Search for residual prostate cancer on pT0 radical prostatectomy after positive biopsy Reported incidence of no residual prostate cancer -LRB- i.e. pathological stage pT0 -RRB- on radical prostatectomy ranges from 0.07 to 4.2 % . The incidence is higher after neoadjuvant endocrine treatment . The aim of this study was to search for residual cancer on radical prostatectomy -LRB- RP -RRB- specimens when an initial sampling failed to find the cancer in patients with positive biopsy . Our database of 1,328 consecutive patients whose biopsies and RP specimen were both examined at the Polytechnic University-United Hospitals of the Marche Region between March 1995 and June 2006 was reviewed . The radical prostatectomies were grossly completely sampled and examined with the whole mount technique . We identified eight patients -LRB- i.e. 0.6 % ; three untreated and five hormonally treated preoperatively , i.e. 0.3 and 0.8 % , respectively , of the total number of RPs included in the study -RRB- with positive biopsy and with no residual cancer in the initial routine histological examination of the RP . The RP of this group of eight was subjected to additional sectioning and evaluation of the paraffin blocks of the prostatectomy , also after block-flipping , immunostaining with an antibody against CAM 5.2 , p63 , PSA , and alpha-methylacyl-CoA racemase , and DNA specimen identity analysis . There were no cases with a false positive biopsy diagnosis , and cancer was not overlooked or missed in the initial routine histological examination of any of the 8 pT0 RPs . A minute focus of cancer -LRB- the diameter was always below 2.0 mm -RRB- was found on the additional sections in five . In particular , cancer was found after block-flipping in one of them . In an additional case , cancer was eventually discovered after immunostaining tissue sections for cytokeratin CAM 5.2 , for p63 and PSA . In the remaining two cases -LRB- one untreated and the other hormonally treated -RRB- , cancer was not found -LRB- 0.15 % of the 1,328 RPs included in the study -RRB- ; the review of the description of the macroscopic appearance of the RP and of its slides revealed that part of the peripheral zone corresponding to the site of the positive biopsy was missing , i.e. not removed from the patient at the time of the operation at least in one of the two . DNA specimen analysis confirmed the identity of the biopsy and prostatectomy in both . An extensive search for residual cancer reduces the number of pT0 RPs after a positive biopsy from 0.6 to 0.15 % . It is recommended to have the needle biopsy reviewed , carefully look again at the radical prostatectomy , do deeper sections and then flip certain paraffin blocks . In addition , atypical foci should be stained for basal cell markers and often AMACR , especially in hormone-treated cases . If a block is missing part of the peripheral zone -LRB- capsular incision -RRB- , this should be commented on . DNA analysis for tissue identity should be performed when the other steps have been taken without finding cancer . Introduction In 1995 , Goldstein et al. -LSB- 9 -RSB- introduced the term vanishing cancer phenomenon referring to cases with minute or no cancer on radical prostatectomy after a positive biopsy . They reported 13 patients with minimal -LRB- 11 patients -RRB- or no -LRB- two patients -RRB- cancer in prostatectomy specimens . In two cases with no residual cancer on RP , they confirmed the identity of the biopsy and the prostatectomy tissue by DNA matching . The Johns Hopkins Hospital group documented a fivefold increase in the incidence of no residual cancer on prostatectomy in patients in whom both biopsies and prostatectomies were performed at that institution between 1997 and 2005 -LRB- 0.07 % in 1997 , 0.13 % in 2004 and 0.34 % in 2005 -RRB- -LSB- 5 , 7 , 30 -RSB- . In their first study , they also documented two cases , one in which the biopsy review revealed only high-grade PIN and in which a diagnosis of cancer had been established in another institution , and a second case in which the possibility of specimen switching could not be ruled out due to DNA mismatch between the biopsy and the prostatectomy . Most recently , they have reported a series of 46 patients , 11 with no residual cancer on prostatectomy and 35 with minute cancer , and in 40 cases , they documented specimen identity -LSB- 5 -RSB- . In five of the six remaining cases , the results could not be interpreted due to technical problems , and in one case , the tissue from the biopsy with cancer did not match the tissue from the radical prostatectomy . Bostwick and Bostwick -LSB- 4 -RSB- found that 38 patients with no cancer on prostatectomy , identified among 6,843 radical prostatectomies performed at Mayo Clinic during a 30-year period , showed no disease recurrence or progression after a mean follow-up of 10 years . In their experience , the incidence of vanishing cancer declined tenfold , comparing prostatectomies performed before 1980 -LRB- 2.1 % incidence -RRB- to a more recent time interval from 1993 to 1995 -LRB- 0.2 % incidence -RRB- . They have estimated the current incidence of vanishing cancer at 2 per 1,000 radical prostatectomies -LSB- 4 -RSB- . Recently , Trpkov et al. -LSB- 28 -RSB- found an incidence of no residual cancer on prostatectomy of 0.67 % after ten-core positive biopsy . They concluded that in most cases , finding no residual cancer on prostatectomy after additional sectioning and evaluation may indicate minimal patient disease . Very recently Zynger et al. -LSB- 32 -RSB- reported that their frequency of finding