Mixed Primary Small Cell Carcinoma of Prostate and ...prostate and primary adeno-carcinoma of...

Article ID: WMC003170 ISSN 2046-1690

Mixed Primary Small Cell Carcinoma of Prostate andPrimary Adenocarcinoma of Prostate: A Report ofTwo Cases and Review of the Literature on SmallCell Carcinoma of ProstateCorresponding Author:Mr. Anthony Kodzo - Grey Venyo,Urologist, Urology Department. North Manchester General Hospital - United Kingdom

Submitting Author:Mr. Anthony Kodzo - Grey Venyo,Urologist, Urology Department. North Manchester General Hospital - United Kingdom

Article ID: WMC003170

Article Type: Case Report

Submitted on:17-Mar-2012, 03:46:45 PM GMT Published on: 18-Mar-2012, 06:57:28 PM GMT

Article URL: http://www.webmedcentral.com/article_view/3170

Subject Categories:UROLOGY

Keywords:Small cell, Carcinoma, Carboplatin, Etoposide, Chemotherapy, Radiotherapy, Hormonal treatment,CD56, Synaptophysin, Chromogranin

How to cite the article:Venyo A , Baiden-Amissah K , Benatar B , Ahmed K . Mixed Primary Small CellCarcinoma of Prostate and Primary Adenocarcinoma of Prostate: A Report of Two Cases and Review of theLiterature on Small Cell Carcinoma of Prostate . WebmedCentral UROLOGY 2012;3(3):WMC003170

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Mixed Primary Small Cell Carcinoma of Prostate andPrimary Adenocarcinoma of Prostate: A Report ofTwo Cases and Review of the Literature on SmallCell Carcinoma of ProstateAuthor(s): Venyo A , Baiden-Amissah K , Benatar B , Ahmed K

Abstract

Background: Small cell carcinoma of the prostategland is a rare pathologic subtype of prostate cancerwith ‘unique’ clinical features.Aims: To report the investigation and management oftwo patients with small cell carcinoma of the prostategland within our health trustTo review the literature on small cell carcinoma ofprostateCase ReportsCase 1: A 78-year-old man presented with a history ofincreasing lower urinary tract symptoms. Hisinvestigations which included a trans-rectal ultrasoundscan of the prostate and a biopsy as well as anMRI-scan of the abdomen and pelvis confirmed thathe had a mixture of primary small cell carcinoma ofprostate and primary adeno-carcinoma of prostatewhich was staged as T3b / 4, N1, M1b.He was treated by means of LHRH analogue, and 3cycles of chemotherapy (Carboplatin and etoposide).However, after 7 months there was evidence ofprogression of the disease as well as evidence of bonymetastasis for which he had radiotherapy. He is beingmanaged by a multidisciplinary team and beingfollowed up at six weekly intervals.Case 2: A 66-year-old man presented with discomfortfrom his haemorrhoids and difficulty evacuating hisrectum. His investigations including clinicalexamination, trans-rectal ultrasound scan biopsies ofprostate as well as MRI scan of abdomen and pelvisconfirmed he had aT4 primary mixed small cellcarcinoma and adenocarcinoma of prostate. He wastreated by means of (a) hormonal treatment (casodexand zoladex initially and later on stilbesterol); (b)Combination chemotherapy (carboplatin andetoposide) as well as (c) radiotherapy.He continued to have progressive disease and diedafter 3 years as a result of the small cell carcinoma.Discussion: Small cell carcinoma is a rare variant ofprostate cancer.Small cell carcinoma is extremely aggressive andresistant to available therapies with a median survival

range of 5 to 17 months.Literature review indicates that there is no standardchemotherapeutic regimen for the treatment of smallcell carcinoma of prostate. At the moment chemotherapy using cisplatin incombination with etoposide in addition to radiotherapyis the most common treatment for small cell carcinomaof prostate.Conclusions: Because of the aggressive nature ofsmall cell carcinoma of prostate which eventuallytends to lead to the death of pat ients amulti-disciplinary team approach is required in themanagement of patients at various stages of thedisease and this should include Urologists, oncologists,pathologists, radiologists, Urology specialist nurses,pain team and palliative care team who have variousroles to play in the diagnosis, treatment, follow-up andcontinuing supportive care, of the patients at all stagesof the disease.In view of the poor prognosis of the diseaseassociated with the current available treatmentmodalities there is an urgent need to search for newtherapeutic regimens that would improve upon theprognosis of patients with small cell carcinoma ofprostate.

Introduction

Neuroendocrine differentiation in carcinoma of theprostate assumes one of three forms which include:

Small cell carcinoma●

Carcinoid like tumours●

Conventional adenocarcinoma of the prostate in●

association with focal neuroendocrine differentiation[1].

Small cell carcinoma of the prostate is a pathologicsubtype of prostate cancer with unique clinicalfeatures which accounts for about 1% to 2% ofmalignancies of the prostate gland.

Small cell carcinoma of the prostate, unlike the typicaladenocarcinoma of the prostate, does not have bonetropism; it also does not express prostate specific



antigen (PSA) at the same levels as those ofadenocarcinoma of the prostate [2].

In addition to disparities in the distribution ofmetastases, there are disparities in the characteristicsof the bony metastases emanating from small cellcarcinoma in comparison with those emanating fromadenocarcinoma [2].

Adenocarcinomas of the prostate are characterized bythe development of dense blastic metastases,whereas small cell carcinomas of the prostate typicallyproduce lytic bone metastases [2]. These uniquefeatures permit clinicians to suspect the diagnosis ofsmall cell carcinoma of the prostate before thehistological confirmation of its presence [2].

In view of the fact that cases of small cell carcinoma ofthe prostate are rarely encountered by clinicians, mostclinicians may not be conversant with the biologicalbehaviour of these aggressive tumours.

