSAP PSA PSAP
28 29
66 88
Yes, per report: NA Yes: Radical prostatectomy Yes, by IHC Yes: TURP diagnosed after met. NA Yes: TURP
NA 3+5 = 8
NA No
Yes No
Bulbar urethra Head of penis
None PSA, P501s, NKX3.1
Other Histologic Findings
Small cell carcinoma—primary & mets. Extensive LVI Sarcomatoid carcinoma in met. Extensive LVI
LVI
Adenosquamous features
Extensive LVI Extensive LVI
bx. indicates biopsy; Dx., diagnosis; IHC, immunohistochemistry; LVI, lymphovascular invasion; met., metastasis; NA, not available; NSE, nonspecific enolase; P501s, prostein; PSA, prostate-specific antigen; PSAP, prostate-specific acid phosphatase; PSMA, prostate-specific membrane antigen.
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FIGURE 2. A, Gleason pattern 5 adenocarcinoma with comedonecrosis undermining penile skin. B, Papillary prostatic ductal adenocarcinoma. C, Cribriform prostatic adenocarcinoma with ductal and acinar features. D, Papillary prostatic ductal adenocarcinoma with foamy gland features undermining penile urothelium (upper right). E, Needle core biopsy of the penis with cribriform acinar prostate adenocarcinoma. F, Sheets of Gleason pattern 5 adenocarcinoma with relatively uniform cytology, prominent nucleoli, and delicate eosinophilic cytoplasm (all images stained with hematoxylin and eosin).
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Metastatic Prostate Adenocarcinoma to the Penis
FIGURE 3. A, Penile metastasis with prostatic adenosquamous carcinoma (hematoxylin and eosin). B, Extensive vascular invasion of prostate adenocarcinoma beneath penile skin (hematoxylin and eosin). C, Crushed high-grade adenocarcinoma (left) verified as being of prostatic origin with PSA immunoreactivity (right). D, Poorly preserved, scant, and crushed carcinoma involving the penis in a man with a history of prostatic adenocarcinoma, Gleason score 4+4 = 8 (left). PSA positivity confirms the diagnosis of metastatic prostate adenocarcinoma (right).
PSMA, and NKX3.1) and had no known history of prostatic adenocarcinoma by any report. In the remaining 3 cases, the history of prostate cancer was not known at the time of the penile metastasis and was determined after a clinical history search (case 6) or after prostate biopsy performed following the penile diagnosis (cases 2 and 27) revealed the history of prostatic adenocarcinoma. The median interval between the diagnosis of the primary lesion and the penile metastasis was 3.2 years (range, 6 mo to 23 y). Three cases were misdiagnosed as invasive poorly differentiated urothelial carcinoma (cases 20, 22, and 27). In 1, there were concurrent biopsies of the prostatic urethra and penis diagnosed at the outside institution as urothelial carcinoma, which after workup at a second outside institution were PSAP positive, and a subsequent TURP confirmed the diagnosis of prostatic adenocarcinoma (case 27). The second penile metastasis r
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misdiagnosed as urothelial carcinoma on review at our institution was positive for PSA and NKX3.1 and was diagnosed as Gleason score 5+5 = 10 (case 22) (Figs. 1A–D). The third case had a history of urothelial carcinoma, and the penile lesion was diagnosed as urothelial carcinoma. We reviewed and diagnosed this lesion as metastatic prostate adenocarcinoma with focal ductal features, as it was NKX3.1 and P501S positive (case 20).
Histology Histopathologic information about the prostatic primary was obtained in 17/29 (58.6%) cases. Overall, the primary lesion was diagnosed by needle biopsy in 12 cases. Three cases were diagnosed by TURP, 2 by radical prostatectomy, and in 2 cases information on the resection method was not available. The Gleason grades of the primary lesions were as follows: 5+5 = 10 (n = 2), www.ajsp.com |
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5+4 = 9 or 4+5 = 9 (n = 3), 4+4 = 8 (n = 6), 3+5 = 8 (n = 1), 3+4 = 7 (n = 1), and unknown (n = 4). Ductal features were noted in the primary lesion in 8/16 (50%) cases with available information; 1 case was pure ductal adenocarcinoma of the prostate. Of the 29 cases, 16 (55.2%) revealed ductal features in the metastasis (Figs. 2B–D). Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis (Table 1). The remaining penile metastases with the following exceptions were usual acinar adenocarcinoma (Figs. 2E, F). Other variant morphologies in metastases included sarcomatoid carcinoma (n = 1), small cell carcinoma (n = 1), and adenosquamous carcinoma (n = 1) (Fig. 3A). Angiolymphatic invasion was present in 5 metastases (Fig. 3B). Immunohistochemical markers to confirm prostatic origin in difficult cases (PSA, PSAP, PSMA, and NKX3.1) were variably used in 22 cases (Figs. 3C, D).
