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The potential for the formation of teratomas or other neoplasms is a major safety roadblock to clinical application of pluripotent stem cell therapies. Preclinical assessment of the risk of tumor formation in this context poses considerable scientific and regulatory challenges, especially because animal xenograft models may not properly reflect the long-term tumorigenic potential of human cells. A better understanding of the biology of spontaneously occurring teratomas and related tumors in humans can help to guide efforts to assess and minimize the potential hazards of embryonic stem cell or induced pluripotent stem cell therapeutics. Here we review the features of teratomas derived experimentally from human pluripotent stem cells and argue that they most closely resemble spontaneous benign teratomas that occur early in both mouse and human life. The natural history and pathology of these spontaneously occurring teratomas provide important clues for preclinical safety assessment and patient monitoring in trials of stem cell therapies.

In April 1946, Archives of Pathology published H. G. Schlumberger's seminal study on anterior mediastinal (AM) teratomas that provided insights into the clinical behavior, pathologic features, and pathogenesis of these enigmatic neoplasms. To review key points of Schlumberger's study, add more recent information, discuss the different types of mediastinal teratoma and germ cell tumors (GCTs), and consider the origin of the neoplasms. Schlumberger's article, PubMed-indexed articles on the topic, and personal observations. Pure teratomas of the AM in children are benign type I GCTs that may dedifferentiate to yolk sac tumor, possibly from embryonic-type neuroectoderm. Mature teratomas in postpubertal patients, comprising ∼95% of GCTs in females but only ∼30% in males, are hybrid type I and type IV teratomas. Such cases show organoid structures and benign cytology. They derive from nontransformed germ cells and lack metastatic potential. Immaturity does not alter the outcome in children. In contrast, many teratomas in postpubertal males are type II GCTs, derived from malignantly transformed germ cells that initially form a primitive GCT, with subsequent teratomatous differentiation. These teratomas, consequently, are components of mixed GCTs and show cytogenetic abnormalities, including overrepresentation of chromosome arm 12p. They are cytologically atypical and less commonly organoid; their most frequent associated GCT is yolk sac tumor, which may be the source of somatic-type malignancies of type II AM GCTs, especially the virtually uniquely associated hematologic malignancies and vascular neoplasms of GCT origin. All AM GCTs are believed to derive from mismigrated germ cells.

Neuroblastoma is rare in the adult population, especially in thoracic or mediastinal locations, with only 25 previously reported cases. We report an additional example of primary thymic neuroblastoma in a previously asymptomatic 71-year-old man with an anterior mediastinal mass who underwent robotic excision with pericardium and adjacent lung. The tumor was a 5.2 cm partially encapsulated, white-tan and rubbery mass with grossly identifiable areas of necrosis (25%) and hemorrhage. Histologically, the specimen showed a rim of adipose tissue and residual thymic tissue with areas of cystic thymic epithelium and prominent lymphoid tissue containing Hassall’s corpuscles. The tumor was composed of uniform, round cells with scant cytoplasm and small nuclei with inconspicuous nucleoli set within a background of conspicuous neuropil. Mitotic figures were easily found. By immunohistochemistry, the tumor cells expressed synaptophysin, chromogranin, NKX2.2 (diffuse, nuclear), GFAP (patchy), SMI31 (neurofilament) (focal, cytoplasmic), and TdT (diffuse, nuclear), while lacking expression of CD99, TTF-1, CK 20, MCPyV, PHOX2B, Olig2, OCT3/4, CD45, CD3 and PAX5. S100 protein was negative in the neuroblastic cells, with scattered positive cells in a vague sustentacular-like pattern. Fluorescence in situ hybridization for isochromosome 12p and EWSR1 gene rearrangement were negative. As thymic neuroblastoma is extremely rare in adults, a neuroblastic tumor of germ cell origin (either primary or metastatic) or spread from a sinonasal tract tumor should be excluded because of differing treatments and prognoses. The properties of these rare neoplasms appear similar to olfactory neuroblastoma rather than pediatric-type neuroblastoma.

Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ . Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair ( κ- value=0.34). The intraobserver κ -value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall κ -value=0.50) was observed ( P =0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.

