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Foamy gland microcarcinoma in needle prostatic biopsy
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Annals of Diagnostic Pathology 12 (2008) 349 – 355
Foamy gland microcarcinoma in needle prostatic biopsy Julian Arista-Nasr, MD⁎, Braulio Martinez-Benitez, MD, Nancy Camorlinga-Tagle, BSc, Jorge Albores-Saavedra, MD Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Tlalpan D.F. 14000, México
Abstract
Keywords:
Foamy gland carcinoma is an uncommon variant of prostatic carcinoma. Foamy microcarcinoma of the prostate has not been studied in detail in needle biopsy. We describe here useful criteria for the diagnosis of foamy gland microcarcinoma of the prostate in needle biopsy. We reviewed 6 cases of foamy gland microcarcinoma. All tumors measured less than 1 mm and involved less than 5% of the biopsied tissue. A range of 4 to 40 foamy neoplastic glands were found in the 6 tumors. The original diagnosis of foamy gland microcarcinoma was made in 3 cases. They were composed of 21 to 40 glands lined by cuboidal to columnar cells with abundant foamy cytoplasm and small picnotic nuclei. Infiltrating and nodular patterns were readily identified, and absence of basal cells was shown by cytokeratin stains. The remaining 3 cases were designated as atypical foamy glands and consisted of similar but fewer glands (4-20). The diagnosis of foamy gland microcarcinoma was not made because of lack of nucleomegaly and prominent nucleoli and because an infiltrating pattern was less apparent. Subsequent biopsies confirm the diagnosis of microcarcinoma. The number of glands lined by voluminous foamy cells with hyperchromatic nuclei, an infiltrating pattern, and the absence of basal cells with high-molecular-weight cytokeratin were the most useful features in the diagnosis of foamy microcarcinoma. The presence of few atypical foamy glands in needle biopsy requires detailed analysis because they may represent foamy gland microcarcinoma. © 2008 Elsevier Inc. All rights reserved. Foamy gland microcarcinoma; Needle biopsy
A variety of terms, including limited prostatic carcinoma [1], minimal carcinoma [2], minimal volume adenocarcinoma [3], and minimal focus adenocarcinoma [4], have been used for carcinomas of the prostate measuring less than 1 mm and involving less than 5% of the biopsied tissue. We prefer the term microcarcinoma for this type of prostatic carcinoma. In a review of 5 series of prostatic microcarcinomas [1-5], we found 22 histologic criteria considered to be useful in the diagnosis. The most useful were an infiltrative pattern of small or medium-sized glands growing between benign glands, nucleomegaly, prominent nucleoli, amphophilic cytoplasm, pink or blue intraluminal secretions, and crystalloids. According to the authors, 3 or more of these criteria had to be present to establish the diagnosis [1]. Other features considered of limited usefulness included nuclear margination and multiple nucleoli [5]. ⁎ Corresponding author. Fax: +52 5 5485 3489. E-mail address: [email protected] (J. Arista-Nasr). 1092-9134/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2008.04.006
Foamy gland carcinoma is a recently described uncommon prostatic neoplasm [6]. The diagnosis in needle biopsy is difficult because of its deceptively benign histologic appearance. Moreover, useful criteria for the diagnosis of conventional adenocarcinoma, such as nucleomegaly and prominent nucleoli, are frequently absent in the foamy variant. Likewise, areas of conventional adenocarcinoma often present in radical prostatectomy specimens may be absent in needle biopsies. In our experience, when foamy gland microcarcinoma is limited to a few microscopic fields containing less than 20 glands, pathologists are reluctant to recognize them as microcarcinomas largely because they lack the nuclear features of conventional adenocarcinomas. The objective of this study was to analyze the clinical and pathologic features of 6 cases of foamy gland microcarcinoma of the prostate, provide useful criteria for its identification in needle biopsies, and emphasize the diagnostic difficulties. Because foamy gland carcinomas seem to be
350
J. Arista-Nasr et al. / Annals of Diagnostic Pathology 12 (2008) 349–355
more aggressive than conventional adenocarcinoma, early recognition is essential to improve prognosis.
