Gastric teratomas account for less than 1 % of teratomas in children [86, 87] and 1.6 % of all abdominal teratomas [88, 89]. Approximately 110 cases have been reported to date [88]. Gastric teratomas nearly always occur in infants, especially in neonates [90] (type I GCT), although there are cases reported in older children and adults [86]. The predominance of these tumors in male children is striking [87].

Clinically, gastric teratomas usually present as palpable masses with associated symptoms such as abdominal distention, vomiting, hematemesis, melena, respiratory distress, anemia, fever, weakness, abdominal pain, eating problems, constipation, failure to thrive, and spontaneous gastric perforation mimicking meconium peritonitis [86, 88, 91].

Gastric teratomas are essentially benign neoplasms, and although several so-called immature teratomas have been described in the stomach [92], only one case in an 83-year-old man has shown malignant transformation [93]. Recurrence has been associated with incomplete surgical resection or to the presence of a YST component [94, 95]. An example with a “focus of Wilms tumor with predominant epithelial component” [96] and another one with “small foci of neuroblastoma” [97] has been reported. A further association with Beckwith-Wiedemann syndrome and gliomatosis peritonei has been observed [90, 98], presenting as a scrotal sac mass [99]. Furthermore, a tumor composed of independent components of adenocarcinoma and immature “neuroepitheliomatous” monodermal teratoma has been reported [100]. Some of these random polydifferentiated neoplasms show a strong similarity with the multiple GCT patterns originated from somatic neoplasms in the female genital tract addressed in Chap. 6 that possibly arise from iPSC found in somatic tumors, representing type VI GCT.

Differential diagnosis includes diverse lesions such as mesenteric lymphangioma, pancreatic cyst, mesoblastic nephroma, neuroblastoma, Wilms tumor, hepatoblastoma, pancreatoblastoma, rhabdomyosarcoma, pheochromocytoma, angiomyolipoma, liposarcoma, and retroperitoneal teratoma [101, 102].

Gastric teratomas present as large exogastric (65 %), endogastric (9 %), or mixed endo/exogastric (26 %) [103] masses reaching up to 22–23 cm in size [90, 92]. Although they are found in any portion of the stomach, the greater curvature and posterior wall are the most common sites [89]. This could be explained by the more rapid growth of the posterior margin of the stomach in its expansion from the central part of the primitive anterior intestine [104].

As previously noted, immature tissues are not infrequent in gastric teratomas and show a good prognosis after complete surgical resection without neoadjuvant therapy [87, 91] [86], unless a concurrent yolk sac component exists [94, 95].

Gastric choriocarcinomas are rare tumors, accounting for approximately 0.08 % of all gastric cancers [105]. They are usually associated with a gastric adenocarcinoma (70 %) [105], sometimes with a transition between both components. Choriocarcinoma arises from adenocarcinoma as a phenomenon of tumor heterogeneity, as shown by the presence of identical TP53 mutations and similar genomic imbalances in both gastric adenocarcinomas and coexisting choriocarcinoma [106, 107]. The existence of pure forms could be explained by an overgrowth of the choriocarcinomatous area [108]. Heterogeneity is reflected by cases of pure gastric adenocarcinoma with choriocarcinomatous metastases. Moreover, in examples of gastric adenocarcinoma with choriocarcinomatous areas, a divergent pattern of metastases of both components has been observed [108]. Other differentiated patterns of GCT such as YST [106], hepatoid [109], or neuroendocrine components [110] can occur in association with gastric choriocarcinoma.

Gastric choriocarcinomas occur in the same age groups as adenocarcinoma and present as grossly bulky masses [108] with a necrotic and hemorrhagic appearance, an average size of 7 cm (range 2–18 cm), and a location similar to gastric adenocarcinoma [105]. Clinical symptoms include gynecomastia, precocious puberty, and, especially, gastrointestinal bleeding [108]. Endoscopic biopsies are rarely diagnostic due to the necrotic and hemorrhagic quality of these tumors [105, 111]. Although gastric choriocarcinomas show elevated serum β-hCG, the diagnosis of choriocarcinoma must be histopathological, since raised β-hCG has also been observed in otherwise conventional gastric adenocarcinomas without choriocarcinomatous features [112].