no residual cancer in RP specimens has increased from 0 % in 2002 to 4.2 % in 2006 . In Canada , Srigley -LSB- 25 -RSB- has estimated the incidence of no residual cancer after positive biopsy in his practice at less than 0.5 % . In Germany , the incidence of pT0 in patients with prostate cancer without neoadjuvant treatment was analysed by Herkommer et al. -LSB- 13 -RSB- . Based on a database of 3,609 patients , no residual prostate cancer was found in 0.8 % after RP . Most men in this pT0 series had previous TURP or open prostatectomy , which may have eliminated prostate cancer , whereas in two patients , cytology was used for primary diagnosis . Only in 0.3 % of men with positive prostate needle biopsies was no residual tumour detected in the prostatectomy specimen -LSB- 13 -RSB- . The incidence of pT0 patients in a very recent French study was reported to be 0.5 % -LSB- 6 -RSB- . No residual cancer may also result from preoperative endocrine therapy -LSB- 11 , 12 , 15 , 16 , 19 , 24 , 26 -RSB- . The incidence of pT0 after neoadjuvant endocrine therapy for prostate cancer is reported to be higher than in untreated patients -LSB- 11 -RSB- . Kollermann et al. -LSB- 16 -RSB- analysed a group of 174 men who underwent prolonged androgen deprivation therapy and observed a pT0 in 36 of 174 men -LRB- 21 % -RRB- . Several questions are addressed to explain why cancer is not present in a small proportions of prostatectomies . Cancer is missed during the examination of the RP , all prostatectomy tissue is not sampled , and the cancer is overdiagnosed in the biopsy . Pathologists face additional challenges in eliminating the possibility of laboratory error resulting in specimen -LRB- blocks , slides -RRB- mislabelling or switching and excluding an information system error resulting in specimen mix-up -LSB- 28 -RSB- . The aim of this paper was to report the results of a search for residual cancer on RP after an initial stage pT0 evaluation in eight patients with positive biopsy . Materials and methods We reviewed our database of 1,328 consecutive patients whose biopsies and RP specimen were examined between March 1995 and June 2006 at the five Pathological Anatomy Services associated with the Polytechnic University-United Hospitals of the Marche Region , Ancona , Italy . Most of the biopsies and all the RPs of this series of 1,328 patients were reported by the same pathologist -LRB- RM -RRB- . Seven hundred patients were untreated before the operation , whereas 628 had received neoadjuvant endocrine treatment for approximately 3 to 6 months . The biopsies and RPs were routinely processed as follows . The core biopsies from each site were submitted in separate containers . In brief , during biopsy processing , no more than two biopsy cores were embedded in paraffin blocks , and all blocks were sectioned at 3 μm and were stained with haematoxylin -- eosin -LRB- HE -RRB- . All cores were sectioned in two separate levels represented on separate slides , with each slide containing three additional sections -LSB- 28 -RSB- . All radical prostatectomy specimens -LRB- tissue was not harvested for research -RRB- were fixed en bloc in 10 % buffered formalin for at least 24 h and were grossly completely sampled using a standard protocol -LSB- 17 , 18 , 28 -RSB- . In particular , each specimen was painted over the surface with India ink . The seminal vesicles were amputated at the prostate junction and were grossly completely sampled . The remainder of the specimen was serially cut with a domestic electric food slicer calibrated and set to deliver slices which are 3 -- 4 mm in thickness , representing transverse planes parallel to the initial apical and basal sections . Each prostate slide was processed into complete whole mount section , and one HE slide was routinely sectioned per block . The apical and basal transverse 2 - to 3-mm margins were sectioned perpendicularly to assess the prostatic apical and basal margins . Prostatectomies were grossly sectioned in 8.5 slices -LRB- mean ; range , 6 -- 16 -RRB- , and 15.3 slides -LRB- mean ; range , 10 to 20 -RRB- were generated per prostatectomy . Slides from pelvic lymph nodes were not included in the reported number of examined slides . We identified eight patients with positive 6 - to 12-core biopsy and with no residual cancer -LRB- pathological stage pT0 -RRB- in the initial routine histological examination of the RP and successively subjected to additional sectioning and evaluation . Search for residual cancer Since 1995 , a special cancer searching protocol has been applied to those RPs in which an initial routine-based examination does not show residual cancer -LSB- 18 -RSB- . As mentioned earlier , this is basically done in those cases whose biopsies and RP specimen are both examined at the Ancona institution . The following successive steps were undertaken by two pathologists -LRB- RM and RMa -RRB- . The procedure was usually stopped at the step where cancer is found . The diagnostic needle biopsies were reviewed to exclude the possibility of a false positive biopsy diagnosis and to assess the approximate location of the biopsy with tumour , such as apex , mid-zone and base , both left and right.The slides of the surgical specimens were reviewed for residual cancer that was initially overlooked or missed.If the prostate was not totally embedded , the remaining prostate tissue was processed in toto . If the prostate was completely sampled , then this step was skipped . This type of information was usually contained in the pathology form where the all the steps of the processing procedure were