Colonic Adenocarcinoma Metastasizing as a Germ Cell Neoplasm.

A Case Report and Review of the Literature

Reports of colonic adenocarcinoma with germ cell elements are rare. To date, only 9 cases, to our knowledge, have been reported in the English-language literature.[1-9] Eight cases were choriocarcinoma in combination with adenocarcinoma, one of which also had yolk sac tumor elements. The ninth had only yolk sac tumor elements with the adenocarcinoma.

This is the second reported case, to our knowledge, of a colonic adenocarcinoma with mixed germ cell elements of yolk sac tumor and choriocarcinoma. The neoplasm metastasized as the yolk sac component.

REPORT OF A CASE

A 29-year-old white man presented to the emergency department with increasing abdominal girth that was accompanied by nausea, vomiting, diarrhea, lower-extremity edema, and dark urine. The patient had experienced decreased appetite and fatigue for approximately 1 month. The patient's medical history was significant for a traumatic brain injury at the age of 5 years, resulting in a refractory seizure disorder and developmental delay. Physical examination revealed scleral icterus and a markedly distended abdomen with hepatomegaly.

Laboratory tests produced the following values: aspartate aminotransferase, 348 U/L; alanine aminotransferase, 97 U/L; lactate dehydrogenase, 1294 U/L; alkaline phosphatase, 592 U/L; and total bilirubin, 92.3 [micro]mol/L (5.4 mg/dL). Seven months earlier, all test results had been normal. Antibodies to hepatitis A, B, and C were negative. Plasma ceruloplasmin and ferritin levels were normal. The level of [Alpha]-fetoprotein (AFP) was markedly elevated at 745732 [micro]g/L. The serum [Beta]-human chorionic gonadotropin level was also elevated at 729 IU/L.

Ultrasound and magnetic resonance imaging of the abdomen demonstrated numerous hepatic masses consistent with metastases. On the second hospital day, the patient underwent an ultrasound-guided biopsy of the liver. A testicular ultrasound revealed normal testicular parenchyma.

On hospital day 6, the patient developed mental status changes accompanied by increasing serum potassium and creatinine levels due to spontaneous tumor lysis. He died secondary to hyperkalemic cardiac arrest.

PATHOLOGIC FINDINGS

Liver Biopsy

The biopsy specimen contained a papillary neoplasm with marked nuclear pleomorphism and multiple intracytoplasmic and extracytoplasmic hyaline globules. The hyaline globules were highlighted with periodic acid--Schiff stain following digestion (Figure 1, A). Occasional Schiller-Duval structures were identified (Figure 1, B). The neoplastic cells were positive for AFP, focally positive for placental alkaline phosphatase, and negative for carcinoembryonic antigen. These findings were consistent with a metastatic germ cell tumor with yolk sac differentiation.

[Figure 1 ILLUSTRATION OMITTED]

Autopsy Findings

A complete autopsy was performed. The abdominal cavity contained 700 mL of serosanguineous fluid. There was no retroperitoneal mass. Mild lymphadenopathy was present, with one prominent lymph node near the porta hepatis. The liver, 5300 g, was 80% to 90% replaced with necrotic nodules.

The proximal transverse colon was loosely adherent to the liver. Corresponding to this area, there was an ulcerated mass, 3 x 2 cm, which obstructed but did not fully occlude the colonic lumen. Several firm nodules were present in the adjacent pericolonic adipose.

Microscopically, the colonic lesion was an adenocarcinoma with mucinous elements that invaded through the muscularis propria into the pericolonic adipose (Figure 2, A). Undifferentiated areas marked by a lack of gland formation and marked nuclear pleomorphism were easily identifiable. The adenocarcinoma merged with the undifferentiated areas (Figure 2, B). The undifferentiated neoplasm filled vascular spaces (both intramural and extramural) with occasional papillary structures. These undifferentiated areas did not stain for carcinoembryonic antigen (Figure 3, A) and were positive for AFP (Figure 3, B), whereas the reverse was true for the more typical adenocarcinoma. Within the neoplasm, there were occasional nodules with a pattern of choriocarcinoma (Figure 3, C). The nodules were composed of cytotrophoblast-like cells intermingled with multinucleated syncytiotrophoblast-like giant cells separated by hemorrhage and necrosis. The multinucleated cells stained with antibody to human chorionic gonadotropin (Figure 3, D). Metastases were noted throughout the liver, within adjacent pericolonic lymph nodes, and in the prominent porta hepatis lymph node. Metastases were primarily composed of the papillary (yolk sac tumor) form of the neoplasm with foci of undifferentiated neoplasm.

