A 29-year-old man with no history of inflammatory bowel disease or malignancy undergoes a screening enteroscopy, during which multiple polyps were identified in the small bowel. Resection and retrieval of the lesions were complete, and representative histology is shown.

Image 1: Polyp 20x
Image 2: Polyp 50x

90% of individuals with this syndrome will have a mutation in which of the following genes?

  • SMAD4
  • STK11
  • MLH1
  • PTEN

The correct answer is ...


Image 3:PJS Polyp with Pseudoinvasion

The histology specimen shows a polypoid proliferation of glandular epithelium arranged in a lobular fashion. A hallmark feature is the branching smooth muscle bands in a so-called “arborizing” pattern. These are features of polyps arising in Peutz-Jeghers syndrome (PJS), an autosomal dominant cancer predisposition syndrome. A germline mutation in the STK11 tumor suppressor gene can be identified in 90% of cases. An important pitfall seen in approximately 10% of PJS polyps, particularly those arising in the small bowel, is the phenomenon of pseudoinvasion, in which traumatization of the polyp causes epithelium to be misplaced within the submucosa, muscularis propria, and even subserosa in extreme cases (see photo). Clues that pseudoinvasion is occurring include similar cytologic and architectural features between the pseudoinvasive and uninvolved components (as opposed to a higher grade of atypia typically seen in true invasive carcinoma), the presence of inflammation and/or hemorrhage, and a lack of desmoplastic response. PJS carries an increased risk of multiple types of malignancies, with up to 85% of patients developing cancer by age 70. Besides gastrointestinal sites, tumors have been documented in the breast, pancreas, and gonadal organs.

The other genes listed are all related to other cancer predisposition syndromes encountered in the GI tract. MLH1 is a mismatch repair gene mutated in Lynch syndrome and hypermethylated in sporadic MSI-high carcinomas. Polyps and tumors in Lynch syndrome do not have specifically distinguishing morphologic features, though they often display tumor-infiltrating lymphocytes and a medullary phenotype.

PTEN hamartoma tumor syndrome — also known as Cowden syndrome — is the result of mutations in the PTEN tumor suppressor gene. Patients develop multiple types of polyps across the GI tract, including hamartomas, hyperplastic polyps, adenomas, and ganglioneuromas. Mucocutaneous lesions (e.g., trichilemmomas, papillary lesions, and keratoses), however, are considered most characteristic of the disease. In addition, they are at higher risk for developing neoplasms of the breast, thyroid, and endometrium.

A mutation in the SMAD4 tumor suppressor gene is one of the most common mutations found in patients with juvenile polyposis syndrome (JPS). Juvenile polyps are characterized by edematous stroma containing cystically-dilated glands. They, too, can display a lobular architecture, but do not have the arborizing smooth muscle seen in Peutz-Jeghers polyps. Patients with this syndrome carry a higher risk for colorectal, gastric, and pancreatic malignancies. There are also reports of SMAD4 mutations resulting in a combined JPS/hereditary hemorrhagic telangiectasia phenotype.


  1. WHO Classification of Tumours Editorial Board, Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019.
  2. Shepherd NA, Bussey HJ, Jass JR. Epithelial misplacement in Peutz-Jeghers polyps. A diagnostic pitfall. Am J Surg Pathol. 1987 Oct;11(10):743-9. doi:10.1097/00000478-198710000-00001. PMID: 3661821.
  3. Hobert and Eng. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009 Oct;11(10):687-94. doi:10.1097/GIM.0b013e3181ac9aea. PMID: 19668082.
  4. Lawless ME, Toweill DL, Jewell KD, et al. Massive gastric juvenile polyposis: A clinicopathologic study using SMAD4 immunohistochemistry. Am J Clin Pathol. 2017 Apr 1;147(4):390. doi:10.1093/ajcp/aqx015. PMID: 28340255.
  5. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004 Mar 13;363(9412):852-9. doi:10.1016/S0140-6736(04)15732-2. PMID: 15031030.
Photo of Ryan W. Kendziora, M.D.

Ryan Kendziora, M.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic

Thomas Smyrk, M.D.
Clinical Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

A 37-year-old man was found by a hiker in the woods after having been missing for several days. He was found with a single gunshot to the head, with a pistol found at the scene. During the routine autopsy, the following was incidentally identified in the leptomeninges of his brain.

