Mesonephric adenocarcinoma of the cervix: a case report with a three-year follow-up, lung metastases, and next-generation sequencing analysis.

BACKGROUND: Mesonephric adenocarcinoma (MNAC) is a rare tumor of the female genital tract, which originates from mesonephric duct remnants. Its diagnosis is pathologically challenging, because MNAC may exhibit a mixture of morphological patterns that complicates the differential diagnosis. CASE PRESENTATION: The patient in this case was a 48-year-old woman with a polypoid mass protruding into the endocervical canal. The patient underwent a total hysterectomy outside the institution. During biopsy, the mass showed a cerebroid aspect. Histological study revealed a tumor with a predominantly tubular and ductal growth pattern. The immunoprofile showed negative staining for calretinin, carcinoembryonic antigen (CEAm), estrogen receptors (ER), and progesterone receptors (PR), and positive staining for CD10, p16, and PAX2. The Ki-67 score was 46%. Using a next-generation sequencing assay, we documented genomic alterations in KRAS and CTNNB1, low tumor mutation burden (TMB), and an absence of microsatellite instability. In addition, gain of the long arm of chromosome 1 (1q) was also documented using chomogenic in situ hybridization (CISH). Three years later, the patient presented pulmonary nodules in the lingula and left basal lobe that were resected by thoracotomy. The histopathologic study of the pulmonary nodules confirmed the presence of metastases. CONCLUSION: Carcinomas of mesonephric origin are among the rarest subtypes of cervical tumors. We report the first case of mesonephric adenocarcinoma of the cervix with lung metastases showing a CTNNB1 gene mutation.

Malignant mesonephric tumor of the cervix with an initial manifestation as pulmonary metastasis: case report and review of the literature.

Malignant mesonephric tumor (MMT) is a relatively uncommon malignancy of the female genital tract. The diagnosis of metastatic MMT is difficult because cytological, pathological, immunohistochemical characteristics of MMT are under-recognized. The authors present a 55-year-old female with metastatic pulmonary nodules. The bronchial washing cytology revealed three dimensional clusters of bland epithelial cells with slight nuclear grooves. A corresponding lung histology had ductal or tubular clusters of epithelial cells with intraglandular eosinophilic materials. These epithelial cells were positive for immunohistochemical stain of CD10, suggesting metastasis from MMT. The cervical smear showed clusters of bland, gland-forming epithelial cells with intraglandular eosinophilic materials. On histologic examination, mesonephric adenocarcinoma with papillary and solid proliferation was identified in the uterine cervix. A review of the literature for 72 cases of MMT is also included. Clinical and cytopathological features of MMT are herein made available.

Malignant mesonephric tumors of the female genital tract: a clinicopathologic study of 9 cases.

Nine malignant mesonephric tumors were obtained from the consultation files of one of the authors (J.P.) over a 13-year period (1988-2001). There were 4 adenocarcinomas (ACs) and 5 malignant mixed mesonephric tumors (MMMTs). The ACs were found in the cervix (3) and vagina (1). The MMMTs involved the uterus (1), cervix (3), and vagina (1). Most patients presented with abnormal vaginal bleeding. The 4 patients with mesonephric AC ranged in age from 24 to 54 years (mean, 41 years). The tumors measured 2 to 6 cm (mean, 3.7 cm). Two ACs were stage I and two were stage II. Two of the three patients with follow-up information were alive without clinical evidence of disease at 3 and 11.5 years, and the other was alive with recurrent tumor 8.5 years postoperatively. The 5 patients with MMMTs ranged in age from 37 to 62 years (mean, 49 years). The mean size of four tumors was 5.2 cm (range, 3.5-8 cm). The uterine MMMT infiltrated the entire myometrial wall extending to the endometrial cavity where it resembled an endometrial polyp. Although the most common histologic pattern in the current series was the glandular (ductal) pattern, retiform, tubular, and solid growth patterns were also encountered. Among the MMMT subgroup, the sarcomatous component was homologous in 3 cases (endometrial stromal or spindle cell) and heterologous in the other 2 cases (skeletal muscle and cartilage). Of the 4 patients with follow-up information available, 1 (stage II) died of disease 7 months after surgery, another (stage IV) was alive with bone metastases at 3.3 years, and the other 2 patients (stages IB and IC) had no clinical evidence of disease at 1 and 3.7 years, respectively. Evidence of mesonephric hyperplasia was found in 5 (42%) cases. The MMMT that arose in the corpus presented as an endometrial polyp. In this case, histologic differential diagnosis includes serous carcinoma, endometrial stromal sarcoma, and uterine tumor resembling ovarian sex cord-stromal tumor. Immunostainings are not helpful. Mesonephric ACs often present in early stage and have better prognosis than their müllerian counterparts. Surgery alone appears to be the treatment of choice. In contrast, MMMTs may present in advanced stage and are aggressive tumors, similar to malignant mixed müllerian tumors.

