Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_734_Библиотеки_им_академика_М_И_Перельмана.pdf
314
and with or without pylorus preservation, and duodenum-preserving total pancreatectomy, depending on the location and number of tumors [4, 10]. Some studies
also report that radiofrequency ablation and cytoablative therapy can be performed
in addition to surgery as well as IRE (irreversible electroporation) all of which are
being currently studied [13].
Targeted therapy includes tyrosine kinase inhibitors (TKI), mTor inhibitors, and
immune checkpoint inhibitors such as anti-PD1, anti-PD L1, and anti-CTLA4.
These are highly effective for metastatic RCC (mRCC) [8, 12]. However, there is a
paucity of data and lack of evidence that shows this to be effective in treatment for
mRCC to the pancreas specically [1, 12].
The 5-year survival rate for untreated mRCC was 13–47% compared to 65–88%
after surgical resection [1]. Current data show the 1-, 3-, 5-, and 10-year overall
survival after surgical resection to be 88%, 72%, 33–72%, and 32%, respectively [1,
8–10, 14]. The overall survival rate after pancreatectomy for mRCC is longer com-
pared to pancreatectomy for other cancers [4, 11]. The median recurrence-free survival after pancreas metastasectomy was 17.2months with a median recurrence rate
of 44% after 27months, and a 5-year recurrence-free survival of 43% [2, 10, 12]. In
line with the current data, surgical approach in well controlled and resection of isolated mRCC to the pancreas is now an integral part of treatment with good results.
Whether synchronous or metachronous, a complete resection can lead to long-term
survival [1, 2, 10, 11, 14].
R. Mudgway et al.
Colorectal Carcinoma
Introduction/Epidemiology
Colorectal carcinoma (CRC) is the third leading cause of cancer-related deaths in
the United States, with metastasis most commonly occurring to local lymph nodes
(50–70%), the liver (50%), the bones (40%), the lungs (21%), the peritoneum
(15%), the ovaries (15%), and the brain (5%) [15, 16]. Though CRC is one of the
most common origins for metastatic pancreatic lesions, it is exceedingly rare,
accounting for only 1.3–2% of pancreatic metastasis [15–19]. CRC metastasis
occurs via direct invasion through the colon, lymphatic channels, and via hematogenous routes [15, 16]. There are two leading theories that explain the metastatic
pattern of CRC: the mechanical/hemodynamic theory and the seed-and-soil theory
[18]. The mechanical theory is based on anatomical delivery via the venous and
lymphatic drainage systems [18]. The theory explains the colonic tumors spread via
emboli that drain into the portal venous circulation and metastasize to the liver or by
systemic routes to the lung. One study found that pancreatic metastases tend to be
from right-sided tumors, which supports the mechanical spread theory where cecal
tumors spread directly to the pancreas via the ileocolic and superior mesenteric vessels [18, 20]. The seed-and-soil theory is based on metastasizing tumor cells nding
18 Secondary Malignant Neoplasms
315
a tissue bed that is compatible for deposit and growth [18]. Given the rarity and
unique location of the pancreas not found along normal anatomic drainage routes,
seed-and-soil does offer a plausible mechanism [18]. Pancreatic metastases typically occur 3–4 years after initial CRC diagnosis, though some cases have been
reported to be more than 5 and even over 10years later [15–17].
Diagnosis/Radiology/Pathology
The clinical presentation of metastatic CRC) is variable, 45–71% patients with pancreatic metastasis from CRC are asymptomatic [15, 18]. Common presentations of
a primary pancreatic tumor are abdominal pain, weight loss, and jaundice. Clinical
presentation of patients with pancreatic metastasis from CRC is unique [18, 19].
The incidences of those same symptoms were abdominal pain (20%), weight loss
(5%), and jaundice (30%) [19]. A major distinguishing feature is that 55% of
patients whose tumor’s location was in the head of the pancreas did not present with
jaundice, likely related to its location and growth [19].
When symptoms are present or during surveillance, the majority of pancreatic
metastases are initially discovered on abdominal CT with a sensitivity of 68–86%
and specicity of 65% [15]. Diagnosis with imaging alone is difcult [18, 19, 21].
