—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 4 - Papillary Carcinoma of the Thyroid Metastatic to the Kidney

Cristina Magi-Galluzzi
Cleveland Clinic
Cleveland , OH





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Clinical History:
In 1995, the patient was a 63 year-old male with a history of papillary thyroid carcinoma S/P thyroidectomy in 1980, and radical neck dissection in 1982. In 1982, he was diagnosed with bilateral lung metastases; status post iodine-131 treatment in 1986. In 1991 and 1992, he received chemotherapy and radiation therapy secondary to bilateral lung metastases, as well as hemoptysis.

On February 1995, the patient presented with a complaint of two months duration of heartburn, regurgitation after eating, accompanied with nausea, vomiting, and easy satiety. He also reported a weight loss of 10 lb. over a short period of time, and lack of appetite. At about the same time he started having black stools, and reported feeling of dizziness. A duodenal mass was found on endoscopy. An abdominal CT showed a partially cystic mass in the right abdomen originating either in the kidney or in the adrenal gland.

Patient underwent angio-infarction and subsequent (5 months later) resection of a large right kidney mass. During the course of resection, it was discovered that the tumor had eroded into the duodenum with a pyeloduodenal fistula.


Case 4 - Slide 1
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Case 4 - Figure 1
Low power views of kidney and tumor mass.
Case 4 - Figure 2
Low power views of kidney and tumor mass.
Case 4 - Figure 3
Intermediate power views of the tumor showing papillary architecture.

Case 4 - Figure 4
Intermediate power views of the tumor showing papillary architecture.
Case 4 - Figure 5
High power views of papillary structures.
Case 4 - Figure 6
High power views of papillary structures.

Case 4 - Figure 7
High power views of papillary structures.
Case 4 - Figure 8
Intermediate power views of satellite lesion separated from largest tumor mass.
Case 4 - Figure 9
Tumor cells are immunoreactive for cytokeratin 19 (CK19).

Case 4 - Figure 10
Tumor cells are immunoreactive for cytokeratin 7 (CK7)
Case 4 - Figure 11
Tumor cells are immunoreactive for thyroid transcription factor 1 (TTF1).

Case 4 - Figure 12
Tumor cells are immunoreactive for CD57.
Case 4 - Figure 13
Tumor cells are immunoreactive for thyroglobulin.


Histopathologic Findings:
Grossly most of the kidney was involved by a neoplastic process partially solid, cystic and extensively necrotic. The largest solid area of tumor was located in the lower pole and measured 3.0 cm in diameter.

The two morphologic features that best characterized the lesion were the presence of papillae and the nuclear changes. The papillae were formed by a central fibrovascular stalk covered by a neoplastic epithelial lining. The better developed papillae were long with a complex arborizing pattern. Some of the papillae were straight and slender, arranged in a parallel, regimented fashion; others were short and stubby. The thickness and composition of the papillary stalk was variable. In most instances, the papillary stalk was made up of loose connective tissue and variously sized thin-walled vessels. In some cases, it was swollen by edema fluid or occupied by an abundant acellular hyaline material. Occasionally, the stalk was infiltrated by lymphocytes or clusters of foamy or hemosiderin-laden macrophages. Psammoma bodies and other calcific concretions were not present.

The nuclei of the cells lining the papillae had a round or slightly oval shape. The contour appeared smooth on superficial examination, however closer inspection revealed subtle irregularities in the form of indentationsand folds. The nuclear irregularities frequently manifested in the form of grooves. Another peculiar feature of the nucleus was characterized by an empty appearance of the nucleoplasm, which seems almost totally devoid of chromatin strands. These nuclei were similar to the ones previously described as pale, optically clear, watery, empty, ground glass, and "Orhan Annie's eyes".

Immunohistochemical Features:
The tumor cells lining the papillary structures showed positivity for cytokeratin (CK) 19 (Figure 9), CK7 (Figure 10), thyroid transcription factor-1 (TTF-1) (Figure 11), CD57 (Figure 12), thyroglobulin (Figure 13), and negativity for CK20, AMACR, HMWCK, p63, CD10 and RCC Marker. These findings are consistent with the diagnosis of metastatic papillary thyroid carcinoma.

Diagnosis:
Papillary carcinoma of the thyroid metastatic to the kidney.

Discussion:
Metastases of malignant tumor to the kidney are observed rather frequently at autopsy, but rarely found clinically in living patients. Maeda et al. reviewed a total of 136 cases of metastatic renal tumors including 38 cases from the Japanese literature [1]. In autopsies, renal metastases outnumber renal primary tumors by 4:1. Autopsies performed on cancer patients have found that 4.6-7.6% of patients have metastases in the kidney, with frequencies of bilaterality and multiplicity being as high as 71-81% [2]. By contrast, primary renal cell carcinomas are rarely bilateral.

