Teaching Case 7

Available Clinical History

A 68 year old man presented with a 'liver tumor', of which an excisional biopsy was obtained. No further relevant history was available at the time of surgery. Based on the H&E morphology (figures 1-3), the referring pathologist considered a diagnosis of hepatocellular carcinoma (HCC).

H&E images

Low power	High power	High power
The tumor consists of sheets of variably pleomorphic cells in a focally vascular stroma; occasional gland-like structures and abortive lumina are noted. The majority of the cells have abundant finely granular cytoplasm, but in some areas of prominent pleomorphism, intracytoplasmic vacuoles and decreased cohesiveness give a signet ring-like appearance.

Initial immunohistochemical studies performed at the referring laboratory showed no expression of cytokerain 7 (CK7), focal expression of cytokeratin 20 (CK20), and no tumor cell reactivity with the HepPar-1 (hepatocyte/HCC-specific) antibody. These results argued persuasively against the diagnosis of HCC, given the very high sensitivity of that latter antibody for HCC as reported in the literature (1,2). Paraffin blocks were then sent to PhenoPath Laboratories for further characterization.

Results of Immunohistochemistry studies

Polyclonal antibodies to the carcinoembryonic antigen family (pCEA) show a distinctive 'lumenal' pattern on cells within the tumor (fig 4). This pattern-indeed, the absence of a 'bile canalicular pattern'-provided additional evidence against the diagnosis of HCC. Focal CK20 expression was also confirmed in this laboratory (fig 5).

Fig. 4

Fig. 5

Negative studies included:
alpha fetoprotein (AFP),
neuroendocrine markers (synaptophysin and chromogranin A),
villin,
vimentin, and the
renal tubular antigen (gp200).

Initial Impression:
After this initial analysis, given focal expression of CK20 and variable reactivity to pCEA in a distinctive pattern, no definitive diagnosis could be reached, but the findings favored a metastatic carcinoma of gastrointestinal origin.

Additional Clinical History:
After 'completion' of these studies, the referring pathologist was made aware that the patient has a history of prostate cancer. Therefore, additional studies were performed, showing expression of both prostate specific antigen and prostatic acid phosphatase (Figs 6-8).

Fig. 6 Prostate Specific Antigen (PSA)

Fig. 7 Prostate Specific Antigen (PSA)

Fig. 8 Prostatic Acid Phosphatase (PAP)

Final Diagnosis

Metastatic adenocarcinoma of prostatic origin.

Discussion

This challenging case illustrates several important points, but first and foremost it underscores that obtaining an accurate and complete clinical history is of paramount importance in reaching the correct diagnosis.

In retrospect, the pattern of expression of CK7 and CK20 (negative and focally positive) in this case is consistent with prostatic adenocarcinoma. Although the majority of such metastases are negative for both CK7 and CK20, the second-most common pattern reported in prostatic adenocarcinoma is CK7-negative, CK20-positive (3).

Detection of carcinoembryonic antigen expression in prostate cancer is problematic. While the experience in this laboratory and others suggests that only a very small percentage of metastatic prostatic adenocarcinomas express antigens in the CEA family, the literature is quite varied, with occasional studies (4, 5) showing a majority or substantial minority of prostatic adenocarcinomas reacting with antibodies to CEA. The striking variability in results may well be due to differing antigens and methodologies.

In this particular case, the morphology of the tumor cells in combination with expression of CEA antigens in a luminal pattern raised for us the possibility that this tumor is among the small minority of prostatic adenocarcinomas with 'mucinous features'. While the tumor does not meet the diagnostic criteria of mucinous carcinoma (at least 25% of tumor consisting of tumor cells 'floating in lakes of extracellular mucin'[6]), it shares features with other mucin-producing adenocarcinomas.

This case also points out the potential power of tissue-specific and tissue-associated immunohistochemical markers, of which a relatively short list still exists. These are markers which, with variably high sensitivity and specificity, identify the tissue of origin of metastatic carcinomas of unknown primary. Among the most sensitive and specific of these are PSA and PAP (which, used in combination, identify greater than 95% of all metastatic prostatic adenocarcinomas).

Other excellent tissue-specific markers include thyroid transcription factor-1 (TTF-1), expressed in lung and thyroid tissue and neoplasms arising therefrom; thyroglobulin, a sensitive and specific marker of thyroid epithelial origin; and the Wilm's Tumor gene product (WT-1), expressed in papillary serous ovarian neoplasms and mesotheliomas. Antibodies to the microvilli-associated actin-binding protein villin, are highly, but not entirely, specific for neoplasms with gastrointestinal origins. A more recently available tissue-specific antibody, which detects a protein (gp200) in the proximal renal tubules is specific for renal cell carcinomas and relatively sensitive (7).

Several antibodies are helpful in determining tissue of origin, but have limited sensitivity and/or specificity. Antibodies to uroplakins, while very specific for urothelial origin, detect a relatively small proportion of metastatic transitional cell carcinomas. Similarly, the breast- and apocrine-associated marker gross cystic disease fluid protein-15 (GCDFP-15) is specific for mammary and skin adnexal epithelia, but detects only about half of metastatic mammary carcinomas (8).

In summary, this case of a 68 year old male with a 'liver tumor' represents an unusual presentation of a relatively common disease, metastatic prostatic adenocarcinoma. The reactivity with pCEA antibodies is not common, but it does not exclude that diagnosis, and the literature is not clear on this topic. While the most common pattern of CK7 and CK20 expression in prostate cancer is negative-negative, focal expression of CK20 is also seen in a subset of these tumors. Finally, PSA and PAP are among a relatively small number of excellent tissue-specific immunohistochemical markers, whose intelligent and expeditious application occasionally depends on thorough and accurate clinical history.

References

Murakata LA et al. Mod Path 2000;13(8):874-81
Minervini et al. Mod Path 1997;10(7):686-92.
Chu et al. Mod Pathol 2000;13(9):962-972
Genega et al. Mod Pathol 2000;13(11):1186-91
Ordonez NG Histopathology 1997 Dec;31(6):517-24
Young RH et al. Tumors of the Prostate Gland, Seminal Vesicles, Male Urethra, and Penis (Third Series, Fascicle 28, pp 223-5). Armed Forces Institute of Pathology, 2000.
McGregor et al., Am J Surg Pathol 25(12):1485-92, 2001
Wick M et al. Hum Pathol 1989;20(3):281-7