Table 1 - Testicular Tumors with a Tubular Pattern

Sex Cord-Stromal Tumors   Sertoli cell tumors   Sertoli-Leydig cell tumors   Granulosa cell tumors   Mixed and unclassified tumors Germ Cell Tumors   Embryonal carcinoma   Yolk sac tumor   Seminoma   Carcinoid tumor Paratesticular Tumors   Sertoliform rete cystadenoma   Rete carcinoma   Adenomatoid tumor   Malignant mesothelioma   Mullerian carcinomas Metastatic Tumors   Gastric cancer   Carcinoid   Prostatic carcinoma   Others

The features of each neoplasm are reviewed in turn with emphasis on the features of the tubules, or associated findings that lead to the correct interpretation. I approach the topic by considering in turn each of the four major categories which may harbor tumors with a tubular pattern: sex cord-stromal tumors, germ cell tumors, paratesticular neoplasms and, finally, metastatic tumors.

Sex Cord-Stromal Tumors
One of many fascinating aspects of gonadal tumors is the extent to which as striking as their similarities in the sexes often are there also noteworthy differences. This comparative aspect was one focus of the many contributions of the illustrious Danish investigator, Dr. Gunnar Teilum [2]. One of the differences is the great rarity of Sertoli-Leydig cell tumors of the testis such that consideration of them here is not indicated. Although tubules may be seen in other testicular sex cord-stromal tumors, including those in the unclassified group, their differential does not generally revolve around "tubular" tumors. The converse is true, however, for the Sertoli cell tumor, the prototypical tubular tumor of the testis with which I begin.

Sertoli Cell Tumors
As a number of studies of these tumors have appeared recently [3, 4, 5, 6] and I have reviewed them twice in recent times [7, 8] I will not repeat basic clinical and gross aspects easily gleaned from these sources but will rather focus on the issue of the differential diagnosis which has become much clearer based to a large extent on the new information that has accrued from the various studies just noted.

There is one particularly distinctive form of Sertoli cell tumor of the testis, the large cell calcifying Sertoli cell tumor [9, 10, 11] . Occasional other tumors have marked sclerosis and are descriptively referred to as sclerosing Sertoli cell tumors [6]. Unusual Sertoli cell lesions with their own distinctive features occur in boys with Peutz-Jeghers syndrome [12, 13] . Finally, the majority of neoplasms are not in any of the above categories and are simply referred to as Sertoli cell tumors, not otherwise specified [5]. These neoplasms will be discussed as a group below with specific comments where indicated on the special variants.

Microscopic examination shows a spectrum from well differentiated neoplasms with exquisite tubular differentiation to poorly differentiated neoplasms with limited tubular differentiation. Low-power examination often shows striking nodular aggregate of tubules separated by acellular fibrous stroma. The tubules may be hollow, sometimes dilated, or solid. The hollow tubules are usually relatively regular in size and shape but may be irregular. They may be lined by lipid-rich cells but this cell type rarely predominates. Hyalinization around tubules is seen in the peculiar Peutz-Jeghers associated lesions [13]. Thick ribbons and occasionally delicate thin cords may also be present. Rarely the tubules produce a striking ramifying pattern and exceptionally they have a retiform morphology. The usually fibrous stroma may be extensively hyalinized and rupture of blood vessels may result in recent or old hemorrhage. Rare tumors have a diffuse pattern which, particularly when associated with cells with clear cytoplasm and an inflammatory cell infiltrate, may simulate the alveolar pattern of seminoma.

The tumor cells are typically polygonal with moderate to abundant amounts of pale to cytoplasm; vacuoles, due to intracytoplasmic lipid, are conspicuous in almost half of them. A minority (<20 %) of tumors overall have cells with abundant eosinophilic cytoplasm but such are the exclusive cell type in the large cell calcifying tumor which also definitionally have calcified regions, sometimes large mulberry-like masses. Tumors with a well-differentiated tubular morphology generally have absent or infrequent mitotic figures but rarely the mitotic rate is brisk, particularly in tumors with a diffuse growth. In one series of 60 unselected Sertoli cell tumors, NOS only 16% had brisk mitotic rate [3]. Nuclear atypicality is mild at most in about 90% of the tumors [3]. Nuclear grooves may be seen but are generally inconspicuous.

Differential Diagnosis
The tubular pattern of the well-differentiated tumors should be diagnostic in the great majority of cases. Some tumors with a diffuse pattern of cells with abundant eosinophilic cytoplasm can suggest a Leydig cell tumor but focal true tubular differentiation excludes the latter diagnosis. Only two issues are focused on here, tumors with a diffuse pattern versus seminoma and those associated with the large cell calcifying Sertoli cell tumor. Other entities discussed later are obviously also in the differential to varying degrees.

