Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 33  |  Issue : 2  |  Page : 45-49

Rare histolopathologic variants in bladder cancer


1 Department of Urology, University General Hospital of Larissa, Larissa, Greece
2 Department of Urology, “Achillopouleio” General Hospital of Volos, Volos, Greece
3 Department of Reconstructive Urology and Surgical Andrology, Metropolitan General Hospital, Holargos, Greece

Date of Submission14-Oct-2021
Date of Decision15-Oct-2021
Date of Acceptance16-Oct-2021
Date of Web Publication26-May-2022

Correspondence Address:
Diomidis Kozyrakis
264 Mesogeion Ave., 15562, Holargos, Attiki
Greece
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HUAJ.HUAJ_41_21

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  Abstract 


The heterogeneous spectrum of bladder cancer comprises the coexistence of conventional urothelial carcinoma (UC) with its variants as well as the non-urothelial carcinoma (including squamous and glandular tumors). Since the official classification of rare histologic subtypes, by the World Health Organization (WHO) in 2004, uropathologists and urologists are paying more attention to the role of these subtypes as potential prognostic markers. Most of these rare variants have been associated with increased risk of progression and poor prognosis. Therefore, patients diagnosed with some of the histologic subtypes, have been classified to “the very high risk group” of recurrence and progression, although it has not yet been clarified if this is due to advanced stages at presentation and underdiagnosis or due to the aggressiveness of each variant, as an independent factor. This review discusses the most common variants of bladder cancer (urothelial carcinoma with squamous and/or glandular differentiation, pure squamous carcinoma, pure adenocarcinoma, urachal carcinoma, nested pattern, microcystic, micropapillary, small cell carcinoma, plasmacytoid, sarcomatoid, and lymphoepithelial like carcinoma), outlining the recent advances regarding the diagnosis, differential diagnosis, treatment and clinical significance for each one. High index of suspicious is required by the uropathologists for detection of these variants and well-designed multi-institutional studies are necessary in order the specific treatment strategies for these patients to be established.

Keywords: Adenocarcinoma, glandular, histologic variants, lymphoepithelial-like, micropapillary, nested microcystic, plasmacytoid, sarcomatoid, small cell, squamous


How to cite this article:
Tsiakoulas E, Zarkadas A, Tzortzis V, Kozyrakis D. Rare histolopathologic variants in bladder cancer. Hellenic Urology 2021;33:45-9

How to cite this URL:
Tsiakoulas E, Zarkadas A, Tzortzis V, Kozyrakis D. Rare histolopathologic variants in bladder cancer. Hellenic Urology [serial online] 2021 [cited 2022 Jun 25];33:45-9. Available from: http://www.hellenicurologyjournal.com/text.asp?2021/33/2/45/346060




  Introduction Top


Bladder cancer (urological cancer or urinary bladder cancer) is the 10th most common cancer in the world (and the 6th most common cancer among men) with a continuously rising incidence worldwide, especially in developed countries, according to the Global Cancer Statistics-GLOBOCAN 2020.[1] Risk factors such as chemical exposure, including tobacco smoke (polycyclic aromatic hydrocarbons) and occupational exposure, have been highly associated with conventional urothelial bladder cancer, which represents more than 90% of bladder malignancy.[2],[3] Unusual architectural, cytological, and immunohistochemical divergences, others from the conventional urothelial carcinoma (UC), have been noted in the rest 10% of pathologic reports and have lately been characterized as “histological variants” of bladder cancer, after being first added to the World Health Organization classification in 2004. Moreover, conventional urothelial malignancy with concurrent squamous or glandular differentiation may be encountered at rates as high as 20%–25%.[4] According to the more recent WHO classification of 2016,[5] divergent differentiations including pure squamous carcinoma (e.g., due to schistosomiasis in Africa) need to be individuated from UC with squamous differentiation; glandular neoplasm (including primary adenocarcinoma) also needs to be distinguished from UC with glandular differentiation. Apart from the aforementioned, other more rare variants include the nested and large nested variant of UC (NVUC), the microcystic, micropapillary, plasmacytoid, sarcomatoid, and lymphoepithelial-like carcinoma (LELC).[3],[4],[5]

According to the most recent EAU guidelines (2021), some forms of variant histology are considered prognostic factors and are used to substratify high-risk group patients and identify those at the highest risk of disease progression, to whom early cystoprostatectomy is indicated.[3] The detection of these variants may be used as prognostic indicator affecting the overall response to therapeutic treatment and therefore the patient's prognosis and survival.[4] Effective multimodal approaches concerning each variant of bladder cancer are expected to be determined by future studies.


