There are 13 types of histological variants of invasive uroepithelial tumors in the WHO (2004) classification of urological tumors [1], accounting for about 15% of uroepithelial carcinomas. These subtypes also originate from uroepithelial cells and can exist alone or in combination with metastatic cell carcinoma or other subtypes. The clinicopathological characteristics and prognosis of each subtype of uroepithelial carcinoma (UC) are summarized as follows; I. Invasive uroepithelial carcinoma with squamous differentiation If it contains any uroepithelial component, the pathological diagnosis should estimate the proportion of squamous component and the tumors should all be classified as uroepithelial carcinoma with squamous differentiation to avoid misdiagnosis as mixed carcinoma consisting of metastatic and squamous carcinoma [2]. Squamous differentiation is positively correlated with the grading and staging of the tumor and has a worse prognosis than uroepithelial carcinoma alone, and the recurrence rate of uroepithelial carcinoma with squamous differentiation is higher. Patients with such tumors have poor response to chemotherapy and mostly need radical cystectomy.
This type accounts for about 6% of uroepithelial carcinoma of the bladder, most of which are accompanied by invasive uroepithelial carcinoma, and those with glandular differentiation without other invasive carcinoma components are rare. 24 cases were reported by Miller et al [3], among which 12 cases consisted of tumor tissue with glandular differentiation components alone, 12 cases of carcinoma in situ and non-invasive papillary carcinoma, 9 of which eventually progressed to invasive carcinoma, including 2 cases of small cell carcinoma, 3 cases of hypodifferentiated UC, and 4 cases of UC (no specific type). However, none of the patients progressed to adenocarcinoma, showing that there was no direct relationship between glandular differentiation and adenocarcinoma. The current study concluded that those with UC with glandular differentiation had poor prognosis.
Nested variant Uroepithelial nested subtype carcinoma is an invasive tumor, accounting for about 0.3% of invasive bladder cancer. The heterogeneity of surface-coated uroepithelial tumor cells is not obvious, but the heterogeneity of intra-tumor cells is obvious, so it is easy to be misdiagnosed as benign when only the tumor surface is taken. Metastasis can occur early in those with low histological grade but high clinical stage tumors. This subtype is easily misdiagnosed as von Brunn’s nest, cystic and adenocystic cystitis, involute papilloma, and adenoma of renal origin [4]. The marked cellular heterogeneity at the depth of the lesion is the main differentiator between the nested subtype and other benign lesions. The prognosis of the nested variant is relatively good. Cox et al [5] reported 18 cases of transurethral resection of tumor, 2 cases of total ureterectomy and 3 cases of radical total cystectomy, of which 17 were followed up for a mean of 43 months and only 3 cases developed metastasis. This subtype of tumor is not sensitive to chemotherapy, Wasco et al [6] reported that only 13% of 30 cases responded to neoadjuvant chemotherapy.
Microcystic variant This subtype is characterized by the formation of multiple round or oval microcystic structures in the tumor tissue. Microscopically, there may be glandular-like structures, but they are not associated with bladder adenocarcinoma. This variant needs to be differentiated from invasive uroepithelial carcinoma with glandular differentiation, adenoid cystitis, and nest-like subtype of uroepithelial carcinoma with tubular differentiation. The growth pattern and biological behavior of this type of tumor are similar to those of common uroepithelial carcinoma, and Paz et al. reported 3 cases of 12 cases confined to the epithelium, 6 cases invading the lamina propria, and 3 cases invading the muscular layer, with 11 cases being high-grade tumors [7]. Radical total cystectomy is mostly curable in those with muscle layer infiltration [8], and metastasis can occur early in those with infiltrative growth; Radopoulos et al. reported one case with penile metastasis that died 6 months later [9]. This type is mostly insensitive to chemotherapy, and conventional adjuvant chemotherapy is not advocated.
V. Micropapillary variant This type is high-grade uroepithelial carcinoma, more than 50% have carcinoma in situ, and the tumor has already infiltrated the muscular layer when the patient has symptoms. The number and location of micropapillary components correlate with the prognosis, and moderate or large number of micropapillary components predict the progression of the lesion [10]. Since this tumor often has myxoid infiltration, it is recommended that a new biopsy should be taken when the tumor specimen has a micropapillary component on the surface or there is a lamina propria infiltration that has not yet broken through the myxoid layer.Kamat [11] et al. reported 44 cases of 100 non-invasive tumors with bladder preservation and 27 cases of BCG bladder perfusion, of which 67% progressed and 55% underwent radical total bladder resection with a median survival of 43.2 Compérat et al. analyzed 7 2 cases and concluded that the proportion of micropapillary component <10% was an independent factor affecting prognosis [12]. VI. Uroepithelial carcinoma with syncytial trophoblastic giant cells This type is extremely rare. Syncytial trophoblastic giant cells are the result of uroepithelial cell dedifferentiation and morphologically include syncytial trophoblastic layer, choriocarcinoma-like carcinoma, and some uroepithelial carcinomas without trophoblastic cell morphology but expressing HCG, a highly malignant subtype. Changes in serum HCG levels correlate with tumor grade and stage. β-hCG-negative patients have a better prognosis than positive ones, which can be used as an indicator of prognosis. It is now believed that most of the previously diagnosed choriocarcinoma of the bladder is actually uroepithelial carcinoma with syncytial trophoblastic giant cells. To clarify the prognosis, the presence and proportion of trophoblastic differentiation should be indicated in the pathology report. There are reports of no recurrence and metastasis after 10 months of follow-up after transurethral resection [13], and current studies suggest that this type, especially those with elevated β-hCG, should undergo total bladder resection as early as possible, and postoperative adjuvant chemotherapy with MVAC can restore HCG to