Gastric choriocarcinomas usually infiltrate beyond the muscularis propria; thus, they are frequently diagnosed at an advance stage with the presence of metastases to the lymph nodes (68–87 %), liver (45–66 %), peritoneum (15–23 %), or lung (8–28.3 %) [105, 111]. Hepatic failure due to tumor metastasis (29 %) is considered the most frequent cause of death in these patients [105]; gastric choriocarcinomas have a poor prognosis with most deaths occurring within 6 months of diagnosis [105, 108].

YST and AFP-producing gastric carcinomas have been found in association with fetal gastrointestinal, fetal hepatic, and yolk sac tumor differentiation [113, 114]. Gastric adenocarcinoma histology overlaps with both endodermal primitive and somatic YST growth patterns such as hepatoid and glandular gastrointestinal [4]. Additionally, some AFP-producing gastric carcinomas coexpress glypican-3 as well as pluripotency/stem cell factors such as SALL4 [115], thus revealing a YST immunophenotype [116]. This suggests that endodermal differentiation plays a major role in these tumors through reprogramming and later transdifferentiation [117]. AFP-producing gastric carcinomas account for 2.7–5.4 % of all carcinomas of the stomach [115], occurring most often in men, with an average age of 61. They have the same topography as conventional gastric adenocarcinoma [118], but they have been also reported in association with Barrett’s esophagus [119].

As previously mentioned, AFP-producing gastric carcinomas present a variable combination of histological patterns of endodermal differentiation. Clear cell areas are considered to represent a differentiation into fetal gut (Fig. 11.2) [115]. Hepatoid differentiation is the most characteristic pattern [120] and can represent more than 50 % of the tumor [114]. Hepatoid areas express AFP (80 %), glypican-3 (56 %), HepPar-1 (69 %), SALL4 (47 %), as well as palate, lung, and nasal epithelium protein (16 %), neuroendocrine markers, polyclonal CEA and have a reduced CDX2 expression [114, 120–122]. Thus, hepatoid AFP-producing clear cell gastric carcinomas mimic hepatocellular carcinoma and combined hepatocellular-cholangiocarcinoma metastases, especially when accompanied by a conventional gastric adenocarcinoma component. Although SALL4 was initially considered a helpful marker in differentiation, due to its expression in the former and its absence in the latter [114, 115], recent studies refute this idea, relating the presence of SALL4 simply to stem cell pluripotentiality features and poor prognosis [123] (see Sect. 11.7).

Hepatoid AFP-producing gastric carcinomas are aggressive tumors with a short median overall survival time (6 months) and low 3-year survival rate (22.6 %) [122]. Indeed, a morphological analysis of AFP-producing gastric carcinomas revealed that although these tumors usually contain a variable proportion of conventional adenocarcinomas, they also have glandular YST and hepatoid areas that seem related to a capacity for submucosal invasion and a more advanced stage [118]. Pure gastric YST is extremely rare; invariably it has been described in combination with adenocarcinoma [106, 124–127]. Clinically, AFP-producing gastric carcinomas are aggressive neoplasms with high rates of lymphatic (72.2 %) and venous invasion (88.9 %), lymph node metastases (72.2 %), and synchronous or metachronous liver metastases (63.9–75.6 %) [118, 121]. In our experience, metastases to the ovary, especially when they are unilateral, can prompt a misdiagnosis of primary ovarian YST.

Histogenetically, these tumors belong to type VI in the Oosterhuis and Looijenga classification of pluripotential tumors.

Although the retroperitoneum has been classically considered a location for EGGCTs (1–6.4 %) [128, 129], including teratomas [128], choriocarcinomas [130] YST [129], and seminomas [131], probably most retroperitoneal GCTs in postpubertal patients are metastases from primary gonadal lesions, rather than primaries [131]. Diagnostic criteria for rare primary retroperitoneal EGGCT include an encapsulated neoplasm without lymph node involvement or a high retroperitoneal neoplasm with adjacent lymph node involvement but no tumor in the lower aortic, iliac, or pelvic lymph nodes [132]. Testicular GCTs metastatic to retroperitoneum are covered in Chaps. 7 and 10.