  Urothelial Carcinoma with Divergent Differentiation Nested and Large Nested Variant of Urothelial Carcinoma Top


The NVUC, first reported by Stern,[6] is a rare variant of UC with a reported incidence of 0.3% of all invasive bladder tumors.[7] The bland-appearing invading nests of cells are very similar with the von Brunn's nests and therefore can be easily misinterpreted as benign lesions, especially in case of absence of invasion of muscularis propria of the bladder.[8] Small- or large-packed nests, consisting of urothelial cells with focal-to-mild atypia and mild pleomorphism, that infiltrate or not the lamina propria or muscularis propria, are the usual characteristics of NVUC.[8],[9] At presentation, the NVUC is usually diagnosed at locally advanced or metastatic stages, often with the involvement of the ureteric orifices.[9] Large nested variant (LNVUC) consists of a combination of the NVUC (with larger cell nests) and the inverted growth pattern of NMIBC UC. NVUC was first reported as an aggressive entity with poor prognosis, but recently, it was found to have similar clinical outcome with that of conventional UC, probably because of its frequent misclassification in the past.[8] Differential diagnosis includes von Brunn's nests, cystitis glandularis, cystitis cystica, inverted papilloma, and nephrogenic adenoma, alone or in combination. Immunohistochemically, loss of p27 expression is common between NVUC and conventional UC,[9] but the presence of TERT promoter mutation can be suggested as a promising biomarker to distinguish NVUC and LNVUC from benign urothelial lesions.[10] Early radical cystoprostatectomy is recommended in the presence of NVUC-LNVUC variant.[11]


  Squamous Differentiation and Pure Squamous Cell Carcinoma Top


Two categories of malignancies relevant with the squamous pattern (characterized by the presence of intracellular keratin, intercellular bridges, and/or keratin pearls) have been reported: the UC with squamous differentiation and the pure squamous carcinoma.[5] In the former case, the predominant urothelial pattern is accompanied by squamous differentiation at a lesser percentage albeit no official thresholds have been established so far as to determine the extent of the squamous counterpart. Usually, in mixed carcinomas, the squamous pattern corresponds up to 40% of the total extend of the malignancy. Noteworthy, tumors with squamous differentiation may be associated with advanced stages of the disease. There is uncertainty about the way the squamous differentiation can affect prognosis, survival, and response to chemotherapy and radiotherapy, in comparison with the UC.[12],[13]

Pure squamous malignancy is rarely reported in developed countries (1%–7% of the new cases in the United States), but it is the main (almost 60%) cause of bladder cancer in North Africa (due to schistosomiasis caused by Schistosoma haematobium infection). Apart from schistosomiasis, other causes such as chronic inflammation (production of cyclooxygenase COX-2) due to recurrent urinary tract infections,[13] bladder calculi, long-term catheterization, or prior exposure to cyclophosphamide chemotherapy have been recognized as risk factors of squamous carcinoma in developed countries.[12]

Radical cystoprostatectomy remains the treatment of choice for pure squamous carcinoma and UC with squamous differentiation, although the effect of neoadjuvant chemotherapy (NAC) has not been determined yet (NAC has been reported to be beneficial against mixed, but not against pure squamous carcinoma at several studies).[14] A recent study, based on the use of immune checkpoint inhibitors (e.g., pembrolizumab) in patients with mixed or pure squamous bladder carcinomas and PD-L1 expression, reported comparable results with those of patients with pure UC.[15]


  Urothelial Carcinoma with Divergent (Glandular) Differentiation Top


Glandular differentiation–pure adenocarcinoma–urachal carcinoma

Similar to squamous differentiation, a distinction should be made between mixed UC with divergent (glandular) differentiation, pure adenocarcinoma, and urachal carcinoma, all of which have histological similarities with colorectal adenocarcinoma.[12],[16] UC with glandular differentiation is encountered in 16% of conventional UC, while pure adenocarcinoma has an incidence of only 0.5%–2% representing the third most common bladder cancer after urothelial and squamous carcinomas.[17] Urachal carcinoma, corresponding to 10% of all bladder adenocarcinomas, is the subset of primary bladder adenocarcinomas that arises from the urachal remnant to the bladder dome.[12]

The presence of small tubular or gland-like spaces with extracellular or intracellular mucin in conventional UC usually indicates the diagnosis of UC with glandular differentiation, whereas bladder tissue with complete glandular differentiation is diagnosed as pure adenocarcinoma (associated with bladder exstrophy, intestinal metaplasia, and chronic obstruction as risk factors) and a differential diagnosis between primary and metastatic tumors from gynecologic or colon malignancies must be made.[18] Enteric, clear cell, signet ring cell, mucinous, hepatoid, and mixed types are included as subcategories of pure bladder adenocarcinoma.[18]