Even if, theoretically, all solid tumors may give rise to renal metastasis, secondary lesions to the kidney occur more commonly in patients with lung tumors, breast cancer, melanoma, gastric carcinoma and lymphoma [3, 4, 5, 6, 7, 8, 9, 10]. Reports in the literature suggest rates of non-lymphoma renal metastases of 1.5-1.8% of the general population [5, 6].

Metastatic renal tumors present a worse prognosis than primary renal cancer. This seems to be because the former progresses rapidly after its discovery. Renal metastasis should be suspected whenever there is a known primary. Imaging features are rarely pathognomonic. In fact, many renal masses are small and asymptomatic as the widespread use of CT and ultrasound has led to increased incidental detection.

CT is the most sensitive modality for detecting renal metastases. It can be used to evaluate the extent of disease as well as other sites of involvement. Even so, small, solitary metastases can be indistinguishable from small primary malignancies. Metastases are usually multiple, bilateral, and iso- to hypodense (10-40 HU) on an unenhanced scan. They typically demonstrate limited enhancement after contrast (5-15 HU), except in the case of highly vascular tumors (such as melanoma).

Papillary carcinoma of the thyroid is more common in women, with a ratio F:M ranging between 2:1 and 3:1. The mean age at the time of diagnosis ranges from 31 to 49 years. A total of 4-20% of patients with papillary carcinoma develops distant metastasis during the course of their disease. Common sites of distant metastases of differentiated thyroid cancer upon presentation include cervical lymph nodes, lung, and bone; less common sites of metastases are the brain, liver, and skin.

Metastasis to the kidney caused by thyroid and follicular cancers is found in 2.8-3.8% and 6-20% of cases, respectively [6]. However, detection of thyroid carcinoma with clinically apparent kidney metastases is rare, with 20 cases reported in the literature [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. Clinical and pathological features were only accessible in a subset of cases (Table 1). The most common presenting symptom or sign was hematuria, 7 to 37 years after having being treated for thyroid cancer [13, 15, 17, 18, 29]. Of the 20 cases of renal metastases associated with well-differentiated thyroid carcinoma, 11 were from papillary carcinoma (most of which were follicular-variant papillary carcinomas), and 8 were from follicular carcinoma. Metastatic tumor involved the right kidney in 6 cases, and the left kidney in 8. In 4 cases there was bilateral involvement. One patient presented with an abdominal mass 3 years following resection of a follicular carcinoma of the thyroid [1]. In 3 patients the disease was discovered incidentally during retrograde pyelography [12], ultrasound [26], and autopsy [19].

In the vast majority of the cases, the patients had known thyroid neoplasms at the time the renal metastases were identified. Rarely, metastases to the kidney preceded the knowledge of the primary thyroid neoplasm and were treated surgically as primary renal tumors.

Ruggiero et al. [28] reported a case of papillary thyroid carcinoma that presented with abdominal pain in a 25-year-old woman with no previous history of thyroid disease. The patient underwent radical nephrectomy for a right renal mass, which was diagnosed as papillary thyroid carcinoma-follicular variant. During subsequent evaluation, metastatic disease was also identified in the patient's lungs.

Liou MJ et al. [25] reported a case of papillary thyroid microcarcinoma with renal metastasis in a patient with widely disseminated disease, including renal, pulmonary and pelvic bone metastases.

The management of patients with distant metastatic well-differentiated thyroid cancer includes surgical resection of the primary tumor, radiotherapy, and ablation treatment with 131I. Thyroid cancer metastatic to the kidney is rare clinically, but can be amenable to treatment with good long term results [18]. As many as 75% of patients with distant metastases caused by well-differentiated thyroid cancer die within 5 years of diagnosis [30]. Nevertheless, in patients with solitary late distant metastasis of thyroid cancer, complete surgical resection may be proposed, in order to offer a better chance of prolonged survival [24].

In conclusion, thyroid carcinoma should be considered in the differential diagnosis of a renal mass, particularly in patients with a high serum thyroglobulin level, even if the renal mass is solitary and unilateral, or no history of thyroid cancer is involved.
Table 1.