recorded . The information was further confirmed by searching the specimen 's container for residual pieces . As we routinely sample completely all prostatectomies , this step was skipped.Additional deeper sections -LRB- i.e. three to five sections -RRB- of the prostatectomy area -LRB- paraffin block -RRB- corresponding to the location of the core with cancer were re-cut . Further sections were also obtained from all the other paraffin blocks.Additional deeper sections -LRB- i.e. three to five sections -RRB- of the area corresponding to the location of the positive core as well as of all the remaining blocks were re-cut after block-flipping . Immunostains for p63 and alpha-methylacyl-CoA racemase -LRB- AMACR -RRB- were performed to evaluate suspicious foci -LRB- When these two were not yet available , we used 34betaE12 immunostaining -RRB- . Immunostain for cytokeratin CAM 5.2 , for p63 and for PSA -LRB- prostate specific antigen -RRB- was performed to identify the so-called `` minimal residual cancer '' especially in patients receiving neoadjuvant hormonal therapy -LSB- 17 -RSB- . Review the description of the macroscopic appearance of external and cut surfaces of the surgical specimen as well as inspect the contour of the tissue sections on the slides for hint or clues that might indicate that part of the tissue was missing either due to the surgical procedure or for technical reasons.DNA specimen analysis was performed on formalin-fixed tissue to confirm the identity of the biopsies and prostatectomies whenever necessary . DNA specimen identity analysis Tested samples in an individual case included the biopsy core with cancer and a random block for the corresponding RP . The tissue was obtained as a direct section from formalin-fixed and paraffin-embedded blocks . DNA was extracted from paraffin-embedded tissue using the QIAmp DNA mini kit -LRB- Qiagen -RRB- according to manufacturer 's protocol -LRB- Promega , Madison , WI , USA -RRB- . Fifteen microsatellites and amelogenin locus were co-amplified by the AmpFlSTR identifiler kit -LRB- Applied Biosystems , Foster City , CA -RRB- , and the amplified fragments were electrophorized on an ABIPrism3130 genetic analyzer -LRB- Applied Biosystems -RRB- . Fragment sizing and allele designation were established by GeneMapperID v3 .2 software -LRB- Applied Biosystems -RRB- , and genetic profiles from both biopsy and prostatectomy samples were compared . Results Residual cancer was not found in eight RPs after an initial routine examination . They represent 0.6 % of the 1,328 consecutive patients . Three -LRB- 0.2 % -RRB- of them were from the group of untreated patients , whereas five -LRB- 0.4 % -RRB- were from those who had received neoadjuvant treatment . The latter figure represents 0.8 % of the treated patients . Patients ' clinical data are summarised in Table 1 . The mean age of the patients was 65 years -LRB- range , 58 -- 71 years -RRB- . Mean serum PSA pre-biopsy was 5.1 ng/ml -LRB- range , 1.25 -- 9.0 ng/ml -RRB- . Mean gland volume was 43.9 ml -LRB- range , 28.1 -- 93.5 ml -RRB- . Digital rectal examination was abnormal in 37 % of patients , and 25 % of patients had abnormal transrectal ultrasound . Table 1Patients ' clinical dataPatient no.Age -LRB- years -RRB- PSA Prebiopsy -LRB- ng/ml -RRB- Digital rectal examinationTRUSGland volume -LRB- cc -RRB- 1689.0 AbnormalNormal47 .92715.4 NormalAbnormal31 .43646.1 NormalNormal28 .14671.25 AbnormalNormal93 .55605.9 NormalNormal36 .66663.0 AbnormalNormal47 .97583.9 NormalAbnormal29 .38666.5 NormalNormal36 .6 Mean -LRB- range -RRB- 65 -LRB- 58 -- 71 -RRB- 5.1 -LRB- 1.25 -- 9.0 -RRB- 43.9 -LRB- 28.1 -- 93.5 -RRB- PSA Prostate-specific antigen ; TRUS transrectal ultrasound Patients ' biopsy findings are shown in Table 2 . In all patients , carcinoma was found in one core . Seven patients demonstrated biopsy Gleason score of 6 -LRB- 3 + 3 -RRB- , whereas in one , it was 7 -LRB- 3 + 4 -RRB- . Cancer occupied approximately 5 % of the core length -LRB- Fig. 1 -RRB- in 6 and 10 % of the core in two . The positive biopsy location was variable , and there was no side predilection . Table 2Biopsy findingsPatient no.No . of positive coresGleason scoreCancer length -LRB- % of involvement -RRB- Positive core location11/123 + 3 = 65Right apex21/103 + 4 = 710Right apex31/63 + 3 = 65Left mid-zone41 / 63 + 3 = 65Right mid-zone51 / 63 + 3 = 65Right mid-zone61 / 123 + 3 = 610Left mid-zone71 / 103 + 3 = 65Right mid-zone81 / 123 + 3 = 65Left baseFig . 1Biopsy finding of a small groups of atypical acini -LRB- a -RRB- devoid of basal cells -LRB- b -RRB- . Section immunostained for p63 -LRB- case no. 5 -RRB- . The diagnosis is acinar adenocarcinoma , Gleason score 3 + 3 = 6 . -LRB- The prostatectomy findings are those seen in Fig. 2 -RRB- Search for residual cancer There were no cases with a false positive biopsy diagnosis -LRB- step 1 -RRB- . Cancer was not overlooked or missed in any of the eight prostatectomies -LRB- step 2 -RRB- . Each prostate had been totally embedded -LRB- step 3 -RRB- . Cancer was found on deeper sections -LRB- steps 4 and 5 -RRB- in five cases . Cancer was in the right and left apex , respectively , in two of them . Cancer was in the mid-zone in another two , one in the left and the other in the right . The fifth was in the left base . In particular , the cancer found in the right apex was discovered after block-flipping -LRB- i.e. step 5 ; Fig. 2 -RRB- . The location corresponded to site of the positive biopsy in four cases . Two out of five cases were from the untreated group and showed a Gleason score of 3 + 3 = 6 . Three cases