The presence of UC with glandular differentiation classified the patients in the very high-risk subgroup of disease recurrence and progression, so immediate radical cystectomy is strongly recommended.[19] In these patients, the administration of NAC may also be beneficial.[12] Partial cystectomy (resection of urachal ligaments and umbilicus with lymph node dissection) is recommended to urachal carcinomas. Encouraging results emerge from several studies investigating the benefits of 5-fluorouracil-based chemotherapy and immune checkpoint inhibitors.[20]

Microcystic urothelial carcinoma

Microcystic UC is a very rare variant, with an incidence of 1%, characterized by microcysts, macrocysts (whose shape varies from round to oval and size up to 2 cm).[9] This variant can be easily misinterpreted as benign lesion and must be differentially diagnosed from cystitis cystica, cystitis cystica glandularis, and nephrogenic adenoma but also from bladder adenocarcinoma, especially in the presence of tubules and cysts with glandular structures. The overall survival seems similar to that of conventional UC although more robust evidence is required.[18]

Micropapillary urothelial carcinoma

Micropapillary UC is a variant associated with an incidence of almost 6%, male predominance (male-to-female ratio of 5:1 to 10:1 compared with the estimated ratio of UC which is 3:1) and with papillary configuration (tight small or larger nests of neoplastic urothelial cells gathered in lacunae or stromal retraction spaces).[12],[21],[22] This variant may resemble the papillary serous carcinoma of the ovary although the presence of psammoma bodies, a usual finding in ovarian tumors, is rarely encountered in micropapillary malignancy.[22] The variant seems to progress through the luminal pathway and the chromatin-remodeling complex RUVBL1 and mi-RNA-296 seem to play a crucial role in its pathogenesis; these targets can be used for treatment in future research.[21] At presentation, the higher percentage of this variant seems to indicate poorer outcomes and it is usually associated with aggressive behavior, advanced stages, lymphovascular invasion (50%), early lymph node metastasis, wide metastatic spread and therefore, decreased survival and prognosis.[22] in a review of 100 patients the 5-and 10-year survival have been estimated to be 51% and 24% respectively.[23] Intravesical BCG therapy appears ineffective in T1 patients with the micropapillary variant (very high risk of disease recurrence and progression group), so early cystoprostatectomy is recommended.[24] Moreover patients with muscle-invasive micropapillary varant treated with cystoprostatectomy and platinum based chemotherapy in neoadjuvant or adjuvant settings had no survival benefit, in comparison to conventional UC with NAC of the same stage.[25],[26]

Small cell carcinoma

The presence of any percentage of small cell histology on bladder tissue provokes the pathologist to diagnose the primary small cell carcinoma of bladder, rather than UC with small cell differentiation. This happens because it is the small cell histology that determines the aggressiveness, the poor prognosis and the brief survival of this rare disease (<1% of all bladder cancers).[12] Histopathologically, it is similar to other small cell malignancies, such as the undifferentiated small cell lung carcinoma; it is characterized by scant cytoplasm, nuclear crowding, necrosis and frequent mitosis without any specific pattern of diffuse growth. At the time of diagnosis, almost 95% of the patients have MIBC, 65% have metastasis and the 5-year survival does not exceed the rate of 40%.[22] The majority of the cases is positive for chromogranin and synaptophysin and must be differentially diagnosed from malignant lymphoma, inflammation, UC with scant cytoplasm and alveolar rhabdomyosarcoma.[22] Cisplatin and etoposide agents, which are used in small cell lung cancer, are also recommended against small cell bladder carcinoma in neoadjuvant settings. Radical cystectomy should be offered to the patients, including those with earlier stages (cT1), although multimodal treatment could also be considered, as there is no standard care for these patients.[27]