Two cases of mixed primary small cell carcinoma ofthe prostate and primary adenocarcinoma of prostateare reported in this paper together with a review ofliterature on small cell carcinoma of the prostate.

Case Reports

Case 1A 78-year-old man was referred with a 2 to 3 monthhistory of increasing difficulty in urinary-voiding; hepresented with a history of poor urinary flow, anddribbling of the urine. The referring doctor had startedhim on Tamsulosin 400 micrograms orally daily andthis had produced some benefit. However, his IPSSscore at his initial consultation was 22/33 and hisquality of life score was 3/6 indicating persistentmoderate urinary tract symptoms. His co-morbiditieswere noted to be ischemic heart disease andhypertension.His general examination on initial consultation wasunremarkable; on abdominal examination there wasevidence of a painless palpable bladder. On rectalexamination his prostate gland was found to bevery-enlarged with the right lobe feeling hardsuggestive of stage T2 to T3 prostatic neoplasticdisease. A provisional diagnosis of chronic retention ofurine due to a stage T2/T3 prostatic carcinoma wasmade. He was therefore admitted to haveinvestigations and monitoring of his urine output.Some of his initial investigations and results wereas follows:- Full blood count – Haemoglobin 13.9 g/dL (normalrange 13.0 – 18.0), White blood cell count (WBC) 7.9 x10*9/L, (normal range 4.0 -11.0);Platelets 179 x 10*9/L

- Coagulation screen INR 1.1 (normal range 0.9-1.1);PT 13.0 s (normal range 10-15); Fibrinogen Derived4.0 g/L (normal range 1.7 – 4.0)- Serum Urea and Electrolytes – Serum Sodium 145m-moles/L (normal range 136 – 145), SerumPotassium 3.2 m-moles/L, (normal range 3.5 – 5.4),Serum Creatinine 88 umol/L, (normal range 62-115),Serum Urea 4.6 m-moles/L (normal range 2.5 -6.7),Estimated GFR (eGFR “MDRD formula”) 70 mL/min(normal range > 60).- Serum PSA – 17.9 ug/L (normal range- Mid stream urine - flow cytometry studies Whiteblood cells 3 /uL (normal range 0-10), Red blood cells5 / uL (normal range 0-35 Epithelial cells normal);culture no growth.

He had a trans-rectal ultrasound scan of the prostategland on the same day which revealed a prostate sizeof 60 cc (60 grams) with evidence of bilateral hypoechogenic areas; the prostatic capsule and seminalvesicles looked normal. Prostate biopsies were taken(10 specimens from each lobe). He was thencatheterised per urethra draining 1,000 ml of clearurine.

The following findings were made on histologicalexamination:(a) Right lobe of prostate – total number of cores 13;total length of cores 113 mm; evidence ofadenocarcinoma with modified Gleason score 7 (3+4)(see illustrations 1 and 2); cores containing tumour 1of 13; total percentage of cancer 5%; additionalmicroscopic features of peri-neural invasion; there wasno evidence of associated high grade PIN; there wasevidence of chronic inflammation; the adenocarcinomawas confirmed by the absence of basal stains withCK34BE12/p63 and granular cytoplasm withRacemase; there was also evidence of a small cellcarcinoma present in 7 out of 13 cores (seeillustrations 1, 2, 3 and 4) and this accounted for 10%which showed positive staining for neuroendocrinemarkers (CD56 and synaptophysin [see illustrations 5and 6]) and TTF1 (see illustration 7); this small cellcarcinoma tumour was negative for prostate markers(PSA and PAP) as well as negative for CDX2. Basedupon these findings it was felt that the tumour shouldbe best regarded as a combined adenocarcinoma anda small cell carcinoma but the possibility of ametastatic small cell carcinoma could not be entirelyexcluded. It was recommended that the case shouldbe discussed at the next multi-disciplinary teammeeting with a full clinicopathological and radiologicalcorrelation.(b) Left lobe of prostate – total number of cores 11;



total length of cores 148 mm; histological diagnosis ofsmall cell carcinoma; cores containing tumour 11 of 11;total percentage of cancer 40%; additional microscopicfeatures of perineural invasion; associated high gradePIN was not found; other histological features seenwere acute inflammation and chronic inflammation;small cell carcinoma was confirmed with a positivestaining for neuroendocrine markers (CD56; and TTF1;the tumour was negative for prostatic markers (PSAand PAP) and also negative for CDX2; It was felt thatthe tumour should be best regarded as a combinedadenocarcinoma of prostate and a small cellcarcinoma of prostate however, it was advised that thepossibility of metastatic small cell carcinoma could notbe entirely concluded and the case should bediscussed at the next multi-disciplinary team meetingwith full clinicopathological and radiologicalcorrelation. Further assessment of the tumour was done by thefollowing radiological investigations:CT scan of thorax, abdomen and pelvis which wasreported as follows:The prostate gland was enlarged, with bilateraldilatation of the seminal vesicles; there was urethralcatheter in situ; explaining the low sensitivity ofCT-scan, there was no evidence of significantlocal/regional lymph-adenopathy and no evidence oflymph node within the left and right groins (a singlelymph node, 6 mm, was noted along the left internaliliac vessels); it was difficult to assess the bladderbecause it was partially filled with contrast andbecause of the catheter in situ. There was no evidence of any distant metastaticchanges involving the lung parenchyma, liver, spleen,and no evidence of ascites or pleural effusion and nomediastinal lymphadenopathy.There was a large aneurysm of the infra-renal part ofthe abdominal aorta, 6.5 cm, to the level of thebifurcation;MRI-scan of the pelvis (for local staging) – Aggressivebilateral prostate cancer with involvement of bothseminal vesicles; extensive stranding in theperi-prostatic fat and possible bladder baseinvolvement; no definite extension into the rectum orpelvic side walls; there were suspicious rounded pelviclymph nodes and a suspicion of early rounded pelviclymph nodes (see illustrations 8 and 9) and asuspicion of early bony metastases in the left iliacbone and sacrum. Radiologically, the stage appearedto be T3b / 4, N1, M1b.Isotope Bone-scan – Osteoarthritic changes wereseen in the cervical spine and minor osteoarthriticchanges were also noted in the thoracolumbar spineand knees but there was no evidence of bone