Malignant mesonephric neoplasms of the uterine cervix. A report of eight cases, including four with a malignant spindle cell component.

Eight mesonephric adenocarcinomas of the uterine cervix, four of which had a malignant spindle-cell component, occurred in women aged 34 to 71 (median 43, mean 54.5) years, bringing to 14 the number of cervical mesonephric carcinomas in the literature. The tumors with a malignant spindle-cell component ("malignant mesonephric mixed tumors") are, with one possible exception, the first reported examples at this site. The patients, almost all of whom presented with vaginal bleeding, underwent hysterectomy; five also had a pelvic lymph node dissection. The tumors were all stage IB, although microscopic lymph node metastases were found in two cases. Gross examination revealed an invasive cervical mass in each case. On microscopic examination, seven tumors were adjacent to mesonephric hyperplasia, which in five cases was florid and focally atypical; in the remaining case, occasional non-neoplastic mesonephric tubules were found only within the tumor. The adenocarcinomas typically exhibited a variety of patterns, including a ductal pattern resembling endometrioid adenocarcinoma, a small tubular pattern, a retiform pattern, a solid pattern, and a sex-cord-like pattern. These disparate patterns frequently caused diagnostic difficulty. The spindle-cell component generally resembled endometrial stromal sarcoma or a nonspecific spindle-cell sarcoma; one tumor also contained multiple foci of osteosarcoma and another, a single chondroid focus. Immunohistochemical staining for a variety of antigens failed to reveal a distinctive profile, although all the carcinomas were immunoreactive for vimentin. Follow-up in six cases revealed three patients to be alive without evidence of recurrence at postoperative intervals of 2 to 3 years. Recurrent tumor developed in a fourth patient 1 year after hysterectomy; she was treated with chemotherapy and was alive and free of disease at 2 years. Another patient had intra-abdominal recurrences (including liver metastases) at 9 and 11 years and was alive with tumor at 13 years. Death at 8.5 months in a final patient was probably due to an independent stage IIc ovarian clear-cell carcinoma. These and prior observations in the literature suggest that malignant mesonephric tumors of the cervix may be more indolent than their müllerian counterparts, from which they should be distinguished. Mesonephric carcinomas in this site should also be distinguished from florid mesonephric hyperplasia, with which they are usually associated.

[Brain metastasis of testicular yolk sac tumor with massive hemorrhage: case report].

A rare case of yolk sac tumor of the testis which metastasized to the brain parenchyma with repeated intra-tumoral hemorrhage is reported. The patient was a 38 year-old-man admitted to the Department of Urology with the chief complaint of painless swelling of the left testis for a period of one year. He underwent orchiectomy with highly suspected malignancy, because chest X-ray examination demonstrated metastatic coin lesions. Pathological examination of the operated specimen showed typical yolk sac tumor of the testis. Postoperative clinical course was uneventful. However, on the 4th postoperative day, the patient suddenly fell into a coma with left hemiplegia and dilated right pupil. CT scan demonstrated an intra-parenchymal hematoma in the right parietal lobe. Emergency craniotomy with evacuation of the hematoma clot was performed. Histological examination of the hematoma clot showed the same histology (yolk sac tumor) as found in the operative specimens of the left testis. After regaining full consciousness, chemotherapy (PEB and PVB) was started. It was effective to reduce the high serum AFP level and the size of the metastatic coin lesions in the lung. However, it was not effective in preventing brain metastasis. He again relapsed into coma due to a newly-developed intra-tumoral hematoma with multiple brain metastasis and died 6 months after the orchiectomy. Yolk sac tumor of the testis is rare in adult Japanese and there is no previous report of its metastasis to the brain parenchyma with intratumoral hemorrhage. We have reviewed the previously reported cases and discussed the brain metastasis of this malignant urogenic tumor.

Analysis of a non-ras 21-kDa protein in patients with metastatic testicular germ-cell tumors.

