Prostate sclerosing adenopathy: A clinicopathological and immunohistochemical study of twelve patients

lNTRODUCTlON

Sclerosing adenopathy of the prostate is a rare pseudomalignant proliferative lesion with a distinct histomorphological and immunohistochemical phenotype that often resembles acinar adenocarcinoma but may also resemble sarcomatoid carcinoma[1]. It can manifest as single or multiple lesions, in which good small glands and scattered single-cell components can be seen, forming the impression of cell-like features. These lesions are benign pseudotumor hyperplasia lesions that are very similar to those of small alveolar prostate adenocarcinoma and are often misdiagnosed as prostate cancer by primary pathologists due to their characteristic interstitial spindle cell proliferation and small glandular architecture. They are observed in 2% of the transurethral prostatectomy or prostatectomy specimens and are rare in small samples derived from prostate needle biopsy[2-4]. The glandular components show nuclear atypia, including nuclear enlargement and prominent nucleoli. However, sclerosing adenopathy tends to be a more focal lesion than sarcomatoid carcinoma, which is thought to arise from the myoepithelial cells surrounding the prostate, high molecular weight cytokeratins. Moreover, the lesions are often positive for muscle-specific actin staining. Compared with that prostate adenocarcinoma, sclerosing adenopathy has a lower incidence and a higher misdiagnosis rate. Furthermore, since it is a rare lesion, to date, no large samples have been available for clinical pathology experiments. In clinical treatment, surgical resection is still the best treatment option for sclerosing adenopathy of the prostate. To further understand this condition, we aimed to investigate the histopathological morphology and immunohistochemical phenotype of this very rare prostate lesion and to further explore its associated biological significance and underlying mechanisms.

MATERlALS AND METHODS

Thirteen patients with prostate sclerosing adenopathy that visited the Second Affiliated Hospital of Kunming Medical University from January 2015 to November 2021 were enrolled and followed up.Their clinical history, imaging data, and disease were analyzed and further confirmedthe relevant immunohistochemical analysis. Twelve specimens were routinely fixed using 4% neutral formaldehyde,paraffin-embedded, and tissue-sectioned to a thickness of 4 μm, followed by HE staining and immunohistochemical analysis. The HE-stained slides were reviewed by three pathologists to confirm the diagnosis. We reviewed the gross specimen characteristics and read the immunohistochemical product instructions, the expiration dates of the antibodies, the localization of the positive antibodies, and the staining intensity interpretation criteria in detail. The required immunohistochemistry AR, CKH, P63,CD56, CK5/6, calponin, S100, P504S, prostate-specific antigen (PSA), PSAP, P53, and Ki-67 markers were obtained from the Fujian Meixin Company, China, and the procedures were carried out strictly according to the instructions, and positive and negative controls were routinely set up.

装备在车内的嵌入式系统可以安全、便捷地将人们送到目的地，装备在玩具飞机中的嵌入式系统，可以使传统无线电控制的玩具飞机达到新的高度，引入嵌入式系统的GPS技术可以让户外运动者随心所欲欣赏沿途风光，而不用担心迷路，这些都要归功于嵌入式系统的发展。

Prostatic sclerosing adenopathy is highly misdiagnosed as prostate adenocarcinoma or other tumor-like lesions. Therefore, it should attract the attention of clinicopathologic researchers.

None of the 12 patients in this study had received prior radiotherapy, chemotherapy, immunotherapy, or drug therapy. Complete clinical and pathological data were obtained for all 12 patients, and intraoperative histological specimens were obtained. The study was approved by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University (approval number: trial-PJ-2021-142).Since the study was performed using medical records and biological specimens obtained from previous clinical consultations, all conditions were met to exempt patients from informed consent.

1)Constraints on NP:if something such as articles and novels etc uoods,its meaning is realized or known.

In addition, there are no studies that show that the PSA value is related to the occurrence and development of prostate sclerosing adenopathy. In this study, the PSA value of the vast majority of patients with sclerosing adenopathy was within the reference range. Therefore, patients with sclerosing adenopathy should be informed that long-term follow-up and observation are required. If the PSA value increases significantly compared to the original value, and clinical symptoms such as frequent urination, urgency, dysuria, hematuria, and dysuria appear, patients should promptly consult their doctor, since they may have prostate cancer.