metastases.The case was discussed at the Special istMulti-Disciplinary Team meeting and after reviewingthe patient’s notes, the histology of the tumours aswell as the CT-scan, MRI-scan and the bone scan theMulti-Disciplinary Team concluded that the histologyrevealed a mixture of adenocarcinoma of prostate andsmall cell carcinoma of prostate (this was a primarymixed tumour of the prostate); the staging of thetumour was T3b/4 N1. The Multi-Disciplinary Teamrecommended that the patient should be commencedon hormonal treatment for the adenocarcinoma andchemotherapy for small cell carcinoma of prostate.He was reviewed by the urologist as well and was alsoseen by the Urology specialist nurse who explainedthe diagnosis and the recommended plans ofmanagement to him. He was treated by means ofcyproterone acetate 100 mg orally three times a dayfor a month and his LHRH analogue injections werestarted after two weeks of commencement of thecyproterone acetate medication. He was also referredto an oncologist as recommended by the SpecialistMulti-Disciplinary Team.He initially had a successful trial without catheter butwas readmitted 3 months later in retention of urinerequiring catheterisation but failed subsequent trialwithout catheter and was re-catheterised anddischarged home with a urethral catheter in-situ.He was also seen by the oncologist two months later,by which time he had had monthly injections of LHRHagonists. The oncologist observed that the patient’sgeneral condition had deteriorated significantly overthe preceding 4 to 6 weeks despite being treated withLHRH agonist. He was counselled and consented forsingle agent Carboplatin in the first instance. It wasalso explained to him that he was at risk of bleedingwhich puts him at risk in view of the fact that he had anabdominal aortic aneurysm. It was explained to himthat chemotherapy would provide him with the bestchance of gaining control of his small cell carcinoma ofprostate. His General Practitioner was advised tochange his LHRH monthly injections to a 3 monthlypreparation in order to limit the number of injections hewould have in a year. He received his initialCarboplatin chemotherapy and was scheduled to havefollow-ups at 3 weekly intervals. He tolerated thesingle agent Carboplastin very well following which hehad an MRI Scan which showed slight diseaseprogression within the vesico-prostatic mass and leftsacral metastasis; other lymph glands showed stabledisease. Following this he had 3 cycles ofCarboplastin and Etoposide. During his chemotherapytreatment he was anaemic and required a total of 4units of blood transfusion. He tolerated his further



chemotherapy well and MRI scan 6 months after hisinitial diagnosis showed some slight improvement inthe lymph nodes and a small increase in size in thebone metastasis which was considered not significant.He then received 8 fractions of palliative radiotherapy30Gy in 8 fractions to his pelvis which he completedby end of the 7th month after his initial diagnosis. Hisserum PSA at 7 months was 2.0 u-g / L. He remainedin good spirit and was scheduled to attend Oncologyfollow-up after six weeks and Urology follow-up afteranother 3 months. He would continue to have regularOncology and urology follow-ups as well as further CTscans, and blood tests in order to assess his progress.Case 2A 66-year-old man was referred to a general surgeonbecause of discomfort from his haemorrhoids. He hadalso been having some difficulty evacuating his rectumand in passing urine. In addition he had noticed thathis long standing right inguinal hernia had become abit uncomfortable / painful recently. He did not haveany other significant past medical history and was noton any medication. His general and systematicexaminations were reportedly normal except for thepresence of a large right inguino-scrotal hernia. Oninspection of his anal region large skin tags andprolapsing haemorrhoids were found and on digitalrectal examination the general surgeon found arock-hard rectal mass which extended anteriorly andthis mass was adjudged to be extra-rectal butcontiguous with the prostate gland and this finding inthe opinion of the general surgeon was suspicious of aprostate cancer. In view of these findings the patientwas referred for a urological opinion.

At the first urology consultation, clinical examination ofthe patient confirmed the presence of a rightinguino-scrotal hernia, an expansile infra-renal aortaconsistent with an abdominal- aortic aneurysm;external anal skin tags, haemorrhoids and in additiondigital rectal examination findings were consistent witha large stage 4 prostate cancer. In view of the fact thatthe patient’s serum PSA done at the general surgicalconsultation was reported to be 7.0 ug /L, the urologistsuspected that the pat ient may have anundifferentiated prostate cancer. The followinginvestigations which were done were reported asfollows:Trans-rectal prostate biopsy – histologicalappearances of the biopsy specimens were consistentwith very poorly differentiated tumour with differentialdiagnoses of prostate cancer, bladder cancer, andrectal cancer. The tumour on immunohistochemistrywas negative for PSA but positive for PAP. Thepathologists making the diagnosis were of the opinion

