| Abstract|| |
Renal cell carcinomas accounts for an approximately 2% of human malignancies with atleast ten different histological subtypes recognized by the World Health Organization (WHO) 2004 classification. Composite carcinomas with dual divergent epithelial differentiation in kidneys are extremely uncommon. We report an unusual case of a 37-year-old female who presented with symptoms related to renal tumor for the last three years. Computed tomography scan revealed a large heterogenously contrast enhancing left kidney mass comprising of two distinct histological components of low grade adenocarcinomatous and carcinoid-like low grade neuroendocrine carcinomas with presence of hilar lymph nodal metastases of both the components. The component of adenocarcinoma was immunoreactive to E-cadherin, cytokeratins 7 and 19 with negativity for cluster of differentiation 10, cytokeratin 20, CD117, and vimentin; while the neuroendocrine component was immunoreactive for vimentin, chromogranin and synaptophysin with negativity for CD10, CD117, and cytokeratins 7, 19 and 20. MIB-1 labeling index in the both the components was 2-3%. The present case is the first of its kind to be reported in the kidney and emphasizes the diversity potential of kidney tumors.
Keywords: Adenocarcinoma, composite kidney tumor, neuroendocrine carcinoma
|How to cite this article:|
Deshmukh MK, Epari S, Menon S, Desai SB, Tongaukar H. Composite epithelial kidney tumor comprising of adeno and neuroendocrine carcinomatous components: An unusual variant of renal cell carcinoma. Indian J Pathol Microbiol 2011;54:809-13
|How to cite this URL:|
Deshmukh MK, Epari S, Menon S, Desai SB, Tongaukar H. Composite epithelial kidney tumor comprising of adeno and neuroendocrine carcinomatous components: An unusual variant of renal cell carcinoma. Indian J Pathol Microbiol [serial online] 2011 [cited 2019 Jun 16];54:809-13. Available from: http://www.ijpmonline.org/text.asp?2011/54/4/809/91528
| Introduction|| |
Renal cell carcinoma (RCC) accounts for approximately 2% of all human adult malignancies.  These tumors arise from the epithelium of renal tubules. The 2004 World Health Organization (WHO) classification recognizes at least ten different subtypes of RCC including the subset of unclassified. The present WHO classification marks the transition from pure histomorphological features to the inclusion of cytogenetic features for defining an entity. Xp11 translocation associated RCCs are one of the distinct subtype of translocation associated RCCs which show a mixed clear cell and papillary morphology. Mucinous tubular and spindle cell carcinomas are the other recently WHO recognized entities. In addition to the aforementioned two new subtypes of RCCs, the latest WHO classification also includes mixed epithelial and stromal tumors as a distinct from RCCs.  Tubulocystic RCCs are the other recently described entities which are yet to be included in the recent WHO classification. 
Unlike the above mentioned typical epithelial tumors, composite tumors in kidneys are extremely rare with very few isolated single case reports in the literature and have no separate mention in the latest WHO classification. ,, But in other visceral sites esp. gastrointestinal tract, pancreas etc., these tumors are not uncommon.  The recent WHO classification has no mention of composite epithelial tumors and suggests all those tumors that do not correspond to any of the described classes to classify under RCC, unspecified (NOS) group. 
We report a rare primary kidney tumor with composite epithelial morphology comprising of low grade mucinous adenocarcinomatous and neuroendocrine carcinomatous components with lymph nodal metastases of both the components.
| Case Report|| |
A 37-year-old woman presented with symptoms of gross hematuria for one week, lump in left flank for one month, and dull aching pain in the left flank for the last three years. She was diagnosed as hypertensive one year back and was put on antihypertensive since then without any investigation for the same. In addition, history of pulmonary tuberculosis was noted seven years back.
Computed tomography (CT) scan [Figure 1]a and b revealed a large heterogeneously contrast enhancing left kidney mass involving the upper and middle portion with specks off calcification within. Along with those mentioned above, paraaortic lymphadenopathy was also noted, based on which, a diagnosis of RCC was made.
|Figure 1: (a and b) CT scan of abdomen revealed a large heterogeneously enhancing mass showing calcifications was seen arising from the upper and mid pole of left kidney, abutting the psoas muscle extending to splenic hilum, (c) Photograph of the cut surface of the specimen showing a tumor involving upper and mid pole of kidney with thick mucoidy and firm fleshy areas|
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Left radical nephrectomy along with paraaortic nodal dissection was done by retroperitoneal approach (through excising 11 th rib). Intraoperatively, the mass was seen involving and confined to the left kidney with intact Gerota's fascia. Additionally, a mass was seen in the hilar region adherent to renal vein. The kidney with mass, Gerota's fascia, and adrenal gland were removed en-bloc. Hilar lymph nodal mass was dissected from the renal vein and removed with no intra-operative and immediate postoperative complications.