Table 2 Foamy gland microcarcinoma in needle prostatic biopsy Architectural features
1. Materials and methods We reviewed 800 needle biopsies of prostatic carcinomas from the files of the Department of Pathology in the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, collected during a 7-year period, from 2000 to 2006. Forty-three (5.3%) carcinomas that measure less than 1 mm and involved less than 5% of the biopsied tissue were designated as microcarcinomas. Five (0.6%) of these cases corresponded to foamy gland microcarcinomas and form the basis of this report. A consultation case sent to one of us (JAS) was included in the series. The diagnosis of foamy gland carcinoma was made according to the proposed criteria by Nelson and Epstein [6]. The clinical variables recorded for these 6 cases included age, digital rectal examination, prostatic-specific antigen serum levels, original diagnosis, metastasis, and follow-up status. In each specimen, the following histologic characteristics were reviewed: number of tissue fragments per biopsy, number of neoplastic glands, size of the neoplastic glands, infiltrative pattern, nodular growth pattern, shape of the cells (columnar, cuboidal, round, etc), straight luminal borders, intraluminal eosinophilic or basophilic secretions, nucleomegaly, prominent nucleoli, small hyperchromatic nuclei (“picnotic” nuclei), marginal nucleoli, multiple nucleoli, mitotic figures, amphophilic cytoplasm, crystalloids, collagenous micronodules, glomerulations, high-grade prostatic intraepithelial neoplasia, and perineural invasion. In 5 of the 6 cases, histochemical studies were performed, including colloidal iron, Alcian blue, and periodic acid-Schiff (PAS) stains with and without diastase, as well as immunohistochemical analysis for highmolecular-weight cytokeratin (HMWCK clone 34BE12; Dakocytomation, Glostrup, Denmark; 1:50 dilution) and cytokeratin (CK) 5/6 (Dakocytomation; 1:150 dilution) to evaluate the presence or absence of basal cells. 2. Results 2.1. Clinical findings Clinical data, Gleason grade, treatment, and follow-up for each case are summarized in Table 1. The patients' ages
No. of glands Infiltrative pattern Nodular pattern Size of the glands Straight luminal borders HGPIN Original diagnosis
Case 1
2
3
4
5
6
23 Yes Yes S/M No Yes FGC
40 Yes No S/M Yes No FGC
18 Yes No M/L No No AFG
20 Yes No M/L No No AFG
4 Yes No M/L No No AFG
22 No Yes S/M Yes No FGC
S indicates small; M, medium; L, large; HGPIN, high-grade prostatic intraepithelial neoplasia; FGC, foamy gland carcinoma; AFG, atypical foamy glands.
ranged from 59 to 72 years (mean age, 67 years). Prostaticspecific antigen serum level varied from 5.9 to 25.2 ng/mL (mean, 12.3 ng/mL). An indurate nodule was palpated in the prostate during rectal examination in 3 patients. The remaining 3 patients had enlargement and induration of the entire gland. The 2 patients with tumors confined to the prostate are disease-free and with normal prostatic-specific antigen serum levels 3 and 4 years after radical prostatectomy. Three patients are living with active disease, and one died with metastases. 2.2. Pathologic findings The main architectural histologic changes of the 6 cases are shown in Table 2. As a group, the 6 biopsies featured small to medium and medium to large glands, showing nodular or infiltrative growth patterns (Figs. 1-8). Three cases were originally diagnosed as microcarcinomas (Figs. 1-4 and 8) and the remaining 3, as atypical foamy glands (Figs. 5-7). The 3 tumors identified as foamy gland microcarcinomas were characterized by small to medium-sized glands (21-40 glands), lined by cuboidal and columnar cells with abundant foamy cytoplasm that was colloidal iron and Alcian blue positive and PAS negative. The nuclei were small and hyperchromatic. Only 1 tumor had some cells with large nuclei and prominent nucleoli. An infiltrating pattern was readily apparent in 2 tumors (Figs. 1 and 2), and nodular aggregates of foamy glands were recognized in another (Fig. 8). Variable amounts of eosinophilic glandular secretions were present in all 3 cases (Figs. 1-4 and 8).
Table 1 Clinical and pathologic features of foamy gland microcarcinoma in needle prostatic biopsy Case
Age (y)
PSA (ng/mL)
Met
Gleason sum
Treatment
Follow-up
1 2 3 4 5 6
61 72 71 70 69 59
5.9 17.5 25.2 10.8 9.6 5.1
No No Yes Yes Yes No
6 6 7 6 7 6
Radical prostatectomy Radiotherapy Radiotherapy Unknown Radical prostatectomy Radical prostatectomy
Alive, disease-free, 3 y after surgery AAD AAD Unknown Died with metastatic disease Alive, disease-free, 4 y after surgery
PSA indicates prostatic-specific antigen; Met, metastasis; AAD, alive with active disease.
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Fig. 1. Case 1. (A) Foamy gland microcarcinoma. Most glands are medium sized and are seen between benign ducts. (B) The high-molecular-weight CK (HMWCK clone 34BE12). Stain is negative in the foamy carcinoma and highlights the basal cells of adjoining benign duct.