Confusion of malignant Sertoli cell tumors with a seminoma-like low-power pattern and seminoma may be a clinically consequential error [14]. For the most part the clinical background is of no aid although five of the 13 seminomas-like Sertoli cell tumors recently reported occurred in men over 55 years, when typical seminoma is uncommon. Grossly the Sertoli cell tumors are more often firm with some yellow aspect to their sectioned surface but ultimately microscopic differences are crucial. Although the inflammatory cell infiltrate, with even germinal center formation in a few cases, is one of the confusing issues it is also pertinent to note that this infiltrate more typically contains many plasma cells than does the infiltrate in seminomas. Areas of definite tubular differentiation are of course helpful but were prominent in only 3 of the 13 seminoma-like Sertoli cell tumors being considered here. Cytologic differences between the cells and the two tumors are most important. Nine of the Sertoli cell tumors had distinct cytoplasmic vacuoles, an often helpful clue to the diagnosis of Sertoli cell tumor, even on low power examination. Most importantly, the nuclei of the Sertoli cell tumors were generally smaller with less prominent nucleoli than those of seminoma and had rounded rather than "squared-off" nuclear contours, the latter being typical of seminoma nuclei. Five Sertoli cell tumors did, however, have prominent nucleoli indicating the overlap that can make this a difficult interpretation. It should also be noted that both tumors may have cytoplasmic glycogen. A granulomatous infiltrate, if present, would favor seminoma not having been seen in a Sertoli cell tumor to out knowledge, so also would intratubular germ cell neoplasia in adjacent seminiferous tubules. The above differences and immunohistochemical ones will enable the two neoplasms to be distinguished provided the pathologist is aware of this pitfall.

On microscopic examination the large cell calcifying Sertoli cell tumor [9, 10, 11] has various patterns, sheets, nests, ribbons or cords, and small clusters but at least focally solid tubules are present and they are often conspicuous. They may be multifocal. The large oxyphilic cells and calcification should make the diagnosis straightforward. In contrast to other sex cord tumors, intratubular growth is relatively frequent. The majority of the neoplasms have bland cytologic features but rare neoplasms are locally infiltrative, sometimes with atypical cytologic features and some of these neoplasms have been clinically malignant. Rare testicular Sertoli cell tumors resemble this tumor except that they lack the defining calcification.

Germ Cell Tumors with a Tubular Pattern

1. Non-Seminomatous Primitive Germ Cell Tumors
   
   Tubules are most familiar within the embryonal carcinoma and generally do not pose any issue in differential diagnosis, having the classic appearance of the primitive glands of that neoplasm. Occasionally the glands have a somewhat more differentiated morphology and viewed in isolation can mimic tubules of other neoplasms, but the "company they are keeping" is generally enough to make it readily evident what they are. A similar comment pertains to occasional non-specific appearing tubules that occur in the yolk sac tumor of the testis.
   
   
2. Seminoma
   
   Much more challenging diagnostically than the above are tubular formations that may be seen in the seminoma. That the seminoma may have a tubular pattern has been recognized for some time [14, 15, 16, 17, 18, 19, 20] but only an upcoming study of 28 seminomas with various unusual patterns, including tubular, presents an appreciable number of cases [21]. In that series cases tubules were seen in almost half the 28 cases. Seminomas with this variant morphology do not appear to differ clinically or grossly from conventional seminomas, but the unexpected findings under the microscope may result in considerations as diverse as Sertoli cell tumor and yolk sac tumor. Sertoli cell tumor is suggested when solid tubules are present and indeed the low- power mimicry of Sertoli cell tumor can be quite remarkable inasmuch as the pattern is associated with the characteristic abundant clarity of cell cytoplasm of seminoma, which imparts a resemblance to the lipid-rich cytoplasm of some Sertoli cell tumors. In other seminomas small, round, hollow tubules are present. Although somewhat confusing, these are actually so different from the formations seen in other testicular tumors that, particularly given the background, they should not really cause too much difficulty. They can be problematic when they become dilated and result in microcysts, which occasionally become somewhat irregular in their shapes and can result in a pattern that brings to mind the microcystic pattern of yolk sac tumor. Compounding the problem in some of these cases is that in almost half of them the tumors have a dearth of the characteristic lymphocytic infiltrate of seminoma. However, the cytologic features of the tumor cells in the areas with tubules are the familiar ones of typical seminoma and as in evaluating gonadal tumors in general, particularly the germinomas, architecture and low power each have to be given emphasis, attention to one or the other in isolation occasionally leading to errors in diagnosis. With regard to specific the differential diagnosis with yolk sac tumor, it is relevant to point out that in the yolk sac tumor spaces that are present have a more random individual morphology and distribution. Additionally the cells lining microcysts are often at least focally flattened with compressed nuclei in contrast to familiar the large cells with abundant cytoplasm that typify the usual seminoma cells. It should be remembered that the yolk sac tumor, just to complicate things, can have solid foci that can suggest seminoma, but those cells typically have less prominent nucleoli than those of seminoma.
   
   Establishing the diagnosis of seminoma with a tubular pattern is obviously aided in this era by immunostains. Tubular seminomas are positive for FLAP, c-kit, and OCT 3/4, these being negative in Sertoli cell tumors which conversely are inhibin and calretinin positive [22, 23, 24] .
   