Enhanced CT of pancreatic metastases from CRC will show a hypodense mass that
is occasionally accompanied by the dilation of the distal main pancreatic duct, a
similar nding to that of a primary pancreatic cancer which makes it difcult to
discern in this context, also taking into account risks for a second primary [21].
Imaging may only be good to differentiate between CRC and RCC origin, which
shows an intense enhancement during the arterial phase [18, 21].
In these cases, EUS-FNA has a sensitivity of 75–95%, specicity of 60–100%,
and accuracy >91% [15, 21]. EUS typically reports pancreatic metastatic lesions as
hypoechoic, heterogeneous masses with well-dened margins, and other ndings
suggestive of secondary lesions are multiples lesions, lack of a retention cysts, pancreatic duct dilation, and pancreatic atrophy [15]. There is controversy over the
necessity of biopsy with EUS-FNA for informed treatment decisions. The opposition argues the risk of tumor cell dissemination, while advocates argue for accurate
staging diagnosis with biopsy for the following indications: “(1) all other diagnostic
measures failed; (2) pathological examination demonstrates certain markers or gene
mutations that are needed for initiation of specic treatments; (3) biopsy results will
inuence therapy; (4) biopsy results can avoid or minimize surgery; and (5) locoregional staging of pancreatic tumors” [18].
Immunohistochemical ndings are helpful in differentiating pancreatic metastasis from primary pancreatic cancer [15, 17, 21]. Immunochemical staining shows a
specic pattern (CK20+, CK7-, and CDX2+) [18, 21]. The respective rates of CK20
and CK7 positivity were 100% and 5% in colorectal cancer, and 62% and 92% in
pancreatic cancer [21]. CDX2 is expressed positively in the majority of CRC, while
in contrast the rate is only 0–50% in pancreatic carcinomas [18, 21]. When
316
performing EUS-FNA, an adequate sample of the specimen is needed [21]. Use of
a thicker needle or performing a rapid on-site evaluation to assess the quantity is
recommended [21].
R. Mudgway et al.
Treatment/Prognosis
Treatment for CRC metastasis to the pancreas is primarily chemotherapy and metastasectomy of solitary lesions without extrapancreatic metastasis, as determined on
an individual basis [15]. Early pancreatic metastasis could be treated surgically with
most of the diagnoses coming at advanced stages with inltration of local organs,
local nodes, or distant metastasis. However, only about 20% of patients are referred
for surgery [16]. These surgeries include total pancreatectomy, distal pancreatectomy, pancreatoduodenectomy, and pylorus-preserving pancreatoduodenectomy
[16, 19]. Tumor proximity to the SMV or PV in well-selected patients is not a contraindication to resection based on previous reviews of the topic [16]. Palliative
surgery is performed to provide adequate biliary or alimentary passage which
includes biliary-intestinal anastomoses and gastrointestinal anastomoses [16].
The 5-year survival of CRC with metastasis to the pancreas is 14–50% with
mortality and morbidity to be 1.4% and 48.3%, respectively [17]. Patients also have
a median survival time of 16.5 months, and a disease-free survival period of
1.5–43 months, with 100% of symptomatic relief until recurrence of death [18].
Though data is scarce for CRC metastasis to the pancreas, and the optimal treatment
is yet to be established. Multiple literature reviews and case studies agree that pancreatic resections may provide a denitive diagnosis as well as a survival benet and
should be considered in patients who are well selected, t for surgery, free of metastasis to other organs, and are discussed properly in multidisciplinary fashion
[15–19].