that the tumour was a poorly differentiated prostaticcarcinoma.Isotope Bone ScanCT scan – locally invasive prostate cancer (T4) andpara-aortic nodal mass but there was no evidence ofdistant diseaseFlexible cystoscopy – the urethra, urinary bladder andboth ureteric orifices were normal; the prostatic urethraand the trigone were slightly distorted.Based upon the provisional histology results theurologist commenced the patient on casodex andZoladex and referred him to an oncologist to beconsidered for radical radiotherapy. Three monthslater his lower urinary tract symptoms had improved inthat his previous nocturia had improved to voiding onlyonce at night and his serum PSA was reported as 0.5nanograms /ml.At urology follow-up nine months after his initialreferral his perineal discomfort had increased andclinically rectal examination revealed that the prostatictumour appeared more locally advancedTen months after his initial referral he was admitted asan emergency with a 4 weeks history of increasingdifficulty in passing urine. Clinical examinationrevealed he had retention of urine and oncatheterisation he was found to have a residual urinevolume of 1600 millilitres; his serum creatinine wasthen 992 u-mol/L (normal range 62-115 u-mol/L); andultrasound scan showed right hydronephrosis. He wasthen transferred to the regional oncology centre.At the Regional Oncology centre the histology of theprostate biopsy specimen was reviewed. Theconsensus opinion was that there was a mixture ofpoorly differentiated adenocarcinoma and small cellcarcinoma of the prostate gland (see illustrations 10and 11 which show the small cell carcinomacomponent of the tumour and 12 to 15 which illustratethe immunohistochemical staining of the small cellcarcinoma). In view of the diagnosis he was givenchemotherapy in the Regional Oncology centre wherehe received Carboplatin and Etoposide therapyfollowing which he was adjudged to have stabledisease 13 months after his initial referral. At follow-up13 months after his initial referral he had some pelvicsymptoms therefore the oncologists felt that it wouldbe reasonable for him to be given palliativeradiotherapy and also in view of the fact that he hadan initial good response to hormonal therapy a secondline hormonal treatment would be appropriate. He wastherefore started on stilbeostrol 1 mg orally once a dayaccompanied by Aspirin 75 mg once a day.Twenty six months pursuant to his initial referral hewas admitted to the urology unit with voidingdifficulties and raised serum creatinine of 340



(u-mol/L). His serum PSA during this admission was3.5 ng / ml. He had an ultra-sound scan of renal tractwhich showed gross hydronephrosis of the rightkidney and moderate left hydronephrosis. He was alsodiagnosed with a right common femoral and poplitealdeep vein thrombosis. A supra-pubic catheter wasinserted under ultrasound scan guidance in theatre torelieve the bladder obstruction. He was commencedon warfarin and after his serum urea and electrolyteshad gradually improved he was discharged home andalso referred to the Regional Oncology centre forfurther assessment in order to be considered foradditional treatment that may be advised by theOncologists. An MRI scan was requested whichconfirmed extensive carcinoma of prostate infiltratingthe right ureter, bladder, and rectum. He alsocomplained of lower back pain and the MRI scanshowed some metastases in the sacral area in view ofthis the oncologists were asked to consider forradiotherapy.He received palliative radiotherapy but subsequentlyhis general condition gradually deteriorated over aperiod of one year and he was managed by theUrology team, the oncology team as well as thepalliative care team. His main problems were:Intermittent haematuriaGross lymphoedema and inability to mobilise due todiscomfort and size of his genitals; Clinicalexamination revealed gross lymphoedema to thescrotal area, the penis, pelvis, and both distal andproximal region of the legsHe had left nephrostomy inserted for obstructed leftureter which required regular changes of nephrostomytubes at intervals and flushing of blocked nephrostomytube.

The management of his lymphoedema included:(1) An extra large support made to measure fittingprovided(2) Below knee hosiery in attempt to improve mobility(3) Simple lymphatic drainage techniques weredemonstrated(4) Being referred to a podiatry team(5) Being placed on diuretics which were reviewed bythe patient’s general practitioner(6) Regular follow-up and continuing support andadvice provided by the lymph oedema

Service team His general state of health continued to deteriorateand he had episodes of agitation / hallucinations andwas provided Macmillan specialist palliative careservice (He had Midazolam for his agitations andDiamorphine for pain control.He eventually died 3 years after his initial referral.

Discussion

Small cell carcinoma of the prostate is a high-grademalignant neoplasm with neuro-endocrinedifferentiation. The typical morphologic featuresinclude:

Small tumour cells with minimal cytoplasm●

Nuclear moulding,●

Fine chromatin pattern,●

Extensive tumour necrosis / apoptosis,●

A brisk mitotic rate [3].●

Small cell carcinoma of the prostate accounts for lessthan 1% of all prostate cancers. About 50% of patientshave pure small cell carcinomas at initial presentation.About 25% to 50% of cases are mixed with aconventional adenocarcinoma of prostate [4].

Another 25% to 40% of cases are initially diagnosedas adenoarcinoma of prostate and recur as small cellcarcinoma after hormonal therapy. The medianinterval between initial diagnosis of adenocarcinoma ofprostate and small cell carcinoma is 25 months [4, 5].

The mean age of diagnosis of small cell carcinoma ofprostate is 65 to 69 years, which is similar to theaverage age of adenocarcinoma of prostate [5].

The risk factors pertaining to the development of smallcell carcinoma of prostate include: age, race, andfamily history [6].

Men older than 60 years of age are typically affectedby small cell carcinoma of prostate and the overall riskincreases with age [5].

Some of the ethnic variations in the incidence ofprostate cancer have been attributed to diet [7].

Red meat consumption and high-fat diet areconsidered possible risk factors. For example Asianshave the lowest incidence of prostate cancer, andAsian immigrants to the USA who have adoptedwestern style diets have an increased incidence butstill less than the white population [5]. Other life stylefactors including sexual practices and occupation areat present not considered to be important factorsrelating to the development of prostate cancer [5].

Some prostate cancers may have a geneticcomponent. There is a ten-fold increased risk forpatients with two or more relatives. A patient who hasa first-degree-relative with adenocarcinoma of theprostate has a two-fold increased relative risk [5]. Therisk of prostate cancer decreases with distance in the‘family tree,’ that is first versus second cousins [5].

