Foamy gland high-grade prostatic intraepithelial neoplasia on core ...

Human Pathology: Case Reports 10 (2017) 32–36

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Case Report

Foamy gland high-grade prostatic intraepithelial neoplasia on core biopsy and subsequent radical prostatectomy: An in depth case report of a rare variant Paul Friedman, M.D. a, Daniel Costa, M.D. b, Payal Kapur, M.D. a,⁎ a b

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, United States

a r t i c l e

i n f o

Article history: Received 16 January 2017 Received in revised form 16 April 2017 Accepted 26 April 2017 Available online xxxx Keywords: Prostate Foamy gland HGPIN

a b s t r a c t A 69-year-old man underwent a robotic-assisted laparoscopic prostatectomy after a biopsy proven diagnosis of prostatic adenocarcinoma (PCa). Both the biopsy and the prostatectomy specimens revealed an organconfined conventional PCa of Gleason score 3 + 4 = 7 involving the left posterior lobe. In addition, the right lateral lobe revealed a separate large focus of high-grade prostatic intraepithelial neoplasia (HGPIN) involving enlarged, pale glands with tufted and micropapillary architecture. The neoplastic cells shared cytology of foamy gland carcinoma and had pseudostratified, small to pyknotic nuclei and abundant xanthomatous cytoplasm. Immunohistochemistry revealed positive racemase expression in the acinar cells, and basal cells were highlighted by p63 and high molecular weight cytokeratin, confirming a diagnosis of foamy gland HGPIN. No invasive foamy gland carcinoma was identified. Foamy gland HGPIN has limited mention in the literature and can easily be missed. Knowledge and recognition of this rare variant of HGPIN may be of significance in core biopsies in the absence of PCa. HGPIN is regarded as a precursor of PCa. Interestingly, both the foamy gland HGPIN and invasive conventional PCa showed ERG overexpression, however, only HGPIN showed loss of PTEN. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Background Our understanding of high-grade prostatic intraepithelial neoplasia (HGPIN) and its significance has evolved over time. Initially known as intraductal dysplasia [1], the current term, prostatic intraepithelial neoplasia (PIN), was accepted by consensus in 1989 [2]. It was initially divided into 3 degrees, and then subsequently classified into low or high-grade [3]. It was later recommended that low-grade prostatic intraepithelial neoplasia (LGPIN) not be reported, due to lack of specificity and clinical significance [4]. It is, however, recommended that HGPIN continue to be reported, due to its association with prostatic adenocarcinoma (PCa) [2,5]. Four main architectural patterns of HGPIN have been described, which include tufted, micropapillary, flat, and cribriform [6]. Conventional HGPIN is composed of medium to large glands lined by crowded epithelial cells with abnormal cytologic features, including hyperchromasia, nuclear overlap, enlarged nuclei, prominent nucleoli, and amphophilic cytoplasm. In classic cases, these features

⁎ Corresponding author at: Department of Anatomic Pathology, Clements University Hospital, 6201 Harry Hines Boulevard | Room 04.257, Dallas, TX 75390, United States E-mail address: [email protected] (P. Kapur).

can often be distinguished from benign glands on low power. Unusual variants of HGPIN have been described, including small cell neuroendocrine, signet-ring cell, mucinous, and inverted (hobnail) HGPIN [7,8]. The first case report of foamy gland variant of HGPIN was described and illustrated by Berman et al. in 2000 [9]. Two other cases of this variant have been published subsequently [2,10]. In this manuscript we describe and illustrate a case of foamy gland HGPIN, discuss the biology and importance of recognizing this rare variant and describe its magnetic resonance imaging (MRI) findings. 2. Case report A 69-year old man underwent a magnetic resonance imaging/ transrectal ultrasound (MRI/TRUS) fusion core biopsy of his prostate in August 2015 after an elevated serum prostate-specific antigen (PSA) level of 4.2 ng/mL was detected and MRI revealed two suspicious lesions. On physical examination, the prostate was enlarged, firm, nontender, and non-nodular. A diagnosis of Gleason score 3 + 4 = 7 PCa and foamy gland HGPIN were rendered. The patient underwent a robotic-assisted laparoscopic prostatectomy with right-sided nerve sparing and bilateral pelvic lymph node dissection in October 2015.