RESULTS

Clinical data

A total of 7674 surgically resected prostate specimens were collected between January 2015 and November 2021, including 625 radical prostatectomy specimens, 1155 prostate puncture specimens, and 5894 transurethral electrodesiccation prostate specimens. A re-read of the 7674 prostate specimens revealed 12 cases of sclerosing adenopathy (0.2%), 2 of which were found in radical prostatectomy specimens, and 10 were found in transurethral resection specimens, with no lesions found in the prostate puncture specimens. The clinical data, laboratory tests, pathological morphology, and immunohistochemical phenotype of these 12 cases of prostatic sclerosing adenopathy were analyzed and are summarized in Table 1.

All 12 patients were elderly men with an average age of 71.7 years (age range, 62-83 years). In terms of clinical symptoms, 11 patients presented varying degrees of hematuria, urinary frequency, urinary urgency, and difficulty in urination, and one patient had increased blood pressure. After admission to the hospital, the laboratory tests revealed that 11 of the 12 patients had serum total prostate-specific antigen (PSA) values within the normal reference range, and only one patient had a slightly higher than normal value. Rectal finger examination showed hyperplastic changes in all the prostate tissues, with varying degrees of prostatic hyperplasia visible intraoperatively, mainly in both lobes and on the right wall. Among the 12 cases, transurethral resection of the prostate was performed in 10 of them, and total cystectomy and bowel replacement with total cystectomy and double ureterostomy for bladder cancer was performed in two cases, respectively.

Imaging features

In the 12 patients, the computed tomography examination results showed an enlarged prostate with single to multiple calcified foci and, in three cases, localized protrusion into the bladder trigone with uneven enhancement (Figure 1). The preoperative ultrasonography results showed an enlarged prostate morphology, an enlarged inner gland, a thinning of the outer gland under pressure, and inhomogeneous parenchyma with one to multiple strong echogenic spots in all the 12 patients (Figure 2,Table 2).

共和县处于藏区，人们的饮食习惯主要是面食、青稞炒面以及肉类为主，对于蔬菜的需求量不是太大。2017年，共和县蔬菜产量分布如下：

Histopathological findings

Specimen analysis showed that 10 cases presented a fragmented prostate tissue, two cases presented the complete cystoprostate tissue, which was grayish-red, along with a tissue multi-sectional cut that was tough. No obvious nodules or masses were seen. The microscopic observation results revealed that all 12 cases of prostate sclerosing adenopathy presented modularly distributed lesions indicative of benign prostatic hyperplasia. The lesions only had a few millimeters, had a nodular shape with varying degrees of small alveolar hyperplasia, without an obvious envelope, and with a growth pattern that mimicked the infiltration pattern of "prostate adenocarcinoma" (Figure 3A). The hyperplastic mesenchyme extruded the gland into ductal (Figure 3B), lacunar, and linear (Figure 3C) forms, and the glandular epithelium was covered with eosinophilic spike-like cells. Some of the glands were extruded to form vacuoles, and the increased number of vacuolated cells could form a structure similar to that of printed ring cells (Figure 3D). The interstitium was collagenous or mucinous and consisted of cells with a mildspindle-like morphology (Figure 3E). Observation at high magnification showed an eosinophilic cytoplasm with nuclei located at the base and small nucleoli but no nuclear division (Figure 3F).

妈妈印象最深刻的就是吃红薯，她告诉我，早上吃的是“整猪整羊”，意思是光吃蒸红薯，中午是“芝麻拌糖”，意思是在饭上蒸一点红薯，晚上则是“吹吹打打”，吃的是煨红薯，需要拍灰吹打……

Immunohistochemical phenotype

The basal cells of all the 12 cases of prostatic sclerosing adenopathy expressed molecules such as AR(Figure 4A), CKH (Figure 4D), P63 (Figure 4E), and CK5/6 (Figure 4C) to varying degrees, and also myoepithelial markers such as calponin (Figure 4B), S100 (Figure 4H), and smooth muscle actin (SMA)(Figure 4G). Nine of the 12 cases did not express P504S (Figure 4F), and the remaining three cases showed only a weakly positive expression of P504S. In addition, the prostate-specific markers PSA and PSAP were also expressed, P53 was not expressed, and the Ki67 proliferation index was in the 1%-3%range (Table 3).