had the morphologic appearance of cancer with evident regressive changes due to endocrine therapy . The diameter of the tumour , measured on the slides , was always below 2.0 mm . In one of the three treated cases , an additional focus of cancer was seen at a distance from to that of the positive biopsy . Fig. 2Paraffin blocks , original sections and additional sections before and after block-flipping in case no. 1 . a Is the right apex . b Is the left apex . c Includes the whole mount sections of the body of the prostate . d Is the right and left base . e Includes the seminal vesicles and deferens . A1 is the paraffin block . A2 is the original H-E-stained section . A3 includes the additional sections before block-flipping . A4 refers to the additional sections after block-flipping -LRB- Block-flipping was done only for a and b -RRB- . The dotted area -LRB- see also the red arrow -RRB- on the A4 slides is that of the cancer . It corresponds to the lesion of the biopsy seen in Fig. 1 . The same identification procedure applies to b. Concerning c and d the paraffin blocks , the original sections and the additional sections -LRB- block-flipping was not done -RRB- are shown . For e the paraffin blocks and the original sections are shown . -LRB- Other slides contain some annotations and abbreviations to indicate additional findings , slide orientation , and section order , etc. -RRB- The definitive diagnosis was established on steps 6 and 7 in an additional case -LRB- the patient was hormonally treated before RP -RRB- where cancer was not seen in the additional sections even after block-flipping . Immunohistochemistry for p63 and AMACR was applied to a small suspicious focus of crowded acini . There were a few scattered p63 positive -LRB- basal -RRB- cells , whereas AMACR was negative . The focus was considered to be benign -LRB- i.e. atrophy -RRB- . Cancer was discovered after immunostaining for cytokeratin CAM 5.2 , for p63 and PSA . It was represented by scattered isolated cells positively immunostained with the antibody against CAM 5.2 -LRB- Fig. 3 -RRB- and with PSA and negative for p63 -LRB- Fig. 3 -RRB- . The diameter of the focus was 1.0 mm . The block selected for immunohistochemistry corresponded to an H&E - stained slide with hypercellular stroma . There was no exact correspondence with the site of the positive biopsy . Fig. 3Cancer is discovered after immunostaining for cytokeratin CAM 5.2 -LRB- case no. 6 -RRB- . It is represented by scattered isolated cells . The same cells are negative for the basal cell marker p63 and positive for PSA . Part of an atrophic duct is also present In the remaining two cases -LRB- one untreated and the other treated preoperatively -RRB- , cancer was not found on steps 4 through 7 . The review of the description of the macroscopic appearance and the inspection of the contour of the tissue sections on the slides revealed that part of the peripheral zone of the prostate was missing -LRB- Fig. 4 -RRB- . This corresponded to the location of the positive biopsy -LRB- step 8 -RRB- . DNA specimen analysis confirmed the identity of the biopsy and prostatectomy in both cases -LRB- step 9 ; Table 3 -RRB- . Incidentally , prostate tissue was documented clinically in one of the two patients -LRB- patient no. 7 , hormonally treated before operation ; the same patient whose prostate is shown in Fig. 4 -RRB- . In particular , a biopsy of the residual fragment showed normal prostate tissue and adenocarcinoma with features identical to those seen in the preoperative biopsy . Fig. 4Whole mount section -LRB- case no 7 -RRB- . Part of the peripheral zone , posteriorly , is missingTable 3Results of the search for residual cancerPatient no.Neoadjuvant treatmentCancer foundID test done1NoIn recutNo2NoIn recutNo3YesIn recutNo4YesIn recutNo5YesIn recut after block-flippingNo6YesAfter cytokeratin stainNo7YesNot in RPaYes , identical8NoNoYes , identicalaA post-operative biopsy of the residual prostate fragment in the patient showed normal prostate tissue and adenocarcinoma with features identical to those seen in the preoperative biopsy . Discussion Reported incidence of no residual cancer on RPs ranges from 0.07 to 4.2 % -LRB- 1 -- 11 , 20 -RRB- . It is higher after neoadjuvant hormonal treatment -LSB- 16 -RSB- . There are multiple reasons why cancer may not be found on RP after a positive biopsy . In some cases , the cancer may be minute and completely removed by the initial procedure , either needle biopsy or transurethral resection of prostate . Small cancers may be removed from the RP during the technical preparation of the specimen , such as leveling of the paraffin blocks . Small cancer foci can also be completely obscured if the patient has undergone antiandrogen therapy or the RP shows extensive inflammation or granulomatous inflammation . Other reasons include false-positive diagnosis on the initial biopsy , resulting in cancer overdiagnosis , or false-negative diagnosis rendered on the RP . Review of the material by a second pathologist or a specialist in urological pathology can often resolve the latter scenario . Lastly , errors may occur either before a specimen is submitted for pathological assessment or in the pathology laboratory . These errors include switching of patients ' requisitions , mislabelling or switching of specimen containers , mislabelling or switching slides or blocks and information system errors -LRB- e.g. incorrect case entry in the information system or mixed accession numbers -RRB- -LSB- 28 -RSB- . In our study , the incidence of RPs with no residual cancer after an initial