Melanoma
Introduction/Epidemiology
Melanoma is one of the most common malignancies that metastasizes to the gastrointestinal tract and usually affects multiple organ sites [22, 23]. Autopsy data have
revealed gastrointestinal tract involvement in 50–60% of patients with melanoma;
however, the clinical diagnosis is only made in 1.5–4.4% of melanoma patients
[24]. Solitary organ involvement of melanoma to the pancreas is extremely rare,
occurring in <1% of metastatic melanoma cases [22, 23, 25]. There are <200 cases
18 Secondary Malignant Neoplasms
317
of pancreatic metastasis from malignant melanoma found in the literature [22, 23],
with the major primary site being cutaneous and ocular [23]. Cases of melanoma
metastasis from the nasal cavity to the pancreas have been reported [23]. The primary lesion of melanoma may be difcult to identify. Studies have shown patients
with metastatic melanoma to the pancreas who underwent pancreatic resection
demonstrate a median time between the treatment of the primary melanoma and the
detection of pancreatic metastases of 6years (range 14months to 34years) [22, 26].
A long disease-free interval of more than 2years after primary melanoma treatment
was associated with improved survival in patients with intrapancreatic metastases [26].
Diagnosis/Radiology/Pathology
Obtaining a pre-operative diagnosis of a metastatic pancreatic tumor can be difcult
[27]. Positron emission tomography-computed tomography (PET-CT) scan has a
high sensitivity and specicity for detection of metastasis from malignant melanoma [28]. On contrast-enhanced CT and MRI imaging, metastatic lesions from
malignant melanoma demonstrate hypervascularity and rim enhancement [23, 29].
Metastatic melanoma lesions will demonstrate hyperintensity on T1 MRI, an indication of changes caused by the paramagnetic properties of melanin [30, 31].
Malignant melanoma may or may not show hyperenhancement on contrastenhanced endoscopic ultrasound (CE-EUS), and the lack of characteristic ndings
makes diagnosis of malignant melanoma by CE-EUS difcult [23, 32]. EUS reports
of malignant melanoma to the pancreas have demonstrated hypoechoic, heterogenous lesions [33].
Pathological examination is necessary to conrm the diagnosis of metastatic
melanoma to the pancreas. EUS-FNA with effective sampling and immunohistochemical analysis is important in providing a cytological and histological diagnosis
[23]. EUS-FNA with rapid on-site evaluation provides effective sampling and
allows a cytopathologist to ensure the samples are adequate for assessment [34].
Aspirate samples of melanoma are cellular and consist of noncohesive malignantappearing cells with nuclear pleomorphism and prominent nucleoli admixed with
malignant, pigmented epithelioid and spindle-shaped cells, and can include the
presence of melanin [22]. Pathology reports of melanoma lesions in the pancreas
have demonstrated normal pancreatic parenchyma inltrated with a tumor composed of sheets of heavily pigmented and atypical epithelioid cells with high
nuclear-cytoplasmic ratio, eosinophilic cytoplasm, hyperchromatic nuclei with
marked pleomorphism, and numerous atypical mitoses [33]. On immunohistochemical analysis, the markers S100, Melan A, and HMB-45 have a reported 97–100%,
75–92%, and 69–93% sensitivity for identifying metastatic melanoma. S100 and
318
R. Mudgway et al.
Melan A have a reported 75–87% and 95–100% specicity, respectively [23, 35].
The era of precision medicine has found that approximately 29–66% of melanoma
cases are positive for activating mutations in the BRAF gene, with the most common mutation being the V600E substitution [22].
Treatment/Prognosis
Metastatic melanoma has a poor prognosis with a median life expectancy of
6–12months in cases of gastrointestinal metastasis [33]. The prognosis of metastatic melanoma to the pancreas specically is unknown. Pancreatic resection for
metastatic melanoma is controversial, and there are no guidelines for indications of
pancreatic resection for metastatic melanoma cases [23]. As seen for all isolated
pancreatic metastases, the benet of resection on overall and disease-free survival is
not clearly established but may provide some benet in selected patients [36].