There were crystalloids in case 1 and blue secretions in case 2. A basal cell layer was absent with the highmolecular-weight CK stains in the 3 microcarcinomas. High-grade prostatic intraepithelial neoplasia of foamy type was identified in case 1 [7]. Perineural invasion was not
recognized in any of the tumors. The radical prostatectomy specimens showed foamy gland carcinoma with a component of conventional adenocarcinoma. The 3 tumors originally interpreted as atypical foamy glands consisted of similar but fewer foamy glands (4-20)
Fig. 2. Case 1. (A) The neoplastic glands show columnar cells with abundant foamy cytoplasm, basal hyperchromatic nuclei, dense intraluminal secretions (center, bottom), and apical secretions. (B) Strong positive reaction to Alcian blue stain in foamy gland carcinoma.
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Fig. 3. Case 2. (A and B) Foamy gland microcarcinoma. The diagnosis is easy because the glands are numerous and have a clear infiltrative pattern.
with an equivocal infiltrating pattern (Fig. 5). The abundant foamy cytoplasm of the neoplastic cells was colloidal iron and Alcian blue positive. The basal or eccentric nuclei were small and hyperchromatic. There were no prominent nucleoli or perineural invasion. A basal cell layer was not seen with the high-molecular-weight CKs. Subsequent biopsies confirmed the diagnosis of foamy gland carcinoma. 3. Discussion Foamy gland carcinoma is a rare, recently described prostatic neoplasm with distinctive histologic features. The
Fig. 4. Case 2. Pink and blue secretions in foamy gland microcarcinoma. The nuclei are small and hyperchromatic (“picnotic” nuclei).
largest series reported so far included 38 cases diagnosed in needle biopsy [6]. Because the neoplastic cells show abundant xanthomatous or foamy cytoplasm, the authors named this variant of prostatic neoplasm as foamy gland carcinoma. In contrast with conventional adenocarcinoma, the foamy carcinoma cells usually show small “picnotic” nuclei lacking prominent nucleoli. Their study included cases in which the foamy change represented more than 20% of the prostatic carcinoma. On average, each neoplasm was 72% foamy, and 11% were entirely foamy. In addition, these authors found that foamy carcinoma was an aggressive neoplasm. In 15 patients in whom subsequent radical prostatectomies were performed, only 5 were organ confined. Tran et al [8] studied 6 cases of foamy gland carcinoma in radical prostatectomy specimens. In this study, the patients' ages ranged from 50 to 73 years (mean, 65 years), with preoperative prostate-specific antigen serum levels ranging from 2.7 to 37.5 ng/mL (mean, 12.3 ng/mL). All 6 cases were bilateral high-volume tumors. Of the 6 patients, 5 had extraprostatic extension. The foamy tumor cells were negative for mucin and lipid stains but were positive for colloidal iron and Alcian blue stains, as in our cases. Ultrastructurally, the foamy cells displayed intracytoplasmic vesicles and numerous polyribosomes. The authors concluded that the foamy appearance of the tumor cells was the result of intracytoplasmic vesicles and not the consequence of the presence of lipid or neutral mucin. Subsequently, an isolated case was published [9]. The histologic diagnosis of foamy gland microcarcinoma of the prostate is difficult to establish in needle biopsies
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353
Fig. 5. Case 3. (A) Foamy gland microcarcinoma composed of medium-sized and large glands. Intraluminal eosinophilic secretion and small hyperchromatic nuclei are seen. Although an infiltrating pattern is present, because of the absence of nucleomegaly and/or prominent nucleoli, the original diagnosis of atypical glands with xanthomatous changes was made. (B) Second biopsy. The neoplasia shows glands of medium and large size; some of them are similar to those seen in the first biopsy. In contrast, glands on the right side are smaller and correspond to a high-grade foamy carcinoma. Fused glands can be seen.
because of the small number of glands. Moreover, the foamy cells usually lack nuclear features of conventional prostatic adenocarcinoma, and foci of conventional adenocarcinoma are often absent [6]. The differential diagnosis of foamy gland adenocarcinoma includes xanthogranulomatous prostatitis, Cowper glands, mucinous metaplasia, low-grade carcinomas, and clear cell cribriform hyperplasia [6-14]. Xanthogranulomatous prostatitis is characterized by sheets of foamy histiocytes that are admixed with other inflammatory cells, predominantly lymphocytes and plasma cells; moreover, the histiocytes contain lipid and do not form
Fig. 6. Case 4. Medium-sized glands with xanthomatous and a haphazard growth pattern, which were diagnosed as “atypical foamy glands.”
