Leydig cell tumors belong to the group of sex cord-stromal tumors of the testes and constitute only 1-3% of all testicular neoplasms, making them a rare occurrence in clinical practice [1] [2] [3]. Leydig cells are located in the interstitium, and are responsible for the production of testosterone, but also estrogen to a lesser extent, which is why signs and symptoms are often related to the excess effects of androgen hormones caused by abnormal cellular proliferation [1] [3] [4]. The tumor is diagnosed in two age groups - in prepubertal boys, and more commonly, in adults between 30-60 years of age [1] [3] [5] [6]. In children, excess testosterone results in the development of precocious puberty - the early growth of pubic hair, the penis and the musculoskeletal system [1] [4]. On the other hand, increased estrogen production will induce feminization (gynecomastia and tenderness of the breasts, as well as feminine hair distribution) [1]. This clinical presentation is also seen in adults, but they are accompanied by loss of libido, impotence, erectile dysfunction, infertility, and most importantly, an enlarged testicle [1] [4]. Studies have confirmed the rare appearance of a bilateral testicular mass, but in the vast majority of patients, a unilateral and sometimes painful intratesticular mass is typical for Leydig cell tumors [1] [2] [4]. It is exclusively benign in infants, but the potential for malignant transformation in adults, seen in 10% of cases, implies that early recognition of the tumor is vital, as dissemination through the retroperitoneal lymph nodes into the liver, the lungs, and the skeletal system has been observed [1] [5] [6]. Thus, signs and symptoms that indicate a disbalance in androgen hormones should alert the physician to conduct a meticulous workup.

• Precocious Puberty

  We report two boys who developed true precocious puberty after surgical treatment of a Leydig cell tumor of the testis that presented peripheral precocious puberty. [frontiersin.org]

  In children, excess testosterone results in the development of precocious puberty - the early growth of pubic hair, the penis and the musculoskeletal system. [symptoma.com]

  Clinical presentation is testicular mass, pain and hormone alteration such as precocious puberty and gynecomastia. We present one case of LCT and his conservative management after an incidental finding. Literature is reviewed. [ncbi.nlm.nih.gov]

• Pathologist

  Thus, this was a very rare case which created a challenge for pathologists, especially on frozen sections. © 2015 by the Association of Clinical Scientists, Inc. [ncbi.nlm.nih.gov]

  ©1984International Society of Gynecological Pathologists Related Articles [journals.lww.com]

  These factors are tumor grade and a particular pattern or appearance that the pathologist can identify: 1. Well-differentiated (grade 1) 2. Intermediately differentiated (grade 2) 3. Poorly differentiated (grade 3) 4. [ovariancancer.about.com]

• Falling

  Leydig cell tumours fall in the [[w:Sex cord-stromal tumour|sex You cannot overwrite this file. [commons.wikimedia.org]

  Serum AFP levels were measured at follow up, which showed drastic fall after treatment. Figure 4 shows the fall of AFP level during her treatment. Serum testosterone was normal. Her virilization signs have reduced in 6 months follow up. [npplweb.com]

  There are cases which fall into gray zone in between benign and malignant ends of the spectrum and need to be followed up carefully for metastasis and pose difficult diagnostic problem on histology. [ijpmonline.org]

  The cells usually had pale to occasionally densely eosinophilic cytoplasm, but 6 tumors were composed of cells with prominent foamy cytoplasm, falling in the category of "lipid-rich" Sertoli cell tumor, and one had cells with clear non-foamy cytoplasm [thedoctorsdoctor.com]

• Weakness

  AFP is negative and cytokeratins are negative or weak. [path.upmc.edu]

  […] cancers are not as dangerous as germ cell cancers, because they are not as likely to spread or metastasize The cause of Leydig Cell Tumor of the Testis (a testicular cancer type) is generally unknown, although several risk factors, such as family history, weak [dovemed.com]

  Immunoreactivity was graded as weak/strong (W/S), and the proportion of strong staining cells was coded as follows: S1 = 50%, respectively. [thedoctorsdoctor.com]

• Anemia

  Abstract A 50-year-old peri-menopausal woman presented with hard palpable mass on her lower abdomen and anemia from heavy menstrual bleeding. [ncbi.nlm.nih.gov]

