Clinical experience created the general concept that the spleen is an organ rarely affected by solid tumors metastases. Although there have been published series of spleen metastases discovered during surgery or post-mortem examination, the majority of papers on the subject deal with single occurrences. The spleen's anatomical, metabolic, and immunological properties have been proposed as possible explanations for this strange incidence. The possibility that palpation in the past was the main way to detect an enlarged spleen, versus the modern imaging techniques of today which made the task easily enough, could explain the potential that solid tumors metastasizing to the spleen are becoming more common. Notable the frequency of organs spreading to the spleen varies in the reports. The objective of this study was to analyze the cases and series of primary tumor-bearing organs that spread to the spleen and the significant contribution of imaging techniques for the early diagnosis of spleen metastases. 

Basic research on the histology and function of the spleen revealed that it plays a crucial role in immunomodulation, the prevention of infections, and thromboembolism, [1-3], and quickly dispelled the impression that the spleen is a mysterious organ. Specific functions of the spleen, such as phagocytosis or humoral factors [4], as well as anatomical characteristics, like angulation between the splenic artery and celiac trunk, scarcity of lymph routs towards the spleen, and abundance of immune cells have been forwarded to explain the rarity of spleen metastases from malignant tumors [5- 9]. Less than 1% of all metastases are located in the spleen [9]. However, the frequency of cases with solid cancer with splenic metastases is rising due to advancements in medical imaging technology. Breast, lung, colorectal, ovarian, and melanoma tumors are the cancers causing the most splenic metastases, according to Comperat et al. [10]. The development of splenic metastases may occur between two and ten years after initial treatment [11] and, in one instance, even after fifteen years [12]. Depending on the time passed between the initial tumor's discovery and its dissemination, the spleen metastases may be synchronous or metachronous. It has been suggested that tumors with metachronous metastases in the spleen have relatively better prognosis [13]. Solitary metastases are uncommon. In 93 cases of solitary splenic metastases evaluated by Comperat et al. [10]   from 2003 to 2007, the time between the diagnosis of the initial tumor and the discovery of the metastases ranged from 0 to 264 months. In rare cases spontaneous rupture of the spleen may be the first sign of underlying malignancy [14]. In most cases metastases to the spleen appear at the late stages of disseminated malignant disease [15,16]. In a research by Sauer et al. [17] on 6,137 patients with malignant tumors, 59 patients (0.96%) had spleen metastases. It seems that in cases of gastric cancer dissemination to the spleen, hilus lymph nodes are more affected than the spleen itself. In a series comprising 112 patients  with proximal gastric cancer (35 women and 77 males) aged 28- 89 years the number of patients with metastases in the hilus was 11 (9.8%), whereas metastases in the spleen were found in two only (1.78%) [18]. Tumor-bearing organs that most frequently spread to the spleen are different between the reports. In a sonographic study comprising 168,000 patients, spleen metastases were found in 59, accounting for 0.03% of cases. Lung cancer was diagnosed in 11 patients, followed by those with ovarian cancer -7 patients,  colorectal in 6, breast in 6, melanoma in 5 and others in 12. In twelve patients the primary tumor was not detected [19]. According to an autopsy analysis of 1,898 people who had solid malignant tumors, 3% of those patients had splenic metastases [20]. In a series of 92 Chinese patients [21] the incidence of metastases in the spleen at autopsy was 0.6%, and at splenectomy 1.1% The lung was the most common primary tumor-21%, stomach 16%, pancreas 12%, liver 9% and colon 9%. The remaining sites of the primary tumors were rare according to the authors.  In other autopsy series spleen metastases were found in 3.1% [22] and even in 7% of the cases [23]. The aim of the present report is to review the published cases of splenic metastases from malignant tumors in various organs. Reports describing single cases of metastases from different organs are given in Table 1. The number of single patients with malignant tumors in various organs is shown in Fig. 1.  

Tumors of the digestive tract 

 Esophageal carcinoma 

The overall conception is that splenic metastases from esophageal cancer are uncommon. The infrequency of their occurrences is highlighted by the fact that the majority of articles on esophageal cancer with splenic metastases cover a single case only. In most cases esophageal carcinoma metastasizes to the regional lymph nodes, lung, liver, bones, adrenals and brain [24 ]. In a series of 147 individuals with M1 stage cancer out of an overall 837 recorded between 1982 and 1993 the most commonly affected areas included the abdominal lymph nodes (45%), liver (35%), lung (20%), cervical lymph nodes (18%), adrenals (5%), brain (2%) and spleen (1%) [25]. However, tumor spreading can reach uncommon sites. In a review on 164 patients with squamous cell carcinoma (60%) and adenocarcinoma (40%) of the esophagus carried out between 1982 and 2017 Shaheen et al. [24] reported  spleen metastases in 6 patients (3.65%), while in the majority of the cases the tumor spread toward the head and neck (42%). Males made up the bulk of the patients, with two thirds of them having lower esophageal tumors (84%). In the greater part of the patients the primary esophageal tumor was squamous cell carcinoma. The time of detection the metastases in the spleen ranged from 6 [26] to 15 months [27] after esophagectomy. 