normal levels [14]. vii. Tamas [15] et al. studied 28 cases of lymphoepithelioid carcinoma of the bladder and those who presented with LELC alone had a better prognosis with a 12%-15% chance of metastasis. Those with coexisting adenocarcinoma and squamous carcinoma had a poor prognosis. LELC of bladder alone has better chemotherapy and good prognosis. When the lymphoepithelioma-like carcinoma component is present in typical uroepithelial carcinoma, the biological behavior is the same as that of uroepithelial carcinoma. The 43 cases reported in the literature were retrospectively analyzed and classified into three types according to their pathological types: simple LELC (40%), combined with other carcinomas (23%) and LELC-based combined with other carcinomas (37%), and the simple type and LELC-based type require urothelial tumor resection and chemotherapy when necessary to achieve complete cure. In the case of LELC complicated with adenocarcinoma or squamous carcinoma or muscle infiltrating LELC, total cystectomy with adjuvant chemotherapy should be performed [16]. VIII. Lymphoma-like and plasma cell-like subtypes It refers to tumor cells resembling malignant lymphoma or plasma cell tumor. Some cases are misdiagnosed as lymphoma/plasmacytoma at initial biopsy, especially in biopsy specimens with predominantly this tumor component or small sampling without other components, and the literature reports 11 specimens with plasma cell component of 30% to 100%, all with clinical stage T3, 8 with lymph node metastasis, average follow-up of 7 months, and 9 deaths [17]. Although myxoid infiltration of the tumor has occurred, there is often no sarcoid hematuria in the early stage, and the cystoscopy shows a thickened and stiff mucosa [18], even without a sarcoid mass, making early diagnosis and treatment difficult, and the prognosis is poor due to the high malignancy of the tumor. Although the best treatment option remains undefined, radical surgery combined with chemotherapy is the main option [19]. IX. Sarcomatoid subtypes Malignant tumors with morphological and immunohistochemically confirmed differentiation to epithelial and mesenchymal tissues belong to the sarcomatoid subtype of uroepithelial carcinoma, which is currently molecularly confirmed as a monoclonal tumor with different differentiation. Among them, 39.8% had multiple tumors, 53.9% underwent transurethral resection only, 35.8% underwent total or partial bladder resection, and 15.8% underwent radiotherapy combined with surgery, with a mean survival of 14 months. Therefore, radical surgery should be performed as early as possible after clear diagnosis, and neoadjuvant chemotherapy with surgery can be used for those with metastases to obtain long-term remission [21]. 10.Uroepithelial carcinoma with giant cells High-grade uroepithelial carcinoma can present with epithelial tumor giant cells, and in some cases, the giant cell reaction is so extensive that it resembles giant cell tumor of bone, and its biological behavior was previously thought to be benign. pelvic metastasis. The current study concluded that the giant cell component accounts for approximately 20% to 100% of tumor specimens, often combined with uroepithelial carcinoma, and has a poorer prognosis than giant cell tumors of bone [23].Lopez-Beltran [24] reported 7 of 8 cases mixed with metastatic cell carcinoma, all staged ≥ PT3, 75% with lymph node metastases, with a mean follow-up of 20 months, 5 deaths, 2 with metastases surviving 11 and 19 months There were 5 deaths, 2 with metastases survived 11 and 19 months, and 1 tumor-free case survived 74 months. There is no standard treatment plan, and it is recommended that surgery with bladder preservation should be considered for superficial simple giant cell tumors, while radical resection should be performed as early as possible for those with other cancerous components, especially those with infiltrative growth. The clear cell subtype is a type of clear cell with intracytoplasmic glycogen, which can grow focally or diffusely. It has been previously reported as mid-renal adenocarcinoma, but in recent years most scholars believe that it originates from Mullerian duct [25]. The clinical manifestations are non-specific, and hematuria and bladder irritation signs can be seen, and treatment is mostly based on radical total cystectomy. XII. Lipid cell subtype Uroepithelial carcinoma is rare and rich in adipocytes similar to adenocarcinoma of printed cells, which belongs to high-grade uroepithelial carcinoma with poor prognosis. The main differentiation should be with liposarcoma and indolent cell carcinoma.Lopez [26] reported 27 cases with 10% to 50% of the variant lipid cell component in the tumor tissue, 17 cases of total bladder resection, including 3 cases of postoperative chemotherapy and 1 case of radiotherapy; 10 cases of transurethral tumor resection and 3 cases of intermediate postoperative BCG perfusion with a mean survival of 33 months. Most of the patients died or developed metastasis within 5 years. Leroy et al [27] reported 5 cases were diagnosed after transurethral resection and only 1 case survived after surgery, and 4 cases had tumors invading the bladder wall and renal pelvis, respectively, and all died within 6 months. Undifferentiated carcinoma This diagnosis includes other tumors that cannot be classified, such as small cell carcinoma, large cell undifferentiated carcinoma, etc. This type is extremely rare, highly invasive and has poor prognosis. Small cell carcinoma of the bladder has a neuroendocrine phenotype and often coexists with common uroepithelial carcinoma. Molecular studies have shown that small cell carcinoma and uroepithelial carcinoma originate from the same clonal group, and therefore small cell carcinoma is considered a special subtype of uroepithelial carcinoma. Radical surgery should be the first choice for treatment, while surgery alone or chemotherapy and radiotherapy have poor results, and surgery combined with radiotherapy can improve the efficacy [28]. In conclusion, there are many different variants of urothelial carcinoma, which need to be specifically noted in the pathology report for clinicians to choose treatment options. Clinicians must be aware of rare subtypes of urothelial carcinoma of the bladder, and the pathologic features, prognosis, and treatment of variant uroepithelial carcinoma are different from those of typical uroepithelial carcinoma, and a full understanding of these is important for selecting treatment options and judging prognosis [29].