  Indications for Leydig Cell Tumor of the Testis include: Loss of libido Overdevelopment of breasts in males (gynecomastia) Breast pain, especially if accompanied by enlargement Trouble breathing Headache Low blood pressure Anemia Testicular pain, lump [dovemed.com]

• Cough

  The case of malignant LCT was seen in another 47 year old male who presented with cough. On examination, a testicular swelling was found, and after orchidectomy, he was diagnosed to have malignant LCT on histopathologic examination. [ncbi.nlm.nih.gov]

  […] accounts for less than 0.2% of all testicular cancers as evidenced by metastatic spread and poor survival. [3] We report an interesting case of malignant LCT with mediastinal and lung metastasis in a 38-year-old man who presented with a complaint of dry cough [sjkdt.org]

• Pneumonia

  A chest radiograph showed pneumonia in whole lung and CT showed multiple nodules and diffused ground glass opacities in both lung fields. Lung biopsy confirmed a diagnosis of Leydig cell tumor with lung metastasis. [ncbi.nlm.nih.gov]

  Two patients with Stage II disease developed post-operative complications of acute kidney injury (n = 1) and pneumonia (n = 1). Median length of stay was 8 days (range = 6-11). [springerplus.springeropen.com]

• Hemoptysis

  […] and E, ×400); (c) immunoperoxidase stain for vimentin showing strong cytoplasmic positivity and the nucleus remains unstained (IHC, ×100) Click here to view Case 2 We report another case of a 47 year-old man who presented with dry cough and later with hemoptysis [ijpmonline.org]

• Vomiting

  Case presentation We report a case of an 18 year old unmarried girl who presented to us as hoarseness of voice and excessive hair growth since 3 years and pain abdomen with vomiting since ten days. [npplweb.com]

• Hypertension

  Quantitative analyses for the serum peptides and their clinical utility for pregnancy-induced hypertension. [hosp-urayasu.juntendo.ac.jp]

• Testicular Mass

  Hereby, we present the case of two brothers affected by 11-β hydroxylase deficiency and presenting with bilateral testicular masses. [ncbi.nlm.nih.gov]

  Studies have confirmed the rare appearance of a bilateral testicular mass, but in the vast majority of patients, a unilateral and sometimes painful intratesticular mass is typical for Leydig cell tumors. [symptoma.com]

• Amenorrhea

  A 33-year-old woman presented to an endocrinology clinic with a 5-year history of secondary amenorrhea. 2 years before presentation, she had noticed progressively worsening signs of virilization. [ncbi.nlm.nih.gov]

  […] ovary Disease definition Malignant Sertoli-Leydig cell tumor of ovary is a rare malignant sex cord stromal tumor of ovary (see this term) occuring typically in young women and characterized by manifestations of androgen excess (hirsutism, hair loss, amenorrhea [orpha.net]

• Cryptorchidism

  Besides, Leydig cell tumors are described in cases of KS, but never documented in the Klinefelter variants.We describe a young adult of 22 years old who presented with hyper gonadotropic hypogonadism, delayed puberty and bilateral micro-cryptorchidism [ncbi.nlm.nih.gov]

  A few are seen in cryptorchidism. Presents a painless testicular mass. Tumor cells may produce androgen, estrogens or both and presents with gynecomastia or precocious puberty; symptoms usually regress with excision. [auanet.org]

  Males typically have cryptorchidism or hypospadias. Treatment & Prognosis Radical orchiectomy is the primary treatment of choice. [health.am]

  Furthermore, the patient has a family history of cancer and at birth he had cryptorchidism. These data require careful monitoring and correct therapeutic decisions. [bmcresnotes.biomedcentral.com]

• Testicular Pain

  In the other patients diagnosis was made by ultrasound performed for testicular pain (4 patients, 16.6%) or the appearance of gynecomastia (3 patients, 12.5%). Frozen section examination was done in 20 of 24 patients (83%). [ncbi.nlm.nih.gov]

  Indications for Leydig Cell Tumor of the Testis include: Loss of libido Overdevelopment of breasts in males (gynecomastia) Breast pain, especially if accompanied by enlargement Trouble breathing Headache Low blood pressure Anemia Testicular pain, lump [dovemed.com]