[Figures 2-3 ILLUSTRATION OMITTED]

The brain contained infarcts consistent with the patient's remote history of closed head injury. There was no pineal mass. There was no mediastinal mass. The testes were normal. Microscopic examination showed no evidence of intratubular germ cell neoplasia or scar

COMMENT

Various theories of histogenesis for the development of a colonic adenocarcinoma with germ cell elements or other mixed tumors have been proposed. All of the theories seem to point to 2 basic mechanisms, which were initially proposed by Meyer in 1919: collision tumor or combination tumor.[10]

Collision tumors are the incidental coexistence of 2 separate malignant neoplasms that occur in proximity to each other. This may occur through a "field" proliferation in which there is neoplastic proliferation of more than one of the cell types normally present.[1] However, germ cells are not known to be present in the colon. In fact, most extragonadal germ cell tumors develop in midline locations. Another possibility would be a germ cell tumor that metastasized to a colonic carcinoma. In the present case, no primary germ cell neoplasm, gonadal or extragonadal, was found.

In a combination tumor, the various components are believed to derive from a common stem cell. In 1926, Pick proposed that the trophoblastic elements in a visceral carcinoma develop by the process of opisthoplasia or retrodifferentiation of the carcinoma cell.[11] Rather than retrodifferentiation or dedifferentiation, the process might be better described as blocked differentiation or a maturation arrest in stem cells that is controlled by regulation of the genome.[12] Since all somatic cells contain 46 chromosomes, in theory, each cell has totipotentiality. The genetic instability of neoplastic cells leads to the development of a clonal population that has a more primitive differentiation due to changes in the structure and regulation of the genome.

This case seems to best fit as a combination tumor. Again, no primary germ cell tumor was identified. Furthermore, the colonic neoplasm contained a histologic transition as demonstrated by morphology and immunohistochemistry. In addition, the only positive lymph nodes were those in proximity to the tumor.

A search of the literature for colonic adenocarcinoma with germ cell elements revealed only 9 cases.[1-9] These are summarized in the Table. The age range is 28 to 74 years, with a median age of 45 years. There is a female predominance. Most of the lesions have been reported in the rectosigmoid area. There has been no previous report of a lesion occurring in the transverse colon. The tumors range in size from 2 to 10 cm. Histologically, most are combinations of choriocarcinoma and adenocarcinoma. Only one report uses the term yolk sac tumor or endodermal sinus tumor, although another alludes to it. The present case represents the second case with multiple germ cell elements. Interestingly, as in this case, the metastases usually take the form of the germ cell element, suggesting that the more primitive component has the metastatic potential. Finally, all of the cases were rapidly fatal, with a median survival of 4.5 months from the development of symptoms. All of the patients died within 12 months.

Reports of Colonic Adenocarcinoma With Germ Cell Elements(*)

Source, y                   Age, y/Sex   Serum Markers   Location

Park and Reid,[1] 1980         49/F      HCG-NR          Sigmoid
                                         AFP-NR

Nguyen,[2] 1982                74/M      HCG-400         Sigmoid
                                         AFP-WNL

Kubosawa et al,[3] 1984        50/F      HCG-230 000     Sigmoid
                                         AFP-WNL

Ordonez and Luna,[4] 1984      35/F      HCG-1612        Cecum
                                         AFP-WNL

Metz et al,[5] 1985            42/F      HCG-154 000     Sigmoid
                                         AFP-NR

Yu et al,[6] 1992              54/F      HCG-NR          Rectum
                                         AFP-5126