Only rare examples of primary splenic GCT have been reported and are restricted to clinical and radiological case reports with incomplete histology [133, 134]. Splenogonadal fusion may be associated with concomitant GCT such as embryonal carcinoma and seminoma [135].

The retroperitoneal location of the head, neck, and body of the pancreas can be a source of confusion in the diagnosis of primary pancreatic EGGCTs, and a possible infiltration by a retroperitoneal EGGCT into the pancreas must always be ruled out. However, rare pancreatic EGGCTs have been reported to date; almost all are teratomas [136–140].

Pancreatic teratomas have been described predominantly as cystic masses in the head, neck, body, tail, or uncinate process in patients with an age range from 4 months to 74 years [137, 138]. Male to female ratio is 1.5:1 and most tumors are larger than 2 cm [138]. Pancreatic teratomas are usually symptomatic, causing nausea, vomiting, anorexia, weight loss, fatigue, fever, and abdominal and back pain [137, 141]. Histologically, most teratomas reported are cystic lesions with a squamous lining epithelium, sebaceous structures, and lymphoid and connective tissue, although other combinations of ectodermal, endodermal, and mesodermal elements have been described, including an immature teratoma [142].

Teratomas should be distinguished from a broad spectrum of pancreatic cystic lesions such as lymphoepithelial and epidermoid cysts arising in an intrapancreatic accessory spleen, ciliated foregut cyst [143], and mucinous cystic neoplasms [138].

Three cases of choriocarcinoma with seemingly incomplete clinicopathological evaluation have been reported [144–146]. Additionally, three cases of pancreatic YST have been reported and were radiological studied with minimal histological detail. Two were aggressive with hepatic and lymph node metastases and elevated AFP serum levels. The third was a mixed GCT with a teratomatous component in a pediatric patient [136, 139, 147].

Only metastases of seminoma to the pancreas have been reported [148].

Primary teratomas of the liver account for less than 1 % of hepatic tumors, with approximately 30 reported cases [149, 150]. They occur in children, the majority females below the age of 3 [149]. Hepatic teratomas are usually incidental findings [149] and often located in the falciform ligament [151], where they may become as large as 20 cm [150] and cause florid symptomatic cholangitis [152]. Teratomatous tissues may be associated with aggressive neuroendocrine tumors [153] and with a small proportion of hepatoblastomas [154], and some are chemotherapy related [155]. They are variably intermixed or in abrupt transition with hepatoblastoma tissue [150, 156, 157]. However, the presence of mesenchymal components such as osteoid, mesoblastic-like myxoid areas, smooth muscle cells, and squamous epithelium alone does not justify a diagnosis of teratoid hepatoblastoma [155]. The immunohistochemical expression of AFP, glypican-3, HepPar-1, and SALL4 [158] in hepatoblastomas is shared with YST, pointing toward an overlapping histology and phenotype among embryonal endodermal tumors.

Hepatic choriocarcinomas have been reported in both adults and children [159, 160]. Clinically, choriocarcinoma syndrome is defined by a massive spontaneous hemorrhage of choriocarcinomatous nodules [161] in visceral extragonadal locations such as the liver and lung; rupture may occur which could cause a potentially lethal hemoperitoneum [162] related to the invasion of small blood vessels [71]. In such cases, diagnosis of hepatic choriocarcinoma is difficult; there is a substantial risk of hemorrhage if a needle biopsy is performed; furthermore, this may yield only blood and necrotic tissue.