routine examination of the 1,328 specimens was 0.6 % . This figure includes both untreated and hormonally treated patients . The incidence was 0.2 and 0.4 % , respectively , of the total number of RPs included in the study , or 0.4 % -LRB- 3 out 700 untreated patients -RRB- and 0.8 % -LRB- 5 out 628 treated patients -RRB- when the two groups were considered separately . The former is well in the range of values reported in the literature for untreated patients and very close to the figure published by Herkommer et al. -LSB- 11 , 13 -RSB- . The latter value seen in our treated patients is much lower than that observed by Kollermann et al. -LSB- 16 -RSB- . Additional sectioning and evaluation of the cases can reduce the number of pT0 RPs after a positive biopsy . In particular , the current study showed that the final incidence was 0.15 % and included only two RPs with missing parts , probably due to incomplete removal of the prostate . One of these two patients was hormonally treated preoperatively . Our findings on the role of immunohistochemistry to detect residual PCa cells are in agreement with previous studies . Gleave et al. -LSB- 8 -RSB- found that 50 % of the cases that exhibited no residual cancer on routine pathologic assessment had remaining foci of cancer discovered by immunostaining . Without the aid of additional step sections and immunostaining for cytokeratin , these cases would have been reported as being stage pT0 -LSB- 2 -RSB- . DNA identity on formalin-fixed tissue from the paraffin blocks is a useful test to establish specimen identity and to exclude the possibility of laboratory error when no residual cancer is found on RP after a positive biopsy . In particular , DNA analysis is a useful test that eliminates the possibility of specimen mishandling or switching by establishing the identity of the tissue from the positive biopsy and the RP . It can be performed in the formalin-fixed tissue from the paraffin blocks . Different methods are used to investigate tissue specimen identity . These include immunolabeling of blood group antigens -LSB- 22 -RSB- , sex chromosome targeting using fluorescence in situ hybridization -LSB- 21 -RSB- and microsatellite analysis . According to some authors , microsatellite analysis is the gold standard for investigating tissue identity -LSB- 1 , 10 , 23 , 28 , 31 -RSB- . In our study , the clinical and the biopsy data in patients with no initial residual cancer on radical prostatectomy after positive biopsy are similar to the findings from a recent study in patients with single-core positive biopsies and minimal cancer on biopsy -LSB- 28 , 29 -RSB- . The majority of patients with no residual cancer on prostatectomy demonstrated minute cancer foci in one or two biopsy cores with Gleason score of 6 , which , in many cases , may reflect minimal disease -LSB- 28 -RSB- . Rare small-volume cancers of higher grade may also be encountered -LSB- 28 -RSB- . Follow-up investigations have , in general , shown that no pT0 patient has clinical or biologic evidence of prostate cancer recurrence or progression -LSB- 6 , 14 , 20 , 27 -RSB- . There are four aspects that we have not explored in our study . One is that the carcinoma could be lost in facing off of the paraffin blocks . We are fully aware of this potential problem . Our technicians are instructed so that they have to collect tissue sections and not waste material when the paraffin blocks are levelled off . The second is whether the time , effort and expense of the sampling described in this paper are warranted on a routine basis for all pT0 cases . We have not done any analysis in these respects due to the fact that the number of cases is very small and that time and expense do not represent an issue of concern in our institution . The third is what degree of sampling would be necessary to serially section through the entire prostate . Probably thousands of sections would be required , and we were prepared to cut as many sections as needed to find cancer . The fourth is whether there is an outcome difference when the initial pT0 carcinomas are detected after more thorough sampling vs pT0 cases without additional sampling . This was not addressed in our study because the basic aim was to avoid that a pT0 report is rendered to the clinician and to the patient , thus triggering a potential legal issue with all the problems related to it . There are few observations in the literature on pT0 cases and preoperative diagnosis of cancer made in TURP specimens . The real incidence of no residual cancer after cancer detected by TURP material is not known and is reported to be seen in 6 to 39 % of cases -LSB- 9 -RSB- , presumably due to tumour ablation during the initial resection . However , studies of this phenomenon are limited by variations in the number of tissue sections submitted for histological evaluation and by the small number of cases -LSB- 3 -RSB- . Conclusions and recommendations The current study showed that an extensive search for residual cancer reduces the number of pT0 RPs after a positive biopsy . To achieve this , it is recommended to have the needle biopsy reviewed , carefully look again at the radical prostatectomy , do deeper sections and then flip certain paraffin blocks . In addition , atypical foci should be stained for basal cell markers and often AMACR , especially in hormone-treated cases . If a block is missing part of the peripheral zone -LRB- capsular incision -RRB- , this should be commented on . DNA analysis for tissue identity should be performed when the other steps have been taken without finding cancer .