http://dx.doi.org/10.1016/j.ehpc.2017.04.006 2214-3300/Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

P. Friedman et al. / Human Pathology: Case Reports 10 (2017) 32–36

3. Materials and methods The prostate biopsy specimen was received in formalin and in 8 different parts, as per the currently suggested extended-pattern 12-core biopsy scheme by the National Comprehensive Cancer Network (NCCN) [11]. Six of the parts consisted of the typical biopsy locations (bilateral apex, mid, and base) with 2 core biopsies each. The remaining two parts consisted of lesion-specific biopsies that were detected using MRI. The subsequent radical prostatectomy specimen was received fresh. The prostate was inked and fixed in formalin before sectioning. The

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prostate was submitted using a method deemed appropriate by the latest International Society of Urological Pathology (ISUP) recommendations for handling prostatectomy specimens [12,13]. Triple immunohistochemical stains High Molecular Weight Cytokeratin (HMWCK), p63 (both labeled in brown), and racemase (labeled in red), were performed on selected sections of the biopsy and prostatectomy specimens. Immunostaining for ERG and phosphatase and tensin homolog (PTEN) was performed on representative sections of the prostatectomy specimen to compare immunoprofiles between PCa, and foamy gland HGPIN. ERG (mouse monoclonal; CM421C;

Fig. 1. Multiparametric MR imaging revealing a suspicious lesion in the right mid prostate peripheral zone (dashed area) as a low signal intensity region on axial T2-weighted images (A) and restricted diffusion on apparent diffusion coefficient images (B). Biopsy map generated during the targeted MR imaging-transrectal ultrasound fusion biopsy (C) confirms the location of the core (red line) revealing foamy HGPIN within the suspicious area. The same MR examination revealed a second suspicious lesion in the left mid prostate peripheral zone (dashed area) with similar imaging features on axial T2-weighted (D) and apparent diffusion coefficient images (E). 3D reconstruction of the prostate (green) generated during the targeted MR imaging-transrectal ultrasound fusion biopsy (F) shows this second region (yellow) and the two cores positive for cancer (red). R, right; L, left; B, base; A, apex. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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1:50; BioCare Medical Concord, CA, USA) and PTEN (rabbit monoclonal; clone D4.3, 1:50; Cell Signaling Technologies, Beverly, MA, USA) immunostains were performed in our CLIA certified clinical laboratory using controls with known genetic expression. For ERG, the endothelial cells served as an internal positive control, while benign prostatic glands provided an internal negative control. For PTEN, adjacent benign glands served as an internal positive control. 4. Results Multiparametric magnetic resonance imaging revealed suspicious areas in the left mid prostate and the peripheral zone of the right mid prostate, shown as an area of low signal intensity on axial T2weighted images. There was restricted diffusion with low values in the apparent diffusion coefficient map values, the same features expected for conventional PCa (Fig. 1). Microscopic examination of the prostate biopsy revealed conventional PCa involving bilateral lobes. Gleason score 3 + 4 = 7 PCa was present in 3 of 4 left sided biopsies, and low-grade PCa (Gleason 6) was present on the right side in 2 of 4 biopsies. Additionally, in the “right mid” biopsy, where MRI had shown a suspicious lesion, in addition to conventional PCa, there were foci of complex glands of normal size that cytologically resembled foamy gland carcinoma, a previously described variant of PCa. These glands were pale with tufting and papillary infoldings and pseudostratified nuclei. The cells had small to pyknotic nuclei, inconspicuous nucleoli, and abundant xanthomatous cytoplasm (Fig. 2A–B). However, no infiltrative pattern of small acini was identified. Triple immunohistochemical stain was performed that highlighted a preserved layer of basal cells, demonstrated by positive nuclear and cytoplasmic staining for p63 and HMWK respectively. Racemase was overexpressed in the glandular cells (Fig. 2C). These architectural, morphologic, and immunohistochemical characteristics are consistent with foamy gland variant of HGPIN. The subsequent radical prostatectomy confirmed all the findings that were observed in the prostate biopsy. A dominant nodule was present in the left posterior lobe in the middle to base slabs and consisted of Gleason score 3 + 4 = 7 conventional PCa (Fig. 3D). A portion of this