Follow-up results

The mean follow-up time was 27.6 mo (3-73 mo), and 11 of the 12 patients survived well with normal rectal examinations and no recurrence or exacerbation of the disease. One patient died 26 mo after surgery due to bladder cancer.

DlSCUSSlON

Patients should be informed that long-term follow-up and observation are required. If the PSA value increases significantly compared to the original value, and clinical symptoms such as frequent urination,urgency, dysuria, hematuria, and dysuria appear, patients should promptly see their doctor, since they may have prostate cancer.

Sclerosing adenopathy is a rare benign proliferative lesion of the small alveoli without a markedly sclerotic stroma that occurs most occasionally after transurethral resection of the prostate, simple prostatectomy, or radical prostatectomy based on benign prostatic hyperplasia. It is detected by pathologists but occurs very rarely[17,18]. The histopathological pattern of sclerosing lymphadenopathy of the prostate is very similar to that of mammary sclerosing lymphadenopathy; however, unlike mammary sclerosing lymphadenopathy, prostatic sclerosing lymphadenopathy results in small lesions,usually with only a few millimeters[19]. It can result in single or multiple lesions, and it mostly occurs in the peripheral area of the prostate. It is difficult to detect the lesionrectal ultrasound, and it cannot be toucheddigital rectal examination. In addition, the serum PSA value is not high; thus, it is very difficult to measure it in clinical practice. In this group of 12 cases of prostate sclerosing lymphadenopathy, ultrasonography and rectal examination showed no abnormalities, and the serum PSA value did not increase. With the continuous improvement of ultrasound-guided technology, the probability of finding prostate sclerosing lymphadenopathy in biopsy tissue samples will increase; however, the possibility of it being misdiagnosed as prostate cancer will also increase. Research analysis found that 2% of the cases with this condition were diagnosed as prostate cancer. T1a stage prostate cancer wasconfirmed to be prostate sclerosing adenopathyreexamination[20]. Therefore, surgeon pathologists should consider prostate biopsy specimens as of great importance to avoid overdiagnosis of sclerosing adenopathy as prostate cancer.

Sclerosing adenopathy of the prostate has clear demarcation, is associated with small and concentrated lesions, nodular growth, no obvious capsule, and an infiltrative growth trend to the surrounding normal prostate tissue, similar to the growth pattern of prostate adenocarcinoma, but in the scope of growth-restricted lesions[21]. On the surface, it has a worrying appearance, with morphological distortions that can form stripes, threads, clusters, nests, and even single-cell arrangements. When the gland overproliferates, it may expand into a cyst, in which the amyloid material disappears and is replaced by a crystalline or myxoid material that is suggestive of prostate cancer[9,12]. In addition,several authors have described the lesion as presenting mild atypia and even small nucleoli, but generally no apparent large nucleoli. When individual cases are accompanied by moderate heterogeneity, heterogeneity, such as large and deep nuclear staining and prominent nucleoli, they are likely misdiagnosed as prostate adenocarcinoma. There is no evidence of the underlying malignancy of this lesion, although follow-up in our cases and others documented in the literature is admittedly limited.

碳酸镍沉淀分离浓密池采用砼衬橡胶，再衬耐酸耐温陶砖的复合衬里结构，橡胶内衬为5 mm厚预硫化丁基橡胶(P- ⅡR- 18)，呋喃树脂胶泥砌筑2层耐酸耐温陶砖(200 mm×200 mm×54 mm)。除铁、除钴帕丘卡空气搅拌槽尝试采用了新方法砼衬橡胶，再衬耐酸耐温陶砖的复合衬里结构[3]；导流筒为乙烯基树脂玻璃钢制作；导流筒支架为TA2材质；槽盖为钢件内外表面衬胶。

In conclusion, sclerosing adenopathy of the prostate is a morphological abnormality with characteristic histological features and immunohistochemical profiles. All the available evidence indicates that it is a benign condition that does not require treatment and is not a precancerous condition of prostate cancer.It is important to note, however, that many of the cases encountered to date have had a short follow-up period, and that it may often co-exist with other unrelated cancers in older men. The pathogenesis of this lesion is unclear, but its most striking feature seems to be the ability of cells to differentiate and proliferate. Studying and better understanding the features of sclerosing adenopathy should lead to its appropriate conservative management.