• Testicular Disease

  Schweyer, Tumoren des Gonadenstromas, Der Pathologe, 2014, 35, 3, 245 CrossRef 11 Giorgio Bozzini, Stefano Picozzi, Dario Ratti, Stefano Casellato, Luca Carmignani, Long-term follow up with sparing surgery for testicular diseases: A safe choice in benign [onlinelibrary.wiley.com]

The initial diagnosis of a testicular tumor can be rather easily made with a proper physical examination that will palpate a mass and a detailed patient history that will assess the course and progression of symptoms [6]. However, a mass may not always be present, especially in the beginning of tumorigenesis. For this reason, a detailed laboratory workup is necessary. In all patients in whom signs of excess androgen production are present, serum values of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, estradiol, progesterone, adrenocorticotropin hormone (ACTH) and cortisol should be evaluated [1] [6]. Testosterone levels will almost always be raised in the setting of precocious puberty, whereas increased estrogen and estradiol are seen in patients who suffer from feminization and gynecomastia [1] [6]. It should be noted that tumor markers for testicular tumors, including alpha-fetoprotein (AFP), beta-human chorionic gonadotropin (β- hCG), lactate dehydrogenase (LDH) and placental alkaline phosphatase (PALP) are negative, as they are only useful for germ cell testicular tumors [1] [3] [4] [6]. In addition to clinical and laboratory studies, imaging procedures, such as ultrasonography (US) of the testes, is the next step in confirming the diagnosis [2] [3] [6]. A homogeneous hypoechoic appearance on US is the hallmark of a benign Leydig cell tumor, but if the lesion is heterogeneous, malignant transformation should be suspected, in which case computed tomography (CT) and magnetic resonance imaging (MRI) of the pelvis and abdomen are recommended to exclude metastatic spread [1] [2] [3] [4] [6]. A definite diagnosis is made after a biopsy and subsequent histopathological examination with immunohistochemistry [1]. α-Inhibin, but also calretinin and Melan-A are reliable markers for differentiation between sex cord stromal tumors and germ cell tumors of the testes [1].

• Polyps

  腎血管筋脂肪腫 22　Autosomal dominant polycystic kidney disease：常染色体優性多嚢胞腎症 Ⅱ．腎盂・尿管・膀胱 23　Infiltrating urothelial carcinoma of the renal pelvis： 腎盂原発浸潤性尿路上皮癌（腎実質破壊性尿路上皮癌） 24　Lymphoepithelioma-like carcinoma of the renal pelvis： 腎盂のリンパ上皮腫様癌 25　Fibroepithelial polyp [igaku-shoin.co.jp]

We report on the--to our knowledge--first treatment experiment with imatinib in a patient with metastatic Leydig cell tumor. Unfortunately, the tumor progressed during treatment. [ncbi.nlm.nih.gov]

Treatment Surgical removal of the affected ovary is the most common treatment -- and usually all the treatment that is necessary. That's because more than 75% of these tumors are found early (grade I) and in only one ovary. [ovariancancer.about.com]

Abstract Malignant Testicular Leydig Cell tumors (leydigomas) are extremely rare to occur and mostly carry a bad prognosis. [ncbi.nlm.nih.gov]

Typically, in a vast majority of cases, the prognosis is excellent, since it is usually a benign tumor In rare case of a malignancy, the prognosis may depend upon several factors including the stage of the tumor and health status of the individual Generally [dovemed.com]

Outlook (Prognosis) Prognosis of SLCT depends on the stage and degree of differentiation of the tumor. Since these tumors are typically benign and their growth is slow, outlook is generally very positive. [knowcancer.com]

It is recommended that all endocrine, nutritional, neoplastic, chromosomal, and drug etiologies of gynecomastia be investigated before surgical resection of the enlarged breasts. [popline.org]

Etiology Mutations in the DICER1 (14q32.13) gene have been found to be a susceptibility factor for SCST, particularly in malignant Sertoli-Leydig cell tumor of ovary. [orpha.net]

(Etiology) The cause of Leydig Cell Tumor of the Testis is unknown. [dovemed.com]