Reference (#) sex/age tumor type presentation years after detection site
J Urol 1968 [11] F/44 follicular abdominal mass 3 bilateral, multiple nodules
Cancer 1979 [12] F/49 follicular incidental finding (IVU} 18 bilateral
J Urol 1982 [13] F/66 follicular gross hematuria 37 left kidney
Minerva Urol Nefrol 1991 [14] F/- follicular neck nodule 23 right kidney
J La State Med Soc 1992 [15] M/53 papillary hematuria 7 right kidney
Surg Today 1994 [16] F/72 PTC-FV - 3 bilateral, multiple nodules
AJR Am J Roentgenol 1995 [17] F/47 follicular hematuria 7 right kidney
Am Surg 1995 [18] M/75 PTC-FV gross hematuria no previous history left kidney
Nephron 1996 [19] F/91 follicular incidental autopsy finding - left kidney
Clin Nucl Med 1999 [20] F/65 follicular neck and sternal mass - left kidney
Nuklearmedizin 2000 [21] PTC-FV bilateral
Ann Urol (Paris) 1999 [22] M/56 papillary low back pain 3 left kidney
Thyroid 2001 [23] F/61 PTC-FV upper back mass - left kidney
Thyroid 2001 [23] F/53 PTC-FV back pain - right kidney
Anticancer Res 2003 [24] follicular 10
Acta Otolaryngol 2005 [25] F/50 PTC-FV low back pain no previous history right kidney
Int J Urol 2002 [26] M/37 papillary incidental finding (US} left kidney
An Med Interna 2002 [27] left kidney
Am J Otolaryngol 2005 [28] F/25 PTC-FV abdominal/flank pain no previous history right kidney
Endocr Pathol 1999 [29] PTC-FV hematuria and flank pain
Present case M/63 papillary nausea, vomiting, easy satiety 15 right kidney

PTC-FV = papillary thyroid carcinoma - follicular variant.

Differential Diagnosis:
The main differential diagnosis is withprimary Papillary Renal Cell Carcinoma (PRCC). PRCC comprises approximately 10% of renal cell carcinomas. The reported mean age at presentation and sex ratio (M:F) ranges from 52-66 years and 1.8:1 to 3.8:1, respectively. PRCC frequently contains areas of hemorrhage, necrosis and cystis degeneration. A pseudocapsule may be identified. Bilateral and multifocal tumors are more common in PRCC than in others renal malignancies.

PRCC is characterized by malignant epithelial cells forming varying proportions of papillae and tubules. The papillae contain a delicate fibrovascular core and aggregates of foamy macrophages and cholesterol crystals may be present. Calcified concretions are common in papillary cores and adjacent desmoplastic stroma. PRCCs typically express CK7, CK8, CK18, CK19, CAM 5.2, RCC CD10, and AMACR.

Micropapillary Urothelial Carcinoma of the upper urinary tract. Micropapillary carcinoma is a rare variant of urothelial carcinoma, first described by Amin et al. in 1994 [31]. The tumor resembles papillary serous carcinoma of the ovary. There is a male predominance (M:F = 3.2:1) and the patient's age ranges from 5th to the 9th decade with a mean age of 68 years. Almost all the reported cases occur in the urinary bladder, but it may also involve the renal pelvis and the ureter [32]. Histologically, two different patterns have been described in the urinary tract: the invasive and the noninvasive. The noninvasive pattern of tumor consists of slender, delicate fine papillary and filiform processes, with central fibrovascular cores. The papillae are lined by cells with high nuclear grade showing either scant or abundant eosinophilic cytoplasm. Psammoma bodies are infrequent. Micropapillary carcinomas are immunoreactive for CK7, EMA, CK20, Leu M1, and CEA. Recognition of this growth pattern is important because of its aggressive behavior and to avoid misdiagnosis with PRCC and with metastasis of papillary carcinoma from other organs.

Metastasis of papillary carcinoma to the kidney from other organs (i.e. lung, and breast) should also be considered in the differential diagnosis.

The diagnosis of primary versus metastatic renal cell carcinoma (RCC) can sometimes be difficult, because of the wide variety of histologic appearances and clinical presentations that RCC can assume. The overlapping profile between PRCC and metastatic papillary thyroid carcinoma highlights the importance of clinicopathologic correlation, and demonstrates the importance of using a panel of antibodies in differentiating these tumors through immunohistochemistry.
Immunohistochemical Comparison of Papillary Thyroid Carcinoma (CA) from Papillary Renal Cell Carcinoma.

TTF-1 thyroglobulin CK17 CD57 AMACR CD117 RCC Ma CD15 CK7 EMA
Papillary Thyroid CA + + + + -/++ - -/+ + +
Papillary RCC - - - - + +/- + + + +
Take Home Points
  • Primary renal cell carcinomas (RCC) are rarely bilateral; by contrast, metastatic tumors to the kidney are frequently (71-81%) bilateral and multiple.

  • Renal metastasis should be suspected whenever there is a known primary.

  • Secondary lesions to the kidney occur more commonly in patients with lung tumors, breast cancer, melanoma, gastric carcinoma and lymphoma.

  • The overlapping IHC profile between some primary RCC and metastatic tumors to the kidney highlights the importance of clinicopathologic correlation, and demonstrates the importance of using a panel of antibodies in differentiating these tumors through immunohistochemistry.
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