A novel protein of 21 kDa (p21) has been detected in the sera of patients with different solid tumors. The serum levels of this p21 protein were measured in seven patients with metastatic testicular germ-cell tumors before and after chemotherapy using an enzyme-linked immunosorbent assay. In five out of six patients who responded to chemotherapy a concomitant decrease of p21 serum levels was found. The decrease of p21 was in accordance with the decline of the established tumor markers alpha-fetoprotein, human chorionic gonadotropin beta-subunit and lactate dehydrogenase in three patients with non-seminomatous tumors and with the decline of lactate dehydrogenase and the clinical response in two patients with seminoma. In one patient the predicted decline of p21 did not occur despite the patient's clinical response to chemotherapy. In the seventh patient, who relapsed directly after chemotherapy, no decline of either p21 levels or tumor markers was observed. The absolute amount of the p21 protein prior to chemotherapy did not correlate with the patients' tumor burden. Elevated levels of p21 were found in patients with seminomatous and non-seminomatous germ-cell tumors. Since seminoma patients do not secrete tumor markers like alpha-fetoprotein or human chorionic gonadotropin beta, the determination of p21 levels may help to evaluate the efficacy of chemotherapy in patients with seminomatous as well as in patients with marker-negative non-seminomatous germ-cell tumors. The biological role of p21 and its clinical significance will be further investigated.

[Pure yolk sac tumor of the testis with brain metastasis: report of an adult case].

Herein we report an adult case of pure yolk sac tumor with brain metastasis. The patient was a 37-year-old male who presented with indulation of his left scrotum for 10 months. The plain computerized tomographic (CT) scan on entry demonstrated tumor metastasis to his lung and liver and serum alpha-fetoprotein (AFP) level was 786 ng/ml. Five days after admission, he developed hemiplegia secondary to the cerebral metastasis and hemorrhage. After chemotherapy and operation of right-posterior lobectomy, PVB (cisplatinum, vinblastine, bleomycin) chemotherapy produced a complete remission and the elevated serum AFP was normalized. However, the second course of chemotherapy had to be discontinued because of drug-induced hepatitis. He died of massive tumor metastasis to his brain 6 months after craniotomy.

Fine-needle aspiration cytology of an endometrioid-like variant of yolk sac tumor.

A 36-year-old male with a history of immature teratoma and embryonal carcinoma of the testis was admitted to the hospital for abdominal pain and fever. A CT scan revealed a large right abdominal mass. The patient's serum alpha-fetoprotein (AFP) was 46.8 ng/ml (reference < 25 ng/ml). Fine-needle aspiration (FNA) of the mass revealed malignant glandular cells. Chemotherapy was instituted, followed by resection of the large abdominal mass. The tumor was grossly encapsulated, consisting of large areas of necrotic, hemorrhagic tissue surrounded by smaller, multiloculated cysts. Microscopically, the tumor had a villoglandular pattern and variably stratified tall columnar cells. A prominent feature of the columnar cells was supranuclear and subnuclear vacuolization. Intracytoplasmic PAS-positive, diastase-resistant hyaline globules were occasionally present. AFP by immunoperoxidase was prominent within the tumor. This recurrence of the previously diagnosed testicular teratoma with embryonal carcinoma represents a yolk sac tumor with components strongly resembling endometrioid carcinoma, a variant only recently described in eight cases of ovarian origin (Clement et al.: Am J Surg Pathol 1987; 11(10):767-778). We believe this is the first reported case of an endometrioid-like variant of testicular yolk sac tumor and also the first report of the FNA cytology findings in this variant.

Brain metastases and testicular tumors: long-term survival.

In this updated and expanded retrospective analysis, the treatment records of 24 patients with brain metastases from nonseminomatous germ cell testicular tumors (NSGCT's) treated at the Indiana University Department of Radiation Oncology from 1975 through 1988 were reviewed. All patients received standard cisplatin-based induction chemotherapy. These patients were divided into three groups. Group 1 (n = 10) consisted of patients who presented initially with brain metastases and had no prior systemic treatment. Group 2 (n = 4) consisted of those patients who, after achieving a complete response (CR) with cisplatin, vinblastine, and bleomycin (PVB) +/- doxorubicin, developed a relapse confined to the brain. Group 3 (n = 10) consisted of those patients who were initially treated with PVB +/- doxorubicin or bleomycin, etoposide, and cisplatin (BEP) and eventually developed progressive disease and brain metastases. Group 1 was treated with whole brain irradiation (WBRT) and PVB +/- doxorubicin or BEP. Group 2 was treated with WBRT, cisplatin-based chemotherapy +/- surgical excision. Group 3 was usually treated with WBRT palliatively. Six patients, three in Group 1 and three in Group 2, are alive and disease-free with follow-up of 5+ years from beginning WBRT. Two additional patients in Group 1 survived 5+ years from beginning WBRT before dying with disease. No patient in Group 3 survived. Patients with brain metastases who have potentially controllable systemic disease should be treated curatively with WBRT (5000 cGy/25 fractions) +/- surgical excision and concomitant chemotherapy.