Ostor et al,[7] 1993           28/F      HCG-16 500      Rectum
                                         AFP-300

Mashiach et al,[8] 1995        47/F      HCG-50 000      Cecum
                                         AFP-NR

Tokisue et al,[9] 1996         29/F      HCG-49 000      Rectum
                                         AFP-WNL

Present case                   29/M      HCG-729         Transverse
                                         AFP-745 732

                          Primary
                           Tumor    Primary
                           Size,    Tumor        Metastasis
Source, y                   cm      Histology    Histology    Survival

Park and Reid,[1] 1980      NR      Adeno        Chorio         4 mo
                                    Chorio       Adeno

Nguyen,[2] 1982             10      Adeno        Chorio         7 mo
                                    Chorio

Kubosawa et al,[3] 1984     6       Adeno        Chorio         4 mo
                                    Chorio

Ordonez and Luna,[4]        5.8     Adeno        NR             8 mo
1984                                Chorio

Metz et al,[5] 1985         2       Adeno        Chorio         1 mo
                                    Chorio

Yu et al,[6] 1992           8       Adeno        YST-like       1 wk
                                    YST-like

Ostor et al,[7] 1993        3.5     Adeno        YST            5 mo
                                    Chorio/YST   Adeno

Mashiach et al,[8] 1995     5       Adeno        NR             5 mo
                                    Chorio

Tokisue et al,[9] 1996      NR      Adeno        Chorio        12 mo
                                    Chorio

Present case                3       Adeno        YST            1 mo
                                    Chorio/YST

(*) HCG indicates human chorionic gonadotropin (reported in IU/L); NR,
not reported; AFP, [Alpha]-fetoprotein (reported in [micro]g/L); WNL,
within normal limits; Adeno, adenocarcinoma; Chorio, choriocarcinoma;
and YST, yolk sac tumor.

Others have reported primary cases of germ cell tumor in the colon. Cho et al[13] reported a primary endodermal sinus tumor in the ascending colon of a 3-year-old boy. Several cases of teratoma have also been reported in the colon.[14-16] Lind and Haghighi[17] reported a primary choriocarcinoma in the ascending colon of a 42-year-old man who died 1 month after diagnosis. Although no adenocarcinoma elements were seen in this case, some of the neoplastic cells stained with carcinoembryonic antigen. One could hypothesize that the tumor started as an adenocarcinoma, which was overtaken by the more aggressive choriocarcinomatous elements.

Although rare, primary mixed tumors of this type in the upper gastrointestinal tract have been reported more frequently.[11,18] Most of the reported stomach tumors contain choriocarcinoma, with only 4 reported cases of yolk sac elements.[19] In addition, most of these tumors (59%) occur in association with adenocarcinoma.[18]

[Alpha]-Fetoprotein is a tumor marker that is typically associated with yolk sac tumors and hepatocellular carcinoma. Elevated levels of AFP have been reported in several cases of colonic adenocarcinoma.[20-22] In one case, the AFP level was extremely high at 267 300 [micro]g/L.[21] All of these patients had extremely poor prognoses, with survival ranging from 2 to 8 months.

In summary, this was the case of a 29-year-old white man who had an unsuspected colonic carcinoma with biphasic differentiation, including adenocarcinoma and germ cell components. The tumor metastasized as the germ cell component. This tumor most likely developed as a combination tumor that arose from a common stem cell. For unknown reasons, these mixed tumors develop clones with more primitive differentiation. These more primitive areas seem to have a more potent metastatic potential and account for the poor prognosis of these mixed tumors.

Special thanks to Henry Appelman, MD, for his diagnostic assistance and review of the manuscript.

References

[1.] Park CH, Reid JD. Adenocarcinoma of the colon with choriocarcinoma in its metastases. Cancer. 1980;46:570-575.

[2.] Nguyen GK. Adenocarcinoma of the sigmoid colon with focal choriocarcinoma metaplasia: a case report. Dis Colon Rectum. 1982;25:230-234.