Left radical nephrectomy specimen measured 16.5 × 11.5 × 9 cm. Externally, Gerota's fascia was intact. On serial slicing, a solid heterogenous tumor measuring 15 × 11.5 × 9 cm was seen involving upper two-third to three-fourth of the left kidney (upper pole, mid pole, and extending up to the lower pole - [Figure 1]c). A compressed rim of adjacent renal parenchyma was seen at the lower pole (shown by the asterick in the [Figure 1]c). The tumor was seen involving the renal sinus. Peri-renal fat was grossly not infiltrated by the tumor. The cut surface of the tumor was solid with mucoid areas. Calcified areas with various few fleshy grayish areas and hemorrhagic areas are noted. Renal pelvis, hilar vessels, and adrenal gland were all free of tumor. The hilar lymph nodal mass was received in separate container and measured 5.5 cm in greatest dimension.
Histological examination showed a malignant tumor with a thick fibrous band of tissue separating the normal kidney parenchyma [Figure 2]a. The tumor showed trabeculae of lamellar bone [Figure 2]b and c with composite epithelial morphology comprising low grade mucinous adenocarcinoma and neuroendocrine carcinoma [Figure 2]d, e and f. Predominant component was low grade mucinous adenocarcinoma (comprising approximately 65-70%) exhibiting tubulo-papillary pattern [Figure 3]a and b composed of columnar to cuboidal shaped cells with low nucleo:cytoplasmic (N/C) ratio, intracytoplasmic mucin, and basally located round nuclei with conspicuous nucleoli [insets of [Figure 3]a and b. The neuroendocrine component (30-35%) was composed of monomorphic round shaped nucleated cells of coarse stippled nuclear chromatin and indistinct cytoplasm in a ribbon-like arrangement [Figure 3]c and d. No necrosis was seen and the mitotic activity was occasional (less than 2 per 10 high power fields) in the adenocarcinomatous component and was insignificant in the neuroendocrine component. Foci of mature lamellar bone with rimming of osteoblasts (occupying approximately 1% of the entire tumor area) were noted within the tumor [Figure 2]b and c. Perirenal fat and the renal sinus showed microscopic tumor infiltration. No sarcomatous or dedifferentiated areas are seen. The left paraortic nodal mass showed tumor metastases interestingly comprised of both the epithelial components (i.e., adenocarcinoma and neuroendocrine components).
|Figure 2: Photomicrographs show a tumor within the kidney (a) area marked with star symbol represents normal kidney) separated by a thick fibrous capsule. The tumor shows a heterologous bone formation (b and c) and comprising of two distinct components (d) neuroendocrine and - adenocarcinomatous) of intestinal adenocarcinoma-like (e) and low grade carcinoid-like neuroendocrine carcinoma (f) (H and E; A-×20, B,C,D,E and F -×40):|
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|Figure 3: (a and b). Photomicrographs showing the distinct adenocarcinomatous area in tubulo-glandular architecture with micropapillary fronds. Insets in both (3a and b) better shows the nuclear features, (H and E – ×80; insets – ×160) (c and d). Photomicrographs showing a monotonous population of polygonal cells with a characteristic cord - like and serpentine arrangement representing neuroendocrine component (H and E – ×80)|
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On immunohistochemical evaluation [Figure 4]a-d, [Figure 5]a-f, [Figure 6]a-h, [Table 1], the mucinous adenocarcinoma component was positive for pancytokeratin (MNF-116), cytokeratin 7 [Figure 4]a and [Figure 5]b, cytokeratin 19 [Figure 4]b, E-cadherin [Figure 5]e and p53 [Figure 5]f; while negative for vimentin [Figure 5]d, cytokeratin 20 [Figure 5]c, CD10 [Figure 5]a, synaptophysin, chromogranin, CD117 (c-Kit), estrogen receptor, and inhibin. The neuroendocrine component showed positivity for vimentin [Figure 6]d, E-cadherin [Figure 6]e, chromogranin [Figure 6]g, and synaptophysin [Figure 6]h; while negative for CD10 [Figure 6]a, cytokeratin 7 [Figure 6]b cytokeratin 20 [Figure 6]c, and p53 protein [Figure 6]f. The MIB-1 (Ki-67) proliferation index is similar in both the components and was approximately 2-3%.