O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O


Invasive carcinomas of the male breast : a morphologic study of the distribution of histologic subtypes and metastatic patterns in 778 cases The current investigation was conducted to evaluate the proportional distribution of the various histologic subtypes -LRB- including newly recognized variants -RRB- of male breast carcinomas , to determine whether any histologic subtypes occur with a frequency that is markedly discordant with the expected frequencies from published data on parallel female breast tumors . We also aimed to document the distribution of malignancies metastatic to the breast . Seven hundred fifty-nine archived cases of primary invasive carcinoma involving the male breast were retrieved and subcategorized into histologic subtypes according to contemporary criteria . Six hundred forty-three -LRB- 84.7 % -RRB- tumors were pure infiltrating ductal carcinoma -LRB- IDC -RRB- not otherwise specified . The most common of the remainder included papillary carcinoma with invasion in the form of IDC -LRB- n = 34 -RRB- , mixed IDC and mucinous carcinoma -LRB- n = 26 -RRB- , and pure mucinous carcinoma -LRB- n = 21 -RRB- . In 19 cases , metastases from other sites involved the breast , most commonly -LRB- 58 % -RRB- cutaneous melanoma . Invasive carcinoma of the male breast appears to display a morphologic spectrum and distribution of histologic subtypes that is comparable to those of the female breast , with some expected variation . Compared with published experience on their female counterparts , there is a two-fold increase in the frequency of invasive papillary carcinoma in the male breast . Finally , the most common tumor metastatic to the male breast in this series was cutaneous melanoma . Introduction Breast cancer in males is relatively uncommon , with approximately 1,450 newly diagnosed cases annually in the United States , and an associated mortality rate that accounts for less than 0.2 % of all cancer-related deaths in men -LSB- 1 , 4 , 9 , 15 , 17 , 20 , 28 -RSB- . However , recent epidemiologic studies suggest that the incidence of male breast cancer has been steadily increasing -LSB- 7 , 14 -RSB- . Utilizing data from the National Cancer Institute 's Surveillance , Epidemiology and End Results database for the 26-year period between 1973 and 1998 , Giordano et al. -LSB- 7 -RSB- found that the incidence of male breast cancer increased from 0.86 to 1.08 per 100,000 population . This increasing incidence , in addition to the better elucidation of the role of BRCA2 mutations in male breast cancer , has renewed interest in specifically identifying the underlying pathogenesis of male breast cancer and clarifying the specific differences , if any , between male and female breast cancer . On a broad demographical level , male and female breast cancers are fundamentally similar with the main differences lying in older age of occurrence and lower incidence of the former . However , significant differences have been noted between male and female breast cancers with respect to the expression of a variety of biologic factors , including hormone receptors such as estrogen receptor , progesterone receptor , c-erbB-2 , estrogen-inducible proteins such as pS2 , Cathepsin D , hsp27 , proteins related to basement membrane and extracellular matrix degradation such as the urokinase system of plasminogen activation and their inhibitors , and protooncogenes such as bcl-2 -LSB- 2 , 6 , 7 , 18 , 21 , 22 , 24 , 27 -RSB- . At the morphologic level , male ductal intraepithelial neoplasia -LRB- ductal carcinoma in situ -RRB- , in contrast to similar lesions in females , displays a distinct histologic profile in which the majority of tumors are of the papillary type , with cribriform , micropapillary , and solid types being much less common -LSB- 13 -RSB- . In particular , the comedo-type of DIN -LRB- comedo DCIS -RRB- is notably rare in the male breast -LSB- 13 -RSB- . For invasive carcinomas , the female and male tumors are morphologically indistinguishable -LSB- 26 -RSB- and many published studies on male breast cancer frequently represent the major histologic subtypes of nonlobular breast carcinoma , such as ductal , medullary , mucinous , and papillary -LSB- 3 , 7 , 8 , 12 , 19 , 22 , 25 -RSB- . However , these studies generally do not have the distribution and relative frequencies of the various histologic subtypes as their main focus , and as such , pathologically important distinctions such as signet ring vs colloid carcinoma -LRB- both subsumed under mucin producing carcinoma -RRB- , or metaplastic carcinoma vs infiltrating duct carcinoma not otherwise specified are not emphasized . Over - or underepresentation of a particular histologic subtype in male breast cancers may provide valuable insight into the etiopathogenetic differences between male and female breast cancers and may provide an important nidus for further studies . In this study , we investigated the frequencies and distribution of the various histologic subtypes in a large data set of invasive carcinomas seen at a large tertiary center over a 40-year period . Our goals are to document these frequencies and distribution and to see whether any histologic subtypes are notably distinct in frequency of occurrence in the male breast , as compared with historical published data on similar lesions in the female breast . The frequencies and sites of origin of metastatic tumors to the male breast during the study period were also investigated . Materials and methods After approval from our institutional research review committee , cases of invasive carcinoma involving the male breast diagnosed between 1957 and 1997 were retrieved from the archived institutional files of the Armed Forces Institute of Pathology -LRB- AFIP , Washington DC , USA -RRB- . The available records and slides on each patient were reviewed . All cases with ambiguous gender -LRB- even if one among the multiple entries for gender was coded as female rather than male -RRB- were excluded -LRB- n = 38 -RRB- . Diagnostic designations were assigned according to contemporary WHO criteria -LSB- 23 -RSB- . All special types of carcinoma inclusive of mucinous , tubular , secretory , adenoid cystic , lobular , metaplastic , etc. -LRB- n = 116 -RRB- were reviewed extensively ; many of these cases had been evaluated repeatedly as part of various previously published studies from the department and slides of good quality were available on these cases for review . Among the 643 cases of infiltrating duct carcinoma not otherwise specified , only cases with good quality and adequate representative slides -LRB- n = 365 -RRB- were graded , using the modified Scarf -- Bloom Richardson scoring system . On 78 cases , the slides were so old that we could only confirm the presence of a ductal type carcinoma . The other 200 cases did not have all of the patients ' slides pertaining to the lesion available and the final interpretation was based on the descriptions of morphology in the AFIP files . Because cases sent to AFIP are mostly for confirmation of diagnosis , information about therapy beyond what was in the surgical pathology report or the accompanying cover letter are generally not available . Some patients had repeated material sent to AFIP as the lesion recurred , which is how follow-up information was collected in a small subset of cases . Information about age , operative procedure , nodal excision , and distant metastases were retrieved from the patients ' AFIP files . Diagnostic designations were assigned largely based on morphologic and not immunohistochemical features since in many cases there were no blocks or unstained slides available for additional studies . Thirty of these cases were the subject of a previous report -LSB- 13 -RSB- , which focused on in situ carcinomas and were reported in 1998 . Another 113 cases , 8 of which were ductal in situ and another 9 papillary carcinomas , were subject of another report in 1969 -LSB- 19 -RSB- Cases of nonhematopoietic or lymphoreticular malignancies metastatic to the male breast during this period were also catalogued . Results Seven hundred and seventy-eight cases of breast carcinoma were reported as involving the male breast during the study period . Seven hundred fifty-nine of these cases were considered primary to the breast and 19 as metastatic to it . The patients ranged in age from 9 to 94 years -LRB- mean 61 years -RRB- . The age distribution available for 520 cases was as follow : 8 were ≤ 30 years , 22 were ≤ 40 years , 205 were 41 to 60 years , 251 were 61 to 80 years , and 34 were over 80 years of age . Among the 490 for whom the racial information was available , 401 were Caucasian , not of Hispanic origin , 82 were Black , not of Hispanic origin , 6 were Asians or Pacific Islander , 1 was Hispanic , and the race was unknown for 269 . The carcinomas ranged from ≤ 1 mm -LRB- microinvasive -RRB- to 12 cm . Many of the cases with multifocal early invasion of 1 to 7 mm were associated with large solitary or multifocal papillary intraductal carcinomas . The various histologic subtypes and their proportional distribution are outlined in Table 1 , whereas representative images are illustrated in Fig. 1 . Pure infiltrating duct carcinoma not otherwise specified was the most common histologic subtype , representing 84.7 % of all cases . Six hundred forty-three cases were in the latter group , including 34 cases associated with Paget 's disease , 17 cases with prominent apocrine features in < 50 % of tumor volume -LRB- i.e. , insufficient to qualify as apocrine carcinomas -RRB- , 4 cases with prominent medullary features -LRB- tumor circumscription , cellular syncytia , sparse lymphocytic infiltrate -RRB- , 2 cases of infiltrating duct carcinoma with signet ring cells -LRB- < 5 % of tumor volume -RRB- , 3 cases of infiltrating duct carcinoma with focal clear cells -LRB- < 5 % of tumor volume -RRB- , and 3 cases of carcinoma with osteoclast-like giant cells . Papillary intraductal carcinoma with invasion in the form of infiltrating duct carcinoma represented 4.5 % -LRB- 34/759 each -RRB- of all cases . Other well-represented histologic subtypes or combinations included mixed mucinous and infiltrating duct carcinoma -LRB- n = 26 , 3.4 % -RRB- , pure mucinous carcinoma -LRB- 21 , 2.8 % -RRB- , and adenoid cystic carcinoma -LRB- n = 8,1.05 % -RRB- . Other variants each constituted less than 1 % of all cases -LRB- Table 1 -RRB- . Notably , there were three cases of lobular carcinoma . As noted previously , these diagnoses were not based on immunohistochemical confirmation by immunostain for E-cadherin , but all three showed archetypal morphologic features of lobular carcinoma with loosely cohesive single cell files and rare intracytoplasmic lumens . Two of these cases had evidence of lobular development in the surrounding breast but the slides available for review did not show lobular intraepithelial neoplasia -LRB- LIN -RRB- . There were also three cases of mixed lobular and ductal carcinomas , in which these areas were spatially separate . The youngest patient , a 9-year-old boy was the only one with pure secretory carcinoma . Five of 759 cases were microinvasive -LRB- invasive focus less than 1 mm in maximum size in a predominantly intraepithelial lesion -RRB- ; three of these five cases were multifocal , whereas the other two were unifocal . Of the 365 cases of infiltrating duct carcinoma not otherwise specified that were graded , 104 were grade 1 , 137 were grade 2 , and 124 were grade 3 . Among the 93 with lymph nodes available for assessment , 61 -LRB- 66 % -RRB- cases had axillary metastases . Forty of the women with axillary node metastases also had distant metastases . The most common distant metastatic sites were lung , adrenal glands , and bone . In addition , there were 19 examples of metastases to the breast that were documented . Of these , 58 % -LRB- 11/19 -RRB- were cutaneous melanomas , and 21 % -LRB- 4/19 -RRB- , 10 % -LRB- 2/19 -RRB- , and 10 % -LRB- 2/19 -RRB- represented carcinomas from the prostate , lung , and larynx , respectively . Table 1Distribution of the various histologic subtypes in 778 invasive carcinomas involving the male breastHistologic subtypeNumber of casesPercentageInfiltrating duct carcinoma not otherwise specified , includinga64384 .7 Carcinoma associated with Paget 's disease34Carcinoma with prominent apocrine features17Carcinoma with medullary features4Carcinoma with osteoclast-like giant cells3Carcinoma with focal signet rings2Carcinoma with focal clear cells2Pleomorphic carcinoma2Carcinoma with no notable distinctive features579Papillary intraductal carcinoma with invasion in the form of infiltrating duct carcinoma344 .48 Mixed infiltrating duct and mucinous carcinoma263 .4 Pure mucinous carcinoma212 .8 Adenoid cystic carcinoma81 .05 Tubular carcinoma60 .8 Small cell carcinoma60 .8 Invasive lobular carcinoma30 .39 Solid neuroendocrine carcinoma30 .39 Mixed lobular and ductal carcinoma30 .39 Adenocarcinoma with spindle cell metaplasia20 .26 Pure signet ring carcinoma -LRB- no in situ component -RRB- 10.13 Invasive cribriform carcinoma10 .13 Secretory carcinoma10 .13 Squamous cell carcinoma10 .13 Total759100Metastatic lesions19Final total778aSubsets included for information only -LRB- not WHO categories -RRB- Fig. 1Representative pathologic images of the various histologic subtypes . a and b Gross and microscopic images of infiltrating duct carcinoma , the most frequently encountered histologic subtype -LRB- b original magnification × 160 -RRB- . c A colloid -LRB- mucinous -RRB- carcinoma -LRB- right field -RRB- occurring in a gynecomastoid breast -LRB- left field -RRB- -LRB- original magnification × 100 -RRB- . d The single case of a secretory carcinoma was in a 9-year-old boy , the youngest patient in this series -LRB- original magnification × 140 -RRB- . e and f Examples of papillary intraductal carcinoma with invasion in the form of infiltrating duct carcinoma -LSB- original magnifications : × 100 -LRB- e -RRB- , × 120 -LRB- f -RRB- -RSB- Discussion The frequency , distribution , and morphologic spectrum of the various histologic subtypes of male breast cancer as compared with its female counterpart may provide a valuable insight into the etiology and/or pathogenesis of both . This was perhaps best illustrated in the study of ductal carcinoma in situ by Hittmair et al. -LSB- 13 -RSB- . The authors showed that in the male breast , papillary DCIS occurred with a much higher frequency -LRB- 46 % of pure lesions -RRB- than expected , while solid , micropapillary , and cribriform patterns occurred with a much lower frequency -LRB- 22 % of pure DCIS combined -RRB- . Notably , only 5 of 114 cases were of comedo-type DCIS and only 7 of 114 cases were considered high grade . The authors concluded that predominance of papillary patterns among intraepithelial male breast lesions is a reflection of the relative abundance of ducts and the poorly developed terminal-ductal lobular units in male breast . Given the rarity of true comedo DIN in male breast , the authors speculated that the fully developed lobular environment and the female type hormonal milieu may be a requirement for development of comedo DIN -LSB- 13 -RSB- . In this study , we investigated in detail the frequencies and distribution of the various histologic subtypes in a large data set of invasive carcinomas seen at a large tertiary center over a 40-year period . Our findings suggest that invasive carcinoma of the male breast displays a morphologic spectrum and distribution of histologic subtypes that is comparable to invasive carcinoma of the female breast and that no specific histologic subtypes are notably over - or underrepresented with the exception of papillary and lobular variants . Papillary intraductal carcinomas basically assumed an infiltrating duct carcinoma pattern once they invaded the stroma -LRB- Fig. 1e , f -RRB- . A papillary component was present in 34 -LRB- 4.5 % -RRB- of 759 cases , representing the second most common histologic subtype . These papillary carcinomas appeared to have invaded either through massive expansion and total disruption of ductal confines with typical invasive patterns at their periphery or only focally disrupted the duct wall and invaded the surrounding stroma as an infiltrating duct carcinoma . The latter represents approximately 2 % -LSB- 5 -RSB- of female breast invasive carcinomas and appears overrepresented in males . In a large population-based study , Giordano et al. -LSB- 7 -RSB- reported that 2.6 % of invasive malignancies in males were papillary carcinomas , as compared with 0.6 % in females -LRB- p < 0.0001 -RRB- . However , the differences between males and females with respect to the frequencies of the other histologic subtypes were also statistically significant . The significance of the papillary histologic subtype or papillary architecture in male ductal carcinoma requires further investigation but is most probably related to the architecture of the male mammary duct system with dominance of larger ducts . The possibility of metastases to the breast should be considered when evaluating breast masses particularly if there is a history of cancer elsewhere . Nineteen cases of carcinoma metastatic to the male breast were seen over this study period , representing 2.4 % -LRB- 19/778 -RRB- of all nonhematopoietic or lymphoreticular malignancies . This is again a twofold increase comparable to the 1.2 % reported in female breast malignancies over a 10-year period -LSB- 11 -RSB- . Of the 19 metastatic tumors , 58 % -LRB- 11/19 -RRB- were cutaneous melanomas , and 21 % -LRB- 4/19 -RRB- , 10 % -LRB- 2/19 -RRB- , and 10 % -LRB- 2/19 -RRB- represented carcinomas from the prostate , lung , and larynx , respectively . It is interesting to note that prostatic carcinoma , which has been the subject of most reports of carcinomas metastatic to the male breast -LSB- 10 -RSB- , was not the most common metastatic tumor in this series . The number of metastatic tumors in this series is relatively small , which is a limitation in interpreting the distribution of originating sites . Nonetheless , in the investigation of metastatic tumors to the male breast of an unknown primary site , our findings provide additional data on some of the most likely sites . This study also confirms the occurrence of lobular carcinoma in the male breast . Three cases of invasive lobular carcinoma , diagnosed purely on a morphologic basis , were present among 759 cases -LRB- 0.4 % -RRB- . Three additional cases of mixed lobular and ductal carcinoma were also diagnosed over this period -LRB- 0.4 % -RRB- . Joshi et al. -LSB- 16 -RSB- found one -LRB- 4 % -RRB- lobular carcinoma out of 27 cases , while Goss et al. -LSB- 8 -RSB- found 4 -LRB- 1.9 % -RRB- cases out of a total of 229 . In the series of Giordano et al. -LSB- 7 -RSB- , lobular carcinomas constituted 1.5 % for their male breast cancers . It is noteworthy that all of these cases were interpreted as lobular based on morphology without E-cadherin immunostain confirmation . In summary , invasive carcinoma of the male breast appears to display a morphologic spectrum and distribution of histologic subtypes , which is comparable to invasive carcinoma of the female breast with some variation . As expected , lobular carcinoma is exceedingly rare but was encountered in this series . There appears to be a twofold increase in the frequency of invasive papillary carcinoma and metastatic cancers to the male breast as compared to published data in the female breast . Finally , the most common tumor metastatic to the male breast in this series was cutaneous melanoma .

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