nodule of PCa containing predominantly Gleason pattern 3 glands extended medially into the right posterior lobe. Adjacent to this PCa was a separate well-demarcated focus of foamy gland HGPIN (Fig. 3A) that involved the middle to apical slabs of the right lateral lobe (Fig. 3 top image). PIN4 immunohistochemical staining was repeated on the resection specimen and confirmed the findings as observed in the biopsy. Rare acini of conventional HGPIN were noted adjacent to the foamy gland HGPIN. Foamy gland PCa was not identified in either specimen. Immunostaining with ERG and PTEN revealed distinct immunoprofiles when comparing between PCa and HGPIN. The foci of PCa showed nuclear overexpression (positivity) for ERG and retained cytoplasmic positivity for PTEN (Fig. 3E–F). In the foamy HGPIN glands, as well as the adjacent conventional HGPIN glands, ERG was overexpressed, however, PTEN was lost (negative) (Fig. 3B–C). The same findings were seen in the core biopsy.

5. Discussion We herein describe foamy gland HGPIN, a rare variant of HGPIN that shares cytologic features with foamy gland carcinoma. Few variants of HGPIN, like signet ring and small cell neuroendocrine HGPIN have been described, and these are associated with infiltrating carcinoma of similar morphologic subtype. However, no foamy gland PCa was present in the core biopsies or sections of the prostatectomy specimen (after complete sampling of the tumor nodules) in our case, which is similar to the previous report of foamy HGPIN [9]. This suggests that foamy HGPIN may occur in the absence of foamy gland carcinoma. Only two cases of foamy gland HGPIN have been reported in the literature. In 1996, Nelson and Epstein [10] described foamy gland carcinoma in 38 needle biopsies. Four of these cases were associated with HGPIN and in one case foamy cytoplasm was present in the HGPIN glands. An illustrated and more comprehensive report, also by Dr. Epstein's group, was reported in 2000 of a case of foamy gland HGPIN involving the left side of the prostate with a separate focus of conventional 3 + 3 = 6 prostate adenocarcinoma involving both sides and extending into extraprostatic soft tissue. No invasive foamy gland

Fig. 2. Low power image of prostate biopsy showing HGPIN with tufted appearance and xanthomatous cytoplasm (middle and left side); benign atrophic glands are present to the right (A). High power image shows pseudostratified and pyknotic nuclei (B). PIN4 immunohistochemical stain highlights basal cells (C).


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Fig. 3. Whole mount H&E section used to display areas of Pca (yellow circle) and foamy HGPIN (green circle) (top). Prostatectomy specimen displaying foamy HGPIN (A) with ERG positivity (B) and loss of PTEN (C). Prostatectomy specimen displaying Pca (D) with ERG and PTEN positivity (E and F). R, right; L, left; A, anterior; P, posterior. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

carcinoma was identified in spite of thorough sampling and review, as in our case. Recognizing foamy gland HGPIN, especially in a needle core biopsy, is even more challenging than foamy gland carcinoma. Cytologically, foamy gland HGPIN is identical to foamy gland carcinoma, with small to pyknotic nuclei, xanthomatous cytoplasm, and inconspicuous nucleoli. Foamy gland carcinoma, however, comprises small, crowded, infiltrative-appearing glands with a complete loss of basal cells. In contrast, in foamy gland HGPIN the glands are large with tufted or micropapillary architecture and preserved basal cells. It is important to distinguish foamy gland carcinoma from foamy gland HGPIN, as this will lead to definitive management, whereas a diagnosis of HGPIN may not. It has been shown that when isolated

HGPIN was present on an initial extensive biopsy, the risk of PCa was 22.9% on repeat biopsy, which is comparable to that observed in patients with negative initial biopsies [14]. In extensive biopsies with isolated HGPIN, the rate of PCa detection in an immediate extensive rebiopsy was found to be less than 3% [15]. Additionally, the number of cores involved by HGPIN may appear to be a predictor of PCa risk in repeat biopsies, with the risk increasing as the number of cores involved by HGPIN increases [14,16–19]. Prostate cancer not infrequently manifests as multifocal disease and is sometimes found adjacent to its presumed precursor lesions- HGPIN. While there is some evidence to suggest that these lesions are related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships remain yet to be defined. Recently,

