Abdominal nodular histiocytic/mesothelial hyperplasia - intraoperative pitfalls, differential diagnosis, literature review: A case report

Abstract

BACKGROUND

Nodular histiocytic/mesothelial hyperplasia (NHMH) is a rare, benign lesion characterized by a proliferation of histiocytes and mesothelial cells displaying a biphasic architectural pattern. First described by Rosai in the 70s, it may closely mimic malignant processes, particularly within the abdominal cavity. NHMH may be indistinguishable from carcinomatosis intraoperatively, potentially altering surgical management. Because nodules typically measure only a few millimeters, their macroscopic appearance and epithelioid features of cell proliferations histologically can closely resemble metastatic implants, particularly during intraoperative frozen section examination. Recognition of this entity is therefore essential to prevent diagnostic errors and unnecessary interventions.

CASE SUMMARY

We report the case of a 57-year-old woman in whom NHMH was incidentally identified during exploratory laparoscopy performed for staging metastatic gastric adenocarcinoma. Multiple small peritoneal nodules (2-5 mm) mimicked carcinomatosis intraoperatively. Frozen section examination interpretation was challenging due to the presence of epithelioid cell clusters with stromal desmoplasia that, together with surface irregularity, suggested metastatic implants, creating a high risk of overcalling carcinoma. Final histopathology demonstrated the coexistence of metastatic gastric adenocarcinoma and NHMH. Immunohistochemistry revealed CD68 positivity in histiocytes, calretinin and WT-1 expression in mesothelial cells, thus confirming the diagnosis.

CONCLUSION

NHMH must be considered in the differential diagnosis of peritoneal nodules identified during staging surgery. Frozen section analysis alone is insufficient and correlation with permanent sections and immunohistochemistry is essential to avoid misdiagnosis and overtreatment during intraoperative decision-making.

Key Words: Nodular histiocytic hyperplasia; Mesothelial hyperplasia; Nodular histiocytic/mesothelial hyperplasia; Peritoneum; Frozen section; Mesothelial cells; Pitfall; Carcinomatosis; Gastric adenocarcinoma; Case report

Core Tip: Nodular histiocytic/mesothelial hyperplasia is a rare benign lesion that may mimic peritoneal dissemination of malignancy, especially during frozen-section examination. This case emphasizes the diagnostic pitfalls arising from its histologic resemblance to metastatic carcinoma and highlights how coexistence with true metastatic implants increases the risk of misinterpretation. Few reports describe concurrent metastatic carcinoma and nodular histiocytic/mesothelial hyperplasia, making intraoperative differentiation particularly challenging. Knowledge of its characteristic morphology and immunoprofile is crucial for surgeons and pathologists.

INTRODUCTION

Nodular histiocytic/mesothelial hyperplasia (NHMH) is a rare, benign lesion that has received limited attention in the literature. About thirty cases have been reported within the abdominal and pelvic cavities, limiting understanding of its clinical and pathological spectrum. Originally identified by Rosai and Dehner[1] in 1975 as “mesothelial/monocytic incidental cardiac excrescence” (MICE), NHMH is now recognized as part of a broader morphological continuum encompassing both MICE and NHMH under a unifying classification[2,3].

Lesions may appear as small reddish excrescences or may be found incidentally during surgery. Histologically, NHMH consists of nodular aggregates of histiocytes intermingled with mesothelial cells. It typically arises in mesothelial-lined serosal surfaces, most frequently the pleura and pericardium and only exceptionally in the peritoneum and pelvic cavity.

The clinical relevance of NHMH lies in its macroscopic and microscopic resemblance to malignant tumors, including metastatic carcinoma and mesothelioma. This mimicry makes intraoperative assessment particularly challenging. Herein, we present a case of NHMH incidentally detected during exploratory laparoscopy for advanced gastric carcinoma, emphasizing diagnostic pitfalls, histopathological findings, and review of the literature.

CASE PRESENTATION

Chief complaints

A 57-year-old Caucasian woman weighing approximately 60 kg presented with a three-month history of postprandial epigastric pain associated with early satiety, intermittent nausea, and progressive weight loss of about 6 kg.

History of present illness

Symptoms were not associated with vomiting, hematemesis, or melena. Initial proton-pump inhibitor therapy provided only partial symptom relief.

History of past illness

She denied any history of previous gastrointestinal disorders or abdominal surgery.