[…] are malignant Sites Origin from testis is demonstrable in most cases Rarely originates from epididymis ( Andrologia 2013;45:430 ) Pathophysiology Produce testosterone, dehydroepiandrosterone and androstenedione, which cause symptoms described below Etiology [pathologyoutlines.com]

Leydig Cell Tumors Epidemiology & Pathology Leydig cell tumors are the most common non-germ cell tumors of the testis and account for 1-3% of all testicular tumors. [health.am]

Epidemiology 1–3% of all testicular tumors. Most common in boys (5–10 years old) and in adults aged 30–60 years. Pathology of the Leydig cell tumor Small yellow-brown tumors, sharply circumscribed in the testicular tissue. [urology-textbook.com]

Summary Epidemiology Age related incidence rate was found to be 1 per 500,000 women. Sex cord stromal tumors constitute about 5% of ovarian malignancies. [orpha.net]

Epidemiology Leydig cell tumours constitute 1-3% of all testicular tumours. Clinical features In children, they may present with isosexual pseudoprecocity. In adults, they present with a mass and/or gynaecomastia. [e-immunohistochemistry.info]

Definition / general Most common sex cord stromal tumor; recapitulates normal development and evolution of Leydig cells Epidemiology 1 - 3% of testicular tumors No predilection based on ethnicity or race ~10% are malignant Sites Origin from testis is [pathologyoutlines.com]

Signs and Symptoms (Pathophysiology) Symptoms can include infrequent or no menstrual periods, the development of facial hair, a hoarse voice, increased muscle mass, acne, and clitoromegaly. [knowcancer.com]

[…] and evolution of Leydig cells Epidemiology 1 - 3% of testicular tumors No predilection based on ethnicity or race ~10% are malignant Sites Origin from testis is demonstrable in most cases Rarely originates from epididymis ( Andrologia 2013;45:430 ) Pathophysiology [pathologyoutlines.com]

^ a b "Leydig Cell Tumors: Practice Essentials, Background, Pathophysiology". 2016-10-27. ^ Biegel, L. B.; Liu, R. C.; Hurtt, M. E.; Cook, J. C. (1995). [en.wikipedia.org]

Background Pathophysiology A German anatomist, Franz Leydig, first described Leydig cells in 1870. [9] Leydig cells are located within the interstitium of the testis, between the seminiferous tubules, and produce testosterone in response to luteinizing [emedicine.medscape.com]

Pathologists have to be familiar with the diagnostic histopathologic features, immunohistochemical panel of this tumor, and its principal differential diagnoses to prevent tumor misdiagnosis. [ncbi.nlm.nih.gov]

[…] the adrenogenital syndrome (which may contain fat) and may prevent misdiagnosis of a LCT with spindle cells as a sarcoma or unclassified sex cord-stromal tumor. [journals.lww.com]

A long term follow-up is needed to prevent possible late relapse. © 2008 Sociedad Española de Andrología. [mendeley.com]

Removal of the testis Debulking surgery to reduce tumor size, followed by chemotherapy Clotting the vessels in the tumor (embolization) Chemotherapy Radiotherapy Undertaking treatment of underlying conditions How can Leydig Cell Tumor of the Testis be Prevented [dovemed.com]

1. Al-Agha OM, Axiotis CA. An in-depth look at Leydig cell tumor of the testis. Arch Pathol Lab Med. 2007;131(2):311-317.
2. Gheorghisan-Galateanu AA. Leydig cell tumors of the testis: a case report. BMC Res Notes. 2014;7:656.
3. Suardi N, Strada E, Colombo R, et al. Leydig cell tumor of the testis: presentation, therapy, long-term follow-up and the role of organ-sparing surgery in a single-institution experience. BJU Int. 2009;103(2):197-200.
4. Albers P, Albrecht W, Algaba F, et al. Guidelines on Testicular Cancer: 2015 Update. Eur Urol. 2015;68(6):1054-1068.
5. Thambi R, Pothen L, Emmanuel KM, Vijayalakhmi A. Leydig cell tumor of testis with indeterminate features. Indian J Cancer. 2015;52(4):529-530.
6. Sönmez N, Ton Ö, Arısan S, Kılınç F, Eken K, Güney S. Bilateral Leydig cell tumor of the testis: a case report. Contemp Oncol (Pozn). 2012;16(4):356-359.