Mucinous tubular and spindle cell carcinoma (MTSCC) is rare subtype of kidney cancer primarily seen in adults, generally with low-grade histological features, low risk of metastases, favorable outcomes and a characteristic combination of loss of several chromosomes. ^1-3

A distinctive female predominance ⁴

Most tumors are discovered incidentally; although signs and symptoms, such as hematuria, flank pain, and abdominal mass, have been reported.  MTSCC can arise in the renal cortex or at the interface between the cortex and medulla.

MTSCC are grossly described as well-defined and well circumscribed tan/white masses with a solid consistency ⁵

MTSCC is a heterogeneous tumor composed of cuboidal cells forming tubules and cords, admixed with spindle cell foci, typically associated with a mucinous/myxoid stroma.(Fig.1) Some cases may be spindle cell poor or spindle cell predominant. Rarely, MTSCC may demonstrate high nuclear grade, necrosis and sarcomatoid transformation. The differential diagnosis is typically papillary RCC (i.e., these tumors can have morphologic overlap).

Fig.1: Morphologic features of MTSCC typically include low grade cytology, tubular and spindle cell growth patterns and an associated myxoid stroma

There are very few immunostains that can definitively confirm the diagnosis of MTSCC.  Like papillary RCC, MTSCC are typically positive for CK7 and AMACR.  In contrast to PRCC, MTSCC are typically negative for CD10; however, this biomarker can be focal to variable in both of these tumor types. Some suggest that Galectin3 and E-Cadherin can help distinguish MTSCC from papillary RCC; however, large series are lacking.  Recently, VSTM2A was shown to be highly expressed, by RNA ISH, in MTSCC while showing either absent or low level expression in the vast majority of other RCC subtypes. ^6,7

MTSCC with classic low-grade morphology has excellent prognosis subsequent to partial or radical nephrectomy. However, a few cases with low grade features have shown metastases to lymph nodes and liver. ⁸ High grade MTSCC with sarcomatoid transformation, and other atypical histomorphologic features  have a higher risk for recurrence, regional lymph node metastases, and distant metastases. ²

Unique and consistent chromosomal copy number loss, involving chrs. 1, 4, 6, 8, 9, 13, 14, 15, and 22, (Fig.2A) and without chromosome 7 or 17 gains, is observed by cytogenetic /FISH analysis, ^9,10 microarray (Fig.2B) and whole genomic sequencing. ^3,11-13

Fig.2: (A) GTG banded karyotype showing the combination of monosomies for chromosomes 1, 6, 14, 15 and 22 (B) Combination of monosomies of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22, detected by microarray analysis

Multiple chromosomal gains, including chrs. 7, 11, 16, 17, and 20 were also reported in some studies. ^11,14,15 However, in such cases, there was overlapping morphology features of with papillary RCC and it is likely that these tumors represent the latter. Therefore, the finding of characteristic patterns of genome-wide copy number alterations strongly support MTSCC and PRCC as distinct entities despite their immunohistochemical and morphologic overlap. ¹³

In some studies of locally advanced/metastatic MTSCC of the kidney, additional cytogenetic alterations were reported; these changes include gain of chromosome 1q or homozygous deletion of the CDKN2A/B gene region, as well as, frequently loss or CN-LOH of chr. 3/3p, loss of chr. 18 /18q (50%), loss of chrs. 19  and 21 and chromosomal gains of chrs. 2, 7, 12, and 20.  ^15-17

Dysregulation of the Hippo-pathway has also been shown to be a common molecular event for MTSCC, present either as bi-allelic loss of the Hippo-pathway tumor suppressor genes and/or evidence of alteration of the Hippo pathway genes mainly PTPN14 and NF2; other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. ¹²