glands. Cowper glands consist of lobules of small glands lined by cuboidal or columnar mucin-producing cells that are not immunoreactive for prostatic-specific antigen. The Cowper glands lack cytologic atypia and an infiltrating growth pattern [13]. In mucinous metaplasia, the cells are bland, contain mucin, and lack an infiltrative pattern. Lowgrade adenocarcinoma may show glands lined by columnar clear cells that superficially resemble those observed in foamy carcinoma [10]; however, the cells do not exhibit the classical foamy appearance, and prominent nucleoli are frequently seen. In cribriform clear cell hyperplasia, there is a continuous basal cell layer at the periphery of the involved acini that depict a complex cribriform pattern. The basal cell layer is often visible with hematoxylin-eosin stains and can be highlighted with high-molecular-weight CKs [14]. Because of the absence of nuclear changes of conventional adenocarcinoma, the diagnosis of atypical foamy glands was made originally in 3 biopsies, despite their focal infiltrating appearance and the lack of basal cells with the CK stains. This decision emphasizes the importance that some pathologists give to nucleomegaly and prominent nucleoli to support the diagnosis of carcinoma. However, hyperchromatic nuclei are frequently seen in foamy gland carcinoma. Iczkowsky and Bostwick [3] have noticed that nuclear hyperchromasia is a staining artifact and a cancer diagnosis “can be supported and hindered by the cells tendency to have hyperchromatic nuclei.” If changes are not convincing of foamy gland carcinoma, the diagnostic term atypical foamy glands can be used.
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Fig. 7. Second biopsy of case 4. (A and B) Areas of poorly differentiated foamy carcinoma infiltrating prostatic stroma are seen.
However, recuts at different levels and immunohistochemical stains for CKs often provide additional information that may facilitate the diagnosis. It is important to keep in mind that subsequent biopsies may clarify the diagnosis as occurred in 3 of our cases.
When an obvious infiltrative pattern, perineural invasion, and crystalloids are present in needle biopsies, the diagnosis of foamy gland microcarcinoma is simplified [6,8,9]. Unfortunately, these features are not common in needle biopsies.
Fig. 8. Case 6. (A) Nodular aggregates of foamy glands. An infiltrating pattern is not readily apparent. (B) Higher magnification shows the foamy nature of the neoplastic cells, the small hyperchromatic nuclei, and the intraluminal dense secretions.
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The diagnosis of foamy gland microcarcinoma can be difficult because the needle biopsy often contains only a few glands, and the infiltrating pattern is not readily apparent. However, if strict criteria for identification of foamy cells are applied and the basal cell layer is absent, we believe that a diagnosis of foamy gland microcarcinoma is possible. We do not know a benign prostatic epithelial lesion composed of foamy cells. In conclusion, the presence of glands lined by cells with abundant foamy cytoplasm and picnotic nuclei in needle biopsy requires detailed analysis. When the glands depict an infiltrative pattern, dense eosinophilic secretions, and lack of a basal cell layer, a definite diagnosis of foamy gland microcarcinoma can be established. If the biopsy shows few glands lined by cells with abundant foamy cytoplasm and a doubtful infiltrative pattern, the diagnosis of atypical foamy glands might be rendered, and additional biopsies are recommended, avoiding delay in the diagnosis. References
[4]
[5]
[6]
[7] [8]
[9] [10]
[11] [12]
[1] Epstein JI. Diagnostic criteria of limited adenocarcinoma of the prostate on needle biopsy. Hum Pathol 1995;26:223-9. [2] Thorson P, Humphrey PA. Minimal adenocarcinoma in prostate needle biopsy tissue. Am J Clin Pathol 2000;114:896-909. [3] Iczkowsky KA, Bostwick DG. Criteria for biopsy diagnosis of minimal volume prostatic adenocarcinoma: analytic comparison with non
[13] [14]
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diagnostic but suspicious atypical small acinar proliferation. Arch Pathol Lab Med 2000;124:98-107. Leroy X, Aubert S, Villers A, Ballereau C, Augusto D, Gosselin B. Minimal focus of adenocarcinoma on prostate biopsy: clinicopathological correlations. J Clin Pathol 2003;56:230-2. Varma M, Lee MW, Tamboli P, et al. Morphologic criteria for the diagnosis of prostatic adenocarcinoma in needle biopsy specimens. A study of 250 consecutive cases in a routine surgical pathology practice. Arch Pathol Lab Med 2002;126:554-61. Nelson RS, Epstein JI. Prostatic carcinoma with abundant xanthomatous cytoplasm. Foamy gland carcinoma. Am J Surg Pathol 1996;20: 419-26. Bostwick DG, Qian J. High grade prostatic intraepithelial neoplasia. Mod Pathol 2004;17:360-79. Tran TT, Segupta E, Yang XJ. Prostatic foamy gland carcinoma with aggressive behavior: clinicopathologic, immunohistochemical and ultrastructural analysis. Am J Surg Pathol 2001;25:618-23. Llarena-Ibarguren R, Lecumberri-Castanos D, Padilla-Nieva J, et al. Foamy carcinoma of the prostate. Arch Esp Urol 2003;56:833-5. Mc Neal JE, Redwine EA, Freiha FS, Stamey EA. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988;12:897-906. Srigely JR. Benign mimickers of prostatic adenocarcinoma. Mod Pathol 2004;17:328-48. Miekos E, Wlodarczcyk W, Szram S. Xanthogranulomatous prostatitis. Int Urol Nephrol 1986;18:433-7. Cina SJ, Silberman BA, Kahane H, Epstein JI. Diagnosis of Cowper's glands on prostate needle biopsy. Am J Surg Pathol 1997;21:550-5. Ayala AG, Srigley JR, Ro JY, Abdul-Karim FW, Jhonson DE. Clear cell cribriform hyperplasia of prostate. Report of 10 cases. Am J Surg Pathol 1986;10:665-71.