In 2016 the World Health Organization published a revised classification of testicular neoplasms based upon advances in understanding their pathogenesis and molecular biology. The rationale for this revision and additional clinically relevant observations were the topics of a talk given to the Houston Society of Clinical Pathologists in April 2017. This paper summarizes that talk. To summarize and explain the most important changes to the classification of testicular neoplasms in the World Health Organization 2016 revision. Peer-reviewed published literature and contributions by individuals with expertise in this area that were also reviewed by genitourinary pathologists. Most changes occurred in the germ cell tumor classification, including replacement of the terms and by ; subdivision of the tumors into 2 main categories, those derived from germ cell neoplasia in situ and those not derived from germ cell neoplasia in situ; distinction of germ cell neoplasia in situ from germ cells with delayed maturation and pre-germ cell neoplasia in situ; expansion of the trophoblastic tumor category to include epithelioid trophoblastic tumor and cystic trophoblastic tumor; and substitution of for and its placement in the non-germ cell neoplasia in situ group. Other revisions included eliminating sclerosing Sertoli cell tumor as a distinct entity; the recognition of intratubular hyalinizing Sertoli cell tumor; and acceptance of the role of undifferentiated gonadal tissue in the pathogenesis of gonadoblastoma.

The American College of Radiology (ACR) recommends that polyps < or =5 mm in size not be reported on computed tomography (CT) colonography studies. Patients with 1 or 2 polyps 6-9 mm in size can be offered \"CTC surveillance\" in 3 years in lieu of polypectomy. The aim of the study was to determine the impact of ACR recommendations on resection of high-risk adenoma findings using an endoscopic polyp/histology database. Excluding patients with inflammatory bowel disease (IBD) and polyposis, 10,034 patients underwent colonoscopy and 10,780 polyps were removed from 5,079 patients over a 5-year interval. High-risk adenoma findings were defined as an advanced adenoma (> or =1 cm in size, high-grade dysplasia (HGD), or villous elements) or 3 or more adenomas of any size, per postpolypectomy surveillance recommendations. A total of 5,079 patients (51%) had at least 1 polyp, 2,907 (29%) had at least 1 adenoma, and 1,001 (10%) had high-risk adenoma findings, of these, 293 (29%) had either 3 adenomas < or =5 mm in size (n=267) or an advanced adenoma < or =5 mm in size (or both) and no polyp of any histology > or =6 mm in size. There were 774 patients with 1 or 2 polyps 6-9 mm in size and no polyps of any histology > or =10 mm in size. Of these patients 184 (18% of the patients with high-risk adenomas) had either 3 or more adenomas < or =9 mm in size (n=149) or an advanced adenoma < or =9 mm in size (or both findings). There were 2,174 patients age > or =50 years with the primary indication of screening of whom 326 (15%) had high-risk adenoma findings. Of these, 108 (33%) had either > or =3 adenomas < or =5 mm in size or an advanced adenoma < or =5 mm in size and no polyps > or =6 mm in size. An additional 75 (23%) had no polyp > or =10 mm in size, 1 or 2 polyps 6-9 mm in size and > or =3 adenomas < or =9 mm in size or an advanced adenoma < or =9 mm in size. If computed tomographic colonography (CTC) rather than colonoscopy were used in this population, assuming 100% sensitivity of CTC for polyps > or =6 mm and ACR interpretation recommendations, then 29% of all patients and 33% of screening patients age > or =50 years with high-risk adenoma findings would be interpreted as normal, and an additional 18-23% of these groups with high-risk adenoma findings, respectively, could have polypectomy delayed at least 3 years.

