Case of the Month

Discussion

What are the key clinical and histologic features of mucinous tubular and spindle renal cell carcinoma?

Mucinous tubular and spindle renal cell carcinoma (MTSRCC) is a recently described distinct rare variant of renal cell carcinoma, which is recognized as such in the 2004 World Health Organization (WHO) tumor classification. It is a low grade tumor polymorphic renal epithelial neoplasm with variable components of tubular architecture, spindle cell areas and extracellular mucinous stroma, previously called low-grade tubular mucinous renal neoplasm, spindle and cuboidal renal cell carcinoma, low-grade myxoid renal epithelial neoplasm with distal nephron differentiation, and low-grade collecting duct carcinoma. To date, about 100 cases of MTSRCC have been reported.

MTSRCC predominantly affects female adult patients with a 1:4 male-to-female ratio. Most MTSRCCs are discovered incidentally during abdominal imaging studies for other unrelated reasons. It commonly presents as a well-demarcated round or ovoid renal mass on CT scan, with tumor less than 5 cm demonstrating homogenous pattern of enhancement while larger ones over 5 cm often showing heterogeneous enhancement pattern. The classic MTSRCC usually carries a favorable prognosis and complete surgical excision appears to be adequate treatment. Metastasis usually occurs in tumors with atypical histological features such as sarcomatoid transformation, therefore a close follow-up is recommended for patients with treated MTSRCC. Our MTSRCC patient underwent radiofrequency ablation, and subsequent imaging six months later showed no evidence of recurrence. He will continue with surveillance.

The key histologic feature of MTSRCC is a mixture of spindle cell and tubular components in a background of variable amounts of mucinous stroma. Spindle cells are commonly observed in parallel bundles or arrays, and spindle cell areas can be a dominant component, which may mimic leiomyoma or myofibroblastoma, thus posing a diagnostic challenge, or it may rarely undergo high-grade spindle cell proliferation and sarcomatoid differentiation, leading to a worse prognosis. Tightly packed ovoid or elongated tubules with collapsed central lumen are composed of bland-appearing cuboidal cells with scant, pale to slightly eosinophilic cytoplasm and indistinctive borders. The nuclei are generally round, uniform and display low nuclear grade characteristics with evenly dispersed chromatin and inconspicuous nucleoli or prominent small single nucleoli. Another prominent feature is the variable amounts of extracellular pale mucinous/myxoid stroma, which may appear as numerous small vacuoles and mimic clear cells.

What are the main IHC markers of MTSRCC?

Immunohistochemistry studies showed that the MTSRCC tumor cells (both tubular and spindle cells) have consistent positive stain for CK7, CK8/18, CK19, PAX2/8, alpha-methylacyl-CoA racemase (AMACR) and E-cadherin; variable stain for RCC marker, vimentin and high molecular weight cytokeratin (34BE12), and often negative stain for CD10/15 (occasionally positive), CK20, GATA3, P63, smooth muscle actin (SMA) and carbonic anhydrase IX. Our MTSRCC demonstrated positive stain for CK7 (Figure 3), AMACR (Figure 4), RCC (Figure 5), PAX8 (Figure 6) and PAX2 (Figure 7), but negative stain for CD10 (Figure 8). Such immunohistochemistry stain profile confirmed the diagnosis of MTSRCC.

What is the origin of this distinct tumor?

The epithelial origin of both MTSRCC’s tubular and spindle cells has been well established, but the exact renal epithelial cell origin has not. It was initially thought to originate from either cells of the loop of Henle or collecting duct epithelium. Recent accumulating evidence suggests a more proximal nephron origin and a histological heterogeneity of MTSRCC with overlapping features of papillary RCC, but MTSRCC is a genetically distinctive entity different from papillary RCC. A very recent study of a multi-institutional cohort of 22 MTSCCs utilizing whole-exome and transcriptome sequencing demonstrated the presence of biallelic alteration and dysregulation of the hippo tumor suppressor pathway in 85% of samples.

What are the main entities for differential diagnosis?

MTSRCC, as its name indicates, is composed of three morphological components in variable amounts: cytologically bland tubules, spindle cells and extracellular mucinous/myxoid stroma. It usually is a low pathological grade circumscribed tumor. The round, uniform nuclei generally display evenly dispersed chromatin and inconspicuous nucleoli or prominent small single nucleoli. The key is to be aware of the histologic spectrum of MTSCCs to ensure their accurate diagnosis. For example, spindle cells or mucin may be a feature dominant or lacking in some cases, mimicking other malignancies and thus posing a diagnostic challenge. MTSRCC can have well-formed papillae, clear cells, necrosis, neuroendocrine differentiation, focal clusters of foamy macrophages, some of which are considered overlapping features with papillary renal cell carcinoma.

The main entities for differential diagnosis are papillary renal cell carcinoma with low grade spindle cell foci, sarcomatoid renal cell carcinoma, collecting duct carcinoma metanephric adenoma, and renal carcinoid, etc.

Papillary RCC usually has a predominant tubulopapillary growth pattern with complex branching well-formed fibrovascular cores, but does not have the characteristic mucinous stroma of MTSRCC, which allows an easy differential diagnosis. Although the recently described papillary renal cell carcinoma with low grade spindle cell foci shows significant morphology of MTSRCC, it still has areas of classic papillary RCC with only scattered foci of bland-appearing spindle, and it is a male predominant tumor and generally does not have mucinous stroma.

Collecting duct carcinoma may have prominent, eosinophilic cytoplasm, but these tumors are of high grade, usually has highly cytologically atypical tubules with desmoplastic stroma and is aggressively invasive. They are often positive for high molecular weight cytokeratin, p63, and CK7, but usually negative for RCC marker, and AMACR. MTSRCC is usually located in renal cortex and generally well circumscribed, with foci of hemorrhage and/or necrosis only rarely seen, and they exhibit consistent positive stain for AMACR, in addition to CK7, CK8/18, CK19, PAX2/8 and E-cadherin, and variable stain for RCC marker.

Sarcomatoid renal cell carcinoma usually has areas of classic renal cell carcinoma and cytologically atypical spindle cells with large hyperchromatic/pleomorphic nuclei and prevalent necrosis. It usually has significant mitotic activity and confers an aggressive behavior, while MTSRCC usually has only bland-looking spindle cells with low nuclear grade and without the characteristic sarcomatoid renal cell carcinoma features.

Metanephric adenoma usually does not have mucinous stroma, and is negative for CK7 expression, while MTSRCC tumor cells are consistently positive stain for CK7.

Renal carcinoid usually has stippled chromatin and trabecular growth pattern, but does have the characteristic mucinous stroma of MTSRCC. Immunohistochemistry stain can easily tell them apart: renal carcinoid usually exhibits diffuse positive stain for chromogranin, synaptophysin, vesicle associated membrane protein (VAMP), syntaxin, neuron-specific enolase, snare protein SNAP 25, prohormone convertase (PC) 1/3 and PC 2; while MTSRCC tumor cells (both tubular and spindle cells) display consistent positive stain for CK7, CK8/18, CK19, PAX2/8, AMACR and E-cadherin.

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