YST, hepatocellular carcinomas, and hepatoid adenocarcinomas. Only 20 cases of primary hepatic YST have been reported [163, 164]; this is not surprising as it is a challenging diagnosis due to the remarkable similarities of YST and pure or predominant endodermal somatic patterns (i.e., hepatoid, glandular) [4] and hepatocellular carcinoma, sharing many histological features, such as a trabecular pattern, hematopoiesis, hyaline globules, and bile secretion. Moreover, pure or mixed hepatoid gastric carcinomas, which frequently metastasize to the liver, sometimes have a hepatoid component (see Sect. 11.3) which is indistinguishable from hepatoid YST. Immunohistochemically, these lesions coexpress markers such as AFP, glypican-3 [116], and HepPar-1 [165]. Although SALL4 was initially described as a marker of fetal gut differentiation, thus supporting the diagnosis of YST and hepatoid gastric adenocarcinoma versus hepatocellular carcinoma [115], later studies have shown conspicuous SALL4 expression in the latter, associated with a poor prognosis [123, 165].

In conclusion, some forms of hepatoblastoma, hepatoid gastric adenocarcinoma, hepatocellular carcinoma, and metastatic hepatoid gastric adenocarcinoma constitute similar entities sharing a common endodermal differentiated phenotype identical to differentiated, somatic YST.

Approximately 20 primary teratomas have been reported in the adrenal gland. They account for 0.7–3 % of primary adrenal tumors [166–168] and are more frequent in infants or children, occurring only rarely in adults. The age of presentation ranges from 2 to 62 years, with a median age of 31 [168, 169]. They are more often located on the right side [170], and the male to female ratio is approximately 1:2 [169]. They are usually asymptomatic, although they may cause abdominal distension, intestinal obstruction, abdominal or low back pain [171], or torsion. If rupture occurs, a leakage to the abdominal cavity is possible, causing a granulomatous reaction with adhesions, hemorrhage, and finally shock [169]. Primary adrenal teratomas have been described mostly as cystic voluminous masses with a maximum size of 38 cm [169], with no reports of any immature variants. Since some teratomas may have an extensive adipose tissue component, the differential diagnosis should include other adrenal lipomatous tumors such as myelolipoma, lipoma, and angiomyolipoma [166–168]. As in the pancreas, it is necessary to discard a primary retroperitoneal origin for these lesions.

No cases of YST, seminoma, or other malignant GCT have been reported in the adrenal gland.

Around 30 cases of renal teratomas have been reported [172–182]. In a recent review, they comprised 0.19 % of all kidney tumors [179]. The age of presentation spans from 6 weeks to 71 years, with no gender predilection, and tumor sizes range from 3.5 to 12 cm. As in other locations, renal teratomas are occasionally related to developmental disorders such as renal dysplasia [175, 180] and ectopic [174] or horseshoe kidney [172, 173, 178, 181].

Similarly to the testis and ovary [183], at least ten examples of carcinoid tumor associated to teratoma have been reported in the kidney [172, 173, 176, 181], with a concurrent horseshoe kidney in some [172, 173, 181] and one synchronous clear cell renal cell carcinoma [181]. Clinically, retroperitoneal teratomas with secondary kidney invasion may be mistaken for renal primaries.

Primary immature teratomas should be differentiated from teratoid Wilms tumor. This nephroblastoma variant shows a predominance of mature heterologous elements composed of adipose, epithelial tissue (Fig. 11.3), skeletal muscle, and cartilage, rarely with neural differentiation [184]. They should be differentiated from ovarian immature teratomas with metanephric areas.

There are some reports of parenchymal renal choriocarcinomas [185, 186] that may have a gestational origin, as demonstrated by the presence of paternal DNA [290]. Clear cell and urothelial carcinomas with trophoblastic components may occur [187, 188].

Only four instances of primary renal YST have been reported [177, 187, 189, 190], one showing venous invasion [190]. Urothelial tumors of the pelvis may present a prominent glandular YST component that may adopt a papillary pattern reminiscent of papillary renal carcinoma (Fig. 11.4) [187], representing type VI tumors. No seminomas have been reported in the kidney.