With regard to location, the distribution of small cell



carcinoma of prostate is similar to that ofadenocarcinoma of prostate. [5] Most patients havemulti-focal disease but also have a dominant nodule,located on the peripheral zone. These tumours may bepalpable by digital rectal examination and can bediagnosed by needle core biopsy; transition zone andcentral zone are not common for clinically importantprostate cancer. [5]

The presenting symptoms, of patients with small cellcarcinoma of prostate, are similar to those of patientswho have adenocarcinoma of prostate. Localizedtumours produce few if any symptoms. Patients whohave symptoms usually have locally advanced ormetastatic disease. [5] A number of patients notice achange in their urinary stream with trouble initiatingand stopping. [5]

Patients with small cell carcinoma of prostate mayhave a number of symptoms including: urinaryurgency, haematuria, haemospermia, or trouble withdefecation. On digital rectal examination a nodule maybe palpable. The development of bony metastasis isassociated with bone pain and or fracture.

The serum prostate specific antigen (PSA) level is notraised in most patients with small cell carcinoma of theprostate unlike those patients with adenocarcinoma ofthe prostate. About 10% of patients with small cellcarcinomas of prostate secrete hormones such as:adrenocorticotrophic hormone (ACTH), antidiuretichormone (ADH) and these patients may present withparaneoplastic syndromes. [8]

Tetu and associates [7] stated that small cellcarcinomas of the prostate tend to invade outside theprostate and more commonly involve the surroundingorgans, regional lymph nodes and distant organs thanconventional adenocarcinomas and that the findings ofmetastatic spread or paraneoplastic syndrome shouldraise the suspicion of a small cell carcinoma.

Gross examination of prostate cancer tends to reveala subtle yellowish-white colour with a firm feelingwithin the peripheral zone. Small cell carcinomas ofthe prostate have the same appearance asadenocarcinomas but they may feel some-what softerif significant necrosis is present. [5]

Nicholson and associates [9] stated that themicroscopic features of small cell carcinomas ofprostate are similar to those seen in small cellcarcinomas in other organs.

Low-power microscopic view of small cell carcinoma ofprostate reveals sheets of dark blue tumour cells withfocal rosette formation and extensive necrosis. Thechromatin of the tumour cells is delicate and may bedamaged easily on the act of tissue processing

leading to crush artefact. The basophilic DNA oftumour cells may also escape the nuclei and becomeentrapped in the blood vessel wall which is known asazzopardi effect.

Microscopic examination of small cell carcinoma of theprostate reveals the following features:

The individual cells tend to be oval or angulated with●

scant cytoplasm;Indistinct borders and nuclear molding;●

The nuclei tend to be small (less than the diameter of●

3 resting lymphocytes), although occasional largercells may be present;The nuclear chromatin is finely granular (a●

salt-and-pepper pattern);The nucleoli are absent or small;●

Necrosis is a common feature as are frequent mitotic●

and apoptotic figures;The Gleason Grading System is not used for small●

cell carcinomas of prostate; as such tumours arepoorly differentiated or high grade.

In patients whose prostatic tumours are co-existingadenocarcinoma and small cell carcinoma, the 2components are intermixed in majority of cases whilstin about 20% of cases, there are distinct zones ofsmall cell carcinomas and adenocarcinomas. [4] Theadenocarcinoma is quite often high-grade (Gleasonscore > 7) and comprises a smaller portion incomparison with the small cell carcinoma. It is quiteoften very difficult to differentiate small cell carcinomafrom high-grade adenocarcinoma, especially Gleason5. In such difficult cases, the presence of rosettes,nuclear molding, and a fine chromatin pattern withoutprominent nucleolus help to identify small cellcarcinoma. Immuno-histochemical staining of thetumours helps in the establishment of the diagnosis ofsmall cell carcinoma of prostate. Morphology remainsthe criterion standard for the establishment of adiagnosis of small cell carcinoma. [10]

Pathologists who are suspicious of small cellcarcinoma of the prostate do confirm the diagnosis bymeans of neuro-endocrine markers. The ensuingtumour markers are typically used (see illustration 16):

Chromogranin A;●

Synaptophysin;●

Neuron-specific enolase;●

CD56.●

Typically, one or more of the aforementioned markersare positive in small cell carcinomas. Nevertheless, ina small proportion of tumours (about 10%), all theneuro-endocrine markers are negative, which doespreclude, the diagnosis of small cell carcinoma as longas the morphology is typical. A useful typical feature is



the clot-like perinuclear staining pattern for cytokeratin.About half of the cases are also positive for TTF-1 witha nuclear staining pattern, [11]

The aforementioned stains have been useful indifferentiating small cell carcinoma from Gleason 5pattern adenocarcinoma of prostate. Furthermore, nonneuroendocrine stains are also helpful in view of thefact that unlike adenocarcinoma of prostate, small cellcarcinomas are often negative for androgen receptor(AR), prostate specific antigen (PSA), prostatic acidphosphatase (PAP), and P504s (AMACR). (See table– Illustration 15)

Neuroendocrine cells can be found focally in allprostate adenocarcinomas. [12]

Immunohistochemical studies against neuroendocrinemarkers, like chromogranin A, highlight a few isolatedcell clusters of neuroendocrine cells among the moreabundant adenocarcinoma cells with luminal secretoryfeatures. [13]

These scattered neuroendocrine cells that are presentin adenocarcinoma of prostate, unlike tumour cells insmall cell carcinoma are regarded as post mitotic andnon proliferative. It has been suggested that bothgenetic factors and environmental factors likelycontribute to the development of adenocarcinoma ofprostate. Potential genetic factors which have beensuggested include:

Gene mutation or polymorphism in androgen; ●

AR (androgen receptor)●

Steroid 5-alpha reductase type II (SRD5A2)●

An enzyme responsible for the conversion of●

testosterone to dihydrotestesterone (DHT). [14]

It has been suggested that the length of a polymorphicCAG repeat v region in the first exon of the AR geneappears to explain the racial differences in theincidence of prostate cancer. It has been foundrecently that in about half of the cases there isrecurrent chromosomal rearrangement resulting in thefusion of transmembrane serine 2 (TIMPRESS 2) anda member of the ETS family transcription factors, mostcommonly ERG. [15].