For melanoma, some studies have demonstrated prolonged survival after complete surgical resection of localized metastatic melanoma to the pancreas [23, 37,
38]. Pancreas-sparing pancreatectomies are limited due to the limited margins
obtained and the exclusion of a formal lymphadenectomy, thus the role of these
procedures for isolated pancreatic metastases is not well dened [36]. Standard
pancreatic resections, such as pancreatoduodenectomy and distal pancreatectomy, are associated with signicant morbidity and may only offer the advantage
of improved lymphadenectomy for resection of intrapancreatic metastases,
though may provide control of the disease when indicated and adequately performed [36]. However, some authors advocate that non-standard pancreatic
resections have an increased risk of early local recurrence and higher morbidity
[39, 40]. A retrospective study on survival of patients with isolated pancreatic
metastasis from malignant melanoma who underwent complete surgical resection demonstrated a median survival and 5-year disease-free survival of 24months
and 37%, respectively [38]. This was in comparison to patients with incomplete
pancreatic resections who had a median survival of 8months and 5-year diseasefree survival of 0% [38]. Cases of pancreatoduodenectomy prolonging survival
over 5years for patients with metastatic melanoma to the pancreas have been
reported [23, 36, 41].
The decision to perform pancreatic resection requires exhaustive pre-operative
evaluation and staging, with critical assessment of peri-operative risks and the
expected survival benet. Surgical resection should only be considered if complete
resection is possible [36], yet surgical therapy may provide palliation in selected
cases [42]. Systemic or targeted therapy for melanoma may provide prolonged survival and less morbidity compared to surgical resection for intrapancreatic metastasis and almost always is considered around the planned resection. The role of
systemic or targeted therapy in combination with surgical resection is yet to be
determined.
18 Secondary Malignant Neoplasms
319
Sarcoma
Introduction/Epidemiology
Sarcomas are rare tumors with differentiation toward mesenchymal tissue and
account for approximately 1% of all adult cancers [43]. Metastasis of sarcoma to the
pancreas is extremely rare. Although limited, cases of sarcoma subtypes metastasizing to the pancreas include those from primary osteosarcoma, Ewing sarcoma, mesenchymal chondrosarcoma, leiomyosarcoma, dermatobrosarcoma protuberans,
synovial sarcoma, myxobrosarcoma, and solitary brous tumors [44–50]. Most
sarcomas preferentially metastasize via the vascular system rather than the lymphatic system, and the most frequent sites of metastatic sarcoma are the lung and
bone [51]. The connective interspaces and cavities in which tumor cells can become
entrapped, such as the peritoneum, provide another possible route of metastatic dissemination of sarcoma [52]. The median overall survival for metastatic sarcoma
ranges from 12 to 18months from time of diagnosis [53]. Unlike other forms of
cancer, the prognosis of a sarcoma depends on its grade rather than its specic histological type [51].
Osteosarcoma is the most common primary bone malignancy in all age-groups,
and the highest risk period for onset coincides with the adolescent growth spurt
(10–14years old in females, 15–19years old in males) [45]. Distant metastasis of
osteosarcoma occurs in 10–20% of patients [45]. Incidence rates of mesenchymal
chondrosarcoma are similar between men and women, with the highest incidence in
the second and third decades of life [54]. Approximately 20% of mesenchymal
chondrosarcoma cases have metastatic disease at the time of diagnosis [55].
Dermatobrosarcoma protuberans has a higher incidence in men and commonly
occurs between 20 and 50years of age [48]. Metastasis of dermatobrosarcoma
protuberans occurs in 1–6% of patients, and the brosarcomatous variant has a 15%
risk of distant metastasis [56, 57]. Synovial sarcoma metastasizes in 50% of patients
[58]. Of the three subtypes of synovial sarcoma (monophasic, biphasic, and poorly
differentiated), the poorly differentiated subtype is associated with early recurrence
and metastasis [59].
Diagnosis/Radiology/Pathology
As is the case with other forms of pancreatic metastases, patients with sarcoma
metastasis to the pancreas may be asymptomatic at the time of diagnosis or may
present with generalized abdominal pain. Metastatic sarcoma lesions of the pancreas are often incidentally found on imaging. CT (Fig.18.3) or MRI (Fig.18.4) is
recommended for radiologic evaluation [60]. PET-CT can demonstrate uorodeoxyglucose (FDG) uptake in the pancreas [48]. Osteosarcoma metastasis to the pancreas may demonstrate the characteristic calcied lesion of osteosarcoma, but some
320
Fig. 18.3 Contrastenhanced CT scan of
osteosarcoma metastasis to
the pancreas. A
retroperitoneal, mixed
cystic and solid mass with
central calcications
centered on the lesser sac
is demonstrated
R. Mudgway et al.
lesions may be indistinguishable from primary pancreatic malignancies and cystic
masses have been reported [45]. Mesenchymal chondrosarcoma may demonstrate
granular irregular calcications with a surrounding hypodense tumor on CT scan,
and low-intensity calcied areas surrounded by a high-intensity tumor on
T2-weighted MRI [46].