   Gastric carcinoma

 The metastases of gastric carcinoma to the spleen are isolated [5,6,28-30] or multiple [31,32]. The most common cancer that metastasizes to the spleen is adenocarcinoma. However, it has been documented that a few very uncommon gastric cancers, including neuroendocrine carcinoma [33] and hepatoid adenocarcinoma [34 ], can metastasize to the spleen. Adenocarcinoma with spleen metastases has a dismal prognosis, but cases of long survival and no indications of tumor recurrence have been documented [31 ]. On the other hand the prognosis of gastric cancer with solitary spleen metastasis after surgery seems to be better and a case with 5-year recurrence free survival has been reported [35]. In 92 patients, the median time between the diagnosis of the main tumor and the discovery of spleen metastases was 6.7 months; however in 14 of these patients, the latent period was longer than 2 years [21]. In single reports the spleen metastases were detected during surgery or appeared from one [6,29 ] to four years after gastrectomy [30]. Most of the patients were male. 

   Colorectal cancer.

Because of their propensity for malignancy and high mortality, colorectal cancers are notorious. They spread through the lymphatic vessels, the liver being the most frequent size. Splenic metastases were discovered in 2% of cases with colorectal cancer in a large series of autopsy examinations described by Place et al. [36].  Abdu et al. [37] reviewed 31 cases of isolated metastases from colorectal cancer to the spleen between 1969 and 2015, the patients being 13 women and 18 men with an age range between 33 to 84 years (mean 62.7 years). Eight patients had the original tumor in the sigmoid, six in the ascending colon, five in the descending colon, three in the splenic flexure, three in the rectum, two in the cecum, and one in the hepatic flexure and transverse colon, according to the investigators. The original tumor was found in the sigmoid in four of the 22 single patients hereby reviewed, in the ascending colon in three, the splenic flexure in three the rectum in three, and in the cecum, transversal, and descending colon in one for each site. Capizzi et al. [16] reported one instance of rectal cancer with single splenic metastases and noted another case while evaluating the literature. The interval between the diagnosis of the primary tumor and discovery of metastases was between 3 months and 12 years [18]. Involvement of the hilus nodes was detected in 54% of the patients compared to the relatively lower percentage (9.8%) in the same location reported in the cases of gastric cancer [18]. The main tumor spreading to the spleen was adenocarcinoma.

 Pancreatic carcinoma

For its aggressive nature, treatment resistance, and generally short post-operative and medication survival times, pancreatic cancer is notorious. Despite their close physical proximity, malignant pancreatic tumors seldom spread to the spleen; as a result, single cases have been documented. The majority of pancreatic tumors with splenic metastases are advanced adenocarcinomas that are found in the head of the pancreas, according to Matsuda et al. [38], who reviewed 31 postmortem cases of pancreatic malignancies.  Tumors considered as rare, such ampullary carcinoma [39] and two patients of neuroendocrine carcinoma of the pancreas with spleen involvement have been described [40,41 ]. Patients with tumors regarded as relative benign, such as pseudo-papillary tumor [42], serous cystic adenomas progressing to cystadenocarcinoma [43] have been reported. It has been detected that the over-expression of the CD44 antigen and is isoforms in HPC-4 human pancreatic carcinoma cell line, as well as in other cancer cells, prompts cell migration and metastasis [44,45 ].

  Hepatocellular carcinoma

Hepatocellular carcinoma is ranked highly on the list of fatal malignant tumors, and while lungs, regional lymph nodes, bones and kidneys are the common organs to which the tumor spreads, the spleen is rarely affected [46]. Splenic metastases were only seen in one patient out of 56 with hepatocellular cancer [47]. Filik et al. [48] presented two cases of hepatocellular carcinoma with splenic metastases with a history of cirrhosis following hepatitis and reviewed 6 other cases previously reported. Yan et al. [46] described one case of pedunculated hepatocellular carcinoma that metastasized right to the spleen. Splenic metastases from hepatocellular tumors are typically discovered following surgery or by nowadays imaging techniques, although occasionally due to their microscopic size they have been detected by histological examination [49]. 

   LUNG CANCER 

Lung cancer is one of the dangerous tumors renowned for its bad prognosis and high tendency for metastasis. In an early study carried out on 935 patients, the most affected organs by tumor spreading were liver, bone, brain, while the spleen appears to be the lesser involved [50]. Notable, isolated splenic metastases from the lung have been designated as “extremely rare” [51,52] and according to Sardenberg et al. [53] only 11 cases have been reported till 2013. Spleen metastases from the lung are detected either synchronous with the diagnosis of the primary lesion, or during the follow-up of the patients. In a unique patient reported by Lachachi et al. [54] spontaneous rupture of the spleen due to metastases from the lung cancer preceded the diagnosis of the primary tumor. In a patient described by Schmidt et al.[52] the time interval from the appearance of the lung tumor to detection of the spleen metastasis was 25 months and commented that reported times in the literature ranged from 0 to 8 years. In an exceptional case solitary metastasis to the spleen manifested 21 years after lobectomy for clear cell lung carcinoma [55] . 