Annals of Diagnostic Pathology 12 (2008) 349 – 355
Foamy gland microcarcinoma in needle prostatic biopsy Julian Arista-Nasr, MD⁎, Braulio Martinez-Benitez, MD, Nancy Camorlinga-Tagle, BSc, Jorge Albores-Saavedra, MD Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Tlalpan D.F. 14000, México
Abstract
Keywords:
Foamy gland carcinoma is an uncommon variant of prostatic carcinoma. Foamy microcarcinoma of the prostate has not been studied in detail in needle biopsy. We describe here useful criteria for the diagnosis of foamy gland microcarcinoma of the prostate in needle biopsy. We reviewed 6 cases of foamy gland microcarcinoma. All tumors measured less than 1 mm and involved less than 5% of the biopsied tissue. A range of 4 to 40 foamy neoplastic glands were found in the 6 tumors. The original diagnosis of foamy gland microcarcinoma was made in 3 cases. They were composed of 21 to 40 glands lined by cuboidal to columnar cells with abundant foamy cytoplasm and small picnotic nuclei. Infiltrating and nodular patterns were readily identified, and absence of basal cells was shown by cytokeratin stains. The remaining 3 cases were designated as atypical foamy glands and consisted of similar but fewer glands (4-20). The diagnosis of foamy gland microcarcinoma was not made because of lack of nucleomegaly and prominent nucleoli and because an infiltrating pattern was less apparent. Subsequent biopsies confirm the diagnosis of microcarcinoma. The number of glands lined by voluminous foamy cells with hyperchromatic nuclei, an infiltrating pattern, and the absence of basal cells with high-molecular-weight cytokeratin were the most useful features in the diagnosis of foamy microcarcinoma. The presence of few atypical foamy glands in needle biopsy requires detailed analysis because they may represent foamy gland microcarcinoma. © 2008 Elsevier Inc. All rights reserved. Foamy gland microcarcinoma; Needle biopsy
A variety of terms, including limited prostatic carcinoma [1], minimal carcinoma [2], minimal volume adenocarcinoma [3], and minimal focus adenocarcinoma [4], have been used for carcinomas of the prostate measuring less than 1 mm and involving less than 5% of the biopsied tissue. We prefer the term microcarcinoma for this type of prostatic carcinoma. In a review of 5 series of prostatic microcarcinomas [1-5], we found 22 histologic criteria considered to be useful in the diagnosis. The most useful were an infiltrative pattern of small or medium-sized glands growing between benign glands, nucleomegaly, prominent nucleoli, amphophilic cytoplasm, pink or blue intraluminal secretions, and crystalloids. According to the authors, 3 or more of these criteria had to be present to establish the diagnosis [1]. Other features considered of limited usefulness included nuclear margination and multiple nucleoli [5]. ⁎ Corresponding author. Fax: +52 5 5485 3489. E-mail address: [email protected] (J. Arista-Nasr). 1092-9134/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2008.04.006
Foamy gland carcinoma is a recently described uncommon prostatic neoplasm [6]. The diagnosis in needle biopsy is difficult because of its deceptively benign histologic appearance. Moreover, useful criteria for the diagnosis of conventional adenocarcinoma, such as nucleomegaly and prominent nucleoli, are frequently absent in the foamy variant. Likewise, areas of conventional adenocarcinoma often present in radical prostatectomy specimens may be absent in needle biopsies. In our experience, when foamy gland microcarcinoma is limited to a few microscopic fields containing less than 20 glands, pathologists are reluctant to recognize them as microcarcinomas largely because they lack the nuclear features of conventional adenocarcinomas. The objective of this study was to analyze the clinical and pathologic features of 6 cases of foamy gland microcarcinoma of the prostate, provide useful criteria for its identification in needle biopsies, and emphasize the diagnostic difficulties. Because foamy gland carcinomas seem to be
350
J. Arista-Nasr et al. / Annals of Diagnostic Pathology 12 (2008) 349–355
more aggressive than conventional adenocarcinoma, early recognition is essential to improve prognosis.