Endoscopic ultrasound-guided ne needle biopsy (EUS-FNB) to obtain tissue
samples for histological and immunohistochemical analysis (Fig.18.5) can aid in
the diagnosis. Mesenchymal chondrosarcoma is histologically characterized by
poorly differentiated small round cells with an abrupt transition to hyaline cartilage
[60]. Leiomyosarcoma and synovial sarcoma demonstrate proliferation of spindleshaped cells with nuclear atypia on histology [47, 49]. Mesenchymal chondrosarcoma is typically positive for NKX2.2, CD99, S100, and SOX9 tumor markers on
immunohistochemical stains [61]. CD99 is the most commonly reported marker
associated with Ewing sarcoma [50]. Other markers associated with Ewing sarcoma
ab
18 Secondary Malignant Neoplasms
Fig. 18.4 Magnetic
resonance
cholangiopancreatography
scan of osteosarcoma
metastasis to the pancreas.
A large, mixed cystic and
solid mass lesion
originating from the
superior aspect of the
pancreatic tail and
involving the lesser sac
with associated edema of
the pancreatic tail is
demonstrated
321
Fig. 18.5 Metastatic, high-grade osteosarcoma involving the pancreas at 10X magnication (a)
and 20X magnication (b). Osteosarcoma extends into the pancreatic parenchyma. There is perineural invasion and perivascular invasion. Figure18.3b includes the presence of malignant osteoid
322
R. Mudgway et al.
include neuron-specic antigen, vimentin, and synaptophysin [50]. Leiomyosarcoma
is typically positive for α-smooth muscle actin and vimentin on immunohistochemical analysis [47]. Dermatobrosarcoma protuberans will be positive for vimentin
and platelet-derived growth factor receptor (PDGFR) [48]. Synovial sarcoma has
been found to be positive for BCL2, CD99, and cytokeratin on immunohistochemistry and may demonstrate evidence of SS18 gene rearrangement by break-apart
uorescence in situ hybridization [49].
Treatment/Prognosis
The mainstay of treatment for localized sarcoma is complete surgical resection
with or without radiation [53]. For metastatic sarcoma, the mainstay of treatment
is chemotherapy, and there are an increasing number of systemic therapy options
available [62]. Other treatment options for metastatic sarcoma include surgery,
radiation, ablation, embolization, and immunotherapy [53]. There is no standard
treatment for sarcoma metastasis to the pancreas. Tumor size and extent of tumor
invasion to surrounding tissues and structures contribute to treatment approach
and survival. The role of surgical resection for sarcoma metastasis to the pancreas
is not clearly dened, and treatment regimen should be based on a multidisciplinary approach on an individual basis. For peripancreatic lesions minimally
abutting the pancreatic parenchyma, enucleation may be considered [49].
However, involvement of the pancreatic ducts or larger lesion size may warrant
pancreatectomy. Formal pancreatic resections, such as distal pancreatectomy with
splenectomy, have been reported for resection of osteosarcoma metastasis to the
pancreas [45]. Most reports of treatment for mesenchymal chondrosarcoma
metastasis to the pancreas consisted of surgical resection followed by adjuvant
chemotherapy [46]. The optimal chemotherapy regimen is not well established.
Radiation therapy has also been reported [55]. Neoadjuvant chemotherapy followed by pancreatoduodenectomy has been reported for metastatic synovial sarcoma to the pancreas [49]. A single-institution analysis found that factors
associated with long-term survival (more than 3years) included isolated pancreatic metastasis, absence of prior recurrence, >3-year interval between resection of
the primary tumor and development of primary metastasis, and if the primary
tumor was renal cell carcinoma [63].