Image 1
Image 2

What is the most likely diagnosis?

  • Metastatic colon cancer
  • Parasitic larvae from ingesting raw/undercooked pork
  • Focal transitional meningioma
  • Postmortem insect activity

The correct answer is ...

Postmortem insect activity.

As inferred in the question stem, this was an individual who was found several days after an apparent suicide by gunshot out in the wilderness. As expected, the decedent was found with significant decompositional changes, including marbling, skin discoloration, and extensive maggot activity. With the integrity of the skull disrupted by the projectile, insects were more easily able to gain access for feeding and reproduction. While some species of insect will infect living tissue to lay their eggs (e.g., the botfly), adult houseflies are often attracted to open wounds and host orifices to feed and lay eggs.

This particular maggot was found along the leptomeninges of the brain and was submitted as part of the routine histopathology analysis in a typical autopsy. This cross-section satisfactorily highlights the different components of the maggot, with the internal components of the digestive tract, the outer striated muscle along its internal surface, and its surface cuticular spines, which can be most appreciated along the image’s lower-right surface. An indication that this is post-mortem activity (opposed to ante-mortem) is the noted lack of a typical immune reaction or localized cellular response to a parasitic infection.

Maggots have a surprising usefulness in forensic science. For example, the field of forensic entomotoxicology looks at the analysis of toxins and drug content in insects that feed on carrion and post-mortem tissue. This can be especially useful in instances where severe decomposition has occurred and procuring an adequate blood sample may prove difficult.1 Additionally, there are ongoing studies examining the correlation between establishing a time of death and the present insect burden.2 


  1. Joseph I, Mathew DG, Sathyan P, Vargheese G. The use of insects in forensic investigations: An overview on the scope of forensic entomology. J Forensic Dent Sci. 2011;3(2):89-91. doi:10.4103/0975-1475.92154
  2. Ruchi S, Kumar Garg R, Gaur JR. Various methods for the estimation of the post mortem interval from Calliphoridae: A review. Egy J Forensic Science. 2015;5(1):1-12. doi.org/10.1016/j.ejfs.2013.04.002
Photo of Nicholas Boire, M.D., M.Sc.

Nicholas Boire, M.D., M.S.
Resident, Anatomic and Liver Pathology
Mayo Clinic

Catherine Hagen, M.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

An 80-year-old woman was discharged from the hospital after an orthopedic procedure. For pain control, codeine was prescribed. The following day the patient was found somnolent in her living room by her family. The primary provider considered a dose adjustment after ordering pharmacogenetic testing for CYP2D6. The CYP2D6 test revealed a full gene duplication and the genetic variants present in the images.

Figure 1
Figure 2
Figure 3

Based on the clinical presentation and raw data plots, what is the most likely genotype and corresponding metabolizer phenotype for this patient?

  • *2Ax2/*17; ultrarapid metabolizer
  • *4/*5; poor metabolizer
  • *2A/*17x2; normal metabolizer
  • *2A/*4x2; intermediate metabolizer

The correct answer is ...

*2Ax2/*17; ultrarapid metabolizer.

The duplicated allele can be determined by follow-up Sanger sequencing or by review of the allelic ratios. Visual assessment of the VIC/FAM signals on the plots suggest that the patient’s points (run in duplicate) are falling toward the *2A allele for both heterozygous alleles. Thus, this patient’s genotype is *2Ax2/*17. Given the duplication of the *2A allele which has an activity score of 1, this patient has a total activity score of 2.5, and an ultrarapid metabolizer phenotype is the appropriate assignment. Such patients will metabolize codeine to its more active metabolite — morphine — at a faster pace and will consequently be at risk for opioid intoxication.

Incorrect: Poor metabolizer

The *5 allele is a full gene deletion, which is not consistent with the results of the copy number assay that revealed a full gene duplication. Furthermore, the variants depicted in the images are not consistent with those present in a *4 allele. Finally, such patients would be unable to achieve the active, pain-relieving morphine in sufficient concentrations and would stand to experience poor pain control for their condition.