Table 2 Foamy gland microcarcinoma in needle prostatic biopsy Architectural features
1. Materials and methods We reviewed 800 needle biopsies of prostatic carcinomas from the files of the Department of Pathology in the Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, collected during a 7-year period, from 2000 to 2006. Forty-three (5.3%) carcinomas that measure less than 1 mm and involved less than 5% of the biopsied tissue were designated as microcarcinomas. Five (0.6%) of these cases corresponded to foamy gland microcarcinomas and form the basis of this report. A consultation case sent to one of us (JAS) was included in the series. The diagnosis of foamy gland carcinoma was made according to the proposed criteria by Nelson and Epstein [6]. The clinical variables recorded for these 6 cases included age, digital rectal examination, prostatic-specific antigen serum levels, original diagnosis, metastasis, and follow-up status. In each specimen, the following histologic characteristics were reviewed: number of tissue fragments per biopsy, number of neoplastic glands, size of the neoplastic glands, infiltrative pattern, nodular growth pattern, shape of the cells (columnar, cuboidal, round, etc), straight luminal borders, intraluminal eosinophilic or basophilic secretions, nucleomegaly, prominent nucleoli, small hyperchromatic nuclei (“picnotic” nuclei), marginal nucleoli, multiple nucleoli, mitotic figures, amphophilic cytoplasm, crystalloids, collagenous micronodules, glomerulations, high-grade prostatic intraepithelial neoplasia, and perineural invasion. In 5 of the 6 cases, histochemical studies were performed, including colloidal iron, Alcian blue, and periodic acid-Schiff (PAS) stains with and without diastase, as well as immunohistochemical analysis for highmolecular-weight cytokeratin (HMWCK clone 34BE12; Dakocytomation, Glostrup, Denmark; 1:50 dilution) and cytokeratin (CK) 5/6 (Dakocytomation; 1:150 dilution) to evaluate the presence or absence of basal cells. 2. Results 2.1. Clinical findings Clinical data, Gleason grade, treatment, and follow-up for each case are summarized in Table 1. The patients' ages
No. of glands Infiltrative pattern Nodular pattern Size of the glands Straight luminal borders HGPIN Original diagnosis
Case 1
2
3
4
5
6
23 Yes Yes S/M No Yes FGC
40 Yes No S/M Yes No FGC
18 Yes No M/L No No AFG
20 Yes No M/L No No AFG
4 Yes No M/L No No AFG
22 No Yes S/M Yes No FGC
S indicates small; M, medium; L, large; HGPIN, high-grade prostatic intraepithelial neoplasia; FGC, foamy gland carcinoma; AFG, atypical foamy glands.
ranged from 59 to 72 years (mean age, 67 years). Prostaticspecific antigen serum level varied from 5.9 to 25.2 ng/mL (mean, 12.3 ng/mL). An indurate nodule was palpated in the prostate during rectal examination in 3 patients. The remaining 3 patients had enlargement and induration of the entire gland. The 2 patients with tumors confined to the prostate are disease-free and with normal prostatic-specific antigen serum levels 3 and 4 years after radical prostatectomy. Three patients are living with active disease, and one died with metastases. 2.2. Pathologic findings The main architectural histologic changes of the 6 cases are shown in Table 2. As a group, the 6 biopsies featured small to medium and medium to large glands, showing nodular or infiltrative growth patterns (Figs. 1-8). Three cases were originally diagnosed as microcarcinomas (Figs. 1-4 and 8) and the remaining 3, as atypical foamy glands (Figs. 5-7). The 3 tumors identified as foamy gland microcarcinomas were characterized by small to medium-sized glands (21-40 glands), lined by cuboidal and columnar cells with abundant foamy cytoplasm that was colloidal iron and Alcian blue positive and PAS negative. The nuclei were small and hyperchromatic. Only 1 tumor had some cells with large nuclei and prominent nucleoli. An infiltrating pattern was readily apparent in 2 tumors (Figs. 1 and 2), and nodular aggregates of foamy glands were recognized in another (Fig. 8). Variable amounts of eosinophilic glandular secretions were present in all 3 cases (Figs. 1-4 and 8).