|Figure 4: Photomicrographs from the interfacial region of the two distinct components showing differential immunoreactivity, (a) the adenocarcinomatous component is positive for cytokeratin 7, cytokeratin 19 (b) and epithelial membrane antigen (d) without any reactivity in the neuroendocrine component; while both component show negativity for cytokeratin 20 (c) (IHC - ×80)|
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|Figure 5: (IHC x80x). Photomicrographs of the adenocarcinomatous component showing immunoreactivity for cytokeratin 7 [(b) IHC x80], E-cadherin [(e) IHC x80] and for p53 [(f) IHC x80]; while immunonegative for CD10 [(a) IHC x80], cytokeratin 20 [(c) IHC x80] and vimentin [(d) IHC x80]|
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|Figure 6: (IHC). Photomicrographs of the neuroendocrine component showing positivity for vimentin [(d) IHC x80], E-Cadherin [(e) IHC x80], chromogranin [(g) IHC x80], and synaptophysin [(h) IHC x80]; while negative for CD10 [(a) IHC x80], cytokeratin 7 [(b) IHC x80], cytokeratin 20 [(c) IHC x80], and p53 [(f) IHC x80]|
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|Table 1: Details of the antibodies used in the present case and the detection system|
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Based on the above mentioned histomorphological features coupled with radiological findings, a diagnosis of primary renal composite epithelial tumor comprising of low grade mucinous adenocarcinomatous and carcinoid-like low grade neuroendocrine carcinomatous components with metastases to hilar lymph nodes (TNM Stage: T3N2) was made. 99m Tc-methylene diphosphonate ( 99m Tc-MDP) planar bone scintigraphy (BS) did not reveal any bone metastases.
Subsequently, the patient was advised for neo-adjuvant chemotherapy (etoposide, cisplatin, decadan, and graniset) and was advised for follow-up. The patient was fine at the first follow-up of three months, but did not turn up later and was lost to follow-up subsequently.
| Discussion|| |
Renal cell carcinomas (RCCs) are a group of heterogenous epithelial neoplasms with diverse morphological features, molecular etiopathological mechanisms, and different outcomes.  The present case is one such which highlights the heterogeneity and diversity of histomorphological features of RCCs. To date, no report of composite RCC comprising of adenocarcinoma and neuroendocrine carcinoma (adenocarcinoid - like tumor) has been reported in English literature, though occurrence of similar tumors has been well known in digestive tract with the earliest report of the same way back in 1924.
Takashi et al., reported a benign composite epithelial tumor in kidney comprising of somatostinoma and the mucinous cystadenoma.  Apart from that, there is no other report of composite epithelial tumors in the kidney. The present case appears to be the first case of composite kidney tumor with distinct divergent malignant epithelial components to be reported.
In the present case, the confinement of the tumor within the kidney and Gerota's fascia with absence of any primary tumor elsewhere does confirm the site of origin in kidney. The unusual immunophenotype and differential expression in the two distinct components however precludes a speculation for exact histogenetic origin of the tumor in the present case. The combined immunoreactivity for cytokeratin 7 and cytokeratin 19 of the adenocarcinomatous component may possibly suggest distal tubular origin and neuroendocrine component possibly represent the divergent differentiated components of the same.  At the same time, the authors cannot really exclude the possibility of a tumor arising from a pleuripotent precursor cells with divergent differentiation, as both the differentiated components seen in the present case does not have typical morphology of any of the described kidney primary. The other hypothesis, one can argue for, originates from a teratomatous germ cell tumor. But in the case under discussion, though there is distinct identifiable component of mature bone (representing mesenchymal component) but there is no representation of ectoderm to consider the possible origin from a teratomatous lesion. On the other hand, heterologous bone formation has been very well described to occur in RCCs, sometimes associated with marrow components, but in the present case, though no associated marrow components seen, the presence of heterologous bone or osseous metaplasia weighs more in favor of primary kidney tumor (renal cell carcinoma-like) with distinct phenotype.  In addition, presence of both components in the metastases suggests more of a clonal origin of both components. Thus, authors strongly favor the hypothesis of pleuripotent precursor cell origin with aberrant divergent differentiation.
Clinically, the case under discussion had revealed a long history (of at least one year) which correlated well with histology by lack of any aggressive features i.e., mitoses and necrosis except for the presence of nodal metastases. Though lack of proper follow-up period in this case precludes for any prediction of biologic behavior of these tumors, but the presence of nodal metastases possibly suggests a biological behavior similar to other RCCs. Even the composite intestinal tumors did not show any different behavior from adenocarcinoma (NOS).
| Conclusion|| |
The present case re-emphasizes the complexity and heterogeneity in the renal cell carcinoma and possibly adding another dimension to the understanding of biology of the origin of renal cell carcinomas.
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Department of Pathology, Tata Memorial Hospital, Mumbai - 400012
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]