Plasmatocytoid urothelial carcinoma

The plasmatocytoid variant of UC is a rare, aggressive variant, in which histologically infiltrative tumor cells with abundant eosinophilic cytoplasm, resembling plasma cells with eccentric nuclei set in a myxoid stroma, create patterns similar to lobular carcinoma of breast and gastric signet-ring carcinoma.[28] The coexistence with conventional UC or sarcomatoid carcinoma histology is usual. Same histological features can be found at malignant lymphomas, plasmacytomas, melanoma, metastatic carcinomas including lobular and gastric adenocarcinoma, paraganglioma, rhabdomyosarcoma and UC.[22],[28] Lack of E-cadherin expression, due to mutation in gene coding CDH1, is a characteristic of this variant only and is very helpful at the differential diagnosis.[29] At the time of diagnosis, up to 90% of the cases curry at least a pT3 disease and 5-year survival is <30%.[28] Because of its poor prognosis and the suboptimal results reported with NAC in plasmatocytoid variant compared with conventional UC, upfront early cystoprostatectomy is recommended.[30] Recent evidence suggests that PD-1/PD-L1 targeted immunotherapy might be a promising treatment option for patients with advanced disease although more studies are required.[28] Similar to other variants, it has not yet been identified if poor prognosis is due to the variant itself or due to advanced stage at presentation.

Sarcomatoid urothelial carcinoma

Sarcomatoid UC is another very rare variant, representing the 0.3% of all bladder carcinomas, in which both the epithelial and the mesenchymal sarcomatoid features emerge from a common monoclonal cell origin.[31],[32] Others propose that this biphasic variant is the result of two monoclonal tumors emerging at the same time.[33] The term has been registered in the WHO classification and the presence of urothelial malignant cells or in situ helps the very difficult distinction between this variant and a primary (pure) sarcoma.[22] In the sarcomatoid variant pattern, obvious sarcomatoid overgrowth with usually a myxoid background may appear which may be accompanied by urothelial or squamous or small cell carcinoma. The sarcomatoid component can be represented by osteosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, angiosarcoma or a mixture of sarcoma histologies.[22] Pseudosarcomatous myofibroplastic proliferations and primary sarcomas are included in differential diagnosis and positivity for pancytoceratin, p63, CK5/6, HMW cytokeratin or mutation in TP53, RB1 and PIK3CA can be used as diagnostic markers.[31] Moreover, overexpression of PD-L1 genotype has been revealed in sarcomatoid component of mixed tumors.[34] At presentation, the majority of sarcomatoid carcinomas is in advanced stages with development of nodal or distant metastasis (even after surgery) and a very poor prognosis. However, there is much controversy whether the poor prognosis is due to the presence of the variant or to the advanced stage of the disease at time of diagnosis. Although there are not specific treatment strategies for patients with this variant and they are treated with radical cystoprostatectomy, studies show that the benefit of neoadjuvant or adjuvant chemotherapy is debatable and almost 70% of patients succumb 2 years following diagnosis.[35]


  Lymphoepithelioma-Like Carcinoma Top


LELC corresponds to a very rare variant of bladder carcinoma, with a high resemblance to non-keratinizing nasopharyngeal carcinoma (lymphoepithelioma). However, testing for Epstein-Barr virus is uniformly negative and therefore this variant is designated as lymphoepithelioma-like.[36] Syncytial undifferentiated malignant cells, large pleomorphic nuclei, indistinct cytoplasmic borders, lymphoid infiltration and dense inflammation are usual histological features of this variant. The histopathologic characteristic of this variant is the dense infiltration of T-and B-cells, occasionally accompanied by the presence of other inflammatory cells (e.g., eosinophils, plasma cells).[12],[22] Most cases present with muscle invasion, but usually without metastasis. Pure, predominant and focal subgroups have been proposed for this malignancy with more favorable prognosis for the predominant subgroup, compared to the focal.[37],[38] A head to head comparison of cystoprostatectomy in LELC versus cystoprostatecromy in conventional UC has shown similar survival. Due to the variant's chemosensitivity to platina, bladder preservation treatment with chemotherapy has been proposed by some authors but it was associated with higher recurrence rate in the LELC group compared with the conventional MIBC.[37],[38] Future studies are required to define whether the amount of LELC component can be used as a prognostic indicator and whether these patients will benefit by immunotherapy, since the presence of PD-L1 expression is has already been revealed.[39]


  Conclusions Top


Although each one of the presented histologic variants is rare, they overall represent up to one out of four cases of all bladder malignancies; therefore the early identification, quantification and accurate report by pathologists are imperative due to lack of data concerning these patients. Squamous, glandular, sarcomatoid and micropapillary are the most common urothelial variants while pure squamous, adenocarcinoma and small cell carcinoma are the most common non-urothelial counterparts. Small number of patients, poor prognosis and advanced stages at presentation can be considered as obstacles in determining if and how the early and accurate diagnosis of these variants can have therapeutic or prognostic implications. Well-designed multi-institutional studies are necessary in order to clarify the prognostic role of each variant, to define specific biomarkers and to establish specific treatment strategies that will be beneficial for the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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