You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


INTRODUCTION
============

Testicular regression syndrome (TRS) or 'vanishing testis' is acondition which is considered to be due to the subsequentatrophy and disappearance in fetal life of an initially normal testis([@ref1]). The presence of spermatic cord structures is evidence of thepresence of the testis in early intrauterine life. When associatedwith a blind-ending spermatic cord, this entity is named as the''vanishing testis syndrome'' in the urology literature ([@ref2]) or TRSin the pathology literature ([@ref3]), since anatomically it ischaracterized by a rudimentary spermatic cord with absence ofmacroscopically identifiable testicular tissue. This absence of atestis in an otherwise normal 46XY male is usually unilateral andis assumed to be a consequence of intrauterine or perinataltorsion or infarction.

PREVALENCE
==========

TRS or vanishing testis syndrome may be seen in less than 5% of cryptorchidism cases ([@ref4]). Cryptorchidism is not an uncommon condition, with about 3% of full-term neonates having an incompletely descended testis at birth - a prevalence decreasing to about 1% by the age of 1 year ([@ref5]). The testis is nonpalpable in 10% to 20% of cryptorchidism cases, and of these, TRS accounts for 35% to 60% ([@ref6],[@ref7],[@ref8],[@ref9],[@ref10]).

Absence of testis, intra-abdominal testis, inguinal or intra-abdominal vanishing testis are reasons for nonpalpable testis ([@ref11],[@ref12]). Vanishing testis is more common than testicular agenesis in patients with nonpalpable testis ([@ref13]). It is assumed that 40% of this subpopulation harbors a vanished testis, thus as many as 1 male per 1250 may be affected ([@ref14]). An 8-year review of cases of nonpalpable testes at the Children's Hospital of Philadelphia showed that 41% of 447 affected boys (181 patients) had an atrophic remnants or absent testis ([@ref15]). Therefore, it seems that this syndrome is a common phenomenon; however, the optimal management of this condition remains unclear.

Lou and co-workers reported a series of patients with nonpalpable testes, of which 64% had cryptorchidism. Of these, 22.5% had complete absence of testis, vas deferens and epididymis, 15% had only a blindly-ending vas deferens, and 67.5% had a blindly-ending vas deferens with blood vessels in the inguinal canal ([@ref16]).

ETIOLOGY AND PATHOPHYSIOLOGY
============================

Hormonal and mechanical factors have been implicated in the descent of the testes, but a specific factor has not yet been identified for the pathogenesis of undescended or nonpalpable testis. Although the etiology, pathophysiology, and prognosis of TRS and that of the viable undescended testis might be different, TRS is thought to be the result of late antenatal or perinatal vascular thrombosis, torsion, or endocrinopathy ([@ref6],[@ref17],[@ref18],[@ref19]). Recent studies strongly support a vascular accident and antenatal torsion theory rather than an endocrinopathy. The incompletely descended testis is thought to be more prone to torsion during the fetal and perinatal period ([@ref1]). This hypothesis is supported by the presence of hemosiderin-laden macrophages in surgically removed specimens ([@ref20]), consistent with the venous congestion and hemorrhagic infarction secondary to torsion of a structure. On the other hand, trauma to the intrascrotal testis perinatally has been suggested as a risk factor ([@ref21]). Earlier descent of the left testis may account for the side predilection. Of interest, the oldest patient in the literature was a 26-year-old man who presented with markedly small gonad 11 years after orchidopexy for cryptorchidism and this was removed as an atrophic remnant ([@ref4]).

Histopathological comparison of the contralateral testis from patients with unilateral vanishing testis and undescended testis was performed by Huff et al ([@ref22]) and they showed that the patients with an absent testis did not exhibit abnormal, lower germ cell counts suggestive of an endocrinopathic condition.

Testicular regression has been observed in association with genetic abnormality such as microdeletion of the Y chromosome and boys with persistence of Mullerian duct structures have been found to undergo TRS after birth ([@ref23]). Additionally, early loss of both testes in the antenatal period can result in genital ambiguity. However, an association between genetic factors necessary for normal testicular descent and anorchia/vanishing testis syndrome has not been established ([@ref24]).

In the vast majority of cases, TRS appears to be a sporadic occurrence, and the patients are otherwise normal with no significant family history. However, there are now several reports of TRS either in association with other defects, including severe mental retardation in chromosomally normal siblings, or occurring in several members of the same family, suggesting a possible genetic basis for the condition in some subjects ([@ref25],[@ref26]).