Follow-up Of 26 patients with follow-up information, 13 are dead.16 The median interval between the penile metastasis and death (known in 11/13 cases) was 1.7 years (range, 1 to 12 y). Twelve patients are alive at a median of 1.4 years after the penile metastases (range, 9 mo to5.3 y) (Table 2). Most patients had received radiation therapy for their
Volume 39, Number 1, January 2015
primary lesions and androgen deprivation therapy following the penile metastases.
DISCUSSION Penile metastases are exceedingly rare but when present are most commonly from the prostate and bladder.3,15,17 The diagnosis should be considered, particularly in elderly men, or in the setting of a penile lesion or priapism in patients with a known history of bladder or prostate malignancies.4,18 The first case of a metastasis to the penis was reported in 1870 by Eberth,19 and as of 2011, approximately 400 cases have been reported in the literature. Herein we describe the largest series (29 cases) of prostate adenocarcinoma metastatic to the penis. The most prominent histologic finding in our study is the propensity of metastatic prostate adenocarcinoma of the penis to have features of ductal adenocarcinoma. Prostatic duct adenocarcinomas show a variety of architectural patterns, including papillary, cribriform, PIN-like, and individual glands mimicking colonic adenocarcinoma. The defining feature of ductal adenocarcinoma is the presence of tall pseudostratified epithelial cells, in contrast to the cuboidal to columnar single cell layer of epithelium seen with acinar prostatic
TABLE 2. Treatment and Follow-up Interval Primary and Met.
Treatment of Primary/Metastasis
Follow-up
1 2 3 4 5
23 y Primary 2 mo after penis met. NA 4y Concurrent
Radiation/ADT NA NA NA NA
6 7 8 9 10 11
NA 1 y 2 mo 1 y 1 mo NA NA 3 y 2 mo
12 13 14 15 16 17 18 19 20 21
5y 7y 8y 1y 3y 2 y 1 mo 3 y 3 mo 4y NA NA
NA NA NA NA NA Radical prostatectomy, radiation/chemotherapy then ADT Radiation Radiation and ADT NA Unknown, eventually ADT Radical prostatectomy and ADT/radiation NA Radiation and ADT Radiation and ADT NA Radiation and ADT
Dead with lymph node mets. 1 y 8 mo after penis met. NA Dead with 4 y 4 mo after penis met. NA Dead at least 12 y after penis mets. with residual prostate small cell carcinoma Dead date unknown Dead 3 y 6 mo after penis met. Dead lung and bone mets. 9 y after penis met. Dead 1 y 4 mo after penis met. Dead, interval unknown Alive 1 y 5 mo after penis met. and lymph node mets.
22 23 24 25 26 27 28 29
NA 11 mo NA 7 y 8 mo NA Primary 2 mo after penile met. NA 6 mo
NA NA Radiation Radical prostatectomy, radiation, ADT NA Radiation and ADT NA ADT
Case
Dead 1 y 3 mo after penis met. Dead with other mets. 2 y 6 mo after penis met. Alive 4 y 2 mo after penis met. Alive 4 y 1 mo after penis met. Alive 3 y 4 mo after penis met. Also with bladder mets. Dead with bone mets. 2 y 7 mo after penis met. Dead with extensive mets. 1 y 1 mo after penis met. Alive 5 y 4 mo after penis met. Alive 1 y 5 mo after penis met. Dead 1 y after penis met. with liver and multiple lymph node mets. Alive 1 y 3 mo after penis met. Alive 2 y after penis met. Alive 1 y 4 mo after penis met. Alive 11 mo after penis met. Alive 11 mo after penis met. Alive, interval unknown NA Alive 9 mo after penis met.
ADT indicates androgen deprivation therapy; met., metastasis; NA, not available.
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2014 Lippincott Williams & Wilkins
Am J Surg Pathol
Volume 39, Number 1, January 2015
carcinomas. In its pure form, ductal adenocarcinoma accounts for