Sclerosing adenopathy of the prostate is considered a rare variant of adenopathy whose biological behavior remains uncertain, and the research on the risk of prostate cancer following a diagnosis of sclerosing adenopathy is very limited. Sclerosing adenopathy might be one of the precursors of prostate adenocarcinoma; however, this is unlikely because of its rarity and lack of other evidence linking its clinic features or pathology to cancer. When patients with sclerosing adenopathy present with cellular atypia, it is considered atypical sclerosing adenopathy; however, we should emphasize the use of the term "atypical sclerosing adenopathy" does not imply that these lesions are precancerous. Some scholars have found that DNA aneuploidy occurs in some atypical sclerosing adenopathy cases, but all typical sclerosing adenopathy cases are DNA diploid[28]. Whether sclerosing adenopathy can be used as an independent feature to predict the risk of prostate cancer in men is not yet clear, and a large multiinstitutional prospective study is needed for confirmation.

Sclerosing adenopathy has a similar histological pattern to that of the following lesions and is easily misdiagnosed as one of them. In this group of 12 patients with sclerosing adenopathy, two were misdiagnosed as having prostate adenocarcinoma and one was misdiagnosed as having nephrogenic adenoma by the primary pathologist. Therefore, prostate adenocarcinoma sclerosing adenopathy should be distinguished from the following lesions[1]. Prostate adenocarcinoma, which is the most likely misdiagnose. The identification points include: (1) Sclerosing adenopathy is mainly located in the peripheral area, with small and concentrated lesions, unlike cancer, that spreads and whose growth is invasive; (2) Sclerosing adenopathy is glandular hyperplasia with interstitial hyperplasia that is mucoid or fibrous; (3) An eosinophilic basement membrane material is seen around the ducts of patients with sclerosing adenopathy; (4) Mild-to-moderate dysplasia of the glandular epithelium may lead to subnucleation without significantly enlarged nucleoli; (5) There is no amyloid but a myxoid in the glandular follicular lumen. Furthermore, prostate cancer acini are lined with a layer of cuboidal or columnar cells without a distinctly flattened basal cell layer, as evidenced by the negative immunoreactivity for keratin 903[29,30]; and (6) Nephrogenic adenomas differentiate from sclerosing adenomas when they are tubular or solid. Nephrogenic adenomas are usually confined to the lamina propria, covering a single layer of short columnar or subcubical epithelial cells, among which some are shoe-stud-like cells, with round or oval nuclei, visible nucleoli, and most express markers such as CK7, CKH, CKL, and CEA,whereas they do not express the markers P63, PSA, PSAP, GATA3, and CK5/6. Atypical adenomatous hyperplasia is also nodular hyperplasia with clear borders; however, the lesions are often interspersed with a small number of large acinar with a normal structure in the proliferating small glands[31].

沿河地区民居建筑平面形式丰富，正房面阔三间、五间或七间，有相当多采用带檐廊和甩袖的平面形式，部分民居以窑洞为正房；厢房多采用三开间不带甩袖的平面；临时性或附属建筑多为两开间平面。山区民居院内建筑等级差别不大，多为不带甩袖的三开间平面。多开间及带甩袖民居建筑平面的产生与当地不同代际共同生活的居住模式息息相关。以五开间南北向建筑为例，“长辈一般住东边三间，中间会有一个小厅，晚辈住西边两间（图10）。”1）甩袖的做法可以增加室内空间，前后墙一般都会砌筑小土炕，两炕之间用土灶或火炉联系，或者可将土灶砌筑在室外檐廊尽端。