Incorrect: Normal metabolizer

Duplication of the *17 allele would have led to an activity score of 2.0, which corresponds to a normal metabolizer phenotype. Based on genetics alone, a normal metabolizer would be expected to respond appropriately to standard dosing.

Incorrect: Intermediate metabolizer

The variants detected and pictured in the images do not correspond to a *4 allele. Additionally, based on genetics alone, an intermediate metabolizer would be predicted to respond to a standard dose, or potentially require an alternate medication for pain control.


  1. Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther. 2021 Oct;110(4):888-896.
  2. https://www.pharmvar.org/gene/CYP2D6; Accessed 5/31/2022.
  3. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007 Aug;7(4):257-265.
  4. Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A review of the important role of CYP2D6 in pharmacogenomics. Genes (Basel). 2020 Oct 30;11(11):1295.
Mazen Atiq MBBS portrait square

Mazen Atiq, M.B.B.S.
Resident, Clinical Pathology
Mayo Clinic

Ann Moyer, M.D., Ph.D.

Ann Moyer, M.D., Ph.D.
Consultant, Laboratory Genetics and Genomics
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology, Assistant Professor of Pharmacology
Mayo Clinic College of Medicine and Science

A 7-week-old boy who was born at 31 weeks of gestation in a twin pregnancy developed respiratory distress and received positive pressure mechanical ventilation (PEEP: 4 cm of H2O). Initial findings on chest radiography revealed a large cystic abnormality within the right hemithorax, and diffuse infiltrates within the right upper lobe and throughout the left lung. He was also reported to have bilateral pneumothoraces. A right upper lobe resection was performed to investigate the nature of the cyst. Hematoxylin and eosin-stained sections of the lung parenchyma are shown in Figures 1-7.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Given the history and histologic findings, what pathologic diagnosis can be rendered?

  • Diffuse pulmonary lymphangiectasia
  • Infantile lobar emphysema
  • Pulmonary interstitial emphysema
  • Congenital pulmonary airway malformation (CPAM)

The correct answer is ...

Pulmonary interstitial emphysema.

Pulmonary interstitial emphysema is an acquired condition that is caused by dissection of air out of alveolar spaces and into the loose connective tissue of the interlobular septa, the bronchovascular bundles, and the pleura, that in most cases occurs in mechanically ventilated in infants who require respiratory support, but can also be seen in adults.1 The pathogenesis of this condition was first proposed by Dr. Charles Macklin in 1939, who performed experiments in intubated cats, and observed dissection of air throughout the branches of hilar vessels after the instillation of high-pressurized air into the animals’ trachea.2

In a study performed in 205 infants weighting less than 1,500 g at birth, who had been admitted to the neonatal intensive care unit of the King's College Hospital in London,3 pulmonary interstitial emphysema affected 32% of premature infants weighing <1,500 g and occurred at a higher frequency (42%; p<0.02) in infants who weighted <1,000 g at birth. In addition, the same study found that this condition was significantly associated with hyaline membrane disease with and without ventilation (p<0.0005, p<0.025, respectively), with mechanical ventilation in cases that did not present with hyaline membrane disease (p<0.05), and in infants who develop a pneumothorax (p<0.001).3 When severe, the condition may also lead to the development of pneumomediastinum and pneumopericardium.1


Grossly, cyst-like spaces may be noted on the pleural surface, around large bronchovascular bundles, and particularly where interlobular septa intersect the pleura.4 In histological sections, multiple cystic spaces of different dimensions are identified throughout the parenchyma. The cystic spaces diffusely dissect into the loose connective tissue of the subpleural spaces (figure 1), the bronchovascular bundles (figures 2-3), and the interlobular septa (figure 4). A dominant cyst, or larger cysts may also be present (figure 5). Focally, the cysts may form interconnected channels which surround the bronchovascular bundles (figure 6). This condition can be either localized or diffuse, and acute or chronic.5

The histological findings in pulmonary interstitial emphysema vary with the age of the lesion. In acute cases, there are rents in the interstitium in the septa, subpleural space and bronchovascular bundles, that at first glance resemble tissue tears and artifacts.5 When the condition persists for longer time,5,6,7 the cysts develop a poorly formed capsule composed of loose collagen, granulation tissue, and a prominent foreign-body cell reaction composed of histiocytes and multinucleated giant cells protruding into the cystic space (figures 3, 4, and 7).8 No epithelial lining is identified within the cyst's lumina. Prominent fresh hemorrhage may also be seen dissecting throughout the cyst’s walls, the interlobular septa, the subpleural spaces, and the bronchovascular bundles (figures 2, 3, and 7).