Personal and family history

There was no family history of gastrointestinal malignancies. The patient did not smoke and reported occasional social alcohol intake.

Physical examination

Abdominal examination was unremarkable, with no palpable masses or ascites.

Laboratory examinations

Hemoglobin levels were within reference ranges; serum iron was mildly reduced (53 μg/dL). Medical therapy included pantoprazole (40 mg every 8 hours), sucralfate and nutritional supplements.

Imaging examinations

Two months later, an esophagogastroduodenoscopy was performed due to symptoms persistence, which revealed a 10-mm ulcer in the distal gastric body and a 20-mm ulcer on the anterior wall of the antrum, suggestive of malignancy. Biopsies from both lesions showed poorly cohesive gastric adenocarcinoma with signet-ring cell morphology. Immunohistochemical staining was positive for cytokeratin AE1/AE3, claudin 18.2 and E-cadherin, highlighting the epithelial nature of the tumor (not shown).

Contrast-enhanced computed tomography scan revealed antral/pyloric thickening with enlarged perigastric and mesenteric lymph nodes and peritoneal thickening suspicious for early carcinomatosis/circumferential thickening of the gastric antrum and pylorus, with multiple enlarged perigastric and mesenteric lymph nodes and peritoneal thickening suggestive of early carcinomatosis (Figure 1A). One month later, a positron emission tomography-computed tomography scan confirmed hypermetabolic activity in gastric lesions and mediastinal and retrocrural lymph nodes, with mild uptake in pericolic and pelvic regions corresponding to small nodular foci/demonstrated increased fluorodeoxyglucose uptake in the gastric body and antrum, as well as in retrocrural and internal mammary lymph nodes, consistent with metastatic spread. Mild heterogeneous uptake was also noted in the pericolic region and pelvic cavity, where small nodular alterations were visible between intestinal loops (Figure 1B).

Figure 1 Imaging findings. A: Computed tomography scan documented the presence of a multifocal thickening of the peritoneum, with confluent nodules visible in the pelvic cavity; B: Positron emission tomography-computed tomography scan showing uptake of [¹⁸F]-fluorodeoxyglucose in the left pericolic region and pelvic cavity, suspicious for peritoneal carcinomatosis.

FINAL DIAGNOSIS

Two weeks later, given these findings, exploratory laparoscopy was performed. Multiple small nodules were detected on parietal and visceral peritoneum, mesentery, omentum and bowel serosa. Multiple nodular deposits measuring 2-5 mm were identified across the parietal and visceral peritoneum, mesentery, omentum, and bowel serosa. The epithelioid cell clusters, fibrosis, and surface irregularity suggested metastatic implants, creating a high risk of overcalling carcinoma on frozen section (Figure 2A). Definitive histopathological evaluation confirmed metastatic poorly cohesive/signet-ring adenocarcinoma (World Health Organization 2019, MSS, HER2 1+, PD-L1 CPS < 1). In addition, florid nodular proliferations of histiocytes admixed with mesothelial cells demonstrated NHMH, with some containing intermixed isolated carcinoma cells (Figure 2B). Nodules showed CD68 reactivity in the histiocytic cell component, diffuse calretinin and WT-1 expression in mesothelial cell layers, and cytokeratin and CDX2 positivity within single and clustered epithelial gastric carcinoma cells (Figure 3) (for immunohistochemical phenotype, Table 1).

Figure 2 Pathological findings. A: Small nodules of atypical epithelioid cells on the surface of peritoneal serosa noted during frozen section examination (original magnification 200 ×); B: On definitive histopathological analysis, although atypicality of cell proliferation and areas of isolated growth patterns are observed, there is an evident histological overlap between peritoneal carcinomatosis and nodular histiocytic/mesothelial hyperplasia (original magnification 200 ×).

Figure 3 Immunohistochemical findings. A: Immunohistochemical analyses showing cytokeratin AE1/AE3 positivity in both epithelial and mesothelial cell components [immunohistochemistry (IHC); original magnification 200 ×]; B: Intestinal differentiation marker CDX2 mildly expressed in sparse nuclei of neoplastic cells, indicating a gastric origin (IHC; original magnification 200 ×); C: Immunoexpression of calretinin in mesothelial cells (IHC; original magnification 200 ×); D: Note CD68 immunopositivity highlighting the histiocytic component of nodular histiocytic/mesothelial hyperplasia, while mesothelial cells are negative (IHC; original magnification 200 ×).