CONCLUSlON

In daily clinical practice, immunohistochemical markers are relied upon to help determine when lesions are morphologically atypical or when cellular heterogeneity occurs. Moreover, prostate basal cells are not considered myoepithelial cells[22], contrary to the notion of the myoepithelial origin of salivary gland myoepithelial cells, since they do not have actin filaments. S100 protein and smooth muscle actin are not expressed in normal prostate basal cells[23,24]; in contrast, the presence of the S100 protein and SMA immunoreactivity in basal cells of sclerosing adenopathy suggests that they present myoepithelial differentiation, a characteristic feature based on which sclerosing adenopathy is diagnosed. In addition, some scholars have confirmed the existence of microfilaments in the cytoplasm of basal cells of sclerosing adenopathy using electron microscopy, which is consistent with the presence of actin filaments[25]. In rare cases, S100 protein immunoreactivity can be seen in prostate basal cell hyperplasias, such as adenoid basal cell carcinoma, adenoid cystic carcinoma, and atypical basal cell hyperplasia[26]. In addition, we have recently found that D2-40 is a sensitive marker of prostate basal cells[27]; therefore, D2-40 and the combination of P63 and cytokeratin can be used to differentiate sclerosing adenopathy from prostate cancer. However, in practice, due to the severe extrusion of basal cells and myoepithelial cells, the immunohistochemical expression results are not ideal, and some sclerosing adenopathy cases will express P504S to varying degrees, overlapping with the immunohistochemistry results of patients with prostate cancer, posing great challenges during pathological diagnosis.

Sclerosing adenopathy of the prostate is a morphological abnormality with characteristic histological features and immunohistochemical profiles. All the available evidence indicates that it is a benign condition that does not require treatment and is not a precancerous condition of prostate cancer. It is important to note, however, that many of the cases encountered to date have had a short follow-up period, and that it may often co-exist with other unrelated cancers in older men. The pathogenesis of this lesion is unclear, but its most striking feature seems to be the ability of cells to differentiate and proliferate. Studying and better understanding the features of sclerosing adenopathy should lead to its appropriate conservative management.

ARTlCLE HlGHLlGHTS

Research motivation

Sclerosing adenopathy of the prostate is a morphological abnormality with characteristic histological features and immunohistochemical profiles. All the available evidence indicates that it is a benign condition that does not require treatment and is not a precancerous condition of prostate cancer. It is important to note, however, that many of the cases encountered to date have had a short follow-up period, and that it may often co-exist with other unrelated cancers in older men. The pathogenesis of this lesion is unclear, but its most striking feature seems to be the ability of cells to differentiate and proliferate. Studying and better understanding the features of sclerosing adenopathy should lead to its appropriate conservative management.

Research objectives

This study explores the clinicopathological features, diagnosis, and immunohistochemical phenotypes that distinguish prostate sclerosing adenopathy from other conditions. We believe that our study makes a significant contribution to the literature because we show that this condition is benign, does not require treatment, and is not a precancerous condition of prostate cancer. However, notably, many of the cases encountered to date have had a short follow-up period, and this condition may often co-exist with other unrelated cancers in older men.

Research methods

The clinical data, laboratory tests, pathological morphology, and immunohistochemical phenotypes of 12 cases of prostatic sclerosing adenopathy were retrospectively analyzed, and the relevant literature was reviewed.

Research results

The authors summarized the age, clinical symptoms, medical history, serum total prostate-specific antigen (PSA) value, surgical findings, surgical methods, follow-up time, and follow-up results of 12 patients with prostate sclerosing adenopathy in detail (Table 1). The results of the study showed that the patients were all elderly men, with an average age of 71.7 years. The patients had symptoms of hematuria, frequent urination, urgency, and dysuria to varying degrees. Different degrees of prostate hyperplasia was seen during digital rectal examination and surgery, and the bladder was the most common. Lateral lobe hyperplasia is predominant. The mean postoperative follow-up time was 27.6 mo,and only 1 patient died of bladder cancer. In addition, 11 of the 12 patients had PSA values within the normal reference range. From the above description, it is not difficult to find that the clinical features of sclerosing adenopathy of the prostate are similar to those of benign prostatic hyperplasia and prostate cancer, and most of the patients' PSA values are Within the normal range, suggesting that sclerosing adenopathy may be a benign lesion. Pathologically, the lesions are very complex, with single or mixed glandular tubular, cord-like and linear structures, and focal distribution in benign prostate glands.Unlike prostate adenocarcinoma, immunohistochemical Expression of the basal cell (such as P63,CK5/6) and myoepithelial (Calponin, S100, SMA) markers, provides a very meaningful value for the identification of the two. In practice, when it is difficult to identify prostate sclerosing adenopathy and prostate cancer, we can use immunohistochemical markers to distinguish them. In addition, we can also use immunohistochemical PSA, and PSAP to identify sclerosing adenopathy and other neoplastic lesions such as nephrogenic adenoma. The above pathological characteristics can provide effective help for the follow-up in-depth study of the prostate. However, even though we performed a comprehensive systematic analysis of sclerosing adenopathy of the prostate, this study has some limitations. First,although we predicted a certain relationship between sclerosing adenopathy of the prostate and PSA values, there is still a lack of direct evidence for the two relevance of the person. Secondly, the sample size of this study is too small, and it is necessary to further supplement the sample size and explore it in depth. Finally, whether sclerosing adenopathy is a precancerous lesion of prostate cancer also lacks direct evidence to further prove. These issues need to be further explored in future work.