The prostate is a rare location for EGGCT where characteristic gonadal type II GCT, are found, including seminoma, mixed GCT, YST, and teratoma. They probably originate from primordial germ cells trapped on their migratory path in the developing prostate. This possibility is also true for serosal GCTs, including pericardium (Fig. 11.5) [191, 192], peritoneum, omentum, etc. [193–196]. In teratomas of peritoneal locations, the possibility of an ovarian parasitic mature cystic teratoma must be excluded [197].

Fifteen prostatic GCTs have been reported to date [198, 199] presenting with a median age of 40.8 years. They are usually large masses (5–10 cm) that occupy the totality of the prostate gland and frequently invade adjacent structures (bladder neck, seminal vesicle). Clinical symptoms include hematuria, dysuria, obstructive symptoms, hematospermia, and pelvic pain. A curious association with Klinefelter syndrome (also see Chap. 3), which is more frequently related to mediastinal GCTs (see Chap. 8), has been reported [199]. Indeed, according to some authors, a diagnosis of EGGCT in a young male patient should be followed by a clinical/genetic work-up for Klinefelter syndrome [154]. Histologically, the reported cases are pure seminomas, YST, teratomas, and mixed GCT, one of which with embryonal carcinoma. A further case was associated with angiosarcoma as a somatic malignant change [198]. Two seminomas were initially misdiagnosed as prostatic adenocarcinoma and rhabdomyosarcoma [200]. Prostatic invasion from testicular GCT is rare event [201–203].

Teratomas also occur in the urinary bladder with at least ten cases reported [204]. They are sometimes associated with a rectovesical fistula with hypospadias and bladder diverticulum. Clinical symptoms may include the alarming occurrence of pilimiction (trichiura), that is, passing hairs in the urine [205], more frequently due to an ovarian benign cystic teratoma fistula into the bladder.

As previously noted, the reported cases of primary choriocarcinoma of the urinary bladder [206–208] are examples of the much more common diffuse or focal trophoblastic differentiation in an otherwise usual urothelial carcinoma, which may present elevated serum and urine levels of hCG. A choriocarcinomatous tumor of the bladder showed an excess of copies in 12p on molecular analysis, being interpreted as a sign of i(12p) mutation and thus justifying a diagnosis of primary vesical choriocarcinoma [208]. However, a recent genomic study highlighted similar 12p gains in urothelial carcinomas [209].

Two vesical YST, excluding those in the urachus, have been reported, one in a 1-year-old patient [210] and the other, which had an unusual presentation, in a 31-year-old female [211]. We have seen one instance of urothelial carcinoma associated with glandular YST (Figs 11.6a–c). In these cases, the glandular component should be differentiated from adenocarcinoma. When associated with urothelial carcinoma, they represent type VI tumors.

Hepatoid carcinomas have been reported in the bladder, and they should be differentiated from hepatoid YST [212].

The urachus is a 5–6 cm vestigial remnant of the human allantois. The latter is an endodermal evagination of the developing hindgut which becomes surrounded by the mesodermal connecting stalk; thus, the urachus may represent a structure retaining some degree of pluripotency. Nine GCTs have been reported in the urachus: three YST and six teratomas [213–216].

The six reported cases of teratoma affected females between 8 and 53 (median age, 26 years), presenting as urachal cysts or sinuses, with a benign histology [216]. Interestingly, one of the patients presented an associated anti-N-methyl-D-aspartate receptor autoimmune encephalitis, a clinical complication often reported in association with teratomas [217, 218].

YST of the urachus presented as large infraumbilical masses (12–19 cm) in two children (7 months and 2 years) [213, 214] and in a 44-year-old woman [215], with a connection to the urinary bladder dome by a pedicle.

Teratomas have been reported in the anorectal region [219], vermiform appendix [220], biliary tree [221], gallbladder [222, 223], bone [224], small bowel [225], and large bowel [226, 227], including a fetiform teratoma associated with the intestinal duplication [228], penis [229], and skin [230, 231].

Several cases of carcinoma with choriocarcinomatous features have been described in other locations such as the breast [232], skin [233], gallbladder [234], jejunum [235], colon [236], or rectum [237].

Apparent primary YST have been reported in the biliary tree [238] and penis [239].