CLINICAL PRESENTATIONS
======================

The clinical manifestations of testicular regression can be associated with the embryological sequence and can be classified into early and late embryonic, and early, mid and late fetal or early neonatal events ([@ref18]). This disorder may be unilateral or, less commonly, bilateral, with partial or complete absence of testicular tissue and, in the majority of cases, with normal external genitalia ([Figure 1](#f1){ref-type="fig"}).

TRS patients usually exhibit a male phenotype. However, although uncommon, the phenotypic spectrum associated with TRS may vary from normal male with unilateral nonpalpable testis through phenotypic male with micropenis, to phenotypic female ([@ref27]). The phenotype probably depends on the extent and timing of the intrauterine accident in relation to sexual development. These genetically male individuals (46, XY) present with unilateral or bilateral absence of detectable testis structures and Mullerian duct system ([@ref3],[@ref28],[@ref29]) ([Figure 2](#f2){ref-type="fig"}).

Embryonic TRS has been considered to be part of the clinical spectrum of partial 46, XY gonadal dysgenesis ([@ref30]). Most of the patients with TRS exhibit features of intersex or severe micropenis in association with complete uni- or bilateral regression of testicular tissue. The degree of masculinization of the internal and external genitalia depends on the duration of testicular function prior to its loss. Variable degrees of sexual ambiguity have been reported in familial cases, but the nature of the underlying defect is still not clear. Recently, a novel heterozygous missense mutation (V355M) in SF1 gene was found in one boy with a micropenis and TRS ([@ref31]).

DIAGNOSIS
=========

Clinically, a unilateral nonpalpable testis may be associated with TRS, cryptorchidism, retractile testis, or testicular agenesis. Laparoscopy is widely used to distinguish among these conditions while avoiding open abdominal surgery. When, in the setting of a nonpalpable testicle, vas deferens and spermatic vessels are visualized exiting the internal inguinal ring on laparoscopy, a groin exploration may be carried out to identify and remove the testicular tissue remnant associated with a vanished testis ([@ref32]).

Diagnosis of TRS is based on a clinically nonpalpable testis with a blind-ending spermatic cord located within the retroperitoneum or exiting a closed internal inguinal ring. Usually, a small fibrotic nodule is found at the end of this spermatic cord. Fibrosis, dystrophic calcification, and hemosiderin deposition in association with identifiable testicular/paratesticular structures are also features of TRS ([@ref33]).

A number of criteria have been proposed to ascertain the diagnosis of the vanishing testis syndrome. These criteria are: 1) no testis palpated during an examination under anesthesia, 2) visualizing blind-ending spermatic vessels within the retroperitoneum or visualizing spermatic vessels and vas deferens exiting a closed internal inguinal ring.

HISTOPATHOLOGICAL CHARACTERISTICS
=================================

In gross descriptions of the specimens, a spermatic cord with a small mass of firm, fibrotic tissue at one end, as well as elements of the vas deferens, spermatic artery and venous plexuses have been reported.

Smith et al ([@ref20]) in their study have observed that histologically, the distal expansion of most of the specimens was composed of dense fibrovascular tissue in the absence of seminiferous tubules or normal testicular elements; scattered foci of calcification and brown pigment were present. The finding of dystrophic calcification and hemosiderin deposition, in the absence of viable testicular tissue but in the presence of relatively normal spermatic cord elements, supports the hypothesis of remote infarction leading to unilateral and occasionally bilateral anorchia. The young age of the patients and the history of an absent testis from birth are supportive of in utero accident. On the other hand, the above-mentioned histopathological findings are consistent with the hypothesis that in utero torsion may be an underlying factor in the pathogenesis of TRS.

Histopathologic examination has confirmed the presence of germ cells in 11% of testicular remnants. Viable germ cells or seminiferous tubules have been reported in 0 to 16% of excised testicular remnants ([@ref7],[@ref13],[@ref33]). Although the precise fate of these remnants is uncertain, the presence of germ cells at least indicates a potential for germ cell--derived neoplasia. In addition, intratubular germ-cell neoplasia in a testicular remnant has been reported in at least one case ([@ref6]).

RISK OF MALIGNANCY
==================

Le Conte first recognized the tumor potential of the undescended testis in 1851 ([@ref34]). Since then, the increased risk of malignant degeneration of the cryptorchid testis has been estimated to be 20 to 46 times greater than that of the general population ([@ref35]). However, the location of these testes confers a significantly different degree of risk. Intra-abdominal testes are six times more likely to develop a testis tumor than the undescended testis located in an inguinal position ([@ref36]). The infrequent finding of seminiferous tubules or other germinal tissue in the surgical specimens of patients with inguinal vanishing testes also supports the contention that the risk of malignant degeneration is quite low in this population. Cendron et al ([@ref10]) recently presented a histologic evaluation of 25 vanishing testis specimens and noted no identifiable testicular elements in any of these cases.