   
3. Monodermal Teratomas
   
   A germ cell tumor that can have a striking tubular pattern and that can be confused with a Sertoli cell tumor is the carcinoid tumor, by far the commonest monodermal teratoma of the testis [25]. Most testicular carcinoids have the distinctive insular pattern of that neoplasm, albeit often punctuated by tubules. High-power scrutiny will show the typical cytologic features of carcinoid, and if any doubt should remain about the diagnosis, immunohistochemical stains can obviously aid in the distinction between carcinoid and Sertoli cell tumor. Of course if a tubular tumor of the testis is associated with other teratomatous elements that excludes the diagnosis of Sertoli cell tumor.
   
   Other germ cell tumors such as teratomas and primitive neuroectodermal tumors [26] may have tubules but associated features result in the differential, rarely, if ever, being that of a "tubular tumor."

Paratesticular Neoplasms
Although it could arguably be considered juxtatesticular or even testicular lesions in the rete are usually considered separately and it is pragmatically convenient to consider Sertoliform rete cystadenomas here [27]. Although the tubular pattern of this rare neoplasm is indistinguishable from that of Sertoli cell tumors, the location and cystadenomatous nature set them apart and impart a distinctive picture, particularly on low power. Rare frankly malignant rete carcinomas can also occasionally have a Sertoli form tubular pattern.

Each of the familiar mesothelial neoplasms of the testicular adnexa, adenomatoid tumor, and malignant mesothelioma may have a striking tubular pattern. Simple appreciation of the location of the neoplasm can be crucial in leading to the correct diagnosis. Although adenomatoid tumors can impinge upon the testis, they are based either in the tunica albuginea or beyond it in the great majority of cases. It should be acknowledged that some Sertoli cell tumors may be eccentric and abut the tunica, but that having been said, in the usual case there is a significant difference in the location of adenomatoid tumor versus Sertoli cell tumor. A similar comment pertains, of course, to malignant mesothelioma [28], which furthermore usually has a much more diffuse ill-defined gross nature contrasting with Sertoli cell tumors which are well-circumscribed, discrete neoplasms.

On microscopic diagnosis the typical vacuolar formations of adenomatoid tumor are crucial to identify to establish the diagnosis of that neoplasm, although they can be treacherously limited in extent in some cases and we have certainly encountered rare neoplasms dominantly having the solid pattern of adenomatoid tumor, or a tubular pattern viewed in isolation consistent with Sertoli cell tumor, that had been hard to sort out from Sertoli cell tumor. This is particularly so in the cases of infarcted adenomatoid tumor in which diagnostic lesional tissue that is easily recognizable can be minimal in amount [29]. Even in those cases, however, vacuoles can often be identified in a necrotic background and in the more usual case of a non-infarcted tumor, even a minimal vacuolar component is enough to suggest the right diagnosis and lead to immunohistochemical stains, which should readily distinguish adenomatoid tumor from Sertoli cell tumor.

Malignant mesotheliomas that have a tubular pattern are almost invariably associated with other patterns, particularly papillary which are inconsistent with a diagnosis of a Sertoli cell tumor [28]. Rare mullerian-type carcinomas of the testis and, more usually the adnexa, such as serous neoplasms and even more rarely endometrioid carcinomas can have tubules, or at least tubular glands which may be somewhat Sertoli-like on rare occasions but generally speaking significant overlap in morphology with a Sertoli cell tumor is not seen.

Metastatic Neoplasms
In the testis, just as is better known in the ovary, a variety of metastatic tumors to the testis may present a tubular morphology and cause varying degrees of diagnostic confusion. The Krukenberg tumor of the ovary is notorious for sometimes having a Sertoli-like tubular pattern and metastatic gastric cancer in the testis rarely elicits the same impression. Multifocality, vascular involvement, and adnexal involvement are three big clues to the diagnosis of metastatic gastric cancer, should they be seen. Moderately to highly atypical glands of straightforward adenocarcinomatous type are usually also seen. The differential of metastatic carcinoid is as with primary carcinoid except that in secondary cases the aforementioned features suggestive of metastatic disease in the testis, multifocality, vascular invasion and adnexal involvement may also help; of course so also will a primary site if known. Rarely other neoplasms such as malignant melanoma, because of a nested pattern, or renal cell carcinoma because of hollow tubules may be confused with a Sertoli cell tumor [30, 31] .

Role of Immunohistochemistry in the Differential Diagnosis of Tubular Tumors of the Testis
The differential diagnosis of seminoma versus Sertoli cell tumor can be facilitated by staining for markers of seminoma or Sertoli cell tumor, respectively. This includes well known markers such as PLAP for seminoma and a recently described marker, nuclear transcription factor, Oct 3/4, which is consistently negative in sex cord tumors but positive in seminoma. Inhibin and calretinin positivity of course favors Sertoli cell tumor. One of the best known uses of immunohistochemistry, staining of prostate epithelial cells for PSA or PSAP, may have role in testicular pathology in confirming, or arguing against if negative, a diagnosis of metastatic prostatic carcinoma when tubular glands might suggest a Sertoli cell tumor. Markers specific for mesothelial cells may help distinguish adenomatoid tumor from a Sertoli cell tumor, calretinin, of course, not being discriminatory in this regard. Other rare uses of immuno may pertain but in general careful H & E evaluation and thorough sampling are more beneficial.

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