A recent study demonstrated that NKX3.1-positive staining can uncommonly be seen in testicular Sertoli cell tumors (1 of 4 cases). Also, it was reported that 2 of 3 Leydig cell tumors of the testis showed diffuse cytoplasmic staining for P501S, although it was unclear whether it was specific granular staining that defines true positivity. However, Sertoli cell tumors do not typically pose a diagnostic dilemma with metastatic prostate carcinoma to the testis. In contrast, malignant Leydig cell tumors, which are exceedingly rare, can closely resemble Gleason score 5 + 5 = 10 prostatic adenocarcinoma metastatic to the testis. To evaluate the expression of prostate markers in malignant Leydig cell tumors and steroidogenic factor 1 (SF-1) in high-grade prostate adenocarcinoma, as no data are currently published on these topics. Fifteen cases of malignant Leydig cell tumor were collected from 2 large genitourinary pathology consult services in the United States from 1991 to 2019. All 15 cases were negative immunohistochemically for NKX3.1, and all 9 with available additional material were negative for prostate-specific antigen and P501S and positive for SF-1. SF-1 was negative immunohistochemically in a tissue microarray with cases of high-grade prostatic adenocarcinoma. The diagnosis of malignant Leydig cell tumor and its distinction from metastatic adenocarcinoma to the testis can be made immunohistochemically on the basis of SF-1 positivity and negativity for NKX3.1.

* Context.–In April 1946, Archives of Pathology published H. G. Schlumberger's seminal study on anterior mediastinal (AM) teratomas that provided insights into the clinical behavior, pathologic features, and pathogenesis of these enigmatic neoplasms. (Arch Pathol Lab Med. 2026;150:27-36; doi: 10.5858/arpa.2025-0234-RA)

Gonadal germ cell tumors continue to be the cause of diverse, diagnostically challenging issues for the pathologist, and their correct resolution often has major important therapeutic and prognostic implications. They are academically interesting because of the biological diversity exhibited in the two gonads and variation in frequency of certain neoplasms. The most dramatic examples of the latter are the frequency of dermoid cyst in the ovary compared to the testis and the reverse pertaining to embryonal carcinoma. Within the teratoma group, there is strong evidence that ovarian and prepubertal testicular teratomas are derived from benign germ cells, a pathogenesis that likely applies also to the rare dermoid cysts and uncommon epidermoid cysts of the testis. In contrast, postpubertal testicular teratomas derive from malignant germ cells, specifically representing differentiation within a preexistent nonteratomatous cancer. As expected, given the foregoing, teratomas in boys are clinically benign, whereas in postpubertal males they are malignant, independent of their degree of immaturity. On the other hand, immaturity is an important finding in ovarian teratomas, irrespective of age, although its significance in children has recently been challenged. It is usually recognized on the basis of embryonic-appearing neuroepithelium, which shows mitotic activity and apoptosis in contrast to differentiated neuroepithelial tissues, which may occur in mature ovarian teratomas. Rarely it is based on the presence of cellular, mitotically active glial tissue. Fetal-type tissues alone are not sufficient for a diagnosis of immature teratoma. Further differences between the teratomatous tumors in the two gonads are the relative frequency of monodermal teratomas in the ovary in contrast to the testis, where only one subset, carcinoids, is seen with any frequency. When uncommon somatic-type malignancies (usually squamous cell carcinoma) occur in mature cystic teratomas of the ovary, this is a de novo form of malignant transformation; similar tumors in the testis, a very rare event, represent overgrowth of teratomatous elements that originated from malignant, nonteratomatous germ cell tumors and, therefore, had previously undergone malignant transformation. Germinomas may have several unusual features in each gonad; these include microcystic arrangements that suggest yolk sac tumor, tubular patterns that mimic Sertoli cell tumor, apparent increased cytological atypia that causes concern for embryonal carcinoma, and prominent syncytiotrophoblast giant cells that suggest choriocarcinoma. Awareness of these variants, good technical preparations, the retained typical cytological features of germinoma cells, and the judicious use of tailored panels of immunohistochemical stains resolve these dilemmas in virtually all instances. Two aspects of germinomas are unique to the testis. Firstly, intertubular growth of small seminomas may cause them to be overlooked. Secondly, the distinctive spermatocytic seminoma occurs only in the testis. A newly recognized aspect of this tumor is the propensity for some to be relatively monomorphic, making them apt to be mistaken for usual seminoma or embryonal carcinoma, although the characteristic polymorphic appearance in some foci, absence of intratubular germ cell neoplasia, unclassified type, and immunohistochemical stains should prevent this error. Cytoplasmic membrane immunoreactivity for placental alkaline phosphatase and CD117, with usual negativity for AE1/AE3 cytokeratins, is helpful in the diagnosis of germinoma. The recently described marker, OCT3/4, a nuclear transcription factor, is especially helpful in the differential of germinoma and embryonal carcinoma with other neoplasms. Yolk sac tumor continues to be confused occasionally with clear cell carcinoma of the ovary. Glandular (‘endometrioid-like') yolk sac tumors mimic endometrioid carcinomas; predominant or pure hepatoid yolk sac tumors cause concern for metastatic hepatocellular carcinoma or, in the ovary, primary hepatoid carcinoma, and solid patterns, especially in limited samplings, may be misinterpreted as germinoma. The usually younger age of patients with yolk sac tumors helps with the differential considerations with the nongerm cell tumors, as do other clinical and microscopic features and selected immunohistochemical stains. Choriocarcinoma is rare in both gonads, and those in the ovary must be distinguished from metastatic tumors of placental origin. Syncytiotrophoblast cells alone, admixed with other forms of germ cell tumor, still are confused with choriocarcinoma, but this phenomenon, which is much more frequent than choriocarcinoma, lacks the plexiform arrangement of different trophoblast cell types that typifies the latter. Mixed germ cell tumors (which may show almost any combination of components) are common in the testis but rare in the ovary. A separately categorized, rare form of mixed germ cell tumor seen in both gonads is the polyembryoma. It is perhaps the most photogenic of all gonadal germ cell tumors and is also intriguing because of its distinctive, organized arrangement of yolk sac tumor and embryonal carcinoma elements and recapitulation of very early embryonic development, even to the extent of having in its fundamental unit, the embryoid body, a miniature yolk sac, and amniotic cavity. These tumors, which are constituted by innumerable embryoid bodies, almost always contain teratomatous glands in minor amounts, and one way of viewing the polyembryoma is to consider it the most immature form of teratoma. Embryoid bodies are also common as a minor component of many mixed germ cell tumors, particularly in the testis, and the diffuse embryoma is another variant that has a particular arrangement of yolk sac tumor and embryonal carcinoma elements. Regression of gonadal germ cell tumors is a phenomenon restricted to the testis, for unknown reasons. These so-called ‘burnt-out' germ cell tumors can be recognized by a distinctive constellation of findings, including sometimes minor foci of residual recognizable germ cell neoplasia, a well-defined zone of scarring (often having residual ghost tubules), associated lymphoplasmacytic infiltrate, intratubular calcification and, in about 50%, of in situ germ cell neoplasia.