[3.] Kubosawa H, Nagao K, Kondo Y, Ishege H, Inaba N. Coexistence of adenocarcinoma and choriocarcinoma in the sigmoid colon. Cancer. 1984;54:866-868.

[4.] Ordonez NG, Luna MA. Choriocarcinoma of the colon. Am J Gastroenterol. 1984;79:39-42.

[5.] Metz KA, Richter J, Leder LD. Adenocarcinoma of the colon with syncytiotrophoblastic differentiation: differential diagnosis and implications. Pathol Res Pract. 1985;179:419-424.

[6.] Yu Y, Ogino T, Okada S. An alpha-fetoprotein-producing carcinoma of the rectum. Acta Pathol Jpn. 1992;42:684-687.

[7.] Ostor AG, Mcnaughton WM, Fortune DW, Rischin D, Hillcoat BL, Riley CB. Rectal adenocarcinoma with germ cell elements treated with chemotherapy. Pathology. 1993;25:243-246.

[8.] Mashiach R, Kaplan B, Braslavsky D, et al. Carcinoma of the colon associated with high extragenital production of beta-hCG--a case report. Acta Obstet Gynecol Scand. 1995;74:845-848.

[9.] Tokisue M, Yasutake K, Oya M, et al. Coexistence of choriocarcinoma and adenocarcinoma in the rectum: molecular aspects. J Gastroenterol. 1996;31:431-436.

[10.] Nirenberg A, Ostor AG, Quin MA. Collision tumor: serous adenocarcinoma and steroid cell tumor of the ovary. Pathology. 1992;24:60-62.

[11.] Jindrak K, Bochetb JF, Alpert LI. Primary gastric choriocarcinoma: case report with review of world literature. Hum Pathol. 1976;7:595-604.

[12.] Sell S, Pierce GB. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial carcinomas. Lab Invest. 1994;70:6-22.

[13.] Cho KJ, Myong NH, Jang JJ. Effusion cytology of endodermal sinus tumor of the colon: report of a case. Acta Cytol. 1991;35:207-209.

[14.] Russell P. Carcinoma complicating a benign teratoma of the rectum: report of a case. Dis Colon Rectum. 1974;17:550-553.

[15.] Palombini L, Vecchione R, DeRosa G, Cortese F. Benign solid teratoma of the sigmoid colon: report of a case. Dis Colon Rectum. 1976;19:441-444.

[16.] Shah RS, Kaddu SJ, Kirtane JM. Benign mature teratoma of the large bowel: a case report. J Pediatr Surg. 1996;31:701-702.

[17.] Lind HM, Haghighi P. Carcinoembryonic antigen staining in choriocarcinoma. Am J Clin Pathol. 1986;86:538-540.

[18.] Garcia RL, Ghali VS. Gastric choriocarcinoma and yolk sac tumor in man: observations about its possible origin. Hum Pathol. 1985;16:955-958.

[19.] Nakajima T, Okazaki N, Morinaga S, Tsumuraya M, Shimosato Y, Saiki S. A case of alpha-fetoprotein-producing rectal carcinoma. Jpn J Clin Oncol. 1985; 15:679-685.

[20.] Sato Y, Sekine T, Ohwada S. Alpha-fetoprotein-producing rectal cancer: calculated tumor marker doubling time. J Surg Oncol. 1994;55:265-268.

[21.] Hocking GR, Shembrey M, Hay D, Ostor AG. Alpha-fetoprotein-producing adenocarcinoma of the sigmoid colon with possible hepatoid differentiation. Pathology. 1995;27:277-279.

[22.] Suzuki T, Kimura N, Shizawa S, et al. Yolk sac tumor of the stomach with an adenocarcinomatous component: a case report with immunohistochemical analysis. Pathol Int. 1999;49:557-562.

Accepted for publication September 18, 2000.

From the Department of Pathology, University of Michigan Hospitals, Ann Arbor, Mich.

Reprints: C. M. Petricek, MD, Department of Pathology, University of Michigan Hospital, M5240 Medical Sciences 1, 1301 Catherine Rd, Ann Arbor, MI 48109-0602. (e-mail: [e-mail]).