Differential diagnosis

The differential diagnosis includes other conditions that cause cystic lung disease in infants,[5][7] including congenital pulmonary airway malformation (CPAM) also known as congenital cystic adenomatoid malformation (CCAM), infantile lobar emphysema, diffuse pulmonary lymphangiectasia, and diffuse pulmonary lymphangiomatosis. The distinction between pulmonary interstitial emphysema and these four entities is histologic.

In CPAM the cystic spaces are lined by an epithelial layer that can be pseudostratified, columnar to cuboidal (CPAM 0-III), or flat (CPAM IV). In addition, cartilage may be present adjacently to the cysts in some types of CPAM (CPAM 0 and I). The granulomatous reaction seen in pulmonary interstitial emphysema is not present in CPAM.5

Infantile lobar emphysema can get confused on imaging and grossly with pulmonary interstitial emphysema. However, both conditions are easily distinguished between each other on histological grounds. In infantile lobar emphysema, no real “cysts” are seen on tissue sections. Instead, there is marked dilatation of alveoli and terminal bronchioles resembling adult lung parenchyma. The airspace dilatation is the result of marked inflation differences that occur between adjacent lung lobes.5

In diffuse pulmonary lymphangiectasia and diffuse pulmonary lymphangiomatosis, the cyst-like spaces correspond to lymphatic channels lined by lymphatic endothelial cells that may be diffusely dilated in pulmonary lymphangiectasia or may form anastomosing variably sized spaces pulmonary lymphangiomatosis. As in CPAM, a granulomatous reaction in the spaces would be absent. The presence of the endothelial lining can be seen on H&E-stained tissue sections or can be highlighted by immunohistochemistry directed to endothelial markers (e.g., D2-40, CD31).5,9


1. Jalota Sahota R, Anjum F. Pulmonary interstitial emphysema. 2022. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560484/

2. Macklin CC. Transport of air along sheaths of pulmonic blood vessels from alveoli to mediastinum: Clinical implications. Arch Intern Med. 1939;64:913–26.

3. Hart SM, McNair M, Gamsu HR, Price JF. Pulmonary interstitial emphysema in very low birthweight infants. Arch Dis Child. 1983;58:612-5.

4. Stocker JT, Madewell JE. Persistent interstitial pulmonary emphysema: another complication of the respiratory distress syndrome. Pediatrics. 1977;59:847-57.

5. Travis WD, Colby TV, Koss MN, Rosado-de-Christenson ML, Müller NL, King TE Jr. (2002) Non-neoplastic disorders of the lower respiratory tract, AFIP Atlas of Nontumor Pathology, First Series, Fascicle 2. Washington, DC: American Registry of Pathology and the Armed Forces Institute of Pathology.

6. Stocker JT, Madewell JE. Persistent interstitial pulmonary emphysema: another complication of the respiratory distress syndrome. Pediatrics. 1977;59:847-57.

7. Stocker JT, Drake RM, Madewell JE. Cystic and congenital lung disease in the newborn. Perspect Pediatr Pathol. 1978;4:93-154.

8. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-1997. A preterm newborn female triplet with diffuse cystic changes in the left lung. N Engl J Med. 1997;337:916-24. 9. Boland JM, Tazelaar HD, Colby TV, Leslie KO, Hartman TE, Yi ES. Diffuse pulmonary lymphatic disease presenting as interstitial lung disease in adulthood: report of 3 cases. Am J Surg Pathol. 2012;36:1548-54.

Julian Villalba Nunez, M.D.
Fellow, Pulmonary Pathology
Mayo Clinic

Ying-Chun Lo, M.D., Ph.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

The decedent is a 27-year-old woman with a history of depression and anxiety who presented to the Emergency Department after a suicide attempt. The images provided show findings identified on histologic examination of the lungs.

Image 1
Image 2

What do these findings most likely indicate?