陈颐磊驻足，脱下帽子，交与副官，先是给孔圣人三鞠躬，又给孔守真鞠了一躬。嘴里喃喃念到：孔圣人，国难当头，玉石俱焚，借宝地办几件大事，失敬失敬。

Research conclusions

The objective is to investigate the clinicopathological features, diagnosis, and immunohistochemical phenotypes that distinguish prostate sclerosing adenopathy from other conditions.

Research perspectives

In 1983, Chen and Schiff reported a prostate lesion that they considered most notably similar to an adenomatous tumor[5]. Therefore, it was named sclerosing adenopathy[6]. Sclerosing adenopathy of the prostate, first reported in 1987 by Young[7], was previously known as an adenomatous prostate tumor, prostatic pseudoadenoma, and fibroepithelial nodules[8-10]. It was originally used to express the similarity of the lesions to testicular adenomatous tumors but was abandoned due to the recognition that the lesions were of prostatic origin based on the immunoreactivity of PSA in acinar cells. It was subsequently found that sclerosing adenopathy is superficially similar to the breast lesion of the same name, is composed of prostate epithelial cells rather than mesothelial cells, and is characterized by glandular hyperplasia of varying sizes in the intercellular substance[11-14]. Sclerosing adenopathy is well characterized both immunohistochemically and ultrastructurally, and there are currently several case reports and small series of this lesion[15,16].

FOOTNOTES

Feng RL and Tan ZY contributed equally to this work; Feng RL, Tao YP, Fu S, and Wang HF designed the study; Tan ZY and Tao YP contributed new reagents and analytical tools; Tao YP, Fu S and Wang HF analyzed data; Feng RL and Tan ZY wrote the manuscript. All authors have read and approved the final manuscript.

The study was authorized by the Ethics Committee at The Second Affiliated Hospital of Kunming Medical University.

The authors declared that no competing interests exist.

结合恩格斯为《政治经济学批判》所作的书评以及马克思自己在《资本论》第一卷第二版跋中的说法，“我公开承认我是这位大思想家的门人，而在关于价值学说的那一章，我在这里那里用黑格尔特有的表现方法来显示一番”(马克思，1963：第二版的跋XXIII)。必须承认：马克思对于黑格尔辩证法的批判性改造，最直接的表现就是“政治经济学批判”的第一章“商品”。然而，从《政治经济学批判》的“商品”章到《资本论》的“商品”章，虽然在主题与内容上存在连续性，都是叙述从商品向货币再到资本的辩证过渡这一最为抽象的内容，但是二者之间却存在细微的本质的差别。

On reasonable request, the corresponding author will provide the analyzed datasets generated during the study.

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运动训练对中老年冠心病患者PCI术后运动能力、心肺功能和认知功能的作用······················赵梦飞 毛立伟 季 鹏 胡树罡 高 苗 王 磊 (2,198)

China

Run-Lin Feng 0000-0002-3532-9450; Yan-Ping Tao 0000-0001-8868-7166; Zhi-Yong Tan 0000-0002-7771-0962; Shi Fu 0000-0003-4023-7195; Hai-Feng Wang 0000-0002-0891-5120.

Ma YJ

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Ma YJ