Table 1 Immunohistochemical findings in different cell populations.

Antibodies	Histiocytes	Mesothelial cells	Epithelial cells
Cytokeratin AE1/AE3	–	+	+
CK7	–	–	+
CK20	–	–	–
CDX2	–	–	+
CD68Kp1	+	–	–
CD163	+	–	–
WT-1	–	+	–
Calretinin	–	+	–
CD14	+	–	–
CD45	–	–	–
CD34	–	–	–
PAX8	–	–	–
P53	–	–	+
PD-L1	–	–	+

TREATMENT

The patient subsequently received a first cycle of personalized FOLFOX-4 chemotherapy (oxaliplatin 85 mg/m², leucovorin 200 mg/m², and 5-fluorouracil 400 mg/m² bolus followed by 600 mg/m² continuous infusion).

OUTCOME AND FOLLOW-UP

The treatment was initially well tolerated. However, her clinical condition deteriorated rapidly thereafter and she passed away six weeks later due to disease progression.

DISCUSSION

NHMH is an infrequent, non-neoplastic process characterized by a biphasic proliferation of histiocytes and mesothelial cells that may involve serosal surfaces[1-11]. Rosai and Dehner[1] first described it in hernia sacs as “nodular mesothelial hyperplasia” in 1975, followed by Veinot et al[2] in 1994, who reported cardiac cases and introduced the term MICE. Hu et al[3] later unified both entities under a single pathological spectrum. Despite this conceptual unification, NHMH may present in two clinicopathological variants with distinct anatomical, clinical and diagnostic approaches: Thoracic and abdominopelvic. Lesions may appear as small reddish excrescences (2-5 mm) or may be found incidentally discovered during microscopic examination of specimens. NHMH are composed of epithelioid cells with abundant eosinophilic cytoplasm, sometimes with lymphoid aggregates and scattered mesothelial cells within the lesion.

In the present case, frozen section examination posed a diagnostic challenge. The juxtaposition between NHMH and metastatic gastric carcinoma deposits created considerable uncertainty for both the pathologist and the surgeon; the decision not to remove the stomach was guided by the concurrent suspect of peritoneal carcinomatosis. Nonetheless, the reverse clinical scenario could occur, whereby failure to recognize this benign entity may lead to inappropriate staging and thus overtreatment. Awareness of NHMH and its morphological hallmarks features is thus essential, particularly during intraoperative consultations, where further techniques such as immunohistochemical typing are unavailable. Actually, an immunohistochemical comparison of the present case with data in the literature review is not really feasible, due to the rarity of NHMH and the exceptional manifestation of the disease (simultaneous combination with a malignant tumor); the only exception is the persistent expression of CD68 and negativity of epithelial markers in histiocytic cells in all cases described in the literature. With regard to the differential diagnosis, profile of our case paralleled that of previous reports, exhibiting histiocytic and mesothelial differentiation within the NHMH cell component, and epithelial/gastrointestinal nature in scattered malignant cells. Only few cases as the present, describing concurrent metastatic carcinoma and NHMH are reported to date, making intraoperative differentiation particularly challenging. With the present case, the review of the literature identified 34 abdominopelvic cases (Table 2): NHMH was twice as common in women as in men, with the highest incidence observed between the ages of 30 to 60. Moreover, the abdominal cavity was the most common site and essentially all the cases identified in the pelvis were female.

Table 2 Abdominopelvic nodular histiocytic/mesothelial hyperplasia patients with differential diagnoses reported in the literature.