  • Intravenous injection of crushed oral tablets.
  • Exposure to crystalline fragments of plexiglass (Methyl methacrylate).
  • Aspiration of crushed oral tablets.
  • Vaping-related lung injury.

The correct answer is ...

Aspiration of crushed oral tablets.

The decedent in this case presented to the Emergency Department with nausea and vomiting, multiple hours after a polysubstance ingestion. During hospitalization her condition deteriorated, and she died after several days. Histology of the lungs shows polarizable pill material, vegetable material, and muscle fragments within the airways. This is most consistent with aspiration of emesis containing crushed pill fragments. Upon chart review there is documentation of multiple instances of vomiting with emesis containing pill fragments during the decedent’s hospitalization.

Oral tablets contain excipients, which are insoluble particulate filler materials that bind and protect the active drug during production, as well as shape and lubricate the tablet for easy swallowing. Excipients include talc (hydrated magnesium silicate), microcrystalline cellulose, crospovidone, and starch. When crushed tablets are aspirated, particles of excipients can show up as birefringent foreign bodies within the lung airways.

Following a similar process, when oral tablets are crushed and injected intravenously, particles of excipients can show up as birefringent foreign bodies within pulmonary arteries and periarterial interstitium. This triggers pulmonary foreign body angiogranulomatosis, which over months and years of continued use, can lead to progressive pulmonary fibrosis. Some excipient crystals are fine enough to pass through capillaries to pulmonary veins and lodge in the retina, spleen, liver, kidneys, lymph nodes, bone marrow, and spinal cord when intravenously injected.

Methyl methacrylate (MMA) and vaping-related lung injuries would have a different appearance on histologic examination.

Methyl methacrylate is a monomer widely used in medicine and industry. The most important exposure route of MMA is by inhalation. Prolonged exposure has been shown to result in marked pathologic changes in the lungs, including edema, hemorrhage, and necrosis. Furthermore, it may cause a wide range of widespread adverse health effects such as irritation of the skin, eyes, and mucous membranes, allergic dermatitis, stomatitis, asthma, neuropathy, and liver toxicity.

Vaping-related histologic findings are generally nonspecific and require a clinical correlation. These finding include patterns of acute lung injury, including acute fibrinous pneumonitis, diffuse alveolar damage, or organizing pneumonia. Foamy macrophages and pneumocyte vacuolization are also common. In a few cases foreign body reaction to nonbirefringent material, presumed to be glycerin-based oils, found in droplets from e-cigarette vapor, have been described.


  1. Aydin O, Attila G, Dogan A, Aydin M, Canacankatan N, Kanik A. The effects of methyl methacrylate on nasal cavity, lung, and antioxidant system (an experimental inhalation study). Toxicol Pathol. 2002;30(3):350-356. doi:10.1080/01926230252929927.
  2. Butt Y, Smith M, Tazelaar H, et al. Pathology of vaping-associated lung injury. N Engl J Med. 2019;381(18):1780-1781. doi:10.1056/nejmc1913069.
  3. Hoyt B, Aaron D, Yan S, Linos K. Cutaneous crospovidone: A newly described foreign body due to illicit drug abuse. Am J Dermatopathol. 2019;41(8):e84-e86. doi:10.1097/dad.0000000000001374.
  4. Mukhopadhyay S, Katzenstein A. Pulmonary disease due to aspiration of food and other particulate matter: A clinicopathologic study of 59 cases diagnosed on biopsy or resection specimens. Am J Surg Pathol. 2007;31(5):752-759. doi:10.1097/01.pas.0000213418.08009.f9.
  5. Nguyen V, Chan E, Chou S, et al. Pulmonary effects of IV injection of crushed oral tablets: “excipient lung disease.” AJR Am J Roentgenol. 2014;203(5):W506-W515. doi:10.2214/ajr.14.12582.
  6. Ring Madsen L, Vinther Krarup NH, Bergmann TK, et al. A cancer that went up in smoke: pulmonary reaction to e-cigarettes imitating metastatic cancer. Chest. 2016;149(3):e65

Fabiola Righi, D.O.
Resident, Anatomic and Clinical Pathology
Mayo Clinic

Reade Quinton, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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