Epidural metastasis of testicular yolk sac tumor: an unusual cause of spinal cord compression. Case report.

Testicular tumors in the pediatric age group are rare. Yolk sac tumor (YST) is the most common malignant tumor of germinal origin in this group, and it may spread to the retroperitoneal lymph nodes. We have been unable to find any previously published report of metastasis of testicular YST to the epidural space of the spinal cord presenting as a cause of spinal cord compression.

Intracranial and intraspinal dissemination from pineal yolk sac tumor treated by PVB therapy--case report.

A 15-year-old male was admitted because of diplopia and persistent headache. Postcontrast computed tomography (CT) revealed a homogeneously enhanced large mass, 3 x 4 cm in size, in the pineal region and moderate obstructive hydrocephalus. A right ventriculoperitoneal shunt was installed. At that time, the serum alpha-fetoprotein (AFP) level increased to 23,036 ng/ml, but the level of serum beta-subunit of human chorionic gonadotropin was less than 0.2 ng/ml. These data indicated the tumor to be a pure yolk sac tumor. Following cisplatin-vinblastine-bleomycin (PVB) therapy and whole-brain irradiation (50 Gy), the tumor disappeared on CT, although the AFP level did not return to normal. Eight months after the completion of initial therapy, he had lumbago. Spinal magnetic resonance imaging revealed a metastatic mass at the L5-S2 levels, which was subtotally removed and histologically diagnosed as yolk sac tumor. Postoperative local irradiation (30 Gy) was performed. Seven months after the operation, spinal dissemination at the Th7 level occurred and, 1 month later, intracranial dissemination in the left cerebellopontine angle was detected. He died 25 months after the first admission. PVB therapy did not prevent spinal dissemination in this case.

[Omental metastasis in primary ovarian cancer].

Omentectomy was performed in 74 patients with primary cancer of the ovary. Omental metastasis was found in 60.8% (45 cases). The highest rates of omental metastasis were observed in serous carcinoma (56%) and endodermal sinus tumor (67%). Omental metastasis was correlated to types of tumor, amount of ascitic fluid, survival rate and extent of resection of omentum. The authors believe that omentectomy should routinely carried out in patients with primary ovarian cancer.

Endodermal sinus tumor of the ovary: a paradoxical response to chemotherapy.

A patient with ovarian endodermal sinus tumor metastatic to the liver responded unusually to chemotherapy. She experienced histologically documented regression of all intraperitoneal disease with the exception of the liver metastases when given vinblastine, bleomycin, and cisplatin. She eventually died of liver failure. A review of patients with ovarian endodermal sinus tumor who either presented with initial liver metastases or had recurrent disease in the liver leads us to conclude that the liver is a preferential site for spread, that liver metastases carry an ominous prognosis, and that failure to see prompt liver metastatic tumor response after systemic chemotherapy should signal a need for a more aggressive therapeutic approach to the liver lesions.

[Surgical resection of pulmonary metastasis from genitourinary cancers].

Three patients who underwent surgical resection for pulmonary metastases were reviewed. The primary lesion was testicular tumor, bladder cancer and renal cell carcinoma. One of these patients is alive without disease at 30 months after the pulmonary resection, while the others died of recurrence at 3 and 7 months after the surgical resection, respectively. As a factor affecting prognosis, characteristics of the primary lesion, especially its chemosensitivity, was thought to be important. The surgical resection of pulmonary metastasis may be effective, if the indication is assessed carefully.

Detection of AFP and HCG in metastatic testicular cancer after treatment with chemotherapy or radiation therapy.

We used an indirect immunoperoxidase technique to detect alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in tissue sections of nine metastatic germ cell tumors excised after treatment with chemotherapy or radiation therapy, and correlated the results with the serum levels of AFP and HCG. In all but 1 case yolk sac tumor (YST) was the only histologic type that reacted for AFP (AFP+) and syncytiotrophoblasts (STB) were the only histologic type that reacted for HCG (HCG+). Among 5 cases with normalization of the serum AFP before surgery, 3 were associated with YST-/AFP-, 1 with YST+/AFP+, and 1 with YST+/AFP- metastases; and among 4 cases with normalization of the serum HCG all were associated with STB-/HCG- metastases. Among 3 cases with persistent elevation of the serum AFP, 1 was associated with YST+/AFP+, 1 with YST+/AFP-, and 1 with YST-/AFP- metastases; and of 2 cases with persistent elevation of the serum HCG, 1 was associated with STB-/HCG- and 1 with STB+/HCG+ metastases. These data suggest that marker normalization in the face of persistent tumor results primarily from eradication of YST and STB, but also from treatment-induced inhibition of AFP and HCG synthesis or secretion.