Case	Age/sex	Site	Clinical information	Differential diagnosis	Ref.
1	48/female	Pelvis	Diffuse enlargement of the uterus causing DVT	HIFU induced thermal injury, serous ovarian carcinoma, mesothelioma	[4]
2	38/female	Pelvis	Uterine leiomyoma, endometriosis	Metastatic renal cell carcinoma, paraganglioma	[5]
3	36/female	Pelvis	Infertility, dysmenorrhea	Well-differentiated adenocarcinoma, leukemia, lymphoma	[6]
4	37/female	Pelvis	Infertility, endometriosis	Well-differentiated adenocarcinoma, leukemia, lymphoma	[6]
5	56/male	Peritoneum	Umbilical swelling in HIV+	Peritoneal carcinomatosis, peritoneal lymphomatosis, tuberculous, peritonitis	[7]
6	61/male	Peritoneum	Severe peritoneal adhesions with multilocular peritoneal cyst	Benign mesothelioma	[8]
7	32/female	Peritoneum	Endometriosis in the wall of a ruptured ovarian cyst	Endometriosis	[8]
8	69/male	Peritoneum	Deciduous mesothelioma	Peritoneal mesothelioma	[8]
9	48/female	Peritoneum	Fluid from cavum Douglas	Inflammation vs malignancy	[8]
10	33/female	Peritoneum	Hydrocele in inguinal canal	Inflammation vs malignancy	[8]
11	60/male	Peritoneum	Inguinal hernia	Inflammation vs malignancy	[8]
12	5/male	Peritoneum	Spermatocele of funiculus spermaticus	Benign nodule	[8]
13	70/female	Peritoneum	Uterus myomatosus, diverticulitis and severe abdominal adhesions	Inflammation vs malignancy	[8]
14	45/female	Peritoneum	Endosalpingiosis of omentum and ovarian cysts	Carcinoma	[8]
15	36/female	Peritoneum	Multilocular mesothelial cyst	Benign mesothelioma	[8]
16	19/male	Peritoneum	Liver biopsy, nos	Benign nodule	[8]
17	45/female	Peritoneum	Serous cystic tumor of borderline malignancy	Peritoneal tumor implants	[8]
18	29/female	Peritoneum	Pelvic biopsy, nos	Benign nodule	[8]
19	22/male	Peritoneum	Steatonecrosis in fat tissue of the ileum	Benign nodule	[8]
20	31/female	Peritoneum	Biopsy in the Douglas pouch	Benign nodule	[8]
21	67/male	Peritoneum	Hepatocellular carcinoma	Metastasis in the umbilical area	[8]
22	58/female	Peritoneum	Hernia sac	Inflammation vs malignancy	[8]
23	55/female	Peritoneum	Umbilical hernia, ovarian fibromas	Inflammation vs malignancy	[8]
24	33/female	Peritoneum	Ovarian cyst with peritoneal abscess	Inflammation vs malignancy	[8]
25	28/female	Peritoneum	Endometriosis in the wall from ruptured ovarian cyst	Endometriosis	[8]
26	59/female	Fallopian tube and peritoneum	High grade serous carcinoma of the ovary	Peritoneal metastasis	[8]
27	51/female	Fallopian tube	High grade serous carcinoma of the ovary	Peritoneal metastasis	[8]
28	87/male	Right colon	Mucinous adenocarcinoma of the cecum	Lymph node mesenteric metastasis	[9]
29	57/male	Epigastric region	Epigastric pain and incarcerated bowel	Nodules nos vs malignancy	[1]
30	74/male	Pelvis	Bladder papillary transitional cell carcinoma	Nodules nos vs malignancy	[10]
31	44/female	Omentum	Borderline mucinous cistoadenoma	Peritoneal carcinomatosis	[11]
32	41/female	Omentum	Low grade serous cystoadenocarcinoma	Peritoneal carcinomatosis	[11]
33	6/female	Omentum	Juvenile granulosa-cell tumor	Peritoneal carcinomatosis	[11]
34	57/female	Peritoneum	Adenocarcinoma of the stomach post CT	Peritoneal carcinomatosis	Present case

DVT: Deep vein thrombosis; HIFU: High-intensity focused ultrasound; HIV: Human immunodeficiency virus; CT: Computed tomography.

Most cases were discovered incidentally during surgery for malignant disease and frequently misinterpreted as neoplastic nodules. This diagnostic pitfall is of particular importance in oncological surgery, where frozen section examination is employed to guide intraoperative decisions. Unfortunately, information on frozen section examination was unavailable in a substantial number of reported cases of the literature. Immunohistochemistry remains the most reliable ancillary tool to establish a definitive diagnosis and distinguish NHMH from metastatic carcinoma.

CONCLUSION

NHMH must be considered in peritoneal nodules encountered during staging surgeries. Frozen section alone is insufficient, and correlation with permanent sections and immunohistochemistry is essential to avoid misdiagnosis.

ACKNOWLEDGEMENTS

This work was partially supported by “Ricerca Corrente” funding from Italian Ministry of Health to IRCCS Humanitas Research Hospital.