For Ewing sarcoma, patients with localized disease have a 5-year overall survival
of approximately 70%.On the other hand, metastatic disease has a reported 5-year
overall survival between 9% and 41% [64]. Mesenchymal chondrosarcoma has a
5-year overall survival rate of 51% [46]. Synovial sarcoma has a 5-year overall survival rate of 36–76%. Further studies are needed to evaluate the overall survival
benet of pancreatic metastasectomy for sarcoma.
18 Secondary Malignant Neoplasms
323
Conclusion
Secondary malignant neoplasms of the pancreas are rare and account for approximately 1–5% of all pancreatic malignancies [2, 3, 7, 10, 65]. The most common
primary malignant tumor site is of renal origin, followed by colorectal tumors.
Metastasis of melanoma and sarcoma to the pancreas is even less common. Given
the rarity of secondary malignant neoplasms to the pancreas, data to provide consensus guidelines for the diagnosis and treatment of these metastatic neoplasms is
limited. Most reports of metastases to the pancreas are single patient case reports or
single-institution case reviews, yet multi-institutional reviews of published literature have been performed in attempts to summarize these rare diagnoses.
References
1. Ma Y, Yang J, Qin K, et al. Resection of pancreatic metastatic renal cell carcinoma: experience and long-term survival outcome from a large center in China. Int J Clin Oncol.
2019;24(6):686–93.
2. Shin TJ, Song C, Jeong CW, etal. Metastatic renal cell carcinoma to the pancreas: clinical
features and treatment outcome. J Surg Oncol. 2021;123(1):204–13.
3. Cheong D, Rho SY, Kim JH, Kang CM, Lee WJ.Laparoscopic pancreaticoduodenectomy for
renal cell carcinoma metastasized to ampulla of Vater: a case report and literature review. Ann
Hepatobiliary Pancreat Surg. 2018;22(1):83–9.
4. Kitade H, Yanagida H, Yamada M, etal. Pylorus-preserving total pancreatectomy for metastatic renal cell carcinoma: a case report. J Med Case Rep. 2015;9:212.
5. Tosoian JJ, Cameron JL, Allaf ME, etal. Resection of isolated renal cell carcinoma metastases of the pancreas: outcomes from the Johns Hopkins Hospital. J Gastrointest Surg.
2014;18(3):542–8.
6. Ballarin R, Spaggiari M, Cautero N, etal. Pancreatic metastases from renal cell carcinoma: the
state of the art. World J Gastroenterol. 2011;17(43):4747–56.
7. Cheng SK, Chuah KL.Metastatic renal cell carcinoma to the pancreas: a review. Arch Pathol
Lab Med. 2016;140(6):598–602.
8. Malleo G, Salvia R, Maggino L, etal. Long-term outcomes after surgical resection of pancreatic metastases from renal clear-cell carcinoma. Ann Surg Oncol. 2021;28(6):3100–8.
9. Schwarz L, Sauvanet A, Regenet N, etal. Long-term survival after pancreatic resection for
renal cell carcinoma metastasis. Ann Surg Oncol. 2014;21(12):4007–13.
10. Jo S, Yang IJ, Song S.Surgery for metastatic renal cell carcinoma in the pancreatic head: a case
report and literature review. Ann Hepatobiliary Pancreat Surg. 2019;23(1):91–5.
11. Pannala R, Hallberg-Wallace KM, Smith AL, etal. Endoscopic ultrasound-guided ne needle
aspiration cytology of metastatic renal cell carcinoma to the pancreas: a multi-center experience. Cytojournal. 2016;13:24.
12. Sellner F, Thalhammer S, Klimpnger M.Isolated pancreatic metastases of renal cell cancer:
genetics and epigenetics of an unusual tumour entity. Cancers (Basel). 2022;14(6):1539.
13. Benhaim R, Oussoultzoglou E, Saeedi Y, Mouracade P, Bachellier P, Lang H. Pancreatic
metastasis from clear cell renal cell carcinoma: outcome of an aggressive approach. Urology.
2015;85(1):135–40.