There is a high risk of malignant transformation in intraabdominal testes especially when associated with external genitalia anomaly and chromosomal anomaly. A testis tumor may develop even after a successful orchiopexy for undescended testis. However, to date, it is not clarified whether vanishing testis and true undescended testis have same etiopathogenesis and risks. The concern in this situation raises the question about the malignant degeneration of residual germinal tissue in the testicular remnants.

Theoretically, presence of testicular tissue in testicular remnants indicates a potential for malignancy in the long term. Histopathological examination of testicular remnants in nonpalpable testes demonstrated presence of seminiferous tubules and viable germ cells in 0 to 16% of the reported series ([@ref4],[@ref6],[@ref10],[@ref36]). Based on these observations, some authors suggest routine removal of testicular remnant tissue to prevent malignant transformation, but others did not accept this indication because they could not find testicular tissue in testicular remnants.

LAPAROSCOPIC EXPLORATION
========================

Nonpalpable testes are a heterogeneous group; their assessment for differential diagnosis needs to include subsets of absent testes, intra-abdominal testes, and testes or testicular remnants located in the inguinal canal that were missed on physical examination. Because of this heterogeneity, laparoscopy has emerged as a useful tool in the localization and assessment of the nonpalpable testis. Various series report success rates of 90% to 95% in the localization of nonpalpable testes with laparoscopy ([@ref37],[@ref38],[@ref39]).

While diagnostic laparoscopy is a safe and effective method of investigating patients with a nonpalpable testis, a simpler, less invasive and less costly initial step is to first explore the scrotum. Failure to detect the gonad in the scrotum in a patient with spermatic cord duct structures may occur in two situations: the testis has regressed or the surgeon has not yet localized it. The pathologist may play a critical role in the management of these patients. 95% of the testes are localized at or below the internal inguinal ring, therefore, pathologic evaluation of the spermatic cord and confirmation of the testis as regressed in tissues removed at primary inguinal exploration can reassure the surgeon of the correct diagnosis. In the majority of the cases, this pathologic evaluation can also eliminate the necessity for further surgical intervention or for radiologic evaluation.

Some authors argue that routine exploration of the groin is required only if laparoscopy reveals an open internal ring with normal vessels, while this exploration is unnecessary if the findings show hypoplastic vessels entering a closed ring ([@ref19]). Others similarly note that no further action is required if blind-ending vessels are found in the abdomen ([@ref6]).

MANAGEMENT
==========

There is controversy regarding the optimal management of the testicular remnant in cases of TRS. Some urologists recommend surgical exploration, either laparoscopically or via inguinal/scrotal approach, whereas others believe that these procedures are unnecessary ([@ref10],[@ref33],[@ref39]). The variable reports of viable germ cell elements found within the testicular remnants may be the reason for the differences in the opinion concerning the proper management. Previous studies have reported an incidence of 0% to 16% of viable germ cell elements within the remnants ([@ref4],[@ref6],[@ref10],[@ref36]). Some authors recommend surgical fixation of the contralateral testis to prevent torsion in the remaining testicular tissue ([@ref18]). Inguinal exploration could be postponed until the implantation of testicular prosthesis which is a cosmetic option for patients with unilateral or bilateral loss of testes. Thus, testicular prosthesis implantation can be performed as a first inguinal operation and testicular remnants can be removed during the same session ([@ref36]).

CONCLUSION
==========

The histological evaluation of inguinal testicular remnants suggests that these testes became ischemic and atrophied during descent in utero or shortly after birth. The optimal management of the testicular remnants is controversial. Some authors recommend routine excision of remnants, whereas others believe that this is superfluous. A review of the current literature has not identified any report of testicular germ cell tumors which appear to arise from TRS.

![A testicular "remnants" located by the scrotal exploration that was removed from the scrotum with the atretic spermatic cord. Atrophic testicular tissue described as a dense matrix of fibrous connective tissue with widely separated atrophic seminiferous tubules (From the authors' center)](JCRPE-4-116-g1){#f1}

![Moderate undervirilization in a 46XY infant presenting with a micropenis with minimal scrotal development and bilateral cryptorchidism (final diagnosis was testicular regression syndrome) (From the authors' center)](JCRPE-4-116-g2){#f2}