It has been stated that the genetic changes specific toprostatic small cell carcinoma have not been studied ingreat detail. [16]

Tanaka and associates [17] stated that:

The genetic features may be similar to●

adenocarcinoma of prostate but may containadditional genetic alterations which make suchtumours androgen independent and more aggressiveThis may be particularly true in those tumours which●

are recurrent tumours in patients who were treated

with hormonal therapy for a conventionaladenocarcinoma.

Williamson and associates [18] have illustrated that45% to 47% of small cell carcinomas of the prostateharbour ERG gene rearrangement, a number that isseen in adenocarcinoma of prostate.

Lotan and associates [19] showed that in cases ofcoexisting small cell carcinoma and adenocarcinoma,the majority exhibit concordant ERG generearrangement in the 2 components.

The aforementioned observations would suggest thatsmall cell carcinoma of prostate may share a commonorigin with adenocarcinoma. On the other hand, it mayarise from the latter ensuing additional geneticalterations. It is not clear how small cell carcinoma ofprostate may be related to small cell carcinoma inother organs.

It has been suggested that all small cell carcinomas,irrespective of origin possess the identical morphologyand immunohistochemical profile, thus possiblypossessing similar genetic alterations. [20], [21], [22].

Simon and associates [23] showed that CD44, aputative cell surface marker for normal and cancerousstem cells in multiple organs, including the prostategland, is expressed in small cell carcinomas of theprostate but is infrequently expressed in small cellcarcinomas of other organs.

The histological differential diagnoses of small cellcarcinoma of prostate include:

Non Hodgkin’s lymphoma;●

Metastatic small cell carcinoma;●

High grade adenocarcinoma of prostate. [5]●

Erasmus and associates [24] stated that with regard tospread and staging of small cell carcinomas ofprostate:

They may pursue similar routes as adenocarcinoma●

of prostate to spread to other parts of the body.They may invade through the prostatic capsule to●

involve the peri-prostatic soft tissue, seminal vesicles,bladder neck, and rectum locally.They may also metastasize to the pelvic lymph●

nodes, peri-aortic lymph nodes, bone, liver, adrenalglands, lung, and brain.The tumours are aggressive and tend to spread●

much earlier.The tumours present at a higher pathologic stage●

than adenocarcinoma of prostate.The tumour staging is the same as for●

adenocarcinoma of prostate.

Tetu and associates [7] stated that the prognosis ofsmall cell carcinoma of prostate is less than 1 year.



There appears to be no significant survival differencebetween pure prostatic small cell carcinomas andmixed small cell / adenocarcinomas. Tumour stage isconsidered the single most important factor, eventhough any small amount of small cell carcinomacomponent is considered to carry a poor prognosis. [5]

In view of the rarity of small cell carcinomas ofprostate, individual urologists or oncologists havelimited experience in its management. Brown andassociates [25] stated that small cell carcinomas of theprostate do not respond to hormonal therapy orradiotherapy, and surgery is usually not curative.

Amato and associates [26] stated that patients withsmall cell carcinoma of prostate are usually treated inthe same manner as those patients with pulmonarysmall cell carcinomas with a regimen of cisplatin andetoposide.

It has been stated that most patients with small-cellcarcinoma of the prostate are symptomatic atd iagnosis, unl ike pat ients wi th prostat icadenocarcinoma alone. [28] Palgren and associatesstated that the signs and symptoms, in order offrequency, include obstructive, neurologic, andconstitutional symptoms, followed by symptoms fromparaneoplastic syndromes, bone pain, hydronephrosis,abdominal pain, hematochezia, and hematuria. [27]

Some authors have observed that the clinical featuresof small-cell carcinoma of the prostate include amarkedly enlarged prostate, disproportionately lowPSA levels in the presence of metastatic disease,unresponsiveness to hormone therapy, visceralmetastases, and high proportion of lytic to blastic bonelesions. [26], [28], [29]

According to some authors, [1], [30], small-cellcarcinoma of the prostate, accounts for 0.5% to 2% ofall prostate malignancies.

It has been reported that the median survival time ispoor for patients with small-cell carcinoma of theprostate, ranging from 5 months to 17.5 months. [7],[26], [28], [29], [30], [31].

The recommended treatment regimens for small-cellprostate cancer are similar to those for small-cellcarcinoma of the lung and Chemotherapy is regardedas the mainstay of treatment, [7], [27], [28], [29], [31]with radiation used to supplement local control or forpalliation of symptoms in metastatic disease. [7], [28],[29]. Cisplatin and etoposide are the most commonlyrecommended agents, and a recent phase II trialshowed that the addition of doxorubicin to this regimenadded to toxicity but not survival. [31] For localizeddisease, surgery is often included, and it has beensuggested that surgery may be curative. [32]

In one relatively large retrospective-univariate-analysisof 60 patients primary surgery was the onlyindependent prognostic factor found for prolongedsurvival. [33]

Rubenstein and associates observed that in contrastto prostatic adenocarcinoma, PSA is an unreliabletumour marker for small cell carcinoma of prostate andit is usually normal, even when there is metastaticdisease. [6] A study by Rubenstein and associatessuggested that carcinoembryonic antigen is a morereliable marker, because increase and decreases inantigen levels were found with disease progressionand regression, respectively. Recently the tumourmarker neuron-specific enolase has been proposed asa prognostic indicator; high levels suggest a poorprognosis.