BREAST CANCER

Breast cancer, the most common malignant tumor in women continues to be a major issue, especially in its advanced stages, despite innovative diagnostic and therapeutic progresses. 6%–13% of breast cancer cases undergoing post-mortem investigations had splenic metastases, location considered as uncommon [56]. A few unusual cases of squamous cell carcinoma and angiosarcoma as primary tumors of the breast have been reported [57,58]. Revealing the breast tumor and search for its spread leads to detection of the spleen involvement. However three patients who underwent splenectomy because of idiopathic thrombocytopenic purpura showed diffuse breast metastases in the spleen, and even in the accessory spleen in one of them, before the primary tumor was detected [56,59]. After a radical mastectomy, metastases in the spleen can develop anywhere between one year [60] to nine years [61]. There have been attempts to identify the molecular mechanism that causes breast cancer cells to spread to other organs, specifically the spleen. According to research, inhibiting aberrant fibroblast growth factor may boost CD4+ and CD8+ cell infiltration in tumors and spleen while decreasing the viability of breast cancer cells [62]. It was thought that IL-33 had a part in promoting the spread of breast cancer by boosting the quantity and activity of immune-suppressive cells and suppressing antitumor immunity [63]. Cancer development and metastasis have been linked to inhibited spleen tyrosin kinase expression [64]. In one patient reported by Baranyay [65], the metastases in the spleen detected at post-mortem examination were the only finding of occult breast cancer, the phenomenon explained by the patient's and the tumor's blood groups having incompatible antigen determinants.

GENITAL TRACT

   Uterus

Genital tract malignant tumors are quite uncommon. In a study of 50 cases of genital malignancies with metastases to the spleen, the initial tumor was found in the ovary in 30 patients, the endometrium in 11, the cervix in 8, and the tubes in 1 patient [66]. Adenocarcinoma is mostly to blame, which has a tendency to spread to the spleen, especially when the cancer is in its disseminated condition. Rare case of squamous cell carcinoma of the cervix with spleen metastases has been documented [67-71]. According to an early report, there have been 14 cases of solitary spleen metastases recorded up until 1999, four of which came from the endometrium [72]. Later on in 2009 Piura et al. [73] reported 11 documented cases of endometrial cancer and detailed a further patient with the condition. Prevalence of amyloidosis and spleen metastases were both found in one patient with endometrial cancer [74]. The time it takes for uterine tumor metastases to spread to the spleen following surgery varies from 8 months [67], 18 months [66], 5 years [75], and even 10 years [76]. 

 Ovary 

The spleen has been involved in a number of unusual case reports of distant metastases from ovarian cancers. The majority of the tumors are ovarian carcinomas. Earlier in 1990 Carrington et al. [77] reported five patients with ovarian carcinoma and splenic metastases. In 2003 Cormio et al. [78] reviewed 50 patients with ovarian carcinoma and in five of them splenic metastases were detected. Later on in 2011 Olsen et al. [79] reported 30 cases of ovarian tumors with metastases to the spleen. The metastases may be solitary as in the cases described in several publications [12,79-86] or disseminated at other organs [87]. They may manifest simultaneously [13], nine [86], or even twelve [88] years following removal of the initial tumor.  According to Koh et al. [89]    the ovary is the leading organ propagating to the spleen in a solitary way and could be the only indicator of the underlying disease [81]. Nowadays, early diagnosis is greatly aided by imaging techniques [87] and monitoring the levels of the CA125 and CA72-4 markers [88,90].

MALIGNANT MELANOMA

One tumor that supports the meaning of its name, being malignant, is melanoma due to its course, high metastatic potential, and treatment resistance.  The spleen as a site of the tumor spread is rarely affected and most of the repots cover single occurrences. Advanced imaging techniques are used to identify metastases, which can be solitary or disseminated [91- 95]. However, in rare cases the spleen is extremely enlarged [96] and spontaneous ruptures have been reported [97]. Seven of 98 patients who underwent surgical treatment for splenic metastases between 1900 and 2001 were found to have metastases in the spleen from malignant melanoma [98].

RARE CASES

The rare cases with disseminated metastases to the spleen comprise one patient with pleomorphic adenoma of the parotid gland [99] and one patient with testicular cancer sending metastases to the spleen and brain reported by Nguyen et al. [100], who evaluated three previously linked cases. Two individuals with thyroid carcinoma [101, 102] and three patients with renal cell carcinoma [103-105], with a review of four previously reported cases [105], may be placed in the category of uncommon instances. Notable, rare tumors such as glioblastoma may spread to the spleen as described in four case reports and in three found at autopsy examination [106-109].

Detection of splenic metastases 

Metastases to the spleen are typically asymptomatic and are found during the preoperative work-up. While in the past palpating an enlarged spleen in a patient with malignant disease might raise suspicion for any present metastases, modern imaging tools like ultrasonography, CT [28] and PET/CT [29,110] substantially simplify their detection. Görg and Hoffman [19] reported 34 years’ experience with ultrasound abdominal inspection. Out of 168,000 exams, they found 59 patients with spleen metastases, with the majority coming from lung tumors (18.6%), followed by ovarian carcinoma (11.9%), colorectal and breast malignancies (10.2