Angiomyolipoma with epithelial cysts (AMLEC) is a rare variant of renal angiomyolipoma (AML). It is characterized by a conventional AML component admixed with epithelial cysts within an “ovarian-like” stroma. Mixed epithelial and stromal tumor (MEST) is another renal neoplasm featuring epithelial cysts and “ovarian-like” stroma. While there is consensus that in MEST the epithelial and stromal components are neoplastic, in AMLEC it has been hypothesized that the epithelial component may represent renal tubular entrapment or ovarian-like transdifferentiation of tumor cells. The aim of this study was to compare the immunophenotypes of the epithelial-stromal components of AMLEC and MEST, with normal kidney and ovary to provide additional insights into the pathogenesis and relationships of these entities. In this study, we analyzed eight cases of AMLEC and 14 cases of MEST from 2003 to 2023. We used tissue microarrays, full sections, or unstained slides with an immunohistochemical panel including renal and ovarian markers: SF1, ER, PR, AR, PAX8, WT1, GATA3, CA-IX, p16, inhibin A, and BCL2. We compared these cases with ten non-neoplastic ovary and kidney samples. Our findings indicate that the epithelial component of AMLEC and MEST resembles hormone receptor positive renal tubular epithelium (AR + /ER − /PR −). AMLEC’s stromal component resembled hormone receptor positive renal stroma, while MEST’s resembled ovarian stroma, supporting mullerian transdifferentiation. Our study showed that the epithelial and stromal components of AMLEC and MEST are immunophenotypically different and also differ from normal tissues. Our findings suggest that in AMLEC, the epithelial-stromal component represents a hormonally driven proliferation of non-neoplastic renal elements within a dysregulated tumor microenvironment.