Despite treatment with chemotherapy, the prognosis ofsmall cell carcinoma of prostate is extremely poor, witha reported median survival by Patel and associates tobe 7 months. [34] Because of the rarity of the condition,no standard therapeutic regime has been universallyadopted. Reported cases have on the whole beenmanaged by chemotherapeutic regimens similar tothose recommended for small cell lung cancer. Theresults, nevertheless, have not been as favourable.Additionally, small cell carcinoma of prostate, incontradistinction to adenocarcinoma has been foundto be unresponsive to hormone therapy.

A potential target for the treatment of small cellcarcinoma is the relaxin receptor RXFP1. Relaxin is asmall peptide hormone expressed in several cancerssuch as those of endocrine origin. Its receptor, RXFP1(a G-protein-coupled receptor), is expressed inandrogen receptors’ positive and negative cancers, aswell as in prostate germ cells. In PC3 prostate cancercell lines, which include small cell neuroendocrinecarcinoma, treatment of RXFP1 showed significantreduction of tumour size, decrease in cell proliferationand metastatic disease, and increased apoptosis. [35]

It is well known and accepted that Small cellcarcinoma of the prostate is a rare, aggressive, andtreatment refractory form of prostate cancer. No goodform of treatment is yet known for this disease, andmedian survival from initial diagnosis is less than 2years. Nevertheless, new data from a mouse model ofsmall cell carcinoma of prostate (SCCP) hassuggested that combining two well understood andwidely available chemotherapeutic agents may have asignificant clinical effect on patients with small cellcarcinoma of prostate (SCCP). Tung and associates[36] used a mouse model of small cell carcinoma ofprostate (SCCP) to show that:



Irinotecan (at 20 mg/kg/day on days 1-3 and 8-10)●

completely arrested growth of human small cellcarcinoma (SCCP) implants (xenografts) in theirmice, with a small reduction in human tumourvolume and only minor weight loss (7 percent) of themice.Irinotecan (at 12 mg/kg, also on days 1–3 and 8 – 10)●

+ cisplatinum had similar effect, but with less weightloss among the mice.

Tung and associates [36] concluded cautiously that“Irinotecan could be useful for therapy of refractoryprostatic small cell carcinoma, in particular incombination with cisplatin.

The normal prostate gland is constituted of base cell,exocr ine ce l l and nerve endocr ine ce l l(Neuroendocrine cell, NE cell). The NE cell cansecrete various neuro-secretions, includingchromgranin A, B (CgA, CgB), NSE, parathyroidhormone-related peptide, calcitonin and gastrin. TheNE ce l l can be i den t i f i ed t h rough t heimmuno-histo-chemistry method by positive stain of amarker, such as CgA, Syn and NSE [4], [37], [38].

There are currently clinical studies with experimentshaving already confirmed a prostate gland cancersufferer would appear NED inside the focus afterendocrine treatment. Additionally, it has beensuggested that the NED was an important factor whichcauses toleration to the endocrine therapy. [39], [40],[41], [42], [43].

It has been suggested that the research of future workshould include particular emphasis on the research ofthe NED mechanism; especially the selectivityblockade of some signalling molecule to prevent orconvert the NED of prostate cancer cell; there shouldalso be work to identify how the materials the NE cellssecretes through paracrine secretion or autocrine andwhich incentives exist in the growth of thenon-androgen depending cell; there should be adesign or creation of new chemotherapy medicinewhich aims at secretion of NE cell to improve thesufferer’s living quality and survival rate of prostatecancer. [44]

It has been suggested that: the multiple methods, suchas hormone therapy in combinat ion wi thchemotherapy or transfer factor immunotherapy, canbe used to raise the patient’s survival rate; Bombesin /gastrin releasing peptide (BN/GRP) secreted by NEcell are the new therapeutic agents to be employed inthe treatment of small cell carcinomas of the prostate[45], [46].

It is hoped that in the near future, the treatment whichaims at NED mechanisms would bring a new hope forneuroendocrine carcinoma of prostate sufferers. It has

been suggested that the cell-based -drug-efflux assayhopefully can help know the required chemotherapy tobe given to patients accurately and for a much shortertime which significantly benefits cancer patients. [47]

It has been suggested that whether or not aCell-based Drug Efflux Assay can be used to selectsuitable drug for chemotherapy of small cell prostatecarcinoma needs to be investigated through a futurestudy. [45]

Small cell carcinoma of prostate was first described byWenk and associates [48]. Small cell carcinoma ofprostate can occur as an initial event at the time of firstdiagnosis and is then thought to originate fromneuroendocrine cells present in the epithelium ofprostatic ducts / acini and in the endothelium ofprostatic urethra. It may also develop in prostatecancer during progression to castration resistanceinduced by androgen ablation. The most widelyaccepted opinion is that small cell carcinomas ofprostate arise from totipotential stem cells of theprostate that have the ability to differentiate into eitherepithelial or neuro-endocrine type carcinomas. Thelatter type is characterized by the absence ofexpression of androgen receptors (AR) andprostate-specific antigen (PSA) and by positiveexpression of synaptophysin (SYN) neuro-endocrinemarker [49], [50]. Prostatic small cell carcinoma is anaggressive disease, often described as universallyfatal [51]. Small cell carcinoma of prostate is typicallydiagnosed at an advanced clinical stage with rapidprogression and insensitivity to hormonal therapy;patients have a median survival of 5 to 17 months [7],[29]. Prostatic small cell carcinoma shows similarity tosmall cell lung carcinoma (SCLC) in morphologicfeatures [29] and in the expression pattern of somegenes [52]. In view of this, the commonly usedtreatment of prostatic small cell carcinoma, that is,platinum-based chemotherapy and irradiation, wasadopted from SCLC therapeutic modalities. A numberof anti-cancer agents have been used in combinationwith cisplatin, including etoposide, cyclophosphamide,doxorubicin, and vincristine; other combinations thathave been used are carboplatin plus etoposide ortaxanes [27], [31], [53], [54].