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the TMPRSS2-ERG fusion has been described to occur in 50% of prostate cancers, and less commonly in HGPIN. TMPRSS2-ERG positive tumors are enriched for PTEN loss, suggesting cooperation in prostate tumorigenesis [20]. In a recent study that evaluated ERG and PTEN by IHC in prostatectomy specimens with isolated HGPIN without associated invasive carcinoma, 7% (8/107) were positive for ERG and PTEN loss was not seen in any HGPIN lesion (0/88) [21]. Multiple studies have shown that PTEN is the most commonly inactivated tumor suppressor in PCa [22–24], and it is associated with higher grade and stage, aggressive behavior, poor prognosis, and increased risk of lethal progression [25–30]. PTEN loss is less commonly seen in HGPIN [31,32]. The finding of a difference in the immunohistochemical staining pattern of ERG and PTEN between PCa and HGPIN is particularly interesting in our case. These findings suggest that the PCa glands and the HGPIN glands are different clones and temporally separate lesions. Though ERG overexpression and PTEN loss were seen in the foamy gland HGPIN, invasion directly adjacent was not seen. Though foamy gland HGPIN appears bland cytologically, the loss of PTEN suggests an aggressive biology. Studies comparing IDC-P and HGPIN by immunohistochemistry have shown all HGPIN lesions to be positive for PTEN [21,33,34]. It has been reported that a significant fraction of ERG-positive, PTENnegative HGPIN and intraductal carcinoma (IDC-P) lesions are most likely clonally derived from adjacent PTEN-negative adenocarcinomas, indicating that such PTEN-negative HGPIN and IDC-P lesions arise from, rather than give rise to, the nearby invasive adenocarcinoma [35]. One may, therefore, speculate the possibility of an intraductal spread of a foamy PCa in our case. However, no foamy gland invasive carcinoma was found, the two lesions are spatially apart, and except for enlarged caliber of the involved glands the diagnostic criteria for IDC-P are not met. Therefore, the possibility that the lesion we have designated as foamy gland HGPIN represents IDC-P is less likely. In conclusion, foamy gland HGPIN is an unusual variant. Due to its benign-appearing architecture and pale appearance on low power and its small pyknotic nuclei, it can be difficult to recognize. Disclosure None. References [1] J.E. McNeal, D.G. Bostwick, Intraductal dysplasia: a premalignant lesion of the prostate, Hum. Pathol. 17 (1) (1986) 64–71. [2] D.G. Bostwick, J. Qian, High-grade prostatic intraepithelial neoplasia, Mod. Pathol. 17 (3) (2004) 360–379. [3] J.I. Epstein, et al., Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia, Am. J. Surg. Pathol. 19 (8) (1995) 873–886. [4] J.R. Srigley, et al., Updated protocol for the examination of specimens from patients with carcinomas of the prostate gland: a basis for checklists. Cancer Committee, Arch. Pathol. Lab. Med. 124 (7) (2000) 1034–1039. [5] D.G. Bostwick, A. Pacelli, A. Lopez-Beltran, Molecular biology of prostatic intraepithelial neoplasia, Prostate 29 (2) (1996) 117–134. [6] J.I. Epstein, Precursor lesions to prostatic adenocarcinoma, Virchows Arch. 454 (1) (2009) 1–16. [7] A.O. Reyes, et al., Unusual histologic types of high-grade prostatic intraepithelial neoplasia, Am. J. Surg. Pathol. 21 (10) (1997) 1215–1222. [8] P. Argani, J.I. Epstein, Inverted (Hobnail) high-grade prostatic intraepithelial neoplasia (PIN): report of 15 cases of a previously undescribed pattern of high-grade PIN, Am. J. Surg. Pathol. 25 (12) (2001) 1534–1539. [9] D.M. Berman, J. Yang, J.I. Epstein, Foamy gland high-grade prostatic intraepithelial neoplasia, Am. J. Surg. Pathol. 24 (1) (2000) 140–144. [10] R.S. Nelson, J.I. Epstein, Prostatic carcinoma with abundant xanthomatous cytoplasm. Foamy gland carcinoma, Am. J. Surg. Pathol. 20 (4) (1996) 419–426.

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