Ovarian yolk sac tumor arising from an endometrioid carcinoma.

A yolk sac tumor that arose within an ovarian endometrioid adenocarcinoma in a 50-year-old woman is described. The tumor had typical microscopic features, stained immunohistochemically for alpha-fetoprotein, and was associated with an elevated serum alpha-fetoprotein level when metastases appeared. This is the fourth case in which a yolk sac tumor has been reported to develop from a somatic carcinoma and the second in which this tumor has been associated with epithelium of endometrioid type. Tumor heterogeneity or neometaplasia may account for the origin of a tumor of germ cell type from a carcinoma of somatic origin.

Endometrioid-like variant of ovarian yolk sac tumor. A clinicopathological analysis of eight cases.

The clinical and pathological features of eight ovarian yolk sac tumors with glandular patterns resembling those of endometrioid adenocarcinoma are described. The patients ranged in age from 11 to 34 years (mean, 22 years) and presented with abdominal pain or swelling. The serum alpha-fetoprotein (AFP) level was elevated at the time of presentation or later in all seven patients in whom it was measured. Seven tumors were unilateral, one was bilateral, and three had spread beyond the ovary. There was a contralateral streak gonad in two cases. The tumors were 6-35 cm in diameter; seven were solid and cystic, and one was a unilocular cyst with a small solid nodule in the wall. Microscopic examination revealed a prominent, and in two cases, pure endometrioid-like glandular pattern that often simulated that of an early secretory endometrium. Reticular, polyvesicular-vitelline, and hepatoid patterns of yolk sac tumor were also present in five tumors; minor teratomatous foci (squamous epithelium and cartilage) were present in one. Immunohistochemical staining revealed AFP, alpha-1-anti-trypsin (AAT), and carcinoembryonic antigen within the glandular epithelium; AFP and AAT were also present in areas showing the other patterns. Three patients died of recurrent or metastatic tumor 19-60 months postoperatively; in the remaining cases, there was a tumor-free follow-up of short duration. The endometrioid-like pattern reflects an unusual form of endodermal differentiation within yolk sac tumors that should be distinguished from endometrioid carcinoma.

Poorly differentiated carcinoma of unknown primary site: correlation of light microscopic findings with response to cisplatin-based combination chemotherapy.

We have previously reported complete responses and long-term survival in patients with metastatic poorly differentiated carcinoma (PDC) of unknown primary site who received intensive cisplatin-containing chemotherapy regimens. We reviewed the light microscopic specimens from 113 patients with PDC in an attempt to identify common histopathologic features in the chemotherapy-responsive subgroup, and to rule out the presence of previously unrecognized germ cell tumors. Relatively few diagnoses more specific than PDC could be made. We could identify no histopathologic features by light microscopy that distinguished responsive from unresponsive neoplasms. Only one patient was found to have a previously unrecognized yolk sac carcinoma, and in five other patients the possibility of a germ cell neoplasm was considered in the differential diagnosis by at least one reviewer. The remaining tumors had no histologic features suggestive of germ cell neoplasms. Ninety-six patients had received combination chemotherapy (89 with cisplatin-containing regimens); 27 patients (28%) achieved complete remission, and 16 remain free of disease at a median of 65 months after completion of therapy. Patients with PDC of unknown primary site who are responsive to cisplatin-containing chemotherapy regimens cannot be reliably identified by light microscopy. At present, all such patients should be considered for an empiric trial of chemotherapy with cisplatin-based regimens, since cure is achievable in a minority.

Intracranial endodermal sinus tumour--role for chemotherapy.

Pineal tumours are commonly of germ cell origin. The endodermal sinus tumour is a rare histologic subtype that is highly malignant and radioresistant. A single case is described and compared to six reported intracranial cases in which chemotherapy was used in addition to surgery and/or radiation. Although a beneficial effect of chemotherapy cannot be proven, the probable benefit in non-CNS cases requires that it be strongly considered. A uniform approach to diagnosis, investigation and treatment for intracranial tumours of this type is suggested.