Cisplatin-based chemotherapy plus radiotherapy hasdespite initial positive responses, failed to be effectiveand a standard therapeutic regimens for small cellcarcinoma of prostate has not yet been adopted sincethis disease is rare [48].

At the moment chemotherapy using cisplatin incombination with etoposide is the most commontreatment for small cell carcinoma of prostate.



In contrast to prostatic adenocarcinoma, Serum PSAis an unreliable tumour marker for small cell prostatecarcinoma and is usually normal, even when there ismetastatic disease. One study suggested thatcarcinoembryonic antigen is a more reliable marker,because increases and decreases in antigen levelsare found with disease progression and regressionrespectively. [6] More recently, the tumour markerneuron-specific enolase has been proposed as aprognostic indicator; high levels suggest a poorprognosis. [6]

Conclusions

Small cell carcinoma is extremely aggressive andresistant to available therapies with a median survivalrange of 5 to 17 months.Literature review indicates that there is no standardchemotherapeutic regimen for the treatment of smallcell carcinoma of prostate. At the moment chemotherapy using cisplatin incombination with etoposide in addition to radiotherapyis the most common treatment for small cell carcinomaof prostate.Because of the aggressive nature of small cellcarcinoma which eventually tends to lead to the deathof patients a multi-disciplinary team approach isrequired in the management of patients at variousstages of the disease and this should includeUrologists, oncologists, pathologists, radiologists,Urology specialist nurses, pain team and palliativecare team who have various roles to play in thediagnosis, treatment, follow-up and continuingsupportive care of the patients at all stages of thedisease.In view of the poor prognosis of the diseaseassociated with the current available treatmentmodalities there is an urgent need for researchers,oncologists and urologists to search for newtherapeutic regimens that would improve upon theprognosis of patients with small cell carcinoma ofprostate.

Acknowledgement

Acknowledgement to Dr Kenneth Uzoka, ConsultantRadiologist at North Manchester General HospitalUnited Kingdom for putting the arrows on the lymphnodes in the MRI-scan images

References

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Case 1 Haematoxylin and Eosin staining X 2.5 MagnificationProstatic core biopsy containing Gleason 3+4 =7 adenocarcinoma and small cellcarcinoma

Illustrations

Illustration 1

Figure 1



Case 1- Haematoxylin and Eosin Staining X 20 magnificationProstatic core biopsy showing Gleason 3+4 adenocarcinoma

Illustration 2

Figure 2



Haematoxylin & Eosin staining X 10 MagnificationProstatic core biopsy showing a small cell neuroendocrine carcinoma; the tumour iscomposed of poorly differentiated small and large polygonal blue cells with scantycytoplasm.

Illustration 3

Figure 3



Haematoxylin and Eosin staining X 20 MagnificationProstatic small cell neuroendocrine carcinoma composed of poorly differentiatedpleomorphic blue cells arranged in sheets and groups.

Illustration 4

Figure 4



Immuno-staining of CD56 X 20 magnificationProstatic small cell carcinoma showing positive reactivity with CD56

Illustration 5

Figure 5



Immunostaining of Synaptophysin X 20 magnificationSmall cell neuroendocrine carcinoma of prostate showing reactivity withSynaptophysin

Illustration 6

Figure 6



Case 1: “Immunohistochemistry X 20 Magnification”Small cell carcinoma of prostate showing positive staining with TTF1

Illustration 7

Figure 7



MRI-scan of pelvis showing enlarged prostate with tumour and lymph nodeinvolvement of tumour (arrow pointing towards lymph node involved by tumour)

Illustration 8

Figure 8



MRI-scan of pelvis showing pelvic lymph node involvement of tumour (arrowpointing towards lymph node involved)

Illustration 9

Figure 9



Case 2Haematoxylin and Eosin staining X 10 magnificationProstatic small cell neuroendocrine carcinoma exhibiting sheets of pleomorphic bluepoorly differentiated cells

Illustration 10

Figure 10



Case 2Haematoxylin and Eosin staining X 20 magnificationProstatic small cell neuroendocrine carcinoma showing large pleomorphic andhyperchromatic cells interspersed with small cells and spindle-shaped cells

Illustration 11

Figure 11



Immuno-staining for PAP X 60 magnificationSmall cell neuroendocrine carcinoma of prostate showing reactivity with prostaticacid phosphatise

Illustration 12

Figure 12



Immuno-staining of CD56 X 20 magnificationProstatic small cell neuroendocrine carcinoma showing positive staining with CD56

Illustration 13

Figure 13



Immuno-staining for synaptophysin X 20 magnificationSmall cell neuroendocrine carcinoma is showing positive staining withsynaptophysin

Illustration 14

Figure 14



Immuno-staining for chromogranin X 40 magnification. Small cell neuroendocrinecarcinoma is showing positive reactivity with chromogranin

Illustration 15

Figure 15



Immunohistochemical Markers useful for the Differential Diagnosis of ProstaticSmall Cell Cell Carcinoma and Adenocarcinoma

Tumour type PSA PSAP P504s TTF-1

CD56 ChromA

Synapt AR

Small cellcarcinoma

17% 24% 47% 53% 83% 61% 89% 17%

Adenocarcinoma 100% 100% 100% 0% 0% 0% 40% 50%

PSA – Prostate Specific AntigenPSAP – Prostate Specific Acid PhosphataseCK – CytokeratinAR – Androgen ReceptorTTF – Thyroid Transcription FactorCD – Cluster of differentiationChrom A – ChromograninSynap - Synaptophysin

Illustration 16

Figure 16



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Mixed Primary Small Cell Carcinoma of Prostate and ...prostate and primary adeno-carcinoma of...

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