Table 1 Clinical and pathologic features of foamy gland microcarcinoma in needle prostatic biopsy Case
Age (y)
PSA (ng/mL)
Met
Gleason sum
Treatment
Follow-up
1 2 3 4 5 6
61 72 71 70 69 59
5.9 17.5 25.2 10.8 9.6 5.1
No No Yes Yes Yes No
6 6 7 6 7 6
Radical prostatectomy Radiotherapy Radiotherapy Unknown Radical prostatectomy Radical prostatectomy
Alive, disease-free, 3 y after surgery AAD AAD Unknown Died with metastatic disease Alive, disease-free, 4 y after surgery
PSA indicates prostatic-specific antigen; Met, metastasis; AAD, alive with active disease.
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Fig. 1. Case 1. (A) Foamy gland microcarcinoma. Most glands are medium sized and are seen between benign ducts. (B) The high-molecular-weight CK (HMWCK clone 34BE12). Stain is negative in the foamy carcinoma and highlights the basal cells of adjoining benign duct.
There were crystalloids in case 1 and blue secretions in case 2. A basal cell layer was absent with the highmolecular-weight CK stains in the 3 microcarcinomas. High-grade prostatic intraepithelial neoplasia of foamy type was identified in case 1 [7]. Perineural invasion was not
recognized in any of the tumors. The radical prostatectomy specimens showed foamy gland carcinoma with a component of conventional adenocarcinoma. The 3 tumors originally interpreted as atypical foamy glands consisted of similar but fewer foamy glands (4-20)
Fig. 2. Case 1. (A) The neoplastic glands show columnar cells with abundant foamy cytoplasm, basal hyperchromatic nuclei, dense intraluminal secretions (center, bottom), and apical secretions. (B) Strong positive reaction to Alcian blue stain in foamy gland carcinoma.
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Fig. 3. Case 2. (A and B) Foamy gland microcarcinoma. The diagnosis is easy because the glands are numerous and have a clear infiltrative pattern.
with an equivocal infiltrating pattern (Fig. 5). The abundant foamy cytoplasm of the neoplastic cells was colloidal iron and Alcian blue positive. The basal or eccentric nuclei were small and hyperchromatic. There were no prominent nucleoli or perineural invasion. A basal cell layer was not seen with the high-molecular-weight CKs. Subsequent biopsies confirmed the diagnosis of foamy gland carcinoma. 3. Discussion Foamy gland carcinoma is a rare, recently described prostatic neoplasm with distinctive histologic features. The
Fig. 4. Case 2. Pink and blue secretions in foamy gland microcarcinoma. The nuclei are small and hyperchromatic (“picnotic” nuclei).
largest series reported so far included 38 cases diagnosed in needle biopsy [6]. Because the neoplastic cells show abundant xanthomatous or foamy cytoplasm, the authors named this variant of prostatic neoplasm as foamy gland carcinoma. In contrast with conventional adenocarcinoma, the foamy carcinoma cells usually show small “picnotic” nuclei lacking prominent nucleoli. Their study included cases in which the foamy change represented more than 20% of the prostatic carcinoma. On average, each neoplasm was 72% foamy, and 11% were entirely foamy. In addition, these authors found that foamy carcinoma was an aggressive neoplasm. In 15 patients in whom subsequent radical prostatectomies were performed, only 5 were organ confined. Tran et al [8] studied 6 cases of foamy gland carcinoma in radical prostatectomy specimens. In this study, the patients' ages ranged from 50 to 73 years (mean, 65 years), with preoperative prostate-specific antigen serum levels ranging from 2.7 to 37.5 ng/mL (mean, 12.3 ng/mL). All 6 cases were bilateral high-volume tumors. Of the 6 patients, 5 had extraprostatic extension. The foamy tumor cells were negative for mucin and lipid stains but were positive for colloidal iron and Alcian blue stains, as in our cases. Ultrastructurally, the foamy cells displayed intracytoplasmic vesicles and numerous polyribosomes. The authors concluded that the foamy appearance of the tumor cells was the result of intracytoplasmic vesicles and not the consequence of the presence of lipid or neutral mucin. Subsequently, an isolated case was published [9]. The histologic diagnosis of foamy gland microcarcinoma of the prostate is difficult to establish in needle biopsies
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353
Fig. 5. Case 3. (A) Foamy gland microcarcinoma composed of medium-sized and large glands. Intraluminal eosinophilic secretion and small hyperchromatic nuclei are seen. Although an infiltrating pattern is present, because of the absence of nucleomegaly and/or prominent nucleoli, the original diagnosis of atypical glands with xanthomatous changes was made. (B) Second biopsy. The neoplasia shows glands of medium and large size; some of them are similar to those seen in the first biopsy. In contrast, glands on the right side are smaller and correspond to a high-grade foamy carcinoma. Fused glands can be seen.
because of the small number of glands. Moreover, the foamy cells usually lack nuclear features of conventional prostatic adenocarcinoma, and foci of conventional adenocarcinoma are often absent [6]. The differential diagnosis of foamy gland adenocarcinoma includes xanthogranulomatous prostatitis, Cowper glands, mucinous metaplasia, low-grade carcinomas, and clear cell cribriform hyperplasia [6-14]. Xanthogranulomatous prostatitis is characterized by sheets of foamy histiocytes that are admixed with other inflammatory cells, predominantly lymphocytes and plasma cells; moreover, the histiocytes contain lipid and do not form
Fig. 6. Case 4. Medium-sized glands with xanthomatous and a haphazard growth pattern, which were diagnosed as “atypical foamy glands.”
glands. Cowper glands consist of lobules of small glands lined by cuboidal or columnar mucin-producing cells that are not immunoreactive for prostatic-specific antigen. The Cowper glands lack cytologic atypia and an infiltrating growth pattern [13]. In mucinous metaplasia, the cells are bland, contain mucin, and lack an infiltrative pattern. Lowgrade adenocarcinoma may show glands lined by columnar clear cells that superficially resemble those observed in foamy carcinoma [10]; however, the cells do not exhibit the classical foamy appearance, and prominent nucleoli are frequently seen. In cribriform clear cell hyperplasia, there is a continuous basal cell layer at the periphery of the involved acini that depict a complex cribriform pattern. The basal cell layer is often visible with hematoxylin-eosin stains and can be highlighted with high-molecular-weight CKs [14]. Because of the absence of nuclear changes of conventional adenocarcinoma, the diagnosis of atypical foamy glands was made originally in 3 biopsies, despite their focal infiltrating appearance and the lack of basal cells with the CK stains. This decision emphasizes the importance that some pathologists give to nucleomegaly and prominent nucleoli to support the diagnosis of carcinoma. However, hyperchromatic nuclei are frequently seen in foamy gland carcinoma. Iczkowsky and Bostwick [3] have noticed that nuclear hyperchromasia is a staining artifact and a cancer diagnosis “can be supported and hindered by the cells tendency to have hyperchromatic nuclei.” If changes are not convincing of foamy gland carcinoma, the diagnostic term atypical foamy glands can be used.
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Fig. 7. Second biopsy of case 4. (A and B) Areas of poorly differentiated foamy carcinoma infiltrating prostatic stroma are seen.
However, recuts at different levels and immunohistochemical stains for CKs often provide additional information that may facilitate the diagnosis. It is important to keep in mind that subsequent biopsies may clarify the diagnosis as occurred in 3 of our cases.
When an obvious infiltrative pattern, perineural invasion, and crystalloids are present in needle biopsies, the diagnosis of foamy gland microcarcinoma is simplified [6,8,9]. Unfortunately, these features are not common in needle biopsies.
Fig. 8. Case 6. (A) Nodular aggregates of foamy glands. An infiltrating pattern is not readily apparent. (B) Higher magnification shows the foamy nature of the neoplastic cells, the small hyperchromatic nuclei, and the intraluminal dense secretions.
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The diagnosis of foamy gland microcarcinoma can be difficult because the needle biopsy often contains only a few glands, and the infiltrating pattern is not readily apparent. However, if strict criteria for identification of foamy cells are applied and the basal cell layer is absent, we believe that a diagnosis of foamy gland microcarcinoma is possible. We do not know a benign prostatic epithelial lesion composed of foamy cells. In conclusion, the presence of glands lined by cells with abundant foamy cytoplasm and picnotic nuclei in needle biopsy requires detailed analysis. When the glands depict an infiltrative pattern, dense eosinophilic secretions, and lack of a basal cell layer, a definite diagnosis of foamy gland microcarcinoma can be established. If the biopsy shows few glands lined by cells with abundant foamy cytoplasm and a doubtful infiltrative pattern, the diagnosis of atypical foamy glands might be rendered, and additional biopsies